Development of Multifunctional Molecules as Potential Therapeutic


Aug 10, 2018 - Masha Savelieff began her science career in Chemistry at the American University of Beirut, Beirut, Lebanon, where she earned her B.S. ...
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Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade Masha G. Savelieff,†,∥ Geewoo Nam,‡,§,∥ Juhye Kang,‡,§,∥ Hyuck Jin Lee,§ Misun Lee,‡,§ and Mi Hee Lim*,§ †

SciGency Science Communications, Ann Arbor, Michigan 48104, United States Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea § Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea

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ABSTRACT: Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow a negative outlook. Although a large amount of research has been dedicated to elucidating the pathologies of neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, and neurotransmitter deficiencies are pathological features shared across multiple neurodegenerative disorders. In addition, these factors are proposed to be interrelated upon disease progression. Thus, the development of multifunctional compounds capable of simultaneously interacting with several pathological components has been suggested as a solution to undertake the complex pathologies of neurodegenerative diseases. In this review, we outline and discuss possible therapeutic targets in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality. In addition, underrepresented areas of research are discussed to indicate new directions.

CONTENTS 1. Introduction 1.1. Neurodegenerative Diseases 1.2. Design and Discovery of Multifunctional Molecules 1.2.1. Rational Design 1.2.2. Natural Products 1.2.3. High-Throughput Screening (HTS) 1.2.4. Fragment-Based Drug Discovery (FBDD) 1.2.5. Methods to Test Efficacy 2. Alzheimer’s Disease (AD) 2.1. Amyloid-β (Aβ) and Tau 2.2. Metal Ions 2.3. Oxidative Stress 2.4. Cholinesterases (ChEs) 2.5. Additional Targets 2.6. Molecules 2.6.1. Multifunctional Molecules Targeting Aβ and Metal Ions 2.6.2. Multifunctional Molecules Targeting ChEs and Metal Ions 2.6.3. Molecules Targeting Tau 2.6.4. Multifunctional Molecules Directed at Metal Ions and Other Targets 3. Parkinson’s Disease (PD) 3.1. α-Synuclein (α-Syn) 3.2. Metal Ions © XXXX American Chemical Society

3.3. Oxidative Stress 3.4. Additional Targets 3.5. Molecules 3.5.1. Molecules Targeting α-Syn 3.5.2. Molecules Targeting Metal Ions 3.5.3. Molecules Targeting Monoamine Oxidases (MAOs) 3.5.4. Molecules Targeting Dopamine Receptors 4. Amyotrophic Lateral Sclerosis (ALS) 4.1. Superoxide Dismutase 1 (SOD1) and TAR DNA Binding Protein 43 (TDP-43) 4.2. Metal Ions 4.3. Oxidative Stress and Mitochondrial Dysfunction 4.4. Molecules 4.4.1. Metal Chelators 4.4.2. Multifunctional Molecules Targeting Metal Ions and Oxidative Stress 4.4.3. Multifunctional Molecules Targeting Metal Ions and MAOs 4.4.4. Metal Protein Attenuating Compounds (MPACs)

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Special Issue: Metals in Medicine Received: March 2, 2018

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Chemical Reviews 4.4.5. Molecules for Antiaggregation 4.4.6. Antioxidants 5. Concluding Remarks and Outlook Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments References

Review

energy metabolism,22,23 aberrant axonal transport,24−26 and pervasive, sustained chronic inflammation (Figure 1).7,27 Thus, these pathological elements could trigger neuronal loss, alter neurotransmitter levels, and lower the capacity for signal transduction precipitating the progressive decline of cognitive and/or motor function and eventual death. Based on their inter-related roles in the pathogenesis of AD, PD, and ALS, metal ions and other inter-related pathological factors are implicated as important therapeutic targets in these diseases. Thus, the complex bioinorganic prospect of AD, PD, and ALS is covered in this review. Current therapeutic strategies are palliative and only manage symptoms for a short duration of time before cognitive abilities or motor function continue to degenerate. At present, for instance, widely administered treatments for AD are acetylcholinesterase inhibitors (AChEIs) which curb acetylcholine (ACh) degradation and thus maintain levels of neurotransmission.28 This approach, however, invariably fails, and patients eventually succumb to deteriorating cognitive health. Development of efficacious drugs for neurodegenerative illnesses has been challenging because their precise etiology is not completely identified. A thorough comprehension of disease etiology would be beneficial to aid the discovery of effective therapeutics capable of targeting the root cause of neurodegenerative conditions in a disease-modifying manner. For example, the amyloid cascade hypothesis, the most widely held AD hypothesis, posits that the aggregates of Aβ peptides, produced in the brain, are the primary cause of neurodegeneration.29 Drugs altering the production, clearance, and aggregation of Aβ have been developed and many have entered clinical trials. None, however, has successfully yielded significant benefits, although some improvements were observed.30 These failures have prompted a reexamination of the hypothesis suggesting that other factors, in addition to Aβ, may be mutually operating in neurodegeneration.31 Another hurdle is timely treatment because neurodegeneration begins prior to disease onset and diagnosis. Intervening at this stage could halt further damage, but it may not be able to reverse the deterioration, which has already occurred. Compounded with these problems are challenges that come from treating a condition in the brain, which is generally nonregenerative, highly heterogeneous, and insulated by the blood-brain barrier (BBB). Taken together, the multifaceted nature of neurodegenerative diseases suggests that an effective treatment might require a multipronged approach to simultaneously combat several pathological features. Toward this aim, numerous multifunctional molecules capable of targeting and regulating multiple pathological aspects of neurodegenerative disorders have been rationally designed, and studies have been conducted to assess their efficacies. This review describes possible therapeutic targets in AD, PD, and ALS as well as the rational design and discovery of compounds as potential drug candidates for these disorders with special emphasis on multifunctionality that includes metal chelation.

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1. INTRODUCTION 1.1. Neurodegenerative Diseases

Neurodegenerative diseases are characterized by the progressive loss of neuronal function. Despite a herculean effort, neurodegenerative diseases remain incurable. Research is revealing parallels between Alzheimer’s disease (AD), the most prevalent form of dementia which accounts for ca. 60− 80% of cases,1 and other neurodegenerative diseases, including Parkinson’s disease (PD)2 and amyotrophic lateral sclerosis (ALS).3 As the global population ages and the number of individuals expected to develop neurodegenerative conditions increases, the search for an effective cure is becoming progressively more urgent. An obstacle to drug discovery can in part be attributed to the multifactorial nature of most neurodegenerative illnesses. Although the specifics vary, several unifying threads that run through multiple neurodegenerative diseases have been identified. Proteopathy is one recurrent aspect, generally in the form of misfolded and aggregation-prone proteins and peptides, which may occur concurrently with defects in their clearance (Figure 1).4−6 AD is characterized by the deposition of senile plaques (SPs) and neurofibrillary tangles (NFTs), composed of the aggregates of amyloid-β (Aβ) and hyperphosphorylated tau (ptau), respectively.7,8 PD pathology is suggested to be linked to misfolded aggregates of α-synuclein (α-Syn) that accumulate in Lewy bodies.2 In ALS, aggregates of mutant superoxide dismutase 1 (SOD1), TAR DNA binding protein 43 (TDP-43), fused in sarcoma (FUS), and repeat dipeptides from noncanonical translation of mutant chromosome 9 open reading frame 72 (C9ORF72) are observed.3,9 Another prominent theme is metal ion dyshomeostasis in the brains of patients suffering from neurodegeneration.8,10−13 Under normal conditions, metal ions play several critical roles in the brain. They are cofactors for numerous enzymes with important catalytic activities (e.g., energy production) and serve as active participants in metal-dependent neurotransmission. Therefore, proper regulation of metal ions is necessary for normal neuronal function. In neurodegenerative diseases, elevated or lowered levels as well as miscompartmentalization of metal ions are observed, leading to dysregulation of various downstream processes (Figure 1). One important consequence of metal ion dyshomeostasis [especially, redox-active Cu(I/II) and Fe(II/III)] is oxidative stress caused by reactive oxygen species (ROS) overproduction from Fenton-like reactions.11,14 In addition, metal ions are able to bind to amyloidogenic peptides (e.g., Aβ and α-Syn) and consequently modify their aggregation pathways.15−17 Other pathological features common to several neurodegenerative diseases include mitochondrial dysfunction,18−20 elevated oxidative stress,21 defects in

1.2. Design and Discovery of Multifunctional Molecules

The increasingly evident multifactorial nature of AD and other neurodegenerative diseases has ushered in a new paradigm in drug design. In contrast to the previous model which centered on a single target, a more recent approach to drug design for neurodegenerative disorders is to simultaneously combat several pathological features.32,33 The results are multifuncB

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Figure 1. Multifactorial nature of neurodegenerative diseases. (a) Proteopathy of wt or mutant intra- or extracellular unfolded proteins/peptides. Unfolded monomers partially fold and aggregate into oligomers and fibrils. Oligomers may interact with various organelles (e.g., mitochondria) or cell membrane disrupting Ca(II) homeostasis and signaling. (b) Dyshomeostasis of metal ions that, depending on the disease, can bind to misfolded proteins/peptides affecting their aggregation or accumulate in the brain or spinal cord. (c) Elevated oxidative stress resulting from redoxactive metal ions (i.e., Cu and Fe) via Fenton-like reactions or ROS escaping from damaged mitochondria. ROS can attack cellular proteins, nucleic acids, and lipids causing oxidative damage. (d) Mitochondrial dysfunction and defects in energy metabolism that can occur as a consequence of protein/peptide aggregates. (e) Aberrant axonal transport from hyperphosphorylated microtubule binding proteins, mutant tubulin proteins, or mutant motor proteins. (f) Pervasive, sustained chronic inflammation with reactive microglia and astrocytes as well as altered inflammatory signaling pathways.

Figure 2. Illustration of three rational design approaches (linkage, fusion, and incorporation approaches). (a) Linkage of chlorotacrine, an AChEI (yellow), with L2-b, a modulator of metal−Aβ aggregation (blue), through a linker (black). (b) Fusion of 11C-PIB, an imaging molecule for Aβ plaques, with DFP, a metal chelator (blue). (c) Incorporation of donor atoms for metal chelation from clioquinol into p-I-stilbene, a molecule able to interact with Aβ aggregates. Chlorotacrine, 6-chloro-1,2,3,4-tetrahydro-9-acridinamine; L2-b, N1,N1-dimethyl-N4-(pyridin-2-ylmethyl)benzene1,4-diamine; 11C-PIB (Pittsburgh compound B), 2-(4′-[11C]methylaminophenyl)-6-hydroxybenzothiazole; DFP (deferiprone), 1,2-dimethyl-3hydroxypyridin-4-one; clioquinol, 5-chloro-7-iodo-quinolin-8-ol; p-I-stilbene, (E)-4-iodo-4′-dimethylamino-1,2-diphenylethylene.

addition, this approach might counteract redundant biological pathways (i.e., compensatory mechanisms), which can readjust when only one pathological feature is targeted.

tional molecules that possess structural moieties capable of targeting multiple underlying causes of neurodegenerative decline, hopefully in a disease-modifying manner.34−38 In C

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likeness but are the least likely to retain function; however, that may be addressed by multiple rounds of design.46 Drug-likeness for favorable PK can be assessed according to Lipinski’s rule.47 Generally, small molecules as potential drugs for brain diseases may be considered to possess drug-likeness and potential BBB permeability if they have (i) ≤ 5 hydrogen bond donors; (ii) ≤ 10 hydrogen bond acceptors; (iii) ≤ 450 Da molecular weight; (iv) logarithm of octanol−water partition coefficient (log P) < 5.0; (v) polar surface area (PSA) ≤ 90 Å2; (vi) log BB < −1.0, poorly distributed to the brain (logBB = −0.0148 Å x PSA + 0.152 Å × c log P + 0.139; c log P, calculated log P).48−50 An experimental technique, the parallel artificial membrane permeability assay for the BBB (PAMPA-BBB), can be used to predict the potential BBB permeability of compounds by measuring their fraction that moves from a donor compartment to an acceptor compartment across an artificial, lipid-infused membrane.51 Note that Lipinski’s rule is used as a measure of oral bioavailability for compounds.47 Furthermore, the potential of compounds to cross the BBB may be predicted by Lipinski’s rule; however, experimental results are necessary to support their potential BBB permeability. 1.2.2. Natural Products. Natural products have been explored as a source of frameworks that can target pathological features in AD and other neurodegenerative diseases.52,53 This approach has been motivated by epidemiological studies that have demonstrated a correlation between the decreased risk of AD and certain dietary habits.54,55 The efficacy of natural products for AD can be assessed either by in vitro or in silico high-throughput screening (HTS) of a library of natural products56−58 or on a single molecule basis.59−61 Both methods have revealed an enormous number of natural products that target various aspects of neurodegenerative diseases, ranging from Aβ/tau-targeting ability, antioxidant properties, metal chelation, and an influence on signaling pathways.53,62 Naturally occurring molecules with useful properties can be used as a starting point to rationally design their derivatives.63,64 Although starting natural products already possess beneficial properties,52,59 the aim of studying their synthetic derivatives is to (i) determine the structural elements from the natural products that confer their useful properties; (ii) minimize the structures to improve druglikeness; (iii) combine them with other functional scaffolds by rational design. 1.2.3. High-Throughput Screening (HTS). Although not based on rational design, screening platforms can discover hits, molecules with desirable properties, whose potency may be enhanced by derivatization.65 Hits can also be combined by rational design into multifunctional molecules. Screening libraries are powerful because they can explore a large amount of chemical space to search frameworks, much faster than rational design. HTS, however, is often performed in vitro; thus, the selection process does not always factor in essential properties that a molecule requires, such as BBB permeability, in order to be utilized for neurodegenerative diseases. Nevertheless, lead optimization or prodrug formulations can be further employed to improve the PK of HTS hits. Recent Caenorhabditis elegans models that express Aβ3−42 or Aβ1−42 in body wall muscle provide an in vivo screening approach.66−68 C. elegans models have also been generated for PD [expressing yellow fluorescent protein (YFP) fused to human α-Syn]69 as well as ALS (expressing YFP fused mutant human SOD1)70 that may be employed for in vivo screening.71

Multifunctional molecules have several advantages from a pharmacological perspective. Treatment with a single multifunctional drug, rather than several single-target agents, can lower potentially harmful drug−drug interactions.39 In addition, it is more practical because it would require the administration of a single pill, a significant advantage for patients suffering from loss of memory since it facilitates patient compliance.40 Therefore, multifunctional compounds are emerging as a promising avenue to treat neurodegenerative diseases. As a result, varieties of strategies have evolved in the search for multifunctional molecules.34−37 Discovery of multifunctional molecules falls broadly into two categories: rational design and library screening. The two methods are somewhat interconnected, although they are essentially distinct. Hits obtained by screening methods can be assimilated by the rational design process as frameworks on which to base new development. Therefore, although the focus of the review is on the rational design of multifunctional molecules, screening tactics are also discussed briefly. 1.2.1. Rational Design. The basic precept of the rational design is to take two or more molecular scaffolds with known properties or targets (e.g., amyloidogenic peptides, metal ions, and ROS; vide inf ra) and to combine them into a single molecular entity.41,42 Combination can be achieved by three principal schemes (Figure 2): linkage, fusion, and incorporation. One major disadvantage from combining frameworks is the increase in size with a concomitant deterioration in pharmacological properties, such as oral bioavailability and BBB permeability. In this regard, the linkage approach is the least advantageous followed by fusion, and finally by the incorporation approach which has the best prospects for maintaining favorable pharmacokinetics (PK). Another considerable complication when combining backbones or moieties is the retention of biological activity and specificity of the original scaffolds. This aspect is most challenging for the incorporation approach that requires integrating or overlapping structures compared to the linkage approach in which the parent scaffolds can retain the majority of their original identities. The linkage approach entails joining the original scaffolds by a linker (Figure 2a). Despite being relatively straightforward, the length, position, and composition of linkers should be optimized to ensure that the original scaffolds retain their activity.43 For example, the linker cannot join a framework at a position that would prevent it from binding to its target. The linker itself may also interact with the target; thus, its chemical properties need to be tailored in order to maximize interactions between the linker and the target. The fusion approach is basically an extension of the linkage approach with a linker length of zero such that the two scaffolds are directly joined to one another (Figure 2b).44 Although this imparts less freedom to each moiety to move into its target binding pocket, this limits the size, compared to the linkage approach, and hence favors BBB permeability. As for the linkage approach, it also requires structural optimization to ensure that each original framework maintains the potency against its target. The strategy that leads to the most compact size is the incorporation approach in which the scaffolds are integrated into one another (Figure 2c).45 This new molecular entity combines the targeting capabilities of the original molecules into a smaller chemical structure by maintaining the most essential structural portions necessary for the desired functions. These types of molecules are most favorable in terms of drugD

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and fibrils.4 Morphology and size of aggregates produced upon treatment with a compound can be assessed to determine its ability to affect fibril formation. Another method to quantify the amount of β-sheet-rich structure formation is the thioflavin-T (ThT) assay.83 ThT becomes fluorescent upon binding to β-sheet-rich structures; thus, a fluorescent readout is a proxy for a measure of the amount of resultant β-sheet-rich structures and the impact of compounds on formation of βsheet-rich Aβ aggregates. Note that the ThT assay indicates the fibrillary aggregates exhibiting a β-sheet-rich conformation (not for the soluble oligomeric or nonfibrillary forms of Aβ lacking a β-sheet structure). Aggregation of α-Syn (implicated in PD) and SOD1/TDP-43 (implicated in ALS) can be investigated by utilizing experimental techniques applied in Aβ studies [e.g., ThT, TEM, DLS, gel/Western blot, and mass spectrometry (MS)].84−86 For the gel/Western blot experiments, peptide-specific antibodies need to be used to visualize the target peptides (i.e., α-Syn, SOD1, and TDP-43). In addition to the ability of redirecting Aβ aggregation, molecules are tested for their ability to directly bind to Aβ monomers and smaller oligomers (i.e., dimers, trimers, and tetramers). Ion mobility mass spectrometry (IM−MS) is conducted under mild and biologically compatible conditions and can separate Aβ species by volume as well as by mass.87 This volume can give an indication regarding the conformational changes (e.g., structural compaction) of Aβ species. IM− MS can analyze complex mixtures, including Aβ monomers, oligomers, and complexation with small molecules.88 While IM−MS excels for studying the mixtures of resultant Aβ species upon addition of small molecules, it cannot pinpoint the molecules’ binding location to Aβ. To obtain this atomiclevel information, two-dimensional (2D) nuclear magnetic resonance spectroscopy (NMR) with 15N-labeled Aβ can track changes in residue resonances upon introduction of Aβinteracting compounds.79,88 For multifunctional molecules designed to target Aβ and metal ions, the same techniques used to assay their impact on Aβ aggregation can be employed to verify the ability to redirect metal−Aβ aggregation but with the simultaneous addition of metal ions.79,88 These experiments demonstrate the ability of small molecules to specifically influence metal−Aβ aggregation. In addition, binding of compounds to metal ions (i.e., metal− ligand complexation) can be verified by spectroscopic methods, such as UV−visible spectroscopy (UV−vis) and NMR.89 Multiple biochemical assays [e.g., the assays of Trolox equivalent antioxidant capacity (TEAC), 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2′,7′-dichlorofluorescin diacetate (DCFDA), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and oxygen radical absorbance capacity (ORAC)] are available to test the antioxidant capability of compounds.90−96 Antioxidant capacity is generally recorded in comparison to a known antioxidant as a reference standard (e.g., Trolox in the TEAC assay) in order to compare antioxidant capacity across various molecules. Moreover, biochemical assays are employed to test compounds’ inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These assays generally involve purified electric eel (Electrophorus electricus) AChE (EeAChE) or equine serum BuChE (eqBuChE), and Ellman’s reagent [5,5′dithiobis(2-nitrobenzoic acid) or DTNB] is added as a yellow colorimetric readout of enzymatic activity.97 Studies of inhibition against monoamine oxidases (MAOs) are often

1.2.4. Fragment-Based Drug Discovery (FBDD). Fragment-based drug discovery (FBDD) is a modified HTS method.72 Unlike the conventional HTS which screens compounds that are more complex and druglike in size, a FBDD library contains molecules that are usually smaller in size (ca. 150−300 Da) and lower in structural complexity. The premise for this type of drug discovery process is that smaller molecules of lower complexity are likely to bind to a broader range of substrates, but due to fewer reciprocal interactions between fragments and targets, binding affinities are weaker. Binding affinities of hits for targets, however, can be optimized via structure-based drug design. This approach has worked for the drug design of AD:73−75 for example, (i) MK-8931, a βsecretase inhibitor, first identified by FBDD and then optimized to produce a drug candidate and (ii) LY2811376, a β-secretase inhibitor, similarly developed by FBDD.76 As for HTS, the molecules discovered by FBDD can be adopted by rational design to fashion multifunctional molecules. In one strategy, several fragments that bind to different targets can be combined into one molecule in a manner similar to the linkage or incorporation approach in rational design (vide supra).77 In another scenario, a single fragment that interacts with multiple AD targets can be refined to increase its affinity for all targets. In this case, optimization requires balancing sufficient affinity for each of the multiple targets without a very strong preference for one target at the expense of the others. FBDD is rapidly emerging as a promising technique for drug discovery for neurodegenerative diseases. 1.2.5. Methods to Test Efficacy. Intense investigations into the design and discovery of multifunctional compounds to treat neurodegenerative diseases have yielded numerous molecules. Their efficacies can be verified by in vitro biochemical and biophysical studies followed by in vivo testing. In this section, we briefly summarize some methods to test compounds’ efficacies toward metal-free Aβ, metal-bound Aβ (metal−Aβ), and other targets, including ROS and enzymes. The ability of molecules to inhibit or redirect the aggregation pathways of Aβ into nontoxic, off-pathway species is one measure of small molecules’ efficacy.78 The principal biochemical method to visualize Aβ aggregation is gel electrophoresis with Western blotting (gel/Western blot) using an antibody against Aβ. Comparatively analyzing samples of Aβ only versus Aβ with a compound through gel/Western blot can reveal whether the compound can influence Aβ aggregation and affect the molecular weight distribution of Aβ species.79 Another technique, which omits the separation based on size, is dot blot in which Aβ samples are directly applied to a membrane and probed with antibodies against Aβ species (e.g., 6E10, A11, and OC).80,81 Within the linear range of emitted luminescence, intensities of the dot blot can reveal information about the relative amounts of monomers, oligomers, and fibrils. A comparison of Aβ only versus Aβ treated with a molecule can determine whether the molecule can alter the distribution of Aβ species and thus affect peptide aggregation pathways. Dynamic light scattering is a biophysical method used to analyze the particle size of Aβ species generated upon aggregation.82 Variation of Aβ’s size could be obtained by the addition of molecules that target Aβ. Transmission electron microscopy (TEM), atomic force microscopy (AFM), and cryo-electron microscopy (cryo-EM) are useful methods to image Aβ aggregates, such as annular aggregates, protofibrils, E

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mitochondrial complex I activity in the dopaminergic neurons of the substantia nigra pars compacta.105 The main ALS animal models are based on SOD1 and TDP43 mutations.106 Representative models express SOD1G93A, SOD1G37R, SOD1G85R, and SOD1G86R. These mutants exhibit overexpressed SOD1 in the CNS, significant motor neuronal loss, and paralysis within months of age.107−110 Variations in the gene encoding TDP-43 are determined to be associated with ALS, leading to the establishment of multiple rodent models.106 Representative ALS models include TDP-43A315T, TDP-43M337V, and TDP-43G348C.111−115 Motor dysfunction is a common feature in most ALS rodent models. Furthermore, these models are characterized by ubiquitous overexpression of TDP-43 and varying biological traits (e.g., TDP-43 translocation and the presence of peptide inclusions and TDP-43 Cterminal fragments). Mouse models are employed to validate potential toxicity of drug candidates and effective dosage for cognitive improvements. Cognitive function is tested by a battery of tests that gauge various types of memory:116 (i) T-, Y-, and radial arm maze tests for working memory; (ii) Morris water maze (MWM) and variants for spatial memory; (iii) novel object recognition test for recognition memory; (iv) What-WhereWhich task to test episodic-like memory. Due to shortcomings in these tests, recent trends have moved toward touch screen adaptations more akin to tests administered to human patients.116

performed on recombinant human protein or from rat tissue homogenates. Addition of a suitable monoamine substrate initiates the reaction that produces hydrogen peroxide (H2O2), detected by an Amplex red assay.98 Alternatively, endogenous and native MAO from animal brain extracts is treated with either 14C-5-hydroxytryptamine binoxalate (for MAO-A) or 14 C-phenylethylamine (for MAO-B), and the reaction is monitored by the production of radioactive metabolites 5hydroxytryptaldehyde and phenylacetaldehyde.99 Commercial kits, composed of modified pro-luminogenic MAO substrates that release luciferin upon MAO activity, also exist, in which the luciferin acts as a substrate to luciferase to yield a luminescent readout. In addition to the aforementioned methods that measure the influence of small molecules on Aβ peptides themselves, their ability to offer neuroprotective effects to Aβ-treated cells or primary neuronal cultures can also be assessed. More recent techniques, made possible by the advent of induced pluripotent stem cells (iPSCs), have brought a new testing platform to neurodegenerative diseases, including AD.100 iPSCs can be differentiated to neuronal cultures from nonneuronal human samples, such as blood and fibroblasts. CRISPR-Cas9 edited iPSCs can introduce familial AD mutations, and the original cells can serve as the control of non-AD samples. In addition to these advances, threedimensional (3D) cultures of iPSCs offer more realistic testing options to mimic the complexity of the brain more closely than conventional two-dimensional (2D) cultures.100 A number of animal models have been created to uncover the pathophysiology of AD and test candidates of molecules in vivo.101 While AD models of rats, Drosophila melanogaster, C. elegans, and zebra fish are known, the most prevalent are mouse models. Multiple transgenic (Tg) mouse models have been created with variations of the mutant human genes that they express.101 Perhaps the most common are Tg2576 (expressing APPK670N,M671L), 5xFAD (the most extreme quintuplet mutant expressing APPK670N,M671L, APPV717I, APPI716V, PSEN1M146L, and PSEN1L286V), and 3xTg (expressing APPK670N,M671L, PSEN1M146V, and MAPTP301L). These models all lead to Aβ plaque deposition, gliosis, and cognitive impairment. The 3xTg model additionally exhibits the deposition of NFTs. An interesting variant is the APP E693Δ-Tg mouse, modeled on the expression of the Osaka mutant APPE693Δ, a variant which forms soluble Aβ oligomers without plaque deposition. This particular mouse model is useful to test candidates of compounds specifically designed to target Aβ oligomers. Genetic models for PD include transgenic mice with mutations in α-Syn and leucine-rich repeat kinase 2 (LRRK2), which are linked to autosomal-dominant PD. Mutations in parkin, DJ-1, phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) are responsible for autosomal-recessive PD.102 Neurotoxin-induced PD models utilize 6-hydroxydopamine (6-OHDA) and 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).103 Intracerebral administration of 6-OHDA results in significant anterograde degeneration of the nigrostriatal pathway.103 Neuronal degradation is evident within 12 h postinjection, and dopamine depletion is established in 2−3 days. This model is characterized by high levels of nigral neurodegeneration and striatal dopamine depletion among PD models, ranging from 90 to 100% in both cases.104 Systemic MPTP administration is reported to induce selective toxicity against dopaminergic neurons by crossing the BBB and disrupting the activity of

2. ALZHEIMER’S DISEASE (AD) In 1906, Alois Alzheimer introduced the world to a devastating disease widely known today as AD.117 AD is a progressive neurodegenerative disease responsible for 60 to 80% of dementia cases.1,118 According to the World Alzheimer Report, 47 million people worldwide were affected by AD in 2015 and this number is projected to increase to 75 million by 2030.1 With the aging world population, the social and economic impact of AD is expected to rise significantly.119 Since the discovery of AD, a great deal of progress has been made toward understanding its pathogenesis; however, we have yet to pinpoint its causative factors or fully elucidate its pathology. More importantly, there are no treatments for AD that can cure or halt its progression. Current AD therapies either temporarily relieve symptoms by inhibiting AChE to maintain the levels of ACh and cholinergic transmission or regulating the activation of N-methyl-D-aspartate (NMDA) receptors. Five AD treatments approved by the Food and Drug Administration (FDA) are available to relieve the symptoms of AD (Table 1): (i) three AChE inhibitors (i.e., donepezil, galantamine, and rivastigmine); (ii) an NMDA receptor (NMDAR) antagonist (i.e., memantine); (iii) a mixture of donepezil and memantine. The imminent amplification of the socioeconomic impact of AD and the lack of an effective treatment illustrate the urgent necessity to identify the underlying AD pathogenesis. Loss of short-term and long-term memory is the most widely recognized AD symptom. Throughout the progression of AD, patients manifest a general decline in mental ability: language and motor skills, sensory information processing, and memory formation and retrieval.120 The anatomical hallmarks of AD include the shrinkage of the hippocampus and cortex.121 Histopathologically, AD compromises SPs and NFTs composed primarily of Aβ and tau, respectively.29,122,123 Along with its proteopathy, metal ion dyshomeostasis, F

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(CTFα) are formed by α-secretase cleavage.128−130 Subsequent cleavage of CTFα by γ-secretase results in the generation of p3, a nonamyloidogenic peptide. Amyloidogenic APP processing is initiated by β-secretase cleavage [e.g., β-site APP cleaving enzyme (BACE1)] producing sAPPβ and

Table 1. Currently Available AD Treatments

a

Donepezil, 2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3dihydro-1H-inden-1-one; galantamine, (4aS,6R,8aS)-5,6,9,10,11,12hexahydro-3-methoxy-11-methyl-4aH-[1]benzofuro[3a,3,2-ef ][2]benzazepin-6-ol; memantine, 3,5-dimethyl-tricyclo[3.3.1.13,7]decan1-amine; rivastigmine, (S)-3-[1-(dimethylamino)ethyl]phenyl-Nethyl-N-methylcarbamate. bAChE, acetylcholinesterase; BuChE, butyrylcholinesterase; NMDAR, N-methyl-D-aspartate receptor.

Figure 3. Schematic representation of the on-pathway aggregation of Aβ. During the nucleation phase, Aβ monomers aggregate to oligomers through interactions between their self-recognition sites (LVFFA; highlighted in bold and underlined in the amino acid sequence of Aβ). Structured Aβ oligomers are implicated as potential toxic species. Oligomeric Aβ species are further transformed into protofibrils and fibrils. Fragmentation of preformed fibrils, along with secondary nucleation, also contributes to the formation of Aβ oligomers.

imbalance between the production and removal of ROS, and loss of cholinergic transmission are also implicated in AD pathology. Several hypotheses have arisen in an attempt to identify the principal pathological factors in AD: (i) amyloid cascade hypothesis; (ii) tau hypothesis; (iii) metal ion hypothesis; (iv) oxidative stress hypothesis; (v) cholinergic hypothesis. Thus far, therapeutics targeting singular pathological factors presented in these hypotheses have proven ineffective, inferring the intricate nature of AD pathogenesis. Consequently, the contemporary direction concerning AD etiopathology increasingly appreciates its complexity and has transitioned from focusing on individual pathological components to illuminating the interrelations among multiple pathological factors.

CTFβ.128−130 The generated CTFβ is then cleaved by γsecretase at multiple sites within the transmembrane domain, producing a range of Aβ monomers with 38 to 43 amino acid residues.128−131 Aβ peptides possess a propensity to aggregate, which is a subject of intensive research. As an intrinsically disordered protein, Aβ lacks stabilized secondary or tertiary structures; however, it can exist in partially folded states depending on genetic mutations and external factors (e.g., pH, temperature, peptide concentration, and intermolecular interactions).132 During on-pathway aggregation, composed of a nucleation phase followed by an elongation phase, monomeric Aβ species oligomerize through interactions between their self-recognition sites and hydrophobic C-terminal regions (Figure 3).129 These metastable Aβ oligomers can further aggregate into protofibrils and fibrils which exhibit a β-sheet conformation.132 Fibrils have been reported to contribute to the accumulation of Aβ oligomers through fragmentation and secondary nucleation.133,134 Due to their prominent presence in extracellular SPs, fibrils were initially thought to be responsible for neurotoxicity in AD.135,136 A lack of correlation between SP load and the extent of neurodegeneration, however, led to the reevaluation of this notion.122 Recent studies have supported an alternative concept of structured Aβ oligomers as a potential toxic species.80,137−140 The toxic mechanisms of structured Aβ oligomers have been proposed to arise from their interactions with membranes and membrane receptors and the disruption of intracellular processes [e.g., induction of endoplasmic reticulum (ER) stress, lysosomal leakage, mitochondrial dysfunction, and signal interruption].132,141 Furthermore, Aβ transmissibility through a seeding effect has been suggested as a means to spread its toxicity, possibly to

2.1. Amyloid-β (Aβ) and Tau

AD proteopathy is portrayed by two highly recognized AD hypotheses: the amyloid cascade and tau hypotheses. The amyloid cascade hypothesis posits that Aβ, a proteolytic product of amyloid precursor protein (APP), is the causative factor in the course of AD pathology.122 Genetic studies support the pertinence of Aβ in AD pathogenesis. Numerous AD genes are shown to influence Aβ pathology (e.g. APOE, APP, PSEN1, and PSEN2).124 A common polymorphism, ε4, within APOE is reportedly associated with the late onset of AD. This mutation is characterized by elevated Aβ aggregation and reduced Aβ clearance.125,126 Genetic variants in APP are connected with early onset familial AD.127 According to an AD mutation database, 51 APP gene mutations are believed to be linked to the increased Aβ42:Aβ40 ratio as well as the production and aggregation of Aβ leading to AD.124,127 PSEN1 and PSEN2 mutations are indicated to be involved in AD pathology with 219 and 16 variants identified, respectively.127 Genetic mutations to PSEN1 and PSEN2 are shown to enhance the Aβ42:Aβ40 ratio.124 Responsible for the production of Aβ, APP processing can be categorized into nonamyloidogenic and amyloidogenic pathways.128−130 In nonamyloidogenic APP processing, the soluble APPα (sAPPα) and the C-terminal fragment α G

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free fatty acids have been implicated as bridging factors between Aβ and tau.122,148,151,159,160 The interrelationship of Aβ and tau appears to be complex, and further clarification would benefit from agents capable of interacting with both of them.

remote areas, through cell-to-cell transmission mechanisms.142,143 Overall, the amyloid cascade hypothesis presents potential therapeutic candidates directly influencing the production, clearance, and aggregation of Aβ. NFTs, the second prominent histopathological feature of AD, are mainly found within neurons and predominantly contain aggregates of the tau protein.123,144 Proponents of the tau hypothesis links the toxicity in AD to the pathogenicity of tau, whose NFT burden correlates more accurately with neurodegeneration than Aβ plaque load.145,146 Tau, a phosphoprotein, belongs to the family of microtubule associated proteins (MAPs) that stabilize microtubules, promote, among other functions, anterograde (nucleus to periphery) and retrograde (periphery to nucleus) axonal transport, and sustain dendrite structure.147 Thus, properly functioning tau is essential to neuronal trafficking and synapse architecture. Tau is encoded by a single gene on chromosome 17 that gives rise to six isoforms varying in length from 352 to 441 amino acids, which are all found aggregated and hyperphosphorylated in NFTs.123,144 Tau hyperphosphorylation causes a loss-of-function, which hinders its ability to bind to microtubules, inducing the deterioration of axonal trafficking and dendrite structure leading to microtubule depolymerization.123,144,148 pTau aggregation occurs in stages, as for Aβ, first into oligomers and amorphous tangles that mature into paired helical filaments (PHFs) and straight filaments (SFs). Similar to Aβ fibrils, PHFs and SFs also contain a cross-β structural feature but additionally include a β-helix motif.149 Other proteins [e.g., normal tau and alternative MAPs (MAP1/2)] and post-translationally modified and truncated tau/ptau are coaggregated with PHFs and SFs.150 A greater understanding of tau’s aggregation pathway may prove useful in the development of tau-targeting therapeutics. Noble et al. linked the initiation of tau aggregation to cyclin-dependent kinase-5 (cdk5) in a Tg mouse model.151 Further research regarding tau phosphorylation and aggregation in AD is necessary to determine their cause-and-effect relationship leading to neuronal degradation and suggest prospective therapeutic approaches. Gain-of-toxic function from tau is suspected to arise from ptau oligomers rather than from NFTs or SFs. Recent studies on the tau oligomers have increasingly supported their role in the early pathology of AD since they could disrupt anterograde axonal transport and impair long-term potentiation (LTP) in Tg mice.152,153 For the above-mentioned reasons, the modulation of abnormal hyperphosphorylation and aggregation of tau presents a potential approach for drug discovery. Aside from AD, the diseases, known as tauopathies [e.g., sporadic corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia (FTD)], have been linked to tau, suggesting a mutual connection among multiple neurodegenerative diseases.154 Increasing evidence indicates a link between the amyloidogenic proteopathy and tauopathy in AD.155 Tau and ptau have been reported to directly and indirectly interact with Aβ. In a perspective article introducing the amyloid cascade hypothesis, Aβ was accountable for the formation of NFTs.122 The parallel between Aβ and tau with respect to the toxicity of oligomeric forms has led to the suggestion that the oligomeric species of Aβ and tau may synergistically act to induce neurotoxicity and synaptic dysfunction.155−158 Moreover, disruption of calcium homeostasis, glycogen synthase kinase 3 (GSK3), cdk5, and

2.2. Metal Ions

Metal ions are involved in biologically vital processes, such as signal transmission, catalysis, stabilization of proteins’ structures, and metabolism.11,161 The functions of the essential first-row transitions metals (e.g., Fe, Cu, and Zn) have been widely studied. These metal ions are strongly regulated across the BBB due to their pertinent role in biologically essential processes.162 Therefore, dysregulation of these regulatory mechanisms could lead to disease. In fact, previous studies have demonstrated the colocalization of the above-mentioned metal ions in SPs from AD patients’ brain tissue.8,11 The metal ion hypothesis posits that the dyshomeostasis and miscompartmentalization of metal ions contribute to AD pathology.163 In this section, we discuss metals’ functionality, toxicity, homeostasis, and binding to Aβ, as well as the pathological implications of metal−Aβ. Among essential transition metals, Zn is the second-most abundant in biological systems.164 Available in both proteinbound and labile forms in the body, Zn(II) is a d10 metal ion that does not possess a biologically relevant redox activity.164 Zn(II) sites in proteins are tetrahedral or distorted tetrahedral, and as a transition metal ion with borderline hardness, Zn(II) binds to nitrogen (N), oxygen (O), and sulfur (S) donor atoms of amino acid residues.165,166 Zn(II) is heterogeneously distributed throughout the brain with relatively high concentrations observed in the hippocampus, amygdala, neocortex, and olfactory bulb areas.167 Protein-bound Zn(II) [e.g., Zn finger proteins and Cu/Zn SOD1] accounts for over 90% of the total Zn(II) content of the brain. The remaining labile pools of Zn(II), primarily localized within synaptic vesicles of glutaminergic neurons, have been indicated in LTP.164,168 The interactions of Zn(II) with γ-aminobutyric acid (GABA) receptors and NMDARs and its extracellular release following neuronal stimulation have led researchers to propose its involvement as a neurotransmitter and secondary messenger.169−171 Cu, the third-most abundant transition metal in the human body, is found in protein-bound [e.g., cytochrome c oxidase (CcO), Cu/Zn SOD1, ceruloplasmin, and dopamine β monooxygenase (DβM)] and labile forms.164,172 As a redoxactive metal, Cu acts as a critical cofactor involved in enzymatic functions, including the biochemistry of dioxygen (O2).164,173 The two major oxidation states of Cu are +1 and +2. Cu(I) exists under reducing intracellular conditions, while Cu(II) is likely to be present under oxidizing conditions. Cu(I) and Cu(II) are considered as soft and borderline acids, respectively, and bind to N, O, and S donor atoms. Cu(I), like Zn(II), is a d10 metal ion with preferred coordination numbers 2, 3, or 4, indicating linear, trigonal planar, or (distorted) tetrahedral geometries, respectively. As a d9 metal ion, Cu(II) can be coordinated to 4, 5, or 6 ligands, with square planar, square pyramidal, or (axially distorted) octahedral geometries, respectively.174 Cu(I)-/Cu(II)-coordinated proteins can be categorized into two groups based on their relation to metal ions: (i) proteins utilizing the redox chemistry of Cu(I)/Cu(II) to carry out specific functions (e.g., SOD1 and CcO) and (ii) proteins H

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Table 2. Proposed Amino Acid Residues of Aβ for Metal Coordination metal ions

peptides

amino acid residues for metal coordination

Fe(II)

Aβ16 and Aβ40

Fe(III) Cu(I)

Aβ28 Aβ6−14 Aβ10−14 Aβ16 Aβ16 Aβ16 Aβ40 Aβ16

Aβ28 Aβ28 Aβ16 Aβ16 Aβ16 Aβ16 pAβ16 (S8) Aβ16 D7H-Aβ10

N-terminal NH2, (D1 or E3), (D1-A2 or H6-D7; carbonyl from the amide group), H6, and (H13 or H14) n.d.a H13 and H14 H13 and H14 H13 and H14 H13 and H14 H13 and H14 H13 and H14 pH 6.5: H6, (H13 or H14), N-terminal NH2, (D1; side-chain carboxylate group), and (D1-A2; carbonyl from the amide group) pH 9.0: N-terminal NH2, (D1-A2; N from the amide group), (A2-E3; carbonyl from the amide group), and (H6, H13, and H14) pH 6.3: N-terminal NH2, (D1-A2; carbonyl from the amide group), H6, and (H13 or H14) pH 8.0: (A2-E3; carbonyl from the amide group), H6, H13, and H14 pH 6.3: D1, (D1-A2; carbonyl from the amide group), H6, and (H13 or H14) pH 8.0: O (no indication for the specific coordination site), H6, H13, and H14 pH 6.9: H6, Y10, H13, and H14 pH 7.4: N-terminal NH2, H6, H13, and H14 R5, H6, H13, and H14 D1, H6, H13, and H14 H6, H13, H14, and (E11; side-chain carboxylate group) Aβ11−14 residues (E11 and H14) H6, D7, phosphorylated S8, E11, and H14 H6, E11, (H13 or H14), and (D1, E3, or D7) (D1-A2; carbonyl from the amide group), E3, H6, and H7

Aβ28 Aβ28 Aβ28 Aβ40

H6, H13, and H14 H6, H13, and H14 N-terminal NH2, H6, E11, H13, H14, and (Y10 for conformational rearrangement) N-terminal NH2, H6, H13, and H14

Cu(II)

Aβ16 Aβ16

Zn(II)

technique

ref

NMR

215

NMR, ESI-MS EXAFS EXAFS EXAFS, EPR NMR, XANES CP-MD simulation EXAFS, EPR EPR

216 209 209 210 211 212 210 220

EPR

213

EPR

214

NMR, EPR EPR ESI-MS NMR NMR SPR, ESI-MS ITC, ESI-MS, NMR NMR, XAS NMR, EXAFS, MS, ITC NMR, EPR NMR, CD NMR NMR

205 224 200 201 202 203 204 217 208 205 206 207 218

a

n.d., not determined.

in catalytic cycles.164 Labile Fe(II) and Fe(III) are reported to exist in pools at intracellular concentrations of up to 100 μM,164 but the nonenzymatic role of Fe in neurobiology has not been clearly identified. Metal ion homeostasis, balancing functionality against toxicity, is a critical aspect in the proper functioning of biological systems.164,181 Zn(II) homeostasis is managed by proteins, such as SLC30A (Zn transporter 3; ZnT-3), ZRT/ I RT-like proteins (ZI P s), and m etallothioneins (MTs).164,182−184 ZIP transporters bring Zn(II) into the cytoplasm, while Zn transporter (ZnT), voltage-gated calcium channels, and NMDARs are shown to mediate the extracellular release of Zn(II).10 Greenough and co-workers implicated the expression of presenilins, a component of γ-secretase, as a major contributor toward the control of Zn(II) and Cu(I)/ Cu(II) in the brain.185 The dysregulation of Zn(II) can lead to excitotoxicity that may induce cell death via the upregulated activity of glutamate receptors, ROS generation, and overactivation of nitric oxide (NO) signaling.184,186,187 Cu(I)/ Cu(II) homeostasis is regulated by proteins, such as CCS, CTR1, ATP7A, COX17, and Cu metabolism COMM domaincontaining protein 1 (COMMD1) domain.10,175 On the basis of its redox activity, the dysregulation of Cu(I) and Cu(II) can cause the overproduction of ROS leading to oxidative stress. In addition, due to its imperative roles in enzymes, such as SOD1, CcO, and DβM, the colocalization of Cu in amyloid plaques may result in Cu-deficient proteins, causing irregularity in

involved in the Cu transport [e.g., CTR1, ATP7, and CCS].10,175 Cu adopts important roles in the brain. In order to compensate for the high level of O2 metabolism in the brain and the potential accidental release of ROS, neurons and glia require Cu for antioxidant enzymes (e.g., SOD1). Cu is also associated with the homeostasis of neurotransmitters, neuropeptides, and dietary amines by acting as a cofactor for DβM, peptidylglycine α-hydroxylating monooxygenase, tyrosinase, and amine oxidases.164 Micromolar Cu is released into the extracellular space upon neuronal depolorization.176 Although the role of Cu in signal transmission is not fully understood, previous reports suggest that micromolar Cu is capable of antagonizing NMDA, GABA, and glycine receptors.177 In addition, exogenous Cu is reported to affect K(I) and Ca(II) channels.164 Further research regarding the link of labile Cu(II) to neurotransmission is necessary to gain a better understanding of its neurophysiological role. Fe, known for its role in O2 transport and metabolism, is the most abundant transition metal in the human body.178,179 Like Cu, the utility of Fe as a redox-active component manifests the basis of its enzymatic involvement. Fe is an essential element of enzymes (e.g., heme proteins, nonheme proteins, and Fe SOD1) responsible for a spectrum of biological functions, such as electron transfer, O2 chemistry, gene regulation, and regulation of cell growth and differentiation.180 The resting state of Fe in enzymes is mainly found as Fe(II) and Fe(III), while higher oxidation states can be observed as intermediates I

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containing phosphorylated S8 (pAβ). Proposed binding residues are the phosphate group, the imidazole ring of H6, and a backbone carbonyl group of either H6 or D7.204 This binding mode stimulates peptide dimerization with an additional Zn(II) coordinated to two pairs of E11 and H14 from two separate peptide subunits.204 This observation of Zn(II)-induced dimerization provides insight into the initiation of metal-induced Aβ aggregation. Recently, an unprecedented coordination of Zn(II)−Aβ10 was presented with the Taiwanese mutation D7H using a suite of structural characterization methods.208 The 1:1 stoichiometry was confirmed via NMR and isothermal titration calorimetry (ITC). Additionally, the formation of the proposed complex [Zn(II) 2 (D7H-Aβ 10 ) 2 ], which consisted of a binuclear Zn(II) core where both ions were bound to two D7H-Aβ10 peptides, was validated by MS and isotope-edited NMR.208 The NMR investigations revealed that the carbonyl group (D1-A2), carboxyl group (E3), H6 (from one polypeptide chain), and H7 (from the second polypeptide) were bound to Zn(II).208 These observations were theoretically refined and supported by extended X-ray absorption fine structure (EXAFS) spectroscopy.208 The Cu(II)−Aβ binding mode occurs in two forms, components I and II (Figure 4), depending on the pH (i.e., pH 6.5 and pH ≥ 8, respectively).8,192,205,213,214,219−223 At pH ≥ 8, component II is predominant with three main potential binding configurations of Cu(II)−Aβ: (i) 3N1O coordination {e.g., for 3N, [H6, D1 (N-terminal NH2), and D1-A2 (deprotonated backbone amide)] or (H6, H13, and H14); for 1O, carbonyl backbone oxygen (A2-E3)},213,214,220 (ii) 4N coordination with three histidines (H6, H13, and H14) and either N-terminal amino group or deprotonated backbone amide,224,225 or (iii) 5N1O coordination with potential binding sites: N-terminal NH2, the N donor atom from the D1-A2 backbone, carbonyl backbone from A2-E3, H6, H13, and H14.220 Component I is the prevalent Cu(II) binding mode with Aβ at physiological conditions. Several reports have proposed 3N1O coordination involving: (i) the N-terminal primary amino group of D1, an O donor atom from a carbonyl backbone between D1 and A2, H6, and either H13 or H14 or (ii) D1 (N-terminal amine), D1-A2 (a carbonyl backbone), and two histidines among H6, H13, and H14, with the possibility of an additional coordination with D1 (carboxylate).8,192,194,213,214,219−222 Dorlet et al. reported the observation of a 5-coordination mode using electron paramagnetic resonance spectroscopy (EPR) in conjunction with specific isotopic labeling.220 They detected and identified a 3N2O coordination site in Aβ consisted of two histidines (H6 and either H13 or H14), the N-terminal NH2, the carbonyl group between D1 and A2, and the carboxylate group of D1. The carbonyl and carboxylate groups from D1 were reported in the equatorial and axial positions, respectively. The exact binding atoms of D1 in Aβ is controversial. The N-terminal NH2, the carboxylate, and the amide backbone have all been suggested to be possible binding atoms from D1.213,214,220 Moreover, the involvement of Y10, via conformational rearrangement of Cu(II)−Aβ at pH 6.9, has been suggested.205 Previous studies demonstrated that the pH-dependent oxidation state of the Aβ-bound Cu dictates the coordination geometry of the complex.210,226 When Cu K-edge X-ray absorption spectroscopy (XAS) was applied to Cu(II)−Aβ, a square-planar Cu(II) center with mixed N/O ligation, including imidazole groups of

biological functions. Similar to Cu, the notable redox reactivity of Fe makes it a double-edged sword, enabling a wide range of biological functions but generating ROS, whose release can induce toxicity if unregulated and left unchecked. Fe homeostasis is controlled by different types of proteins, including Fe transporters [e.g., divalent metal-ion transporter-1 (DMT1), ferroportin-1, mitoferrin-1, and ZIP14],188 heme transporters (e.g., HRG1 and FLVCR1),189,190 Fe chaperones (e.g., PCBPs), ferrireductases, hepcidin, ferritin, and transferrin.191 The essential function of metals in the brain coupled with the detrimental effects of their dysregulation suggests that metal ion dyshomeostasis could lead to disease.8,10,11,172,192−197 In 1994, Bush et al. discovered the relevance of metal ions in AD pathogenesis.198 They reported the induction of Aβ40 fibrillization in the presence of Zn(II),198 launching intense research into the binding of transition metal ions to Aβ.16 Moreover, highly concentrated Cu(I/II), Zn(II), and Fe(II/III) (ca. 400, 1000, and 900 μM, respectively) were found within SPs compared to healthy age-matched controls, reinforcing their interaction with Aβ in vivo and possible involvement in AD pathogenesis.199 Since binding of Zn(II), Cu(I/II), and Fe(II) to Aβ modifies its aggregation, the investigations of molecular-level interactions between metal ions and Aβ can be challenging. Researchers circumvented this issue by employing Aβ16 or Aβ28 that bind Cu(II) and Zn(II) without significant aggregation.200−217 The proposed coordination of Zn(II), Cu(I/II), and Fe(II) to Aβ is summarized in Table 2 and Figure 4.

Figure 4. Examples of metal coordination to Aβ. Each metal [Zn(II) and Cu(II)] coordination is published in refs 217 and 220, respectively. Possible fifth ligands on the metal centers are not indicated in this figure.

Numerous studies have focused on possible binding modes of Zn(II) and Aβ.200−208,217,218 On the basis of previous findings, the feasible Zn(II) binding sites in Aβ are primarily composed of 4−6 ligands: H6, H13, and/or H14 with additional candidates that include D1 (N-terminal NH2 or side chain carboxylate), E3, R5 (backbone amide), D7, Y10, E11, or water molecules.8,192,194,200−202,205,206,218,219 In addition, Y10 is implicated in a Zn(II)-dependent conformational rearrangement under membrane-mimicking environments.207 Kulikova et al. reported that phosphorylated residues may be involved in Zn(II) binding based on studies with Aβ J

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Table 3. Binding Affinities of Metal Ions to Aβ metal ions

peptides

Fe(II) Cu(I)

Aβ40 Aβ16 H6A-Aβ16 H13A-Aβ16 H14A-Aβ16 Aβ42 Aβ16 Aβ16 Aβ16 Aβ16 Aβ16 Aβ4−16 Aβ28 Aβ28 Aβ28 Aβ28 Aβ28 Aβ28 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 F4W-Aβ40 Aβ42 Aβ42 Aβ16 Aβ16 Aβ16 Aβ28 Aβ28 Aβ28 Aβ28 Aβ28 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 Aβ40 fibrils F4W-Aβ40 Aβ42 Aβ42 Aβ42 Aβ42

Cu(II)

Zn(II)

Kd (× 10‑6 M) 76 (± 20) 2.7 (± 2.1) × 8.9 (± 3.7) × 1.1 (± 0.7) × 1.0 (± 0.8) × 5.3 × 10−2 47 (± 5) 0.1 0.09 0.7 × 10−3 0.3 × 10−3 8 (± 2) 0.1 28 (± 5) 0.07 0.4 (± 0.1) 2.5 (± 0.2) 1.2 (± 0.1) 1.6 (± 0.9) 11 (± 1) ca. 8 0.5 (± 0.2) 1.2 (± 0.4) 3.8 (± 0.9) 30 (± 6) 0.6 (± 0.2) 2.5 (± 0.6) 0.9 × 10−3 0.4 × 10−3 1.6 5.3 × 10−4 0.6 (± 0.2) 2.0 (± 0.8) 0.8 (± 1.0) 22 (± 15) 14 (± 5) 9 6.6 (± 0.2) 1.1 (± 0.1) 3.2 (± 0.1) 12 (± 5) 10 (± 8) 1.2 (± 0.03) 300 (± 100) 7 (± 3) 7 (± 3) 65 (± 3) 124 (± 32) 60 (± 14) 184 (± 30) 9 (± 6) 90 (± 30) 57 (± 28) 7 (± 3) 91 (± 16) 6.2 (± 0.9)

10−9 10−9 10−8 10−8

conditionsa

technique

ref

10 mM Tris, pH 7.4, 100 mM NaCl 20 mM N-ethylmorpholine, pH 7.0 20 mM N-ethylmorpholine, pH 7.0 20 mM N-ethylmorpholine, pH 7.0 20 mM N-ethylmorpholine, pH 7.0 100 mM HEPES, pH 7.4 100 mM Tris, pH 7.4, 150 mM NaCl H2O, pH 7.8 50 mM HEPES, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.2, 150 mM NaCl 20 mM PIPES, pH 7.4, 160 mM NaCl 100 mM Tris, pH 7.4, 150 mM NaCl H2O, pH 7.8 100 mM Tris, pH 7.4, 150 mM NaCl 50 mM HEPES, pH 7.4, 100 mM NaCl 10 mM phosphate, pH 7.2 10 mM HEPES, pH 7.2 10 mM phosphate, pH 6.5 10 mM Tris, pH 7.4, 100 mM NaCl 100 mM Tris, pH 7.4, 150 mM NaCl 20 mM HEPES, pH 6.6, 100 mM NaCl 10 mM Tris, pH 7.3, 100 mM NaCl 20 mM Tris, pH 7.4, 100 mM NaCl 50 mM Tris, pH 7.4, 100 mM NaCl 100 mM Tris, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 100 mM HEPES, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.2, 160 mM NaCl 20 mM HEPES, pH 7.4, 160 mM NaCl 5 mM phosphate, pH 7.3 20 mM PIPES, pH 7.4, 160 mM NaCl 10 mM Tris, pH 7.4, 100 mM NaCl 10 mM Tris, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 20 mM Tris, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 50 mM HEPES, pH 7.1 10 mM HEPES, pH 7.2 10 mM phosphate, pH 7.2 10 mM phosphate, pH 6.5 20 mM HEPES, pH 7.4, 100 mM NaCl 20 mM Tris, pH 7.4, 100 mM NaCl 10 mM phosphate, pH 7.2 10 mM Tris, pH 7.4, 100 mM NaCl 20 mM Tris, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 10 mM Tris, pH 7.4, 100 mM NaCl 100 mM Tris, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 10 mM Tris, pH 7.4, 100 mM NaCl 10 mM Tris, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4, 100 mM NaCl 20 mM HEPES, pH 7.4

fluorescence UV−Vis UV−Vis UV−Vis UV−Vis UV−Vis fluorescence fluorescence ITC ITC ITC fluorescence fluorescence fluorescence ITC fluorescence fluorescence fluorescence fluorescence fluorescence fluorescence fluorescence fluorescence fluorescence fluorescence fluorescence fluorescence ITC ITC NMR ITC fluorescence fluorescence fluorescence ITC UV−Vis UV−Vis fluorescence fluorescence fluorescence UV−Vis ITC NMR fluorescence ITC UV−Vis fluorescence UV−Vis fluorescence fluorescence UV−Vis fluorescence fluorescence UV−Vis fluorescence ITC

230 239 239 239 239 238 234 235 236 243 245 234 224 234 236 218 218 218 230 234 237 229 229 229 229 229 229 240 240 242 245 230 230 229 228 228 233 218 218 218 228 228 218 230 228 228 229 229 229 229 228 230 230 228 229 232

a

Tris, tris(hydroxymethyl)aminomethane; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; PIPES, piperazine-N,N′-bis(2-ethanesulfonic acid); PBS, phosphate-buffered saline. K

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histidine ligands, was indicated.210,227 After reduction of Cu(II)−Aβ, the EXAFS data fit best a linear two-coordinate geometry, with two imidazole ligands coordinated to Cu(I)− Aβ, possibly H13 and H14.209−212,227 Studies of the Fe(II)− Aβ binding via NMR demonstrated a coordination composed of the N-terminal NH2 (D1), a carboxylate from either D1 or E3, a carbonyl group from D1-A2 or H6-D7, and two N donor atoms from H6 and either H13 or H14.215 There is limited information regarding the binding of Fe(III)−Aβ.215,216 Determination of binding affinities of metal−Aβ complexes at different conditions can be valuable, especially toward the development of therapeutics with metal chelating capabilities. Comparative studies regarding binding affinities of metal−Aβ to novel metal chelators may allow researchers to estimate their ability to target labile metal ions and metal−Aβ versus metal ions from metalloproteins essential for biological functions. The reported range of Kd for Zn(II) and Aβ is 10−9−10−6 M.8,46,194,218,221,228−233 The presented Kd values for metal−Aβ are dependent on the experimental conditions and techniques, such as ITC, fluorescence spectroscopy, and potentiometry.194,196,218,228−231 For Cu(II)−Aβ, the Kd value was calculated to be 10−11−10−7 M, while Cu(I)−Aβ showed 10−15−10−8 M in Kd.8,46,193,218,221,224,229−231,234−245 Cu(II) seems to exhibit stronger binding to Aβ than Zn(II). Fe(II) forms less stable complexes (Kd = ca. 10−5 M), compared to those of Cu(II) or Zn(II).230 The reported Kd values of Zn(II)−Aβ, Cu(I/II)−Aβ, and Fe(II)−Aβ are summarized in Table 3. Aβ’s propensity to aggregate poses a challenge in studying its metal binding properties. As a solution, researchers have been utilizing various Aβ fragments with slower aggregation kinetics. Although soluble Aβ fragments enable the study of metal binding and coordination, various conformations of the full-length Aβ (e.g., monomers, oligomers, and fibrils) are expected to exhibit different metal coordination environments.231,244 On the basis of currently available literature, a wide range of binding affinities is reported, since metal binding to Aβ is dependent on the Aβ species, techniques, and experimental conditions (e.g., buffer composition, temperature, concentrations, and peptide purity). The influence of transition metal ions on Aβ aggregation has also been examined in depth since the first description of Zn(II)-dependent Aβ40 aggregation.12,198,246 At physiological pH, Cu(II) and Fe(II/III) also promote Aβ40 aggregation,246,247 although induction by Cu(II) requires a slightly acidic condition (e.g., pH 6.8).248 Even trace metal ions (< 0.8 μM) are sufficient to stimulate Aβ40 aggregation, resulting in less structured aggregates.249,250 Metal-induced Aβ aggregation is shown to be rapid, and it could result in the production of nonfibrillar, amorphous aggregates depending on the ratio of metal to Aβ (vide inf ra). A mixture of Aβ42:Cu(II) in a 1:5 ratio resulted in a diminished fluorescence intensity of ThT, and smaller-sized aggregates as determined by AFM, relative to controls of Aβ42 only.251 This observation was extended to other metal ions, including Zn(II) and Fe(II).252 Ultrafast spectroscopic techniques demonstrated an immediate interaction within milliseconds between micromolar Zn(II) and Aβ40 showing resultant nonfibrillar peptide aggregates that were possibly toxic.253 A detailed study suggested that Zn(II)− Aβ40 species might inhibit fibril formation by interfering with fibril elongation.254 Interaction of Cu(II) with Aβ40 (pH 6.7) was also observed on a time scale of subseconds with the formation of amorphous Cu(II)−Aβ species.255 Likewise, Fe(III) was observed to retard Aβ42 fibrillization by redirecting

the aggregation pathways toward unstructured, less toxic Fe(III)−Aβ aggregates.256 Although the precise nature of metal−Aβ conformations is uncertain, the measurements by circular dichroism spectroscopy (CD) propose that their transition may involve the generation of β-enriched structures, distinct from the fibrillar β-sheet conformation.257 Metal ions appear to increase the proportion of soluble oligomers compared to fibrils.258−260 Since structured soluble oligomers are associated with toxicity,87,261 this may constitute a potential mechanism of toxicity that arises from metal−Aβ species. Addition of Cu(II) to Aβ yielded soluble toxic oligomers enriched in a β-sheet configuration.259 In another report, Cu(II) and Zn(II) triggered the production of transient Aβ oligomers.260 While Zn(II) developed annular Aβ protofibrils without undergoing a nucleation process, Cu(II) and Fe(III) prevented the formation of fibrils by lengthening the nucleation phase.260 The relative ratio of metal ions to Aβ also impacts the aggregation pathways of Aβ.262,263 Increasing the relative amount of Cu(II) to Aβ40 from 0.1 to 0.6 causes a shift from fibrillar structures to amorphous granular aggregates.262 Another study examined a wider Cu(II):Aβ40 range from sub- to supra-stoichiometric amounts.263 The Cu(II):Aβ ratio was found to affect the aggregation kinetics and aggregate morphology, deviating from fibrillar to nonfibrillar with increasing Cu(II):Aβ proportions. Structures of Cu(II)−Aβ aggregates were dynamic. The transient and impermanent nature of metal−Aβ species has made their structural characterization difficult. Still, progress toward an understanding of their general characteristics has been made. A small-angle X-ray scattering (SAXS) study examined the generation of Aβ oligomers at extremely short time scales by combining the technique with in-line rapid mixing.264 Modeling of the scattering data can approximate oligomers’ size (i.e., diameter), molecular weight, and polydispersity. Although the aggregation kinetics, species distribution, and toxicity of metal−Aβ species have been extensively studied, their precise mechanism of toxicity has been still uncertain. Recently, Matheou et al. illustrated the distinct influence of substoichiometric Cu(II) on the aggregation pathways of Aβ40 and Aβ42.265 While fibrillization was favored for Aβ40, oligomeric and protofibrillar forms of Aβ42 were observed in the presence of Cu(II). These species could cause leakage from lipid vesicles in a manner reminiscent of metal-free Aβ oligomers.266 Mutations of Aβ may also impact its aggregation properties in the presence of metal ions and may be one mechanism linking familial forms of AD to pathogenesis. The Taiwanese mutation (D7H) led Zn(II)- and Cu(II)-induced aggregates of both Aβ40 and Aβ42 from fibrillar forms to smaller-sized oligomers.267 The pathogenic A2V mutation imparted different Aβ aggregation kinetics and metal binding properties in response to addition of Cu(II).268 The Cu(II)− AβA2V complex showed a preference for the component I configuration of the Cu(II) center. On the basis of cumulative experimental and theoretical evidence, metal ions have been considered as potential therapeutic targets in AD. The utilization of metal chelators, such as clioquinol and PBT2 (Figure 5), has demonstrated their potential as AD treatments, but further optimization of metal chelators is necessary to develop effective therapeutics.269,270 The design of multifunctional compounds capable of chelating metal ions implicated in AD pathology may offer a successful strategy to battle AD (vide inf ra). Moreover, fineL

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functions, including receptor-mediated signaling pathways and transcriptional activation.277−283 In addition, ROS plays a critical role in cellular homeostasis through regulation of apoptosis. ROS control apoptotic signaling initiated via two pathways:282,284 (i) ROS-triggered death receptors [e.g., Fas (CD95 or APO-1), TNF receptor 1, TNF-related apoptosisinducing ligand (TRAIL) receptor 1 (TRAIL-R1 or DR4), and TRAIL receptor 2 (TRAIL-R2 or DR5)] can mediate the extrinsic pathway of apoptosis by clustering and forming lipidraft-derived signaling platforms, suggested as a major mechanism of apoptotic signaling,284,285 and (ii) ROS are associated with mitochondrial permeabilization by generating pores in the mitochondrial outer membrane, which stimulates the release of proapoptotic proteins [e.g., members of the Bcell lymphoma 2 (Bcl-2) gene family and BAX (Bcl-2 associated X)] that are essential for the activation of apoptosis.282,284,286−288 Various types of ROS can be found in cellular environments.277,278 Prominent biological ROS are hydroxyl radical (•OH), O2•−, and H2O2. Hydroxyl radicals are produced by Fenton-like reactions.8,46 Due to its relatively short half-life (10−9 s), •OH is known to be involved in “site-specific” reactions in the vicinity of its formation site.289,290 O2•−, the product of the one-electron reduction of O2, is generated by multiple systems in organisms of animals and plants (e.g., xanthine oxidase and NADPH oxidase).272,276,278,291 O2•− can react with many substrates by converting into other species.197,278,279 O2•− is capable of transforming into •OH by the Haber-Weiss reaction, which generates •OH from H2O2 and O2 •−.291 Both •OH and O2 •− can initiate lipid peroxidation that can lead to apoptosis.8,193,272,279,291,292 H2O2 is a common byproduct of diverse enzymatic reactions, including those involving SOD.193,197,272,278,279,293 H2O2 is related to a broad range of biological processes: (i) immune response; (ii) oxidative biosynthesis, such as tyrosine crosslinking mediated by peroxidases; (iii) cellular signaling in mediating mitogenic signaling pathways.279,293,294 Under normal conditions, the levels of the above-mentioned ROS are regulated by innate antioxidant defenses.11,197,274,295−297 Pathological conditions, however, can elicit an imbalance between the production and removal of ROS, resulting in elevated ROS levels.10,197,279 Oxidative stress is characterized by dysregulation of ROS and the resultant cellular damage through the oxidation of lipids, proteins, and DNA.172,197,273,277−279 Oxidative stress in biological systems has been strongly implicated as a causative factor for a wide spectrum of diseases and aging.10,197,279 Thus, maintaining proper ROS load is important to the preservation of biological homeostasis. Oxidative stress is believed to be involved in neurodegenerative diseases, including AD.10,11,46,172,196,197,271−273,292,295,297,298 Oxidative stress is a prevailing component in the manifestation of multiple pathological factors (e.g., Aβ, metal ions, and metal−Aβ) as well as toxic mechanisms of these factors.46,193,299 Three major aspects connect oxidative stress to AD pathology: (i) Aβ production and accumulation;295,299−302 (ii) metal ion dyshomeostasis;303 (iii) mitochondrial dysfunction.197,271,273,277,278,298,299 Researchers have suggested that oxidative stress enhances Aβ production by decreasing the activity of α-secretase while increasing the activity of β- and γ-secretases.295,299 In addition, oxidative stress could activate the pathway of c-Jun N-terminal kinase (JNK), which could

Figure 5. Metal chelators and MPACs tested in preclinical and clinical trials for AD treatment. Clioquinol (chemical name indicated in Figure 2); PBT2, 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8ol; DFO (deferoxamine), N′-{5-[acetyl(hydroxy)amino]pentyl}-N[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide; D-penicillamine, (2S)-2-amino-3methyl-3-sulfanylbutanoic acid; DFP (chemical name presented in Figure 2); trientine, triethylenetetramine; DP-109, 2,2′-(((ethane1,2-diylbis(oxy))bis(2,1-phenylene))bis((2-(2-(octadecyloxy)ethoxy)-2-oxoethyl)azanediyl))diacetic acid.

tuning metal binding affinities (Kd) of compounds to specifically target metal ions bound to Aβ without disrupting vital enzymatic activities is an important parameter for rational design. 2.3. Oxidative Stress

O2 is indispensable to aerobic organisms. In metabolic systems, ROS are generated from endogenous processes, such as O2 metabolism and cellular signaling, while exogenous ROS can be produced from environmental stress (e.g., ionizing radiation and heat exposure).271−273 Biologically relevant ROS include superoxide anion radical (O2•−), hydroxyl radical (•OH), hydrogen peroxide (H2O2), hydroperoxyl radical (•O2H), singlet oxygen (1O2), peroxide (O22−), and hydroxide ion (OH−). A membrane-bound enzyme, nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), found in cell membranes, mitochondria, and ER, is responsible for substantial intracellular ROS production.274,275 NADPH oxidase generates superoxide anion radicals (O2•−) by transferring electrons from NADPH within the cell across the membrane.274,276 ROS are necessary for a variety of cellular M

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tory complexes could generate ROS, such as O2•− and H2O2, and increased concentrations of these ROS could produce •OH and react with biomolecules, including lipids and proteins.8,272,279,291,349 Biological systems are observed to protect themselves from oxidative stress by maintaining appropriate levels of ROS with endogenous defensive systems.193,197,271,277−279 For example, (i) Cu/Zn SOD1 binds to Cu and Zn to catalyze the dismutation of O2•− into either O2 and H2O2;10,172,197,272,292 (ii) another important antioxidant is glutathione that is converted to its oxidized form (i.e., glutathione disulfide) upon interaction with ROS;272,278 (iii) catalase catalyzes the decomposition of H2O2 to H2O and O2.293,294 Thus, the imbalance between ROS production and removal could occur by deficient antioxidant defense, inhibition of electron flow, or exposure to xenobiotics.349 Oxidative stress is indicated to play an underlying role in the pathology of AD based upon the impact of ROS on the production and aggregation of Aβ, metal ion homeostasis, and mitochondrial dysfunction. These pathological features could then contribute back to oxidative stress through generation of ROS in direct and indirect manners. Thus, the utilization of antioxidants to reduce ROS levels offers a potential approach for drug discovery in AD. The approach of regulating ROS only with antioxidants, however, has not been successful in clinical trials, possibly due to the multifaceted nature of AD pathology.350 Therefore, recent efforts have been focused toward developing multifunctional antioxidants able to target and modulate additional pathological factors (e.g., Aβ, tau, and AChE) as potential therapeutic candidates.

modulate the expression of β-secretase.295,299 The generated Aβ accumulates in the brain and forms SPs, a hallmark of AD.172,195 Pathological factors of AD (e.g., metal ions, Aβ, and tau) are suggested to be involved in redox-active processes capable of inducing oxidative stress via ROS generation.11,192,304 Multiple in vitro and in vivo studies report that Aβ peptides trigger oxidative stress.305−320 A Tg C. elegans worm model expressing human Aβ42 exhibited enhanced oxidative stress as evidenced by elevated carbonyl levels associated with the oxidation of proteins.317,321 I31 and M35 in Aβ are proposed to be potentially responsible for oxidative damage (vide infra).312,313,315,321 Especially, M35 is reported as a critical amino acid residue for ROS production.305,307,314 The α-helical conformation in the C-terminal region of Aβ allows the S atom of M35 to interact with the O atom from the carbonyl of I31,313,315,320 which could result in the formation of the methionine sulfuranyl radical (MetS•).312,320,322 Aβ can also act as a source of ROS and initiate lipid peroxidation by producing carbon-centered radicals.315,320 Moreover, oligomeric Aβ has been observed to increase the generation of ROS directly by activating NADPH oxidase and indirectly through NMDARs by stimulating the release of arachidonic acid, a retrograde messenger involved in modulating synaptic plasticity.316,323 The dysregulation of redox-active metal ions, including Cu(I/II) and Fe(II/III), in the central nervous system (CNS) is observed in the AD-affected brain.324−327 Furthermore, these metal ions are able to produce ROS through Fenton-like reactions.328,329 Overproduction of ROS by metal ions can result in oxidative stress that causes neuronal death in the brain.11,297,298 Moreover, Zn(II), a redox-inert metal ion, indirectly increases ROS levels.330−334 Mitochondrial uptake of labile Zn(II) from the cytoplasm through the calcium uniporter can alter mitochondrial polarization and disrupt the electron transport chain, leading to the formation of ROS, such as O2•−.330−334 Along with the individual impact of metal ions and Aβ on ROS production, metal−Aβ species have been observed to generate ROS. Redox-active metal ions associated with Aβ [i.e., Cu(I/II)−Aβ and Fe(II/III)−Aβ] can generate ROS via Fenton-like reactions, similar to redox-active metal ions.11,335,336 In vitro studies demonstrate that Cu(I/II)−Aβ or Fe(II/III)−Aβ can overproduce ROS leading to oxidative stress.8,11,297,335,337,338 ROS generation mediated by Cu(I/II)− Aβ has been widely studied.172,215,222,339,340 Cu(I/II)−Aβ is indicated to catalytically form ROS. In the presence of a reductant (e.g., ascorbate), Cu(II)−Aβ could be reduced to Cu(I)−Aβ and transfer an electron to O 2 to yield O2•−.172,339,341 Then, a hydroperoxyl radical (•O2H) can be formed via electron/proton transfer, finally resulting in the production of H2O2 (vide supra).8,11,343 The generated H2O2 can then react with either Cu(I)−Aβ or Cu(II)−Aβ affording •O2H or •OH through Fenton-like reactions.8,172,342 Spectroscopic and spectrometric studies presented that the D1, H13/ H14, and M35 residues in Aβ may be involved in the electron transfer between Cu(I/II) and Aβ, responsible for ROS generation.305,314,339,343−347 Oxidative stress can damage cells by disrupting cell signaling and causing mitochondrial dysfunction.197,271,273,277,299 Mitochondrial function is vulnerable to oxidative stress; however, paradoxically, the mitochondrial respiratory chain is a major source of intracellular ROS.277,299,348 Mitochondrial respira-

2.4. Cholinesterases (ChEs)

The cholinergic hypothesis proposes that the degeneration of cholinergic neurons and the associated loss of cholinergic neurotransmission in the cerebral cortex are contributors to the deterioration of cognitive function observed in the brain of AD patients.351,352 ACh, the neurotransmitter in cholinergic transmission responsible for learning and memory in the CNS, is a cationic agonist of muscarinic and nicotinic receptors.353,354 ACh production from choline and acetylCoA is catalyzed by choline acetyltransferase (ChAT) in neurons.355 Cholinergic transmission is initiated by the ACh release from the presynapse into the synaptic cleft, where ACh diffuses and binds to postsynaptic receptors. Subsequently, ChEs, serine hydrolases abundant in the synaptic cleft, rapidly terminate signal transmission by converting ACh into acetate and choline. To complete the cycle of cholinergic transmission, presynaptic neuronal reuptake of the catabolic products occurs to produce ACh. Cholinergic deficits from decreased ACh levels are a characteristic of the brain affected by AD.356 As the main culprit of this phenomenon, ChEs have been widely studied as a therapeutic target for AD leading to the development of AChEIs for AD treatment (Table 1). There are two main types of ChEs: (i) AChE and (ii) BuChE. AChE is responsible for the majority of ChE activity in the healthy human brain, while the remaining is accounted for by BuChE.357,358 AChE has been a therapeutic target in AD pathology based on its role in hydrolyzing the majority of ACh in the brain.359,360 The active site of AChE is located at the bottom of a gorge, a narrow cavity lined with 14 highly conserved aromatic residues.361 The active site of human AChE (hAChE) is composed of an esteratic site containing the catalytic triad (i.e., S200, H440, and E327), and an anionic site, where the N

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design of multifunctional molecules. Glutamate is a central excitatory neurotransmitter in the mammalian cortex.387 Glutamate receptors, primarily located in the CNS, are involved in synaptic plasticity, learning, and memory.388,389 There are two types of glutamate receptors: metabotropic and ionotropic. Ionotropic glutamate receptors form ion channel pores that allow the nonselective flux of cations upon activation by binding of glutamate.390 Among the ionotropic glutamate receptors, NMDARs, named according to its selective binding of NMDA, have been researched for their role in a range of CNS disorders.391 A majority of NMDARs are tetramers composed of two NR1 subunits, forming the channel, and two NR2A, NR2B, NR2C, or NR2D subunits.392 The physiological and pharmacological properties of NMDARs vary depending on the combination of NR1 and NR2 subunits.393 Under normal conditions, the NMDAR channel is blocked by Mg(II) in a voltage-dependent manner, which can be activated to control the influx of cations [e.g., Na(I), K(I), and Ca(II)].394 The depolarization of NMDARs under pathological conditions is proposed to lead to the loss of Mg(II) from the channel, resulting in its overactivation.395 Dysregulation of NMDAR activation contributes toward disease pathology via cellular Ca(II) dyshomeostasis.396,397 Therefore, the modulation of NMDARs has been suggested as a strategy to develop potential therapeutics for CNS-related disorders. Memantine, an uncompetitive NMDAR antagonist for AD treatment approved by the U.S. FDA (Table 1), has exhibited its effectiveness in attenuating cognitive decline in moderate to severe AD cases.398 The utilization of NMDARs as a target in the past has been challenging due to adverse side effects, a consequence of nonspecific NMDAR recognition.399 Nonetheless, the success of memantine has proven its therapeutic potential, and a more specific approach to antagonize NMDARs targeting the neurons affected by AD could be advantageous.398 Furthermore, fine-tuning various parameters to inhibit NMDARs through the derivatization of uncompetitive NMDAR antagonists could provide insight into the invention of multifunctional molecules as potential drugs for AD. MAOs, a family of enzymes that oxidatively deaminates monoamines, are linked to the pathogenesis of PD since they regulate dopaminergic and serotonergic neurotransmission.400−403 The commonalities and correlated onsets between AD and PD have led researchers to investigate the role of MAOs in the pathology of AD. MAOs, found on the outer mitochondrial membrane, are divided into two isoforms, MAO-A and MAO-B, which exhibit overlapping substrate specificities against dopamine, tyramine, and tryptamine.404 MAO-A, however, is capable of deaminating serotonin, melatonin, norepinephrine, and epinephrine, whereas MAOB is mainly responsible for breaking down phenethylamine. MAO-catalyzed reactions produce H2O2 and ammonia as byproducts.400 Thus, the overactivity of MAOs enhances the generation of H2O2, possibly leading to oxidative stress.400 Inhibition of MAOs has been studied as a promising approach to treat AD.405 Phosphodiesterases (PDEs), composed of 12 families of enzymes responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), play a role in the regulation of intracellular signaling cascades, LTP, and synaptic plasticity.406−408 Various members of PDEs have been implicated in a wide range of disorders, including AD and PD.406 Specifically, changes in the

quaternary ammonium of ACh binds through cation−π interactions. Analysis of the crystal structure of AChE revealed that the anionic site, which binds the quaternary trimethylammonium choline moiety of the substrate via cation−π interactions, is in fact uncharged and hydrophobic due to the presence of numerous aromatic residues.362−364 The cumulative system of intermolecular interactions and geometric constraints of the active site gorge may contribute to the substrate specificity and rapid enzyme kinetics of AChE through mechanisms, such as aromatic guidance.364,365 In addition, the peripheral anionic site (PAS), located near the rim of the gorge, has been reported to transiently bind to substrates as an initiating step of the catalytic process.366,367 Szegletes et al. reported that binding of ACh to the PAS of AChE led to accelerated hydrolysis.367 Like AChE, BuChE can also hydrolyze ACh.368,369 It also possesses a similar overall structure, amino acid sequence, and mechanism of catalysis to AChE.370 While AChE is specific for ACh, BuChE can hydrolyze a range of esters and amides, in addition to ACh. One explanation for this disparity in substrate specificity is the size difference of their active-site gorges based on X-ray diffraction analyses. The reported active-site gorge of BuChE (ca. 500 Å) is much larger than that of AChE (ca. 300 Å).371 Furthermore, BuChE lacks the PAS that contributes toward AChE’s activity.372 The distinct structural characteristics of the two ChEs present a parameter to consider when compounds capable of inhibiting the activity of either AChE, BuChE, or both are rationally designed.373 The physiological and pathological roles of BuChE remain unclear. Specific inhibitors for AChE and BuChE may help clarify their specific impact on cholinergic transmission and AD pathogenesis. Thus, the potential therapeutic benefits of targeting BuChE, explored less than AChE, could provide a valuable direction of research regarding AD. In recent years, the lack of success in halting AD progression with ChE inhibitors (ChEIs) has led researchers to reevaluate the cholinergic hypothesis. A comparative study monitoring the levels of cholinergic markers in human subjects with mild cognitive impairment (MCI) and severe late stage of AD suggested that cholinergic dysfunction may be influential during the later stages of the disease.374 Compensatory responses, such as upregulation of ChAT in the frontal cortex and hippocampus, have been proposed as resistance mechanisms working against the transition from MCI to AD.375 In accord with the current direction in understanding AD pathology, reassessment of the cholinergic hypothesis focuses on the interrelationships between ChEs and other pathological factors, including Aβ, tau, metal ions, and ROS.376−382 Both AChE and BuChE have been found to be colocalized with Aβ aggregates in SPs.383 Moreover, evidence has indicated that AChEs could influence Aβ aggregation383−386 and toxicity via interactions between the PAS and Aβ.376,383 For example, the complexation of AChE and Aβ, at the hydrophobic PAS of AChE, reportedly accelerates Aβ aggregation.383,385 Further research is needed to fully elucidate the pathological relationships involving ChEs. Recently, there has been a large amount of research toward the discovery of multifunctional derivatives of known AChEIs (e.g., donepezil, galantamine, and rivastigmine; Table 1). 2.5. Additional Targets

In this section, we briefly introduce additional pathological factors in AD that may serve as therapeutic targets in the O

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considered for the design of multifunctional compounds as possible drug candidates. Pyroglutamate Aβ (pGlu-Aβ) is a variation of Aβ with an Nterminal pyroglutamate residue implicated for its toxicity.429−432 Glutaminyl cyclase is a catalytic enzyme responsible for the pGlu modification of Aβ.433 Glutaminyl cyclase has been gaining the attention of researchers as a potential therapeutic target for AD due to its upregulation in areas of the brain affected by AD and its potential contribution toward Aβmediated toxicity.430,432−434 Overexpression of glutaminyl cyclase has been shown to induce behavioral deficits in Tg mice, whereas glutaminyl cyclase knockout improved the behavioral phenotype in 5xFAD mice.430 Increasing evidence supporting the effectiveness of inhibiting glutaminyl cyclase implies a tactic that could be valuable to consider in the design of multifunctional molecules as potential therapeutics.432,434,435 Neuroinflammation is a biological response of the nervous tissue initiated in reaction to detriments (e.g., infection and traumatic brain injury).436 Pathological events of AD, including Aβ accumulation and tau hyperphosphorylation, are reported to invoke inflammatory responses in vulnerable regions of the AD-affected brain.437 Gliosis and activated glial cells are two major histopathological signs of neuroinflammation in AD.437 Previous studies suggest that the direct and indirect damage from inflammation may exacerbate the pathological processes through a positive feedback loop.437 The interconnected inflammation pathways can be activated by Aβ aggregates438 and NFTs439 through classical and alternative complement pathways.437 Multiple aspects of AD presented thus far represent a large portion of the research effort devoted toward determining the factors responsible for the neurodegeneration observed in AD. Although a great deal of work has been dedicated to the cause, it is still unclear if the pathological elements mainly indicated in the AD-affected brain serve as causative factors of the disease or are the products of unidentified upstream events. The number of potential pathological features [e.g., peroxisome proliferator activator receptor γ (PPARγ),440,441 phospholipase A2 (PLA2s), 4 4 2 , 4 4 3 cyclophilin D (CypD),444,445 GD3 synthase,446 plasminogen activator,447,448 dickkopf1 (DKK1),449 calpain,450,451 and histone deacetylases (HDACs)452], speculated to play a role in AD pathology, represent the gap between our understanding of the disease and its complexity. On the basis of diverse potential pathological targets and their suggested interconnections toward the pathogenesis of AD, the development of multifunctional molecules would be valuable for investigating the intertwined network of multiple pathological components and in the design of potential therapeutics.

expression of PDE4, PDE7, and PDE8 have been indicated in the AD-affected brain.406−408 PDE inhibitors (PDEIs) have been shown to control signaling pathways by elevating levels of cAMP and cGMP with subsequent activation of the cAMP response element binding (CREB) protein.409,410 Such activation of the CREB protein is involved in LTP and synaptic plasticity.411,412 The incorporation of inhibitory activity against specific PDEs in the rational design of multifunctional molecules could be an effective means to construct them into potential drugs for AD. Furthermore, a link between PDEs and tau has been suggested through the direct relation between cAMP and protein kinase A associated with the phosphorylation of tau.413,414 Apolipoprotein E (ApoE) is recognized as a major determinant in lipoprotein metabolism, cholesterol homeostasis, and cardiovascular disease.415 Research regarding the connection between ApoE polymorphisms and AD led to the discovery that ApoE4 is a strong genetic factor known so far.416−418 ApoE isoforms (i.e., ApoE2, ApoE3, and ApoE4) differ at only one or two amino acid residues; however, they exhibit distinct biological functions.419 For example, the ApoE4 allele is strongly implicated in sporadic AD, while ApoE2 is observed to be linked to neuroprotection.418,420,421 The direct and indirect relationships between ApoE4 and Aβ are controversial with research supporting both ApoE’s pathological (for ApoE4) and remedial roles (possibly, for ApoE2) in AD. ApoE’s effect on Aβ deposition and neuritic degradation was shown to be isoform specific: for example, an increase in the Aβ burden, fibrillogenesis, and neuritic plaque formation through binding with ApoE4 was greater than that of ApoE3 binding.422 Hashimoto et al. presented that ApoE increased the levels of Aβ oligomers in an isoform-dependent manner (ApoE2 < ApoE3 < ApoE4).423 In addition, ApoE4expressing astrocytes were indicated to enhance amyloidogenic processing of APP in neurons, and the lack of ApoE4 reduced Aβ deposition in Tg mice overexpressing human APPV717F.424 On the other hand, Jiang et al. reported the capability of ApoE to promote the proteolytic degradation of Aβ in an isoformdependent manner, where ApoE4 impaired Aβ proteolysis, relative to ApoE2 and ApoE3.425 Upregulated at the sites of elevated inflammation, ApoE3 and ApoE4 were reported to block glial secretion of tumor necrosis factor α (TNFα), implying its connection to inflammatory processes.426 Further research to identify ApoE’s multifactorial role in AD would be valuable to gain a better understanding in order to find a direction for developing effective therapeutics. One approach is to inhibit the interactions between ApoE4 and AD pathological factors (e.g., Aβ) using small molecules. Chen et al. indicated that small molecules able to control the intramolecular interactions between the amino- and carboxyl-terminal domains of ApoE4 could eliminate its detrimental effects in vitro.427 A recent study displayed a link between ApoE4 and tau pathology, further cementing the involvement of ApoE4 in AD pathogenesis.428 Knock-in of human ApoE4 into a mouse model of tauopathy (1N4R P301S tau) resulted in exacerbated ptau pathology compared to that of ApoE2 and ApoE3, while knockout of ApoE had a protective effect.428 ApoE4/P301S mice further displayed more neurodegeneration and neuroinflammation than ApoE2/P301S and ApoE3/P301S mice, and ApoE knockout mice were once more protected from these pathological changes.428 The isoform-dependent genetic implications of ApoE indicate an aspect of AD in connection to Aβ and tau, suggesting its therapeutic potential to be

2.6. Molecules

2.6.1. Multifunctional Molecules Targeting Aβ and Metal Ions. The multitude of dysregulated metal-dependent pathways in AD prompted the exploration of metal chelators as an option for possible treatments against the disease. Earlier attempts employed small molecules that were well-known metal chelators to passivate excess metal ions, such as deferoxamine (DFO) and D-penicillamine (Figure 5), which demonstrated some benefit in AD patients.453,454 Animal studies have since delineated possible mechanisms of action for metal chelators. Intranasal administration of DFO led to improved performance in P301L tau Tg mice on a radial arm water maze test via upregulated phosphorylation of P

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Figure 6. Multifunctional molecules based on the metal chelator, DFP, and Aβ imaging molecules, 11C-BF-227 and 11C-PIB. Metal binding donor atoms in DFP are highlighted in orange. DFP (chemical name shown in Figure 2); 11C-BF-227, 5-[2-[6-(2-fluoroethoxy)-2-benzoxazolyl]ethenyl]N-methyl-N-(methyl-11C)-2-thiazolamine; 11C-PIB (chemical name indicated in Figure 2); DFP-MC-1 Prochelator, 3-(D-glucopyranosyloxy)-2methyl-1-phenyl-4(1H)-pyridinone; DFP-MC-1, 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone; DFP-MC-2, 1-(benzo[d]oxazol-2-ylmethyl)-3hydroxy-2-methylpyridin4(1H)-one; DFP-MC-3, 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2- methylpyridin-4(1H)-one.

toxicity of DFP-MC-1-Prochelator analog, compared to a positive control, cisplatin [cis-diamminedichloridoplatinum(II), [Pt(NH3)2Cl2]; half maximal inhibitory concentration (IC50) = 570 and 35 μM, respectively]. Telpoukhovskaia et al. combined the DFP scaffold with a benzoxazole moiety from the amyloid binding molecule, 11CBF-227, used for in vivo plaque imaging,461 to generate DFPMC-2 (Figure 6).462 IR and NMR were employed to confirm the binding of DFP-MC-2 to Cu(II), Zn(II), Ni(II), Fe(III), and Ga(III), with more detailed speciation studies for Cu(II) (pCu = 7.2 and 8.0 at pH 6.6 and 7.4, respectively), Zn(II) (pZn = 7.8 at pH 7.4), and Fe(II) (pFe = 17 at pH 7.4), where pM is the negative logarithm of the free metal ion concentration and an indicator of the ligand’s chelating strength. The determined pCu, pZn, and pFe values for DFP-MC-2 suggested that it could compete with Aβ for biometals.462 It possessed modest antioxidant capacity, which was lower than that of vitamin E. Generation of ROS by Cu(II)−Aβ species could be initiated by reduction of the Cu(II) center, but Cu(II) complexes of DFP-MC-2 were resistant to reduction by ascorbate, indicating that it could possibly control ROS production.462 DFP-MC-2 could impact metal-free and Cu(II)- and Zn(II)-induced Aβ40 aggregation in a turbidity assay and result in shorter or more amorphous aggregates, confirmed by TEM.462 DFP-MC-2 could bind to Aβ40 fibrils (Ki = 5 μM), while DFP could not, implying that the ability to interact with Aβ40 could be traced to DFP-MC2′s benzoxazole moiety. Finally, it was predicted to exhibit only modest CNS penetration and was relatively toxic to bEnd.3 immortalized mouse neuronal cells [half maximal effective concentration (EC50) = 4.4 and 37 μM for DFP-MC-2 and cisplatin, respectively].462 Molecules based on a similar design concept were reported in a further report by Telpoukhovskaia et al. in which the majority of 11C-Pittsburgh compound B (11C-PIB) was fused to DFP to construct DFP-MC-3 (Figure 6).463 The molecule complied with Lipinski’s rule and increased in fluorescence by 50% upon binding to Aβ40 fibrils. Permeability was observed in bEnd.3 cells, which accumulated fluorescence in their

glycogen synthase kinase 3β (GSK3β) and increased hypoxiainducible factor 1α (HIF1α).455 DFO also decreased memory loss in APP/PS1 mice with concomitant reduction of Aβ load in the brain.456 Another Fe chelator, deferiprone (DFP) (Figure 5), diminished Aβ levels and tau phosphorylation in a cholesterol-induced rabbit model of AD-like pathology.457 Trientine (triethylenetetramine; Figure 5), a known Cu chelator used to treat Cu overload in Wilson’s disease, was found to lower BACE1 activity and amyloidosis via the receptor for advanced glycation end products (RAGE) pathway in APP/PS1 AD mice.458 Administration of the lipophilic metal chelator, DP-109 (Figure 5), similarly reduced amyloid burden in the brains of Tg2576 mice.459 Multifunctional molecules incorporating the scaffold or donor atoms of metal chelators have been designed to decrease potential side effects of metal chelation therapy. This includes a prochelator approach to release the active chelator upon stimulation or the integration of frameworks known to interact with Aβ in order to direct the metal chelator to Aβ species. Numerous molecules have since been designed to improve the properties of metal chelators. Schugar et al. conjugated DFP derivatives to glucose, thereby masking DFP’s chelating groups to prevent systemic metal binding while simultaneously providing a handle for passing the BBB via glucose receptors.37 The resultant prodrug, DFP-MC-1-Prochelator [DFP with a metal chelating portion (MC) (DFP-MC); Figure 6], could be enzymatically cleaved by Agrobacterium faecalis β-glucosidase, generating the metal chelator, DFP-MC-1 (Figure 6) that could inhibit Cu(II)- and Zn(II)-induced Aβ40 aggregation.37 DFP-MC-1 also showed antioxidant activity with a greater capacity than α-tocopherol in a TEAC assay. CNS penetration was confirmed with a radiolabeled version of DFP-MC-1-Prochelator, which could be detected in the brain following administration to rats. Green et al. extended the experiments on DFP-MC-1, demonstrating its ability to disassemble preformed Cu(II)- and Zn(II)triggered Aβ40 aggregates. DFP-MC-1 was more effective at resolubilization of Cu(II)−Aβ40 aggregates.460 Cytotoxicity studies in human breast cancer cells revealed relatively low Q

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molecules might provide a glucose transporter (GLUT)dependent route for import into the brain.464 Two candidates, SALEN-MC-1 and SALEN-MC-2 (Figure 7), were reported with affinities for Cu(II) in the nanomolar range (pCu = 7.9 and 7.5 at pH 7.4 for SALEN-MC-1 and SALEN-MC-2, respectively) and affinities for Zn(II) within the micromolar range (pZn = 4.2 and 3.9 at pH 7.4 for SALEN-MC-1 and SALEN-MC-2, respectively).464 These values suggest that both SALEN-MC-1 and SALEN-MC-2 might compete for Cu(II) and Zn(II) with Aβ, confirmed in experiments of reduced Cu(II)- and Zn(II)-mediated Aβ40 aggregation by both compounds. Moreover, both ligands could quench ABTS radicals at ca. 2 to 2.5 Trolox equivalents.464 Storr et al. further generated similar glucose-substituted multidentate salen-like ligands, except that the glucose in this family was employed to mask a metal binding hydroxyl group (Figure 7).465 Importantly, they verified that Agrobacterium sp. β-glucosidase could hydrolyze the glucose moieties from their lead molecule, SALEN-MC-3-Prochelator (Figure 7), to release the active form, SALEN-MC-3 (Figure 7), although the reaction did not go to completion following a 2 h incubation period. SALEN-MC-3 could control Cu(II)- and Zn(II)-triggered Aβ40 aggregation and possessed antioxidant capacity in a TEAC assay at ca. 1 to 1.5 equiv of Trolox.465 Cyclen and cyclam (Figure 8) are well-known marcocylic ligands composed of N donor atoms.466 They have served as the scaffold for the construction for several multifunctional small molecules. Wu et al. reported on the design and synthesis of cyclen linked to either the KLVFF peptide (CYCN-MC-1) or curcumin (CYCN-MC-2) (Figure 8).467 The KLVFF residues correspond to the sequence of Aβ16−20 that inhibits

periphery upon incubation with DFP-MC-3. The influence of DFP-MC-3 on metal-activated Aβ40 aggregation was not examined despite the interaction with Aβ and the presence of the known metal chelating moiety.463 Storr et al. constructed glucose-substituted multidentate salen-like ligands for metal chelation and regulation of metalinduced Aβ aggregation (Figure 7), while the pendant glucose

Figure 7. Glucose-derivatized multidentate ligands as multifunctional compounds. Salen, 2,2′ -((1E,1′ E)-(ethane-1,2-diylbis(azaneylylidene))bis(methaneylylidene))diphenol (metal binding donor atoms highlighted in orange); SALEN-MC-1, N,N′-bis[(5-αD-glucopyranosyloxy-2-hydroxy)benzyl]-N,N′-dimethylethane-1,2-diamine; SALEN-MC-2, N,N′-bis[(5-α-D-glucopyranosyloxy-3-tertbutyl-2-hydroxy)benzyl]-N,N′-dimethylethane-1,2-diamine; SALENMC-3, N,N′-bis(2-hydroxybenzyl)-ethane-1,2-diamine; SALEN-MC3-Prochelator, N,N′-bis(2-(phenyl-β-D-glucopyranoside)benzyl)ethane-1,2-diamine.

Figure 8. Cyclen- and cyclam-based multifunctional molecules. Metal binding atoms in cyclen and cyclam are indicated in orange. Cyclen, 1,4,7,10-tetraazacyclododecane; cyclam, 1,4,8,11-tetraazacyclotetradecane; curcumin, (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6diene-3,5-dione; lipoic acid, (R)-5-(1,2-dithiolan-3-yl)pentanoic acid; CYCN-MC-1, cyclen-KLVFF; CYCN-MC-2, cyclen-glycine-curcumin; CYCN-MC-3, 5-(1,2-dithiolan-3-yl)-1-(1,4,7,10-tetraazacyclododecan-1-yl)pentan-1-one; CYCN-MC-4, 1,4,7,10-tetraaza-2,6-pyridinophane; CYCN-MC-5, 3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol; CYCM-MC-1, 2-(1,4,8,11-tetraazacyclotetraadecan-1-yl)ethyl-βD-glucopyranoside; CYCM-MC-2, 2-(4,11-dimethyl-1,4,8,11-tetraazacyclotetradecan-1-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide; CYCM-MC-3, 2,20-(4,11-dimethyl-1,4,8,11-tetraazacyclotetradecane1,8-diyl)bis(N-(2-(pyridin-2-yl)ethyl)acetamide); CYCM-MC-4, Co(II)(TMC) (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane). R

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the formation of Aβ40 fibrils by interacting with the same region of Aβ468,469 and thus constitutes an Aβ-targeting moiety in the design. Likewise, curcumin is shown to interact with Aβ fibrils.470 CYCN-MC-1 could sequester Cu(II) from Cu(II)− Aβ42 and control the production of Cu(II)−Aβ42-triggered H2O2 production.467 Cu(II)-bound CYCN-MC-1 was also observed to modify Aβ42 aggregation and induce the disassembly of preformed Aβ42 fibrils. This ability was attributed to cleavage of Aβ40 and Aβ42 by Cu(II)−CYCNMC-1, verified by gel/Western blot and MS.467 This translated into a neuroprotective effect from Cu(II)−Aβ42-induced toxicity in neuroblastoma cells. Similarly, Cu(II)−CYCNMC-2 could inhibit Aβ42 aggregation (IC50 = 11 and 3.0 μM for Cu(II)−CYCN-MC-1 and Cu(II)−CYCN-MC-2, respectively) and protect hippocampal neurons from Aβ42-mediated toxicity.467 Gonzalez et al. considered cyclen for linkage to the known antioxidant, lipoic acid, to invent the hybrid, CYCN-MC-3 (Figure 8).471 There is evidence to suggest that lipoic acid and its reduced form, dihydrolipoic acid, may prevent Aβ fibrillization and destabilize preformed fibrils.472 CYCN-MC3 retained its Cu(II) binding capability but less strongly than cyclen; however, its biocompatibility compared to cyclen was enhanced by conjugation to lipoic acid, and it was much less toxic (EC50 = 749 and 81 μM in mouse HT22 hippocampal cells for CYCN-MC-3 and cyclen, respectively).471 CYCNMC-3 could regulate Cu(II)−Aβ40 aggregation (detected by TEM), protect HT22 cells from Cu(II)−Aβ40-elicited toxicity, and scavenge DPPH radicals. BBB penetration of CYCN-MC3 was anticipated based on computation of the atom/fragment contribution by Moriguchi’s method.471 CYCN-MC-4 (named Pyclen by authors; Figure 8), a backbone originally investigated as a contrast imaging agent, was reported by Lincoln et al. to be an antioxidant and a metal chelator with the capacity to modulate metal-induced Aβ aggregation.473 The binding of CYCN-MC-4 to Cu(II) and Zn(II) was presented (logK = 20 and 14, respectively). Turbidity and fluorescence assays exhibited that CYCN-MC-4 (800 μM) could modify the aggregation and disaggregation of Aβ species (200 μM) in the absence and presence of metal ions [i.e., Cu(II) and Zn(II); 400 μM]. TEM and SEM studies revealed that CYCN-MC-4 decreased the size of the resultant Aβ aggregates by 1−2 orders of magnitude. Furthermore, CYCN-MC-4 was shown to be an effective antioxidant at low nanomolar concentrations, as monitored by the cellular DCFDA assay.473 CYCN-MC-5 (Figure 8), designed based on the structure of CYCN-MC-4 with an additional hydroxyl group on the pyridine ring, was reported for its ability to alter metal-induced Aβ aggregation.474 This molecule was presented as a potential metal binding and potent antioxidant agent. Relative to its parent molecule, the incorporation of the hydroxyl group into the framework enhanced the free radical scavenging capacity of CYCN-MC-5. Furthermore, cell studies showed that the antioxidant properties of CYCN-MC-5 reduced 2-amino-4(butylsulfonimidoyl)-butanoic acid (BSO)-induced toxicity in Fredreich ataxia (FRDA) cells.474 Lanza et al. favored the cyclic tetradentate ligand, cyclam, wherein they linked it to glucose and galactose units for enhanced solubility (Figure 8).475 The best candidate, CYCMMC-1 (Figure 8), was capable of attenuating Cu(II)-treated Aβ aggregation in a turbidity assay and binding to the lectin Ricinus communis agglutinin (RCA120), a model of galectins.

Biological properties of CYCM-MC-1, such as BBB penetration, antioxidant activity, and cytoprotective influence, were not examined.475 Yang et al. adopted the macrocyclic cyclam system for the generation of CYCM-MC-2 and CYCM-MC-3 (Figure 8) that were functionalized with pyridine rings to boost antioxidant capacity and methyl groups to improve lipophilicity and possible BBB permeability.476 Both derivatized compounds increased the fraction of soluble Aβ40 and decreased the proportion of ThT-reactive Aβ40 aggregates in the presence of Cu(II) and Zn(II). They could protect SH-SY5Y neuroblastoma cells from toxicity induced by Cu(II)−Aβ40 and Zn(II)−Aβ40, intracellular generation of ROS, and apoptosis.476 Derrick et al. engaged macrocyclic N-tetramethylated cyclam (TMC) to prepare metal complexes (Figure 8).466 The metal complexes, M(TMC) [M = Co(II), Ni(II), Cu(II), and Zn(II)], exhibited several useful properties and provided insight into the proteolytic cleavage of Aβ by M(TMC) complexes. Cleavage of Aβ40 was demonstrated by MS, which was most effective for CYCM-MC-4 [Co(II)(TMC) by authors; Figure 8].466 This effect of CYCM-MC-4 continued to show the greatest activity against metal-free Aβ40 and Aβ42 aggregation as assayed by gel/Western blot and TEM. The efficacy of CYCM-MC-4 over other M(TMC) complexes was traced to its coordination environment and the acidity of the aqua-bound complexes in promoting amide hydrolysis.466 The potential BBB penetration of CYCM-MC-4 was verified by PAMPA-BBB, and its protective effect toward Aβ-promoted toxicity in SH-SY5Y neuroblastoma cells was confirmed.466 8-Hydroxyquinoline (8-HQ) (Figure 9) has occupied a privileged position in the design of multifunctional molecules targeting metal ions and Aβ (as covered in this Section) as well as metal ions and AChE (as addressed in section 2.6.2). It possesses, in addition to metal chelation, numerous favorable properties, such BBB permeability, antioxidant capacity, and anti-Cu(II)-triggered Aβ aggregation.477 Clioquinol (Figure 5), a 5-chloro-7-iodo substituted 8-HQ, has been studied in AD research.269 Ultimately, it was abandoned due to potential neurotoxic effects478 and difficulty in preventing contamination with di-iodo 8-HQ upon largescale chemical synthesis.270 A second generation of clioquinol, PBT2 (Figure 5), also achieved clinical testing status;479 however, larger trials are needed to ascertain its efficacy. PBT2 is a metal protein attenuating compound (MPAC) that is believed to function by restoring metal ion homeostasis and activating multiple pathways.10,480 Masking the 8-HQ moiety is one strategy to activate it only in the presence of pathological factors associated with AD.477 Chang et al. reported a series of 8-HQ substituted at the hydroxyl group with tetra-O-acetyl- and tetra-O-benzyl-β-Dglucopyranoside and galactopyranosides (8-HQ-MC-1-Prochelator; Figure 9).481 Addition of Cu(II), Zn(II), and Fe(III) caused the deglycosylation of glycosyl-substituted 8-HQ derivatives. Beyond that, the influence of the 8-HQ derivatives on other pathological features was not examined. Dickens et al. described the synthesis of a boronic estermasked prochelator, 8-HQ-MC-2-Prochelator (Figure 9), which could be activated by H2O2.477 The rationale was based on the elevated oxidative stress associated with the ADaffected brain; thus, principally, activation of the prochelator at the centers of H2O2 production might occur. Addition of Cu(II) and H2O2 to 8-HQ-MC-2-Prochelator generated a S

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Figure 9. Multifunctional compounds based on the scaffold of 8-HQ. Metal binding atoms in 8-HQ are presented in orange. 8-HQ, 8hydroxyquinoline; tetra-O-benzyl-β-D-glucopyranoside, 2,3,4,6-tetrakis-O-(phenylmethyl)-D-glucopyranose; rasagiline, (R)-N-(prop-2-ynyl)-2,3dihydro-1H-inden-1-amine; β-cyclodextrin, 2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane; trehalose, α-D-glucopyranosyl-α-D-glucopyranoside; glutathione, (2S)-2-amino-4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2sulfanylethyl]carbamoyl}butanoic acid; 8-HQ-MC-1-Prochelator, 8-(((2S,3R,4S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2Hpyran-2-yl)oxy)quinoline; 8-HQ-MC-2-Prochelator, pinanediol ester-quinoline boronic acid; 8-HQ-MC-3 (M30), 5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; 8-HQ-MC-4 (HLA20), 5-(4-propargylpiperazin-1-ylmethyl)-8-hydroxyquinoline; 8-HQ-MC-5 (VK28), 5-(4(2-hydroxyethyl)piperazin-1-ylmethyl)-8-hydroxyquinoline; 8-HQ-MC-6, 2-[(8-hydroxy-2-quinolinyl)methylene]-hydrazinecarbothioamide; 8HQ-MC-7, 5,7-dichloro-2-(5-hydroxy-1H-indol-2-yl)quinolin-8-ol; 8-HQ-MC-8, 6A-deoxy-6A-[{(8-hydroxyquinolyl)-2-carboxyl}amino]-β-cyclodextrin; 8-HQ-MC-9, 6A-deoxy-6A-[{(8-hydroxyquinolyl)-2-carboxyl}aminoethylamino]-β-cyclodextrin; 8-HQ-MC-10, 6-deoxy-6-(8-hydroxyquinoline)-2-methylamino]-α,α′-trehalose; 8-HQ-MC-11, methyl-N2-acetyl-N5-((R)-3-(((8-hydroxyquinolin-5-yl)methyl)thio)-1-((2-methoxy-2oxoethyl)amino)-1-oxopropan-2-yl)-L-glutaminate.

metal chelators bound to both Cu(II) and Fe(III), with greater affinity for Fe(III), which formed 1:3 Fe(III)-to-ligand complexes.482 In a fluorescence dequenching experiment of calcein, the half maximal dequenching concentration [M]1/2 [a measure of chelator binding affinity for Fe(II)] was 6.5, 5.4, 4.8, or 1.5 μM for 8-HQ-MC-3, 8-HQ-MC-4, 8-HQ-MC-5, or DFO (Figure 5). The ligands also exhibited antioxidant capacity in a lipid peroxidation assay (IC50 = 9.2, 12, and 13 μM for 8-HQ-MC-3, 8-HQ-MC-4, and 8-HQ-MC-5, respectively), were predicted to be cell permeable (8-HQMC-3 and 8-HQ-MC-4), and offered protection from 6hydroxydopamine (6-OHDA)-induced toxicity in adrenal PC12 cells.99,482 A later study by Avramovich-Tirosh et al. established that 10 μM of 8-HQ-MC-3, 8-HQ-MC-4, and 8-HQ-MC-5 decreased the level of holo-APP in SH-SY5Y neuroblastoma cells.483 Additionally, 8-HQ-MC-3 (5 μM) reduced the amount of Aβ secreted by CHO/ΔNL cells [Chinese hamster ovary (CHO) cells stably expressing APPswe (Swedish mutant APP)] and encouraged neurite outgrowth in PC12 and SH-SY5Y cells. The paper did not report the influence of these metal chelators on metal-free and metal-triggered Aβ aggregation. Further consideration of 8-HQ-MC-3 and 8-HQ-MC-4 by Mechlovich et al. demonstrated their capability to protect pancreatic β-cell

UV−Vis spectrum similar to 8-HQ upon treatment with Cu(II). In the absence of H2O2, 8-HQ-MC-2-Prochelator did not have any impact on Cu(II)-triggered Aβ42 aggregation. Following incubation for 30 min with 1 mM H2O2, however, the turbidity of the solutions containing 8HQ-MC-2Prochelator, Cu(II), and Aβ42 decreased while no change was observed in the sample of Cu(II) and Aβ42 without H2O2.477 A Cu(II)−8-HQ complex produced from H2O2activated 8-HQ-MC-2-Prochelator was documented by optical changes and detected by MS.477 Zheng et al. designed a large series of metal chelators inspired by 8-HQ with various substitutions.99 Three candidates that emerged and would go on to be featured frequently were 8-HQ-MC-3 (named M30 by the authors), 8HQ-MC-4 (known as HLA20), and 8-HQ-MC-5 (alias VK28) (Figure 9). In addition to the 8-HQ moiety, 8-HQMC-3 and 8-HQ-MC-4 additionally contained the propargylamine group from the drug for PD, rasagiline (Figure 9).99 Consequently, 8-HQ-MC-3 and 8-HQ-MC-4 could inhibit rat MAO-A and MAO-B (rMAO-A and rMAO-B) with moderate to exceptional efficacy approaching that of rasagiline (IC50 for rMAO-A and rMAO-B = 0.037 and 0.057 μM, respectively, for 8-HQ-MC-3; 300 and 64 μM, respectively, for 8-HQ-MC-4; and 0.41 and 0.004 μM, respectively, for rasagiline).99 The T

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Figure 10. Multifunctional molecules fashioned based on ThT, an imaging agent for Aβ aggregates. ThT (thioflavin-T), 4-(3,6-dimethyl-1,3benzothiazol-3-ium-2-yl)-N,N-dimethylaniline; clioquinol (chemical name presented in Figure 2); DTPA, diethylenetriaminepentaacetic acid; ThT-MC-1, ([(4-benzothiazol-2-yl-phenylcarbamoyl)-methyl]-{2-[(2-{[(4-benzothiazol-2-yl-phenylcarbamoyl)methyl]-carboxymethylamino}ethyl)-carboxymethylamino]-ethyl}-amino)-acetic acid; ThT-MC-2, 2-(benzo[d]oxazol-2-yl)-4-iodophenol; ThT-MC-3, 2-(2-( D glucopyranosyloxy)phenyl)benzoxazole; ThT-MC-4, N-[4-(2-benzothiazolyl)phenyl]-N-(2-pyridinylmethyl)-2-pyridinemethanamine; ThT-MC5, 4-(2-benzothiazolyl)-2-[[bis(2-pyridinylmethyl)amino]methyl]-6-methoxyphenol; ThT-MC-6, 4-(2-benzothiazolyl)-2-methoxy-6-[[methyl(2pyridinylmethyl)amino]methyl]phenol; ThT-MC-7, 2-(N-2-benzothiazolylformimidoyl)-4-nitro-phenol; ThT-MC-8, [trans-Ru(1Hindazole)2(Cl)4](1H-indazol-2-ium)−.

lines from oxidative stress induced by H2O2.484 Carbamate derivatives, mimicking rivastigmine (Table 1) at the 8-HQ hydroxyl group of both 8-HQ-MC-3485 and 8-HQ-MC-4,486 were prepared to additionally endow the molecules with AChE-inhibiting capability. Details on the resultant compounds, DON-MC-1-Prochelator and DON-MC-2-Prochelator (structures depicted in Figure 23, vide infra), are described in section 2.6.2. Gomes et al. presented metal-protein attenuating compounds derived from 8-HQ.487 8-HQ-MC-6 (Figure 9) exhibited potent antioxidant properties and formed complexes with Cu(II) at a 1:1 metal-to-ligand ratio.487 Furthermore, 8HQ-MC-6 was shown to limit Cu(II)-induced Aβ42 oligomer formation in vitro.487 8-HQ-MC-7 (Figure 9) was designed as a multitarget-directed ligand exhibiting antioxidant activity (5.0 Trolox equivalent), potential BBB penetration [Pe = (10 ± 0.1) × 10−6], metal chelation, Aβ aggregation modulation (72 and 86% inhibition for Aβ42 and Cu(II)−Aβ42, respectively; 25 μM of Aβ42, 25 μM of Cu(II), and 50 μM of 8-HQ-MC-7), as well as neurotrophic and neuroprotective activities.488 In vivo studies showed that both intracerebroventricular injections and oral administration of 8-HQ-MC-7 resulted in the proliferation of hippocampal cells.488 This study also presented suitable pharmacokinetic properties of the molecule [i.e., liver microsomal metabolic stability, tolerability (>2 g/kg), oral bioavailability (14%), and logBB (−0.19)]. Additionally, in vivo pharmacodynamics studies indicated that chronic oral administration of 8-HQ-MC-7 ameliorated cognitive and spatial memory deficits in APP/PS1 AD mice with overall reduced Aβ deposits.488

Oliveri et al. adopted the linkage strategy to conjugate 8-HQ to β-cyclodextrin (Figure 9).489 Previous studies had exhibited that β-cyclodextrin conjugates with Mn complexes possessed SOD1-like activity,490 and thus it was anticipated that metalbound 8-HQ-β-cyclodextrin may command ROS-detoxifying SOD1-like activity. In addition, β-cyclodextrin itself has radical scavenging ability and thus is expected to provide another layer of antioxidant capacity.491 Two principle candidates emerged from the series of prepared compounds [i.e., 8-HQ-MC-8 (Figure 9), which bound Cu(II) (logβ1 = 11, logβ2 = 16) and Zn(II) (logβ1 = 8.1, logβ2 = 14), and 8HQ-MC-9 (Figure 9), which bound Cu(II) (logβ1 = 14, logβ2 = 18) and Zn(II) (logβ1 = 8.9, logβ2 = 14)].489 SOD1 activity was confirmed by a nitro blue tetrazolium (NBT) reduction assay, which produced IC50 values of 0.26, 0.39, and 0.51 μM, for 8-HQ-MC-8, 8-HQ-MC-9, and Cu(II), respectively.489 8HQ-MC-9 also exhibited greater antioxidant capacity than Trolox in a TEAC assay, while 8-HQ-MC-8 was similar to Trolox. Although cyclodextrins have been known to impact the aggregation Aβ492 and Aβ fragments,493 this aspect was not investigated for 8-HQ-MC-8 and 8-HQ-MC-9. Oliveri et al. employed the linkage approach to join 8-HQ to glucose and disaccharide trehalose.494 Trehalose (Figure 9) was selected due to previous findings that showed its ability to attenuate toxicity of Aβ by inhibiting the formation of Aβ40 fibrils and oligomers as well as the fibrillization of Aβ42.495 Out of the reported 8-HQ and trehalose conjugates, the best candidate, 8-HQ-MC-10 (Figure 9), bound Cu(II) (logK1 = 16, logK2 = 11) and Zn(II) (logK1 = 12, logK2 = 8.4) and could scavenge DPPH radicals (EC50 = 87 and 61 μM for 1 h U

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and steady state, respectively).494 In addition, 8-HQ-MC-10 could control metal-free and Cu(II)-/Zn(II)-triggered Aβ40 and Aβ42 aggregation as measured by turbidity measurements and gel/Western blot.494 Cacciatore et al. derivatized 8-HQ with glutathione (GSH) tripeptide via the linkage strategy to create 8-HQ-MC-11 (named GS(HQ)H by the authors) (Figure 9).496 Neurodegenerative diseases are associated with a decreased glutathione level; thus, increasing the amount of glutathione may be one approach to counter consequent oxidative stress.497 Additionally, the presence of glutathione transporters could boost entry of glutathione conjugates across the BBB.498 8-HQ-MC-11 bound Cu(II), Zn(II), and Fe(III), and protected SHSY-5Y neuroblastoma cells from H2O2- and 6OHDA-induced damage.496 PAMPA-BBB presented potential, but likely low, BBB permeability of 8-HQ-MC-11. No study of metal-triggered Aβ aggregation, however, was reported.496 Aβ imaging agents are useful scaffolds on which to base the design of multifunctional molecules. They already possess structural elements known to interact with Aβ species, and thus may be used to endow molecules with the ability to interact with Aβ. A large number of such Aβ imaging or interacting scaffolds are now known,461 many of which have been employed in the rational design of multifunctional molecules, including ThT (Figure 10),499 p-I-stilbene (pISTIB) (Figure 11),500 123I-IMPY (Figure 12),501,502 and iodinated diphenylpropynone (125I-DPP) (Figure 14).503 A relatively early attempt in the design of multifunctional Aβ- and metal-targeting molecules employing ThT was performed by Dedeoglu et al., who reported the structure of ThT-MC-1 (named XH1 by the authors) (Figure 10).504 ThT-MC-1 was designed by the fusion of a ThT derivative to either side of a potent metal chelator, DTPA (diethylenetriaminepentaacetic acid; Figure 10). ThT-MC-1 reduced Zn(II)-prompted Aβ40 aggregation in vitro as gauged by a turbidity assay, and its docking to a previously reported Aβ40 NMR structure (PDB 1AML)505 supported an interaction between the molecule and Aβ40. ThT-MC-1 was then examined for the possibility of attenuating APP expression in SHSY-5Y neuroblastoma cells due to the presence of an ironresponse element (IRE) in the 5′-untranslated region of APP mRNA.506,507 Indeed, ThT-MC-1 diminished APP expression in SHSY-5Y neuroblastoma cells and decreased cortical Aβ burden by 32% in the APP/PS1 mouse model of AD, implicating the BBB permeability of the molecule.504 Toxicity studies in rat primary neurons attested to a low toxicity for ThT-MC-1 with viability above 85% at 10 μM of ThT-MC1.504 ́ ́ Rodriguez-Rodri guez et al. created a basic molecular framework combining features of ThT and clioquinol (Figure 10) through the incorporation strategy.508 In silico virtual screening of molecules, conforming to the basic molecular framework, was then employed to identify potential candidates which were then iodinated. The best resultant molecule, ThTMC-2 (alias HBXI; Figure 10), could inhibit Cu(II)-induced Aβ40 aggregation by a turbidity assay.508 It could also bind ex vivo to Aβ plaques in the brain slices of Tg2576 AD mice and in brain tissue samples of AD patients.509 ThT-MC-2 was thoroughly characterized for metal chelation [pCu = 11, logβ1 = 14, logβ2 = 23 for Cu(II); pZn = 11, logβ1 = 14, logβ2 = 22 for Zn(II)], possible BBB permeability (logBB = 0.07; logBB > −1.0 predicted to be permeable510), and potential toxicity (EC50 = 7.8 μM in bEnd.3 cells).508,509 A glycosylated prodrug

Figure 11. Multifunctional compounds produced through utilization of the structured backbone of p-I-stilbene (pISTIB), an agent for imaging Aβ fibrils. pISTIB (chemical name shown in Figure 2); CTX (chrysotoxine), 4-[2-(3,4-dimethoxyphenyl)ethyl]-2,6-dimethoxyphenol; IMSB, 3,3′-[(2-iodo-1,4-phenylene)di-2,1-ethenediyl]bis(6methoxybenzoic acid); pISTIB-MC-1, N1,N1-dimethyl-N4-(pyridin-2ylmethylene)benzene-1,4-diamine; pISTIB-MC-2 (L2-b; chemical name reported in Figure 2); pISTIB-MC-3, N,N-dimethyl-4-(pyridin2-yldiazenyl)aniline; pISTIB-MC-4, 2-((4-(dimethylamino)benzyl)amino)phenol; pISTIB-MC-5, 4-(dimethylamino)-2-(((2(hydroxymethyl)quinolin-8-yl)-amino)-methyl)phenol; pISTIB-MC6, N1-(pyridin-2-ylmethyl)benzene1,4-diamine; pISTIB-MC-7, 3,5dimethoxy-N-(pyridin-2-ylmethyl)aniline; pISTIB-MC-8, N1,N1-dimethyl-N4-(quinolin-2-ylmethyl)benzene-1,4-diamine; pISTIB-MC9, N1-((1H-pyrrol-2yl)methyl)-N4,N4-dimethylbenzene-1,4-diamine; pISTIB-MC-10, N,N-dimethyl-6-((phenylamino)methyl)pyridin-3amine; pISTIB-MC-11, N 1 -((5-(dimethylamino)pyridin-2-yl)methyl)-N4,N4-dimethylbenzene-1,4-diamine; pISTIB-MC-12, 4(3,4-dimethoxyphenethyl)-2,6-dimethoxyphenylbenzoate; pISTIBMC-13, 2,2′-((1,4-phenylenebis(azanylylidene))bis(methanylylidene))bis(benzene-1,4-diol).

Figure 12. Multifunctional molecules produced based upon the framework of 123I-IMPY, an agent for detecting Aβ fibrils. 123I-IMPY, 6- 123 iodo-2-(4′-dimethylamino)phenyl-imidazo[1,2-a]pyridine; IMPY-MC-1, 2-[4-(dimethylamino)phenyl]imidazo[1,2-a]pyridine8-ol; IMPY-MC-2, N1,N1-dimethyl-N4-(pyridin-2-ylmethylene)benzene-1,4-diamine; I-IMPY-MC-2, 6-(6-iodoimidazo[1,2-a]pyridin-2-yl)-N,N-dimethylpyridin-3-amine.

formulation of ThT-MC-2 lacking the iodo substituent was also prepared (ThT-MC-3; named GBX by the authors) (Figure 10).509 ThT-MC-3 had an improved toxicity profile in bEnd.3 cells, exhibiting an EC50 value of 151 μM.509 V

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Hindo et al., who engaged the framework via the incorporation approach and directly installed donor atoms for metal chelation onto the pISTIB structure to produce pISTIBMC-1 (Figure 11).515 The resultant pISTIB-MC-1 retained the ability to interact with Aβ40 as confirmed by 2D NMR. Shifts in several Aβ40 residues were observed upon addition of pISTIB-MC-1. In particular, E11 and H13 were significantly influenced, as were H6 and H14, the proposed Cu(II) binding residues (section 2.2), suggesting that pISTIB-MC-1 could reside close to and interact with the Cu(II) coordination site on Aβ40.515 Cu(II) binding of pISTIB-MC-1 was verified by UV−Vis. Upon confirmation that interactions with both metal ions and Aβ were preserved, pISTIB-MC-1 was tested to identify how this molecule could influence (i) the molecular weight distribution of Cu(II)-generated Aβ40 species upon aggregation and (ii) the disassembly of preformed Cu(II)-triggered Aβ40 aggregates.515 The resultant Cu(II)−Aβ40 aggregates in the presence of pISTIB-MC-1 were observed by TEM to be more amorphous, suggestive of being potentially less toxic.78 Furthermore, it could control the generation of H2O2 in a horseradish peroxidase (HRP)/Amplex red assay, and Lipinski’s criteria suggested possible brain uptake.515 pISTIB-MC-1 was nontoxic to SK-N-BE(2)-M17 neuroblastoma cells and protected them from the death mediated by Cu(II) and Aβ40.515 Further inquiry into the structure−activity relationship (SAR) between structural elements of pISTIBMC-1 and efficacy against Cu(II)- and Zn(II)-promoted Aβ40 aggregation illustrated the importance of the dimethylamino moiety.516 An analog of pISTIB-MC-1 lacking the dimethylamino group was less reactive toward Cu(II)- and Zn(II)triggered Aβ40 aggregation. Therefore, the dimethylamino group was considered an important structural element in the overall design. The utilization of pISTIB-MC-1 was limited by instability in water due to the hydrolyzable bridging imine, restricting potential biological applications. To address this, Choi et al. prepared pISTIB-MC-2 (named L2-b by the authors; Figure 11) by reduction of the bridging imine of pISTIB-MC-1 to an amine.79 Like its counterpart, pISTIB-MC-2 could regulate Cu(II)- and Zn(II)-induced Aβ40 aggregation and disassemble preformed Cu(II)- and Zn(II)-driven aggregates, as determined by gel/Western blot and TEM. Similarly, 2D NMR on 15 N-labeled Aβ40 displayed a comparable pattern of the peak shifts upon treatment with pISTIB-MC-2. It was even efficacious in complex heterogeneous ex vivo AD brain tissue homogenates and afforded a greater proportion of gel permeable and lower molecular weight Aβ species, compared to untreated samples.79 Thus, the reduction of the imine, pISTIB-MC-1, to the amine, pISTIB-MC-2, did not abolish interaction with and reactivity toward metal−Aβ40 but ameliorated the stability of the compound in aqueous media. Detailed investigations of the solution speciation studies regarding the complexes of pISTIB-MC-2 and Cu(II) or Zn(II) were undertaken, indicating the affinities of pISTIBMC-2 for Cu(II) and Zn(II) (Kd = ca. 10−9 and 10−6, respectively) similar to those of Aβ (Section 2.2).79 The potential of pISTIB-MC-2 to pass the BBB was predicted by PAMPA-BBB. pISTIB-MC-2 also improved the viability of SK-N-BE(2)-M17 cells incubated with Cu(II)−Aβ40 and Zn(II)−Aβ40. The same study examined the properties of a pISTIB-MC-2 analog lacking the dimethylamino functionality, emphasizing the importance of this moiety for reactivity

Zhang et al. chose the fusion approach to join a ThT derivative (for binding to Aβ) to di(2-picolyl)amine, a known metal chelator to create ThT-MC-4 (called FC-1 in the report) (Figure 10).511 ThT-MC-4 could modulate Cu(II)and Zn(II)-triggered Aβ40 aggregation, as assessed by a fluorescence assay, which demonstrated a decreasing intensity over time, implying the dissolution of aggregates. This observation was confirmed by TEM, which exhibited smallersized Cu(II)- and Zn(II)-induced Aβ40 aggregates in the presence of ThT-MC-4. Although ThT-MC-4 itself was relatively nontoxic, it aggravated the survival of HeLa cells incubated with Cu(II) and Aβ40, which was attributed to stabilization of potentially more toxic oligomers compared to fibrils.511 Sharma et al. selected the linkage and incorporation approaches in their design of ThT and N-(2-pyridylmethyl)amine conjugates (Figure 10).512 Two multifunctional molecules emerged, ThT-MC-5 and ThT-MC-6 (Figure 10), which were both effective metal chelators [pCu = 10 and pZn = 8.0 at pH 7.4 for ThT-MC-5; pCu = 7.9 and pZn = 7.3 at pH 7.4 for ThT-MC-6]. Their ability to interact with Aβ fibrils was confirmed by fluorescence titrations, revealing Ki values of 180 and 36 nM for ThT-MC-5 and ThT-MC-6, respectively. Upon confirmation of their dual Aβ- and metal-targeting nature, their ability to affect Cu(II)-/Zn(II)-mediated Aβ42 aggregation pathways was confirmed by ThT fluorescence, gel/ Western blot, and TEM. Neither ThT-MC-5 nor ThT-MC-6, however, could protect N2a neuroblastoma cells from Cu(II)/ Aβ42-induced toxicity, which may be related to the possible stabilization of soluble, toxic oligomers.512 Geng et al. fashioned ThT derivatives by incorporating elements of clioquinol for metal binding (Figure 10).513 The primary molecule with the most balanced properties, ThTMC-7 (Figure 10), could inhibit Cu(II)-added Aβ 40 aggregation and disaggregation of preformed Cu(II)-treated Aβ40 aggregates as determined by light scattering and AFM. ThT-MC-7 was not very selective for Cu(II) but could sequester Aβ40-bound Cu(II), and Cu(II)−ThT-MC-7 complexes could also prevent Aβ40 aggregation and disaggregate Aβ40 fibrils. ThT-MC-7 could also attenuate Cu(II)−Aβ40induced H2O2 production, and Cu(II)−ThT-MC-7 complexes possessed SOD-like activity for detoxification of O2•− in a NBT assay. ThT-MC-7 could lower intracellular ROS generation by Cu(II)−Aβ40 species and was less toxic to PC12 cells than clioquinol at a concentration of 10 μM. ThT-MC-8 (Figure 10), a widely studied Ru(III) complex as an anticancer agent, was investigated for its ability to modify the aggregation pathways of Aβ.514 EPR results suggested that ThT-MC-8 could bind to histidine residues toward the Nterminus of Aβ. ThT-MC-8 was able to impede Aβ42 fibrillization at 0.5 to 2 equiv, according to the ThT assay. TEM studies were performed to further analyze the effect of ThT-MC-8 on Aβ42 aggregation, in which the compound was observed to significantly reduce the size of the resultant aggregates and hinder fibril formation. ThT-MC-8 could also modulate Aβ42 aggregation and the assembly of preformed Aβ42 aggregates and attenuate the toxicity of Aβ42 in SH-SY5Y cells.514 p-I-stilbene (pISTIB; Figure 11) is another imaging molecule for Aβ plaques500 and is therefore useful for targeting Aβ. Consequently, it has served as a scaffold for the rational design of several multifunctional molecules.46 Pioneering work on pISTIB-derived multifunctional molecules was reported by W

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against Aβ aggregation.79 Geldenhuys et al. investigated pISTIB-MC-1, pISTIB-MC-2, and a novel azo-bridged derivative, pISTIB-MC-3 (Figure 11), for possible inhibition against MAOs.517 pISTIB-MC-2 (L2-b) emerged as the most effective reversible and competitive inhibitor with some selectivity for MAO-B over MAO-A [IC50 = 0.67 and 0.052 μM for human MAO-A (hMAO-A) and human MAO-B (hMAO-B), respectively; Ki = 0.19 and 0.028 μM, selectivity index (SI) = 6.8]. This report added to the list of properties already exhibited by pISTIB-MC-2.517 Savelieff et al. focused on pISTIB derivatives with altered metal binding specificity by varying N/N donor atoms to N/O donor atoms for metal chelation to generate pISTIB-MC-4 (called L2-NO by the authors) (Figure 11).45 Preference for Cu(II) over other divalent metal ions, including Mg(II), Ca(II), Mn(II), Co(II), Ni(II), and Zn(II), was affirmed by UV−Vis studies except for some interaction with Fe(II). Aligning with this observation was the gel/Western blot and TEM results that exhibited the greatest difference between compound-free and compound-treated samples from Cu(II)induced Aβ40 and Aβ42 aggregation and disaggregation.45 Some minor difference was found for the disassembly of preformed Zn(II)−Aβ42 aggregates. At physiological pH, pISTIB-MC-4 possessed a TEAC capacity greater than Trolox and could control the formation of •OH in a 2-deoxyribose assay.45 Lee et al. employed the incorporation strategy to combine several elements with diverse functions.88 Structural features from 8-aminoquinoline for metal chelation, pISTIB for Aβ interaction,500 and the previously reported pISTIB-MC-2 (L2b) for metal−Aβ interaction79 were merged to invent pISTIBMC-5 (called ML by the authors) (Figure 11).88 pISTIB-MC5 could (i) interact with both metal-free and metal-associated Aβ monomers, oligomers, and fibrils as determined by NMR and IM−MS; (ii) prevent the aggregation of metal-free and metal-bound Aβ and disassemble preformed metal-free and metal-containing Aβ40 and Aβ42 aggregates as observed by gel/ Western blot and TEM; (iii) high antioxidant capacity in vitro in a TEAC assay (ca. 2.6 times greater than Trolox) and the ability to control ROS production in the presence of Cu(II)− Aβ40 species; (iv) potential BBB permeability was assessed by PAMPA-BBB.88 Additionally, pISTIB-MC-5 could improve the survival of N2a neuroblastoma cells stably expressing APPswe upon treatment with metal-free Aβ, Cu(II)−Aβ, and Zn(II)−Aβ.88 The success of pISTIB-MC-5 was attributed to its ability to directly interact with monomeric and oligomeric Aβ, confirmed by the detection of pISTIB-MC-5 in the complexation with metal-free Aβ, Cu(II)−Aβ, and Zn(II)−Aβ by IM− MS.88 Saturation transfer difference (STD) NMR experiments revealed H-bonding, π−π stacking, and van der Waals interactions between structural moieties of pISTIB-MC-5 and Aβ fibrils, suggesting that most of pISTIB-MC-5 interacted with fibrillar peptides. The configuration was supported by docking studies that found the lowest energy state for pISTIB-MC-5 intercalated between the “steric zipper” of the exposed β-strands at the end of the Aβ fiber.88 As for its ability to modulate metal-associated Aβ, this was verified by its metal chelating capability with Cu(II) and Zn(II) showing its preference of forming 1:1 metal-to-ligand complexes (Kd for pISTIB-MC-5 with Cu(II) or Zn(II) in a picomolar or nanomolar range, respectively, at pH 7.4). In research to elucidate the underlying mechanism for the effectiveness of these molecules, Beck et al. prepared and tested

a series of pISTIB-MC derivatives (especially, the four compounds, pISTIB-MC-6, pISTIB-MC-7, pISTIB-MC-8, and pISTIB-MC-9, discussed in this review; Figure 11).518,519 Importantly, the four candidates varied in their ionization potential (IP) and the ease with which they could undergo oxidation of their p-phenylenediamine unit. Studies employing gel/Western blot and TEM on Aβ40 and Aβ42 aggregation under various conditions revealed that (i) only pISTIB-MC-9 was effective for metal-free Aβ samples; (ii) pISTIB-MC-8 and pISTIB-MC-9 were efficacious for Zn(II)generated Aβ aggregation; (iii) pISTIB-MC-6, pISTIB-MC-8, and pISTIB-MC-9 were reactive for Cu(II)-mediated Aβ aggregation [Cu(II):Aβ = 1:1]. Increasing the concentration of Cu(II) during Cu(II)-promoted Aβ40 and Aβ42 aggregation did ultimately lead to some activity for pISTIB-MC-7.518 IM−MS studies demonstrated that diverse species could be detected upon incubation with Aβ40, Cu(II), and compounds. For pISTIB-MC-7, only ternary complexes of pISTIB-MC-7, Cu(II), and Aβ40 were observed. Ternary complexes were similarly observed for pISTIB-MC-6 and pISTIB-MC-8; however, N-terminally truncated Aβ40 and Aβ40 with increased mass corresponding to 256 Da eventually developed.518 For pISTIB-MC-9, oxidized Aβ40 covalently modified with benzoquinone derived from oxidation and hydrolysis of the p-phenylenediamine unit of pISTIB-MC-9 was detected.518 Combined, the results implicated distinct mechanisms for compounds’ modulation toward metal-free and metal-bound Aβ species. pISTIB-MC-7 was proposed to mostly exert its effect on Cu(II)-generated Aβ aggregation via the formation of ternary complexes composed of the compound, Cu(II), and Aβ. In contrast, pISTIB-MC-6 and pISTIB-MC-8 initially formed ternary complexes with Cu(II)−Aβ followed by their oxidation as well as oxidation and/or degradation of Aβ through radical pathways.520,521 Finally, pISTIB-MC-9 underwent rapid oxidation and hydrolysis of its p-phenylenediamine to benzoquinone with consequent covalent adduct formation with Aβ40.50 These distinguishable effects could be traced back to their different IP, which was highest for pISTIB-MC-7, thus being the least likely to be oxidized. All compounds were antioxidants with capacities greater than Trolox in a TEAC assay. Additionally, pISTIB-MC-6, pISTIB-MC-7, and pISTIB-MC-8 could scavenge ROS produced by Cu(I/II)-mediated Fenton-like reactions in a 2deoxyribose assay (note that pISTIB-MC-9 was not soluble under the condition for the assay).518 pISTIB-MC-6 and pISTIB-MC-7 could protect SK-N-BE(2)-M17 cells incubated with Aβ40 and Aβ42 in the presence and absence of either Cu(II) or Zn(II). pISTIB-MC-6 was effective in a MWM test of spatial learning and memory, and increased the time spent in the quadrant with the platform. It also lowered the deposition of Aβ aggregates, noticeably Aβ oligomers.518 Lee et al. conducted a SAR project in order to delineate the roles of (i) the position and number of the dimethylamino moiety, (ii) the metal binding motif, and (iii) the denticity and structural flexibility in the ability to interact with metal-free and metal-bound Aβ.522 Toward this end, several compounds were prepared: pISTIB-MC-10 and pISTIB-MC-11 (impact on the number or position of dimethylamino groups; Figure 11); PMA1 (pyridine-2-yl-methanamine) and PMA2 [6-(aminomethyl)-N,N-dimethylpyridin-3-amine] (effect of metal binding); and DPA1 [bis(pyridin-2-ylmethyl)amine] and DPA2 [6-((((5-(dimethylamino)pyridin-2-yl)methyl)amino)methyl)-N,N-dimethylpyridin-3-amine] (influence of denticX

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ity).522 Ultimately, only pISTIB-MC-11 was found to be effective on metal-free and Cu(II)-/Zn(II)-triggered Aβ40 and Aβ42 aggregation, different from pISTIB-MC-2 (L2-b; Figure 11) that noticeably controlled metal-induced Aβ aggregation over metal-free Aβ analog. pISTIB-MC-11 was also a more potent antioxidant than Trolox in an organic solvent, although it exhibited somewhat diminished capacity in cell lysates (1.9 and 1.1 equiv, respectively). It also improved the viability of SK-N-BE(2)-M17 neuroblastoma cells incubated with metalfree and Cu(II)-/Zn(II)-treated Aβ40 and Aβ42.522 Guan et al. published a series of CTX (chrysotoxine) derivatives as potential multifunctional AD therapeutic candidates.523 Among them, pISTIB-MC-12 (Figure 11) was selected as a lead candidate for AD based on its ability to inhibit self- and Cu(II)-induced Aβ42 aggregation (52 and 58% at 25 μM of the compound, respectively), bind to metal ions, and attenuate Aβ-induced tau hyperphosphorylation at S199, S202, and S396. In addition, the PAMPA-BBB data suggested that pISTIB-MC-12 may cross the BBB.523 pISTIB-MC-13 was constructed based on the IMSB scaffold, a known Aβ imaging agent (Figure 11).524 A notable characteristic of pISTIB-MC-13 is a balanced multifunctional profile, including inhibitory activities against Aβ42 aggregation (IC50 = 7.8 μM), MAO-B (IC50 = 6.4 μM), and free radicals [IC50 (ABTS) = 1.8 μM and IC50 (DPPH) = 15 μM].524 Iodinated, radiolabeled IMPY (as 123I-IMPY; Figure 12) was proposed as a plaque imaging agent in single photon emission computed tomography (SPECT) due to its propensity to bind to Aβ plqaues.501,502 This Aβ-targeting property was capitalized on the first instance of IMPY in the design of multifunctional molecules by Hindo et al., who employed the incorporation approach to produce IMPY-MC-1 (Figure 12).515 IMPY-MC-1 exhibited many properties, including modulation of Cu(II)−Aβ40 aggregation and H2O2 production as well as interaction with Aβ40. Unlike pISTIBMC-1 (Figure 11), however, IMPY-MC-1 could not affect the survival of SK-N-BE(2)-M17 neuroblastoma cells treated with Cu(II)−Aβ40 and was relatively toxic to cells itself.515 Choi et al. tailored a second generation of IMPY derivatives by altering the location of metal chelating atoms to prepare IMPY-MC-2 and its iodinated version, I-IMPY-MC-2 (Figure 12).525 Similar to the original IMPY derivative, both IMPY-MC-2 and I-IMPY-MC-2 presented the reactivity against Cu(II)- and Zn(II)-prompted Aβ40 aggregation, but to a relatively weak extent. Several multifunctional molecules based on the triazole moiety have been published as potential AD therapeutic candidates (Figure 13).526−530 Although triazole’s specific role in these molecules has not been clearly identified, its structural and electronic properties could be responsible for the interaction with Aβ.530,531 Jones et al. reported the synthesis of a series of triazole-derivatized quinoline molecules.526 Gel/ Western blot and TEM presented that the primary candidate, TRZ-MC-1 (also known as QTMorph; Figure 13), could influence Cu(II)-triggered Aβ42 aggregation but was more effective at a superstoichiometric Cu(II) ratio of 1.4:1 [Cu(II):Aβ42] compared to a 1:1 ratio of Cu(II):Aβ42. A 2D NMR study employing 15N-labeled Aβ40 as well as molecular modeling indicated the potential binding between TRZ-MC-1 and the E3, N27, and V18 residues in Aβ40 (Figure 13).526 Triazole-phenol analogues were developed as multifunctional molecules capable of targeting metal ions, Aβ, and ROS.528 The design strategy of TRZ-MC-2 (Figure 13)

Figure 13. Multifunctional molecules containing the 1,2,3-triazole moiety responsible for Aβ interaction. TRZ-MC-1, 4-(2-(4-(quinolin2-yl)-1H-1,2,3-triazol-1-yl)ethyl)thiomorpholine; TRZ-MC-2, 2-(1(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)phenol; TRZ-MC-3, 2-(1(4-(dimethylamino)benzyl)-1H-1,2,3-triazol-4-yl)phenol.

focused on enhancing the molecular interactions with the hydrophobic region of Aβ.528 TRZ-MC-2 was shown to bind to Cu(II) at 1:1 and 1:2 metal-to-ligand ratios at physiological pH. The results obtained by the TEAC assay showed that TRZ-MC-2’s ability to scavenge free radicals was comparable to that of Trolox. 2D NMR studies suggested that TRZ-MC-2 may alter Aβ aggregation through intermolecular interactions. TRZ-MC-2 could modulate the aggregation of both metal-free Aβ42 and Cu(II)−Aβ42. Lastly, TRZ-MC-2 presented the ability to attenuate toxicity triggered by Aβ42 in primary neurons.528 TRZ-MC-3 (Figure 13) was reported as a multifunctional molecule capable of interacting with metal ions, influencing Aβ aggregation, and potentially crossing the BBB.529 A triazole-phenol derivative, TRZ-MC-3, was observed to interact with Cu(II) and modify Aβ42 aggregation by UV−Vis and the ThT assay, respectively.529 Iodinated, radiolabeled diphenylpropynone (125I-DPP; Figure 14) was designed as a plaque binding and potential imaging molecule based on its rigidity.503 Rigidity could limit the degree of freedom around the triple bond, possibly resulting in a tighter fit within the β-sheet binding pocket of Aβ fibrils. Indeed, I-DPP was found to have a greater affinity for Aβ42 aggregates than the previously reported IMPY (Ki = 6.0 and 46 nM for I-DPP and IMPY, respectively).503 Utilizing the DPP scaffold, Pithadia et al. installed one heteroatom into the phenyl group with a minimum disruption to the overall DPP structure to produce DPP-MC-1 (Figure 14) through the incorporation approach.89 DPP-MC-1 bound Cu(II), as determined by UV−Vis (Kd = ca. 10−7 M), and Zn(II), as observed by NMR. It could also affect metal-free Aβ40 aggregation, in addition to Cu(II)-/Zn(II)-induced Aβ40 aggregation.89 A derivative lacking the dimethylamino group had some activity but was less effective, highlighting the importance of this moiety for reactivity with Aβ species. DPPMC-1 was restricted in potential biological applications due to its low micromolar cytotoxicity that was attributed to the ynone Michael acceptor,532 which could form covalent adducts with biomolecules. To address this aspect, Liu et al. performed a SAR study that centered around the triple bond of DPP, synthesizing double-bonded (CHAL-MC-1; chalcone derivative) and single-bonded (CHAL-MC-2; reduced chalcone derivative) DPP derivatives (Figure 14).533 While this approach mitigated the cytotoxicity of the original DPP-MC1, it resulted in a concurrent drop in reactivity against Aβ Y

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activities (76 and 49% for MAO-A and MAO-B, respectively, at 10 μM of the compound).536 Further studies indicated CHAL-MC-4’s low toxicity, anti-inflammatory, and antioxidant (3.3 Trolox equivalents) activities, metal-binding properties, as well as potential BBB permeability.536 Several natural products have served as the scaffold for the rational design of multifunctional molecules.46 For example, resveratrol (Figure 15) has had a history in AD research.537,538

Figure 14. Application of Aβ fibril imaging probes for the preparation of multifunctional molecules. 125 I-DPP derivative, 3-(4(dimethylamino)phenyl)-1-(4-125iodophenyl)-2-propyn-1-one; 125Ichalcone derivative, (2E)-3-[4-(dimethylamino)phenyl]-1-[4[[(2E)-3-125iodo-2-propen-1-yl]oxy]phenyl]-2-propen-1-one; flurbiprofen, 2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid; DPP-MC-1, 3-(4-(dimethylamino)phenyl)-1-(pyridin-2-yl)prop-2-yn-1-one; CHAL-MC-1, (E)-3-(4-(dimethylamino)phenyl)-1-(pyridin-2-yl)prop-2-en-1-one; CHAL-MC-2, 3-(4-(dimethylamino)phenyl)-1(pyridin-2-yl)propan-1-one; CHAL-MC-3, (2E)-1-(4-bromo-2-hydroxyphenyl)-3-[4-(dimethylamino)phenyl]-2-propen-1-one; CHALMC-4, (E)-2-(3′-(3-(4-(diethylamino)phenyl)acryloyl)-2-fluoro-4′hydroxy-[1,1′-biphenyl]-4-yl)propanoic acid.

Figure 15. Multifunctional molecules created by incorporation of metal binding atoms into the backbone of the natural product, resveratrol, and fusion of resveratrol with DFP. Resveratrol, 3,5,4′trihydroxy-trans-stilbene; clioquinol and DFP (chemical names shown in Figure 2); RESV-MC-1, (E)-4-(((2-hydroxyphenyl)imino)methyl)benzene-1,2-diol; RESV-MC-2, 5-hydroxy-2-[2-(4-hydroxyphenyl)-vinyl]-1H-pyridin-4-one; RESV-MC-3, 2-[2-(4-ethoxyphenyl)-vinyl]-5-hydroxy-1-methyl-1H-pyridin-4-one.

species, which was associated with a decrease in structural rigidity and lowered Cu(II) affinity (Kd = ca. 10−5, 10−6, and 10−7 M for CHAL-MC-1, CHAL-MC-2, and DPP-MC-1, respectively).533 Fosso et al. utilized the chalcone scaffold (Figure 14), known for its Aβ imaging properties,534 to generate multifunctional molecules via the incorporation approach.535 The primary candidate to emerge from their family of compounds was CHAL-MC-3 (Figure 14). Cu(II) addition was monitored by UV−Vis, which showed a peak shift indicative of metal binding.535 Aβ experiments were performed with N-biotinylated Aβ42 (bioAβ42) able to form oligomers more readily than Aβ40 at nanomolar concentrations at nearly physiological conditions.535 CHAL-MC-3 attenuated bioAβ42 oligomerization (EC50 = 8.9, 9.8, and 9.3 μM for metal-free Aβ, Cu(II)− Aβ, and Zn(II)−Aβ, respectively), while also bringing about its disaggregation (EC50 = 1.3, 1.5, and 3.8 μM for metal-free Aβ, Cu(II)−Aβ, and Zn(II)−Aβ, respectively).535 CHAL-MC-3 was also tested for inhibition of EeAChE and eqBuChE (IC50 = 2.9 and 4.3 μM, respectively), but activity was abolished in the presence of either Cu(II) or Zn(II).535 CHAL-MC-4 was constructed by combining the structures of chalcone and flurbiprofein, a nonsteroidal anti-inflammatory drug (Figure 14).536 CHAL-MC-4 exhibited the ability to control Aβ42 aggregation in the absence and presence of Cu(II) [78% for self-induced aggregation and 95% for Cu(II)induced aggregation; 25 μM of Aβ42, 25 μM of Cu(II), and 25 μM of the compound] and inhibit MAO-A and MAO-B

The structure of resveratrol is akin to p-I-stilbene (pISTIB; Figure 11) and thus suggests the possibility of interaction with Aβ, which has been validated by reports regarding binding to monomeric and fibrillar Aβ539 and inhibition of forming Aβ fibrils.540 It displays antioxidant properties541 and impacts diverse biological pathways,542 including proteostasis,543 neuroinflammation, and immunity,544 and exhibits neuroprotective effects in APP/PS1 mice.545 The design of multifunctional small molecules reported by Li et al. rested on the incorporation strategy wherein a N donor atom was directly installed into the stilbene alkene group.546 Variation in the position of resveratrol’s hydroxyl group collectively with the N donor atom mimicked the N/O chelation motif from clioquinol. The lead candidate, RESV-MC-1 (Figure 15), was found to possess DPPH radical scavenging capacity (IC50 = 14 μM vs 109 μM for resveratrol) with the ability to inhibit metal-free Aβ42 aggregation (65% at 20 μM of the compound vs 64% at the same concentration of resveratrol).546 RESVMC-1 bound Cu(II) as evidenced by changes in optical features upon addition of Cu(II). RESV-MC-1 could inhibit Cu(II)-induced Aβ42 aggregation by 68% compared to 67 and 63% by clioquinol and resveratrol, respectively. RESV-MC-1 could also reduce Cu(II)−Aβ42-generated H2O2 production by ca. 80% as determined by a HRP/Amplex red assay and improve the viability of SH-SY5Y neuroblastoma cells from H2O2 insults at a concentration of 10 μM.546 It possessed druglikeness, based on the restrictive terms of Lipinski’s rule, and Z

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Figure 16. Natural products, EGCG, myricetin, phlorizin, F2, verbascoside, VPP, rutin, and R2, presented as molecules capable of regulating metal-triggered Aβ aggregation. EGCG [(−)-epigallocatechin-3-gallate], ((2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl)3,4,5trihydroxybenzoate; myricetin, 3,5,7-trihydroxy-2-(3,4,5-trihy-droxyphenyl)-4H-1-benzopyran-4-one; phlorizin, 1-(2,4-dihydroxy-6(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-3-(4-hydroxyphenyl)propan-1-one; F2, (2S,3R,4S,5R,6R)-2-(3,5-dihydroxy-2-(3-(4-hydroxyphenyl)propanoyl)phenoxy)-6-((propionyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl-tripropionate; verbascoside, (2R,3R,4R,5R,6R)-6-(3,4-dihydroxyphenethoxy)-5-hydroxy-2-(hydroxymethyl)-4-(((2S,3R,4R,5R)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-3-yl(E)-3-(3,4-dihydroxyphenyl)acrylate; VPP, (2S,3R,4R,5S,6S)-2-(((2R,3R,4S,5R,6R)-2(3,4-dihydroxyphenethoxy)-5-(((E)-3-(3,4-dihydroxyphenyl)acryloyl)oxy)-3-(propionyloxy)-6-((propionyloxy)methyl)tetrahydro-2H-pyran-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl-tripropionate; rutin, 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy6-((((2R,3R,4R,5R,6S)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)oxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)-4H-chromen-4-one; R2, (2R,3R,4R,5S,6S)-2-(((2R,3R,4S,5R,6S)-6-((2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl)oxy)-3,4,5-tris(propionyloxy)tetrahydro-2H-pyran-2-yl)methoxy)-6-methyl-tetrahydro-2H-pyran-3,4,5-triyl-tripropionate.

tion of the nonamyloidogenic α-secretase proteolytic pathway.549 Furthermore, EGCG could redirect metal-free Aβ aggregation into amorphous and nontoxic forms.78 Given flavonoids’ interactions with both Aβ78,548 and metal ions,550 DeToma et al. performed early investigations into their potential bifunctionality (i.e., metal chelation and Aβ interaction) and the possibility of modulating metal-induced Aβ aggregation.60 Myricetin (Figure 16) was the polyphenol selected for the study, since the earlier work demonstrated its interaction with Aβ40 fibrils.548 It was determined to impact both Cu(II)- and Zn(II)-mediated Aβ40 aggregation and disaggregate preformed metal−Aβ40 fibrils, generating a range of molecular weight species as visualized by gel/Western blot. TEM revealed the production of smaller-sized amorphous Cu(II)−/Zn(II)−Aβ40 aggregates in the presence of myricetin.60 Additional insight on the interaction of polyphenols with Aβ40 was uncovered in a survey of EGCG binding to Aβ40 by Hyung et al. (Figure 16).59 To identify molecular-level details on the interaction between EGCG and Aβ40, the authors adopted physical characterization methods, IM−MS and 2D NMR, which detected the formation of compact complexes composed of EGCG and Aβ40 monomers and dimers.59 A similar observation was made by IM−MS in the presence of Cu(II)-treated Aβ40 with EGCG, which monitored ternary Cu(II)−Aβ40−EGCG complexation. Addition of EGCG to Zn(II)−Aβ40 by 2D NMR caused peak shifts, indicative of an interaction between EGCG and Zn(II)-bound Aβ40.59 Other analytical techniques, surface plasmon resonance spectroscopy (SPR)551 and electrochemical methods,552 have also been used to characterize the metal−Aβ−EGCG interaction, supporting

was relatively nontoxic to SH-SY5Y neuroblastoma cells up to a concentration of 10 μM.546 Xu et al. integrated the scaffolds to resveratrol with DFP, a known metal chelator (Figure 15).547 Their preliminary studies indicated that RESV-MC-2 and RESV-MC-3 (Figure 15) possessed micromolar values for inhibition of metal-free Aβ42 aggregation (IC50 = 11, 8.9, and 12 μM for RESV-MC-2, RESV-MC-3, and resveratrol, respectively). At a concentration of 20 μM, inhibition of Aβ42 aggregation was observed by 58, 65, and 64% for RESV-MC-2, RESV-MC-3, and resveratrol, respectively.547 Both RESV-MC-2 and RESVMC-3 were relatively good metal chelators (pFe(III) = 20 and 19, respectively, vs 21 for DFP) and possessed antioxidant capacity in a ABTS assay (IC50 = 1.7, 4.0, 0.76, and 3.9 μM for RESV-MC-2, RESV-MC-3, resveratrol, and Trolox, respectively).547 ThT and TEM experiments demonstrated that RESV-MC-2 and RESV-MC-3 could affect both Fe(III)- and Cu(II)-triggered Aβ42 aggregation as well as the disassembly of preformed Fe(III)−Aβ42 and Cu(II)−Aβ42 aggregates.547 Correlation in epidemiological studies between prevalence of AD with dietary intake of polyphenols has suggested a potential preventive role of natural products in AD pathology.54,55 Investigations have revealed several possible interactions or activities of polyphenols and their derivatives toward multiple pathological targets, ranging from Aβ interacting ability,78,548 interaction with ptau, antioxidant properties, BACE1 inhibition,57 AChE/BuChE inhibiton,58 and influence on signaling pathways.53,62 EGCG [(−)-epigallocatechin-3-gallate; Figure 16] was found to increase APP cleavage, thereby decreasing Aβ plaque load in Tg mice overexpressing APPswe (Tg2576) with concomitant promoAA

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Figure 17. Synthetic and natural occurring flavones and isoflavones showing multifunctionality. Curcumin and curcumin-gadolinium (Gd) conjugate that possess modest multiple regulating properties. Flavone, 2-phenyl-4H-1-benzopyr-4-one; flavonol, 3-hydroxy-2-phenylchromen-4one; isoflavone, 3-phenyl-4H-chromen-4-one; genistein, 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one; FLAV-MC-1, 3-hydroxy-2-(pyridin2-yl)-4H-chromen-4-one; FLAV-MC-2, 2-amino-7-hydroxy-3-phenyl-4H-chromen-4-one; FLAV-MC-3, 2-amino-3-(3,4-dihydroxyphenyl)-4Hchromen-4-one; FLAV-MC-4, 2-amino-6-chloro-3-(3,4-dihydroxyphenyl)-4H-chromen-4-one; FLAV-MC-5, 2-amino-3-(3,4-dihydroxyphenyl)-7hydroxy-4H-chromen-4-one; morin, 2-(2,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one; quercetin, 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one; galangin, 3,5,7-trihydroxy-2-phenyl-4H-chromen-4-one; luteolin, 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one; curcumin, (chemical name reported in Figure 8); curcumin-Gd, Gd(III)(diethylenetriaminepentaacetate)-linked-2-(4-((1E,4Z,6E)5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3oxohepta-1,4,6-trien-1-yl)-2-methoxyphenoxy)-N-(2-(3-(p-tolyl)thioureido)ethyl)acetamide.

that EGCG could modulate metal−Aβ aggregation. Ternary complex formation has been observed for various other molecules with reactivity against metal−Aβ, such as pISTIBMC-2 (L2-b),79 pISTIB-MC-5,88 and pISTIB-MC-6 (Figure 11),518 suggesting that this could be a unifying mechanism of action (MoA) of active molecules. The IM−MS and 2D NMR findings were corroborated by the results from gel/Western blot and TEM, which divulged a wider molecular weight distribution of Aβ40 species and metal−Aβ species with EGCG and formation of amorphous aggregates when this molecule was present.59 Flavonoids and other natural molecules often occur in a glycosylated form. Among them, verbascoside and rutin were found to impact metal-free Aβ aggregation and toxicity,553−556 while the nonglycosidic version of phlorizin, phloretin, could prevent membrane-associated aggregation of Aβ (Figure 16).557 Korshavn et al. investigated the influence of phlorizin, verbascoside, and rutin and their esterified derivatives, F2, VPP, and R2 (Figure 16), respectively, on metal-free and metal-triggered Aβ aggregation.61 Verbascoside and VPP emerged as the primary molecules with the greatest impact on both metal-free and Cu(II)- and Zn(II)-induced Aβ40 and Aβ42

aggregation and disaggregation, as visualized by gel/Western blot and TEM.61 VPP exhibited more noticeable spectral changes than verbascoside upon Cu(II) treatment, possibly because the esterified glucose hydroxyl groups in VPP may compete to a lesser extent for Cu(II), promoting binding of Cu(II) to the catechol moieties. Zn(II) binding was examined by NMR, which demonstrated selective broadening of resonances associated with the catechol groups of verbascoside and VPP but weak binding for Zn(II) as for Cu(II).61 Studies with 15N-labeled Aβ40 by 2D NMR indicated that (i) both verbascoside and VPP could interact with the Nterminus and (ii) verbascoside was observed to favor both polar and charged residues compared to VPP, presumably due to the more hydrophobic nature of VPP. STD experiments calculated an affinity for Aβ42 fibrils of 7.8 and 7.0 μM for verbascoside and VPP, respectively, at pH 7.4. Verbascoside was ca. 1.4-fold more potent than Trolox in an ABTS radical scavenging assay, while VPP was weaker. This may be due to VPP’s masked glucose hydroxyl groups, which could also scavenge radicals.491 Generally, verbascoside could enhance the survival of the cells treated with metal-free Aβ and metal− Aβ, but this ability was abrogated upon its esterification AB

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(VPP)61 The greater efficacy of verbascoside and VPP versus rutin and R2 suggested that the catechol moiety, not just polyphenols, may be effective at redirecting protein misfolding. Thus, SAR studies could advance our understanding of essential features for reactivity of small molecules against Aβ (vide inf ra). Although natural products and polyphenols provide a wealth of structural diversity, studies with their synthetic derivatives enable the elucidation of structural features that impart reactivity toward Aβ. In this vein, He et al. rationally designed and synthesized a small library of flavone and flavonol derivatives with simplified structures to facilitate characterization (Figure 17).63 They limited the potential number of metal chelation sites relative to natural polyphenols in order to control metal affinity. Among the other features retained for some derivatives was the dimethylamino group from other molecules capable of interaction with Aβ;79,89,522 however, it was not located on p-phenylenediamine, which could be a critical aspect of reactivity for Aβ.522 The most extensively studied molecule from the study, FLAV-MC-1 (Figure 17), could bind Cu(II) (Kd = ca. 10−9 M) and Zn(II) (Kd = ca. 10−6 M) and form mixtures of 1:1 and 1:2 metal-toligand complexes; however, it was not very effective at modifying metal−Aβ aggregation.63 FLAV-MC-1 was not a relatively good scavenger against free organic radicals (assayed by TEAC), but it could control Cu(II)−Aβ40-mediated H2O2 production (measured by a HRP/Amplex red assay).63 DeToma et al. conducted a SAR study among a series of aminoisoflavones related to genistein (Figure 17), a naturally occurring product from soybean.64 Prior studies have shown the ability of genistein to inhibit the fibrillization and oligomerization of Aβ40 and Aβ42.558 The resulting family of synthetic aminoisoflavones varied in the absence (FLAV-MC2; Figure 17) and presence (FLAV-MC-3, FLAV-MC-4, and FLAV-MC-5; Figure 17) of a catechol group, and alteration of a substituent on the A ring modified the electronic and steric properties of the remaining molecules, FLAV-MC-3, FLAVMC-4, and FLAV-MC-5.64 All compounds were found to be active against metal-free and Cu(II)-/Zn(II)-associated Aβ40 and Aβ42 aggregation as well as disaggregation of preformed metal-free and metal-treated Aβ aggregates, but FLAV-MC-2 lacking a catechol group was the least active, implicating it as an essential group for interaction with Aβ and metal ions. FLAV-MC-2 also interacted less strongly with Aβ40 compared to its counterparts. The importance of the catechol group was identified by Aβ reactivity studies with methoxylated forms of FLAV-MC-3 and FLAV-MC-5, which abolished reactivity.64 FLAV-MC-5 bound Cu(II) (Kd = ca. 10−15 M) and formed a mixture of 1:1 and 1:2 metal-to-ligand complexes, while addition of Zn(II) into its solution only resulted in UV−Vis spectral changes following 12−24 h incubation. 2D NMR elucidated the mode of FLAV-MC-5’s interaction with Aβ40, revealing interactions at R5-S8 and H13-L17 of the 310 helix as well as chemical shift perturbations closer to the C-terminus (M35-V40).64 This mode was notably different to the nonspecific interactions observed with the related catechol, EGCG, with Aβ40.59 STD NMR indicated that FLAV-MC-5 interacted with fibrillar Aβ40 (Kd = mM to μM), and that the STD effect was distributed relatively evenly throughout the whole molecule.64 FLAV-MC-5 was comparable in antioxidant capacity to Trolox. Lee et al. selected four naturally occurring molecules, morin, quercetin, galangin, and luteolin (Figure 17) based on

structural variations in the number and position of hydroxyl groups on the B and C rings.559 Prior to this studay, their influence on metal-free Aβ aggregate formation had been reported,560−562 but information on their effects on both Cu(II)- and Zn(II)-dependent Aβ aggregation, along with molecular-level interactions, had not been available. None of the four flavonoids examined appeared to exert a significant influence on metal-free Aβ 40 or Aβ 42 aggregation or disaggregation.559 Reactivity of all candidates, however, was enhanced in the presence of Cu(II), which was noticeably greater than for Zn(II)-induced Aβ40 or Aβ42 aggregation and disaggregation. In all instances, the activity against metalinduced Aβ aggregation was greater for morin and quercetin, the two candidates bearing hydroxyl groups on both the B and C rings, than that of galangin and luteolin.559 In particular, the hydroxyl substituent at the C ring is believed to facilitate oxidation,563 which could subsequently cause the modification and degradation of Aβ.518 Binding to Cu(II) was anticipated due to the presence of either catechol or the combined 3-OH and 4-oxo groups of the C ring, proposed to be involved in metal chelation by quercetin.562,564,565 Indeed, spectral changes were observed upon incubation of Cu(II) with morin, quercetin, galangin, and luteolin in both the absence and presence of Aβ, indicating their interaction with Cu(II) under both conditions.559 Interactions of all four flavonoids with Aβ40 were observed by 2D NMR, revealing modest chemical shifts in diverse areas of Aβ40. The three molecules possessing a 3-OH group had the greatest impact on F20 versus any other Aβ40 residue, suggesting that this amino acid may be critical for interaction of these flavonoids with Aβ40.559 Finally, toxicity studies in SH-SY5Y neuroblastoma cells indicated that morin and quercetin could improve the survival of the cells treated with metal−Aβ by more than 10−20%, while galangin and luteolin affected cell viability very slightly. Curcumin (Figure 17), a natural product derived from Curcuma longa, commonly known as turmeric,566 has been widely studied in AD research due to its ability to inhibit Aβ oligomerization and fibrillization and its capacity to bind to plaques and reduce Aβ burden in vivo in AD Tg2576 mice.470,567 Curcumin also possesses potential metal chelating atoms in the bis-ketone groups of the keto form or the oxo and hydroxyl combination of the enol form. Kochi et al. examined the possibility of targeting both Aβ and metal ions by curcumin during the course of studies investigating it as a control to a curcumin-gadolinium (Gd) complex conjugate (curcumin-Gd) (Figure 17). 568 Neither curcumin or curcumin-Gd was able to significantly impact metal-free or Zn(II)-triggered Aβ40 or Aβ42 aggregation; however, a small effect was observed for Cu(II)-treated Aβ 40 or Aβ 42 aggregation and disassembly of preformed Cu(II)−Aβ40 or Aβ42 aggregates. Cu(II) binding to curcumin was confirmed showing the new shifts in UV−Vis, but Zn(II) binding was shown to be minimal.568 Curcumin could scavenge ABTS radicals with 1.2-fold capacity versus Trolox and was predicted to potentially cross the BBB according to Lipinski’s rule and the results from PAMPA-BBB. The design and synthesis of peptide-based inhibitors for Aβ aggregation have been a widely researched area, and many of them have presented promising properties.569−571 Working along this vein, Rajasekhar et al. reported on a multifunctional peptide-based inhibitor, PEP-MC-1 (named P6 by the authors; Figure 18), which was based on the natural tripeptide, Gly-His-Lys (GHK).572 This natural peptide is present in AC

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to SrVSrFSr (Sr = sarcosine), an unnatural peptide based on the core Aβ recognition sequence (KLVFF).468,574 PEP-MC-1 inhibited Aβ42 fibrillization, revealed by ThT and dot blot assays, as well as attenuated the extent of oligomer formation (assessed by the dot blot assay).572 Inhibition of porelike Aβ42 oligomer formation upon treatment with PEP-MC-1 was observed, employing carboxyfluorescein-loaded liposomes. Addition of Aβ42 led to leakage of the dye from the liposomes, which was diminished in the presence of PEP-MC-1.572 Cu(II) binding to Aβ 42 was monitored by tyrosine fluorescence, which quenched the signal but was recovered upon addition of PEP-MC-1, indicating sequestration of Cu(II) from Aβ42 by the peptide.572 PEP-MC-1 prevented ROS generation in the presence of Cu(II) with and without Aβ42 by both coumarin-3-carboxylic acid and HRP/Amplex red assays. Finally, PEP-MC-1 could increase the viability of PC12 cells in the presence of Cu(II)/Aβ42/ascorbate-induced toxicity while controlling ROS production.572 Although Cu(II) binding to GHK had been reported,573 a detailed study of Cu(II) binding to PEP-MC-1 was not performed, nor its influence on Cu(II)-triggered Aβ aggregation.

Figure 18. Peptide-based inhibitors against Aβ aggregation that can target metal ions.

human serum and forms 1:1 complexes with Cu(II) (Kd = ca. 7.0 × 10−14 M).573 PEP-MC-1 was generated by fusing GHK

Figure 19. Multifunctional molecules rationally designed based on tacrine with known metal chelators via the linkage and/or incorporation approaches. Tacrine, 1,2,3,4-tetrahydro-9-acridinamine; phenothiazine, 10H-dibenzo-[b,e]-1,4-thiazine; tetrahydropyranodiquinolin-8-amine, 9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h′]diquinolin-8-amine; MB (methylene blue), 3,7-bis(dimethylamino)phenothiazin-5-ium; clioquinol (chemical name reported in Figure 2); BQCA (benzyl quinolone carboxylic acid), 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; L2-b (chemical name presented in Figure 2); TAC-MC-1, (from left to right) 1,7-bis(1,2,3,4-tetrahydro-acridin-9-ylamino)-heptan-4-one, N,N′-bis-[2-(1,2,3,4-tetrahydro-acridin-9-ylamino)-ethyl]-oxalamide, N,N′-(2,2′-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(1,2,3,4-tetrahydroacridin-9-amine), N1,N7-bis(1,2,3,4-tetrahydro-9-acridinyl)-1,7-heptanediamine; TAC-MC-2, (left) 9-[10-(1,2,3,4-tetrahydroacridin-9-yl)1,4,7,10-tetraazadecan1-yl]-1,2,3,4-tetrahydroacridine, (right) N-[2-({2-[(1,2,3,4-tetrahydroacridin-9-yl)amino]ethyl}amino)ethyl]-1,2,3,4-tetrahydroacridin-9-amine; TAC-MC-3, 1-(10H-phenothiazin-10-yl)-2-(6-(5,6,7,8-tetrahydroacridin9-ylamino)hexylamino)ethanone; TAC-MC-4, 7(((9-((1,2,3,4-tetrahydroacridin-9-yl)amino)nonyl)amino)methyl)quinolin-8-ol; TAC-MC-5, N-{2-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]ethyl}-1-[(4-methoxyphenyl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxamide; TAC-MC-6, N-{3-[(6-chloro-1,2,3,4-tetrahydroacridin9-yl)amino]propyl}-1-[(4-methoxyphenyl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxamide; TAC-MC-7, 3-iodo-N-[4-(1,2,3,4-tetrahydroacridin-9-ylamino)butyl]benzamide; TAC-MC-8, N1-{[6-((10-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)decyl)amino)pyridin-2-yl]methyl}N4,N4-dimethylbenzene-1,4-diamine; TAC-MC-9, N1-(2-(dimethylamino)benzyl)-N9-(1,2,3,4-tetrahydroacridin-9-yl)nonane-1,9-diamine; TACMC-10, 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h′]diquinolin-8-amine. AD

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molecules capable of targeting ChE and other pathological features, including Aβ aggregation (vide infra), oxidative stress, BACE1, MAO, NMDAR, and other receptor molecules. These efforts have been covered by several review articles from earlier work36 to more recent progress for multifunctional molecules based on tacrine, donepezil, and galantamine.588−593 The metal ion hypothesis (section 2.2),10−13 which has gained traction in recent years, is increasingly represented in multifunctional molecules that target metal ions as well as inhibit AChE/BuChE. While still relatively less common than multifunctional ChEI molecules interacting with other pathological targets,588−593 the rising number of compounds targeting ChEs and metal ions is a testament to the increasingly appreciated role of metal ions in AD pathology. In this section, we review the progress made toward the rational design of molecules directed at AChE/BuChE and metal ions, with recent examples. Crystal structures of AChE as well as AChEIs in complex with AChE have been helpful for the design and refinement of new AChEIs.594,595 The first reported structure was of Torpedo californica AChE (TcAChE) in 1993 followed later by structures of hAChE in complex with pharmacologically important ChEIs.363,596 AChEIs can be classified into two groups depending on how they bind to AChE. Some AChEIs (e.g., tacrine) only bind to the catalytic active site (CAS), composed of the catalytic triad (H447, E334, and S203; hAChE numbering) and W86, which stabilizes the cationic head of ACh.591,592 Other inhibitors, so-called dual site inhibitors (e.g., donepezil), bind to both the CAS and PAS.591,592 The PAS resides at the top of the gorge and is lined with aromatic residues Y124, W286, F295, R296, and F297 (hAChE numbering). In the area spanning the CAS and PAS is a midgorge recognition site lined by the residues Y72, D74, S125, F338, and Y341.592 AChE is found to be colocalized with Aβ in SPs from AD patients’ brain tissue.597 Thus, the discovery that AChE accelerates Aβ aggregation via an AChE-induced mechanism underlined the intertwining of Aβ pathology with the cholinergic hypothesis of AD.383 It also emphasized the potential benefit of simultaneously targeting both pathologies through multifunctional molecules. The ability of AChE to induce Aβ aggregation was traced to its PAS site, a feature absent from BuChE, which does not affect Aβ aggregation.383 This enabled the ability to intentionally incorporate anti-Aβ aggregation capability into multifunctional molecules by enhancing their interaction with the PAS site of AChE. The molecules based on inhibition of AChE and AChE-induced Aβ aggregation were among the earlier multifunctional AChEtargeting molecules, so-called dual binding site AChEIs.36 Most multifunctional molecules have been constructed based on the scaffolds of known ChEIs that vary in their selectivity for AChE over BuChE (SI = 1, equal AChE and BuChE inhibition; SI > 1, AChE-selective).36,588,591−593 Tacrine (Figure 19) and rivastigmine (Table 1) target both AChE and BuChE, while donepezil and galantamine (Table 1) are selective for AChE.28 Earlier attempts were directed toward preferential AChE inhibition since it hydrolyzes ACh, a crucial neurotransmitter in the brain. Recent evidence, however, has supported a potential role for BuChE in AD pathogenesis, particularly via compensatory mechanisms whereby AChE inhibition results in upregulation of BuChE.369,598 Due to the broader substrate specificity of BuChE and uncertain role,599 however, off-target effects of

Another metal-binding peptide was designed by Márquez et al., the nonnatural tetrapeptide, Met-Asp-D-Trp-Aib (PEPMC-2; Aib = 2-aminoisobutyric acid; Figure 18), that combines the metal binding properties of Met-Asp with the β-breaker properties of D-Trp-Aib.575,576 CD and EPR experiments presented the ability of PEP-MC-2 to sequester Cu(II) from Cu(II)−Aβ16. PEP-MC-2 could delay Aβ40 aggregation and resulted in smaller-sized fibrils, as visualized by TEM. It also exerted an influence of Cu(II)-promoted Aβ40 aggregation, diminishing the early formation of large Cu(II)− Aβ40 oligomers, a feature attributable specifically to the metalchelating moiety of PEP-MC-2 since the β-breaker portion (DTrp-Aib) alone exerted no discernible effect.575 Other biological properties of PEP-MC-2 were not tested, however. Overall, various types of multifunctional molecules have been designed to possess a combination of properties and activities: (i) interactions with metal ions and Aβ; (ii) regulation of metal-free Aβ aggregation pathways; (iii) control of metal-triggered Aβ aggregation; (iv) reduction of ROS generation, along with antioxidant capacity; (v) BBB permeability; (vi) low toxicity in living cells; (vii) enhancement of cell survival against metal-free Aβ and metal−Aβ; (viii) improvement of cognitive deficits in AD mouse models. An underlying aspect of controlling the different parameters of Aβ is its impact toward various cellular signaling pathways (e.g., NF-KB, ASK1, CD36, CD40, JNK, cdk5, ERK1/2, p38 MAPK, RAGE, and GSK3β).577−584 Although the exact impact of Aβ on signaling pathways has not been clearly defined, they could provide an idea of how the peptide itself affects cell survival and death.585 SAR studies have also been conducted to identify the underlying mechanisms by which these rationally designed small molecules exert their properties. It is anticipated that these mechanistic studies could shed light on essential structural features required of active molecules, which would aid in the design of candidates with superior properties. 2.6.2. Multifunctional Molecules Targeting ChEs and Metal Ions. Inhibition of AChE has been the mainstay of AD treatment for decades, justified on the basis of the cholinergic hypothesis of AD (section 2.4).351 The first drug approved by the FDA for treatment in AD patients was tacrine (Figure 19) as an AChEI, 586 which was later withdrawn due to unacceptably high hepatoxicity.586,587 Nevertheless, the development of new AChEIs has continued, and presently three others have received the FDA stamp of approval (i.e., donepezil, galantamine, and rivastigmine; Table 1), along with memantine (Table 1), an NMDAR antagonist.28,586 In addition, the design and discovery of new molecules continue to drive the field forward in search of more efficacious and/or selective AChEIs and BuChE inhibitors (BuChEIs) with improved pharmacodynamic and pharmacokinetic properties.586 The benefit of AChEIs for AD treatment has been a widely studied subject, and the body of evidence seems to suggest some improvement followed, unfortunately, by an inevitable decline in cognitive function.28 Thus, current AChEIs are not disease-modifying drugs and offer mostly palliative care. Nevertheless, the demonstration of effectiveness has led to their adoption in multifunctional drug design, operating on the premise that combining the inhibition of AChE and/or BuChE with scaffolds targeting other pathological factors may boost the overall ability of these drugs to alter or halt the course of neurodegeneration. In this vein, the frameworks of several ChEIs have been used to rationally construct multifunctional AE

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could protect SH-SY5Y neuroblastoma cells from rotenoneinduced oxidative stress. Further studies on TAC-MC-4 were performed in APP/PS1 mice, where treatment with TAC-MC4 led to a decrease in Aβ deposition.609 In primary cortical astrocyte cultures, TAC-MC-4 stimulated lysosome-mediated Aβ42 degradation.609 Hepnarova et al. fashioned a series of tacrine-BQCA (benzyl quinolone carboxylic acid) hybrids, including TACMC-5 and TAC-MC-6 (Figure 19).610 TAC-MC-5 and TACMC-6 exhibited the promising ability to inhibit the activities of AChE (hAChE, IC50 = 75 and 42 nM, respectively), BuChE (hBuChE, IC50 = 83 nM and 3.7 μM, respectively), and muscarinic acetylcholine receptor M1 (M1 mAChR; IC50 = 4.2 and 4.0 μM, respectively) with low hepatotoxicity and potential BBB permeability.610 Skibinski et al. reported several tacrine derivatives with iodobenzoic moieties as multifunctional AChE inhibitors.611 Among them, TAC-MC-7 (Figure 19) was highlighted to be the most promising based on its ability to inhibit the activities of AChE (IC50 = 31 nM), BuChE (IC50 = 8.0 nM), and Aβ aggregation (25, 72, 78, and 85% at 10, 25, 50, and 100 μM of the compound, respectively).611 Another instance of a metal chelator bound to a ChEI via the linkage approach was reported by Kochi et al. (Figure 19).43 They combined L2-b [named by the authors (Figure 19); pISTIB-MC-2 shown in Figure 11], a multifunctional molecule capable of metal chelation and modification of metal−Aβ aggregation,79,612 with 6-chlorotacrine through a ten-carbon linker. The resultant molecule, TAC-MC-8 (Figure 19), retained the properties of both parent moieties and could inhibit EeAChE and eqBuChE with IC50 values of 2.4 and 2.0 nM, respectively, compared to the parent compound 6chlorotacrine (IC50 = 2.4 and 2.4 nM, respectively).43 ChE inhibition was influenced by the presence of metal ions and Aβ, but overall the molecule remained effective. Similarly, TAC-MC-8 preserved the capability of L2-b to alter the aggregation pathways of metal-triggered Aβ to less structured forms and could disassemble preformed structures of metal− Aβ in the presence and absence of AChE. PAMPA-BBB predicted the potential CNS availability of TAC-MC-8. Molecular modeling of the energy-minimized structure between TAC-MC-8, TcAChE, and Aβ presented binding of the tacrine portion of TAC-MC-8 within the CAS and the metal chelating moiety close to the PAS and the residues H6, H13, and H14 of Aβ.43 Mao et al. prepared a new class of tacrine derivatives connected to phenol, variously substituted aryl amines, and pyridine through linkers of varying lengths.613 The best performer, TAC-MC-9 (Figure 19), outdid tacrine in EeAChE and eqBuChE inhibition (IC50 = 0.55 and 2.7 nM, respectively, for TAC-MC-9; IC50 = 109 and 16 nM, respectively, for tacrine) and retained the potent activity against hAChE (IC50 = 3.5 nM). TAC-MC-9 also inhibited the self-aggregation of Aβ42 (39% at 20 μM), possessed antioxidant activity (1.2 Trolox equivalents), and interacted with Cu(II), Zn(II), and Fe(II) (as evidenced by shifts in the optical spectra).613 The molecule’s effect on metal-triggered Aβ aggregation was not reported. Dgachi et al. prepared a series of tetrahydropyranodiquinolin-8-amines by structural integration of clioquinol with tacrine (Figure 19).614 A lead molecule, TAC-MC-10 (Figure 19), was determined to show micromolar inhibition of EeAChE, hAChE, and eqBuChE (IC50 = 0.040, 0.75, and 1.3

inhibiting BuChE may be possible. Therefore, the ideal therapeutic approach, AChE-selective versus nonselective, is at present uncertain. Despite its hepatotoxicity, tacrine (Figure 19) continues to be a popular backbone for the rational design of multifunctional molecules targeting metal ions, and numerous examples have emerged, including attempts to render the molecules less hepatotoxic. In one of the earlier attempts, Bolognesi et al. introduced donor atoms for metal binding into the bis-tacrine linking moiety.600 The resultant candidate molecules [tacrinemetal binding 1 (TAC-MC-1); Figure 19] exhibited a relatively reduced ChE inhibiting capacity compared to the parent alkyl heptylene (IC50 = 1.8−20 versus 0.81 nM for hAChE; IC50 = 5.4−35 versus 5.7 nM for hBuChE) but were still significantly more potent than tacrine (IC50 = 424 and 46 nM for hAChE and hBuChE, respectively). Moreover, they retained bis-tacrine’s ability to alter AChE-induced Aβ40 aggregation (54−76% versus 68% for bis-tacrine). Metal binding was demonstrated by spectroscopic changes upon addition of Cu(II) and Fe(II), and stability constants for complex formation were reported.600 The impact of these molecules on metal-induced Aβ aggregation was not examined, however. Qian et al. extended the family of bis-tacrine derivatives with linkers containing potentially better metal chelating groups (TAC-MC-2; Figure 19).601 The study, however, was limited to the molecules’ effectiveness against inhibition of AChE and BuChE and investigated neither prevention of Aβ aggregation nor metal binding. Rather than preparing bis-tacrine linked molecules, Hui et al. designed tacrine-phenothiazine derivatives in order to inhibit both AChE activity and tau hyperphosphorylation (Figure 19).602 Phenothiazine is the key pharmacophore of methylene blue (MB) that is known to prevent the accumulation of soluble tau, tau filament formation, and exhibit neuroprotective properties.603−605 The best multifunctional compound, TAC-MC-3 (Figure 19), could inhibit AChE activity (IC50 = 89 nM versus 275 nM for tacrine) and attenuate okadaic acid-induced tau hyperphosphorylation in living cells (40% inhibition at 10 μM versus 56% for MB at the same concentration).602 In addition, TAC-MC-3 could interact with Aβ40 fibrils (Kd = 5.5 × 10−8 M) as determined by SPR.602 Metal binding was not examined, although literature precedence of molecules with similar linkers suggests that it may occur. Another popular route for the rational development of small molecules targeting ChE and metal ions is to associate ChEinhibiting elements, such as tacrine (Figure 19), with metal chelating molecules. One well-known example of metal chelators, particularly in AD research, is clioquinol (Figure 19),606,607 which has been tested as a potential treatment for AD in clinical trials.269 Fernández-Bachiller et al. adopted the linkage approach in their design of tacrine-clioquinol derivatives.608 Their prime candidate, TAC-MC-4 (Figure 19), was a stronger ChEI than tacrine (IC50 = 5.5 and 20 nM for TAC-MC-4 against hAChE and hBuChE, respectively, versus 350 and 40 nM for tacrine). TAC-MC-4 could also displace 22% propidium from the PAS site, suggesting that it could inhibit AChE-induced Aβ aggregation, although this was not experimentally tested. 608 Likewise, although metal chelation with Cu(II) and Fe(III) was evaluated,608 they did not determine the influence of TAC-MC-4 on metal-triggered Aβ aggregation. Additionally, TAC-MC-4 displayed its antioxidant activity, was potentially CNS penetrant, and AF

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Figure 20. Multifunctional compounds constructed via the linkage and incorporation of tacrine with multiring natural products [i.e., chrysin (an example of flavonoids)] or their derivatives. Tacrine (chemical name shown in Figure 19); chrysin, 5,7-dihydroxy-2-phenyl-4H-chromen-4-one; silibinin, (2R,3R)-2-[(2R,3R)-2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-1,4-benzodioxin-6-yl]-2,3-dihydro-3,5,7-trihydroxy4H-1-benzopyran-4-one; coumarin, 2H-chromen-2-one; rhein, 4,5-dihydroxy-9,10-dioxoanthracene-2-carboxylic acid; TAC-MC-11, 5-hydroxy-2phenyl-7-(3-(4-(3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)propoxy)-4H-chromen-4-one); TAC-MC-12, 5-hydroxy-7-methoxy-4-oxo-N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4H-chromene-2-carboxamide; TAC-MC-13, (3-(4-hydroxy-3-methoxyphenyl)6-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)-2,3-dihydrobenzo[β][1,4]dioxin-2-yl)methyl-4-oxo-4-((6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)amino)butanoate; TAC-MC-14, 2-(4-(2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)ethyl)piperazin-1-yl)-N-(1,2,3,4-tetrahydroacridin-9-yl)acetamide; TAC-MC-15, N1-[2-(1,2,3,4-tetrahydroacridin-9-ylamino)butyl]-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide; TAC-MC-16, 2oxo-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino) hexyl)-2H-chromene-3-carboxamide; TAC-MC-17, 2-[2-(6-chloro-1,2,3,4-tetrahydroacridin-9yl-amino)ethyl]-aminojuglone; TAC-MC-18, 4,5-dihydroxy-9,10-dioxo-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)-hexyl)-9,10-dihydroanthracene-2-carboxamide.

structure of flavonoids.616 Although metal binding was not tested for any of the derivatives, one candidate likely to bind metal ions was TAC-MC-12 (Figure 20)565 that additionally possessed useful alternative properties that included ChE inhibition (IC50 = 1.0 nM for both hAChE and hBuChE) and attenuation of BACE1 activity (83% inhibition at 10 μM, IC50 = 2.9 μM, and Ki = 0.85 μM).616 Chen et al. adopted the strategy of attenuating tacrine’s hepatotoxicity by linking it to the natural product, silibinin, a molecule with known hepatoprotective,617 antioxidant,618 and neuroprotective effects (Figure 20).619,620 Although anticipated to possess metal chelating properties akin to EGCG (Figure 16),59 myricetin (Figure 16),60 and natural polyphenols,559 this feature was not observed for silibinin and the silibinin-tacrine conjugate, TAC-MC-13 (Figure 20).620 The influence of TAC-MC-13 on Aβ aggregation was similarly not addressed, although a thorough investigation of ChE inhibition and liver toxicity was undertaken. TAC-MC-13 inhibited EeAChE and eqBuChE (IC50 = 54 and 50 nM, respectively), though not as potently as tacrine (IC50 = 16 and 3.2 nM against EeAChE and eqBuChE, respectively).620 TAC-MC-13, however, was less toxic to HT22 cells, hepatic stellate cells, and rats (based on histological analyses of the liver tissue of TACMC-13-treated rats). It boosted the ratio of reduced glutathione to oxidized glutathione and decreased lipid

μM, respectively). TAC-MC-10 was predicted to be potentially BBB permeable according to PAMPA-BBB and shown to be less toxic than tacrine in primary human hepatocyte cells.614 TAC-MC-10 also demonstrated its antioxidant activity [1.8 Trolox equivalents in an ORAC assay]; despite the presence of metal chelating atoms designed into TAC-MC-10, no noticeable optical changes were noted upon addition of Cu(II) or Fe(II). To determine the cause of this, metal binding to fragments of TAC-MC-10 was investigated, revealing the possible role of electronic and steric effects in disfavoring complex formation.614 A number of naturally occurring metal chelators have also been joined to tacrine to devise multifunctional molecules targeting ChE, Aβ, and metal ions. Flavonoids have a documented history of metal binding capability and interaction with metal−Aβ.63,562 A series of tacrine-flavonoid derivatives were reported by Li et al. and were found to embody these useful features.615 Their lead candidate, TAC-MC-11 (Figure 20), exhibited the IC50 values of 133 and 558 nM against EeAChE and eqBuChE, respectively, and prevented the aggregation of Aβ42 by 79% at 20 μM (IC50 = 6.5 μM). In addition, TAC-MC-11 bound to Cu(II) and Fe(II) in a 1:1 metal-to-ligand ratio,615 but its ability to modulate metalinduced Aβ aggregation was not tested. Fernández-Bachiller et al. created tacrine conjugates to the 4-oxo-4H-chromene AG

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Figure 21. Multifunctional compounds prepared by the linkage and/or incorporation of tacrine with natural products, their derivatives, and an imaging agent for Aβ fibrils. Tacrine and resveratrol (chemical names presented in Figures 19 and 15, respectively); p-I-stilbene (chemical name indicated in Figure 2); ferulic acid, 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid; caffeic acid, 3-(3,4-dihydroxyphenyl)-2-propenoic acid; melatonin, N-acetyl-5-methoxy-tryptamine; lipoic acid and curcumin (chemical names indicated in Figure 8); TAC-MC-19, (E)-4-piperidyl-2-(4diethylaminostyryl)quinoline; TAC-MC-20, (n = 2) (2E)-3-(4-hydroxy-3-methoxyphenyl)-N-[2-(1,2,3,4-tetrahydroacridin-9-ylamino)ethyl]acrylamide, (n = 3) (2E)-3-(4-hydroxy-3-methoxyphenyl)-N-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]acrylamide, (n = 4) (2E)-3-(4hydroxy-3-methoxyphenyl)-N-[4-(1,2,3,4-tetrahydroacridin-9-ylamino)butyl]acrylamide, (n = 5) (2E)-3-(4-hydroxy-3-methoxyphenyl)-N-[5(1,2,3,4-tetrahydroacridin-9-ylamino)pentyl]acrylamide, (n = 8) (2E)-3-(4-hydroxy-3-methoxyphenyl)-N-[8-(1,2,3,4-tetrahydroacridin-9ylamino)octyl]acrylamide; TAC-MC-21, (E)-2-methoxy-4-(3-((6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)amino)buta-1,3-dien-1-yl)phenol; TAC-MC-22, (E)-3-(hydroxy-3-methoxyphenyl)-N-(8((7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino)octyl)-N-(2-(naphthalen-2-ylamino)2oxoethyl)acrylamide; TAC-MC-23, (E)-3-(4-hydroxy-3-methoxyphenyl)-N-(7-((7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino)heptyl)-N-(2((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)acrylamide; TAC-MC-24, (2E)-3-(3,4-dihydroxyphenyl)-N-[3-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)-propyl]acrylamide; TAC-MC-25, (2E)-3-(3,4-dihydroxyphenyl)-N-{3-[(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino]-2hydroxypropyl}prop-2-enamide; TAC-MC-26, (E)-3-(4-((3,4-dimethylbenzyl)oxy)-3-methoxyphenyl)-N-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)acrylamide; TAC-MC-27, methyl(E)-3-(3-methoxy-4-((5-(4-(2-oxo-2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)piperazin-1-yl)pentyl)oxy)phenyl)acrylate; TAC-MC-28, 2-(4-hydroxy-3-methoxybenzyl)-3-oxo-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)butanamide.

eqBuChE (IC50 = 0.23 μM), and Aβ42 aggregation (68% at 20 μM of the compound). The compound bound to Cu(II) and Fe(II) in a 1:2 metal-to-ligand ratio,621 but its ability to influence metal-triggered Aβ aggregation was not investigated. Hamulakova et al. also explored coumarin-tacrine hybrids joined by a variety of linkers (Figure 20).622 Despite their potential metal binding, an interrogation of the best candidate’s (TAC-MC-15; Figure 20; IC50 = 0.015 and 0.33 μM for hAChE and hBuChE, respectively) metal binding properties was not performed until a later study employed EPR to propose metal binding to the linker region to similar

peroxidation level in rat liver.620 When administered to rats with scopolamine-induced memory deficits, TAC-MC-13, similar to tacrine, decreased the number of errors made in a radial arm maze test. The coumarin fused-ring core structure (Figure 20) is another naturally derived framework to be conjugated to tacrine for construction of multifunctional molecules. Xie et al. linked coumarin to tacrine via a piperazine linker to invent a series of compounds that were tested for controlling ChE activity and Aβ aggregation.621 The primary candidate, TACMC-14 (Figure 20), inhibited EeAChE (IC50 = 0.092 μM), AH

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disaggregation of preformed Aβ42 fibrils was found to be comparable to resveratrol.631 Ferulic acid and the related caffeic acid can bind metal ions632 and have also served as metal chelating portions to be linked to tacrine for the design of multifunctional molecules (Figure 21). An earlier report by Fang et al. presented that the conjugation of ferulic acid to tacrine (TAC-MC-20; Figure 21) did not abrogate AChE and BuChE inhibiting properties of the tacrine moiety [IC50 (for AChE) = 3.2−70 nM for tacrine-linker molecules and 4.4−38.6 nM for tacrine-linkerferulic acid conjugates; IC50 (for BuChE) = 1.4−12 nM for tacrine-linker molecules and 5.9−34 nM for tacrine-linkerferulic acid conjugates].633 Moreover, antioxidant properties were introduced with most tacrine-ferulic hybrids demonstrating Trolox equivalents greater than 1 (vs 0.2 for tacrine), but which was diminished compared to ferulic acid (3.4 Trolox equivalents). Unfortunately, metal chelation was not monitored despite the presence of potential metal binding sites in the linker or within the ferulic acid moiety, nor was anti-Aβ aggregation studied. Other tacrine-ferulic acid conjugates have since been reported.634−636 Pi et al. examined a conjugate belonging to the same family reported earlier by Fang et al. but with a linker length of 6, which had not been previously reported.633,636 The 6-carbon-linked tacrine-ferulic acid, TAC-MC-21 (Figure 21), inhibited self- and AChE-induced Aβ40 aggregation and attenuated cell death and ROS in PC12 cells.636 Moreover, it could ameliorate cognitive defects in a MWM test in an AD mouse model with intracerebroventricular Aβ40 injection. As with the earlier report,633 metal binding was not investigated. Benchekroun et al. reported on a different series of tacrineferulic acid conjugates, which additionally included a substituted glycine substructure in the main α-acylaminocarboxamide backbone.634 Their most interesting compound, TAC-MC-22 (Figure 21), displayed moderate hBuChE inhibition (IC50 = 68 nM), anti-Aβ42 aggregation (66% at 1:1 ratio), and antioxidant activity (4.3 Trolox equivalents by an ORAC assay). As with prior candidates,633,636 its metal binding was not examined. In follow-up work, Benchekroun et al. conjugated a trio of molecules tacrine, melatonin, and either lipoic acid or ferulic acid to one another (Figure 21).637 Melatonin (Figure 21) was included due to its antioxidant capacity638 and protective effect against Aβ.639 Similarly, lipoic acid and ferulic acid (Figure 21) are natural antioxidants,640,641 and lipoic acid defends neurons against Aβ-induced cytotoxicity.640 The leading molecule, TAC-MC-23 (Figure 21), was of moderate potency (IC50 = 1290 and 234 nM for hAChE and hBuChE, respectively) compared to tacrine (IC50 = 420 and 25 nM for hAChE and hBuChE, respectively for tacrine).637 As anticipated of a molecule compromising two antioxidant moieties, TAC-MC-23 exhibited a capacity of 9.1 Trolox equivalents in an ORAC assay.637 PAMPA-BBB predicted potential BBB penetration for TAC-MC-23, as for tacrine, but was much less toxic to hepatocellular carcinoma HepG2 cells (85 vs 64% viability at 100 μM of TAC-MC-23 and tacrine, respectively). The impact of TAC-MC-23 on Aβ aggregation was not investigated, but it could provide neuroprotection to Aβ40-, Aβ42-, and H2O2-triggered death in SH-SY5Y neuroblastoma cells. Even with the presence of ferulic acid, which could potentially bind metal albeit weakly,642,643 this aspect was not investigated.

compounds.622,623 Sun et al. prepared coumarin-tacrine adducts, which were linked via the 3-position on coumarin624 versus the 4-position.622,623 The most potent 3-linked coumarin derivative, TAC-MC-16 (Figure 20), bound to hAChE and hBuChE with the Ki values of 17 and 16 nM, respectively, compared to tacrine, which fared with the Ki values of 36 and 8.7 nM, respectively.624 TAC-MC-16 additionally inhibited BACE1 (IC50 = 17 μM) but was ineffective against Aβ42 aggregation.624 Naphthoquinone (Figure 20) is another fused-ring system that occurs in a wide range of natural products and 1,4naphthoquinone derivatives have demonstrated inhibition toward Aβ aggregation.625 Nepovimova et al. invented a library of tacrine and 1,4-naphthoquinone linked hybrids and identified TAC-MC-17 (Figure 20) as a potent and selective AChEI (IC50 = 0.72 and 542 nM for hAChE and hBuChE, respectively) with moderate anti-Aβ42 self-aggregation (38% at 10 μM of the compound).626 TAC-MC-17 suppressed ROS production in tert-butyl hydroperoxide/sulforaphane-treated glioma T67 cells and protected differentiated N2a neuroblastoma cells from Aβ42-induced toxicity (20 μM) at a concentration of 13 μM. Possible hepatotoxicity for TAC-MC17 was indicated by diminished viability of TAC-MC-17treated human hepatoma cells (HepG2), and BBB permeability was implied by efficacy of TAC-MC-17 for AChE inhibition in intraperitoneally injected mice.626 Unfortunately, despite potential metal binding sites on the core of 1,4naphthoquinone, its metal chelating properties was not studied. Another naturally occurring multiring structure to be employed in the rational design of multifunctional molecules targeting AChE and metal ions is rhein (Figure 20).627,628 Rhein had previously been shown to decrease Aβ load in senescence-accelerated mice and lower inflammation.629 The best candidate of the tacrine-rhein series, TAC-MC-18 (Figure 20), inhibited EeAChE by ca. 5-fold more than tacrine (IC50 = 27 and 135 nM, respectively) but was around four times less active against eqBuChE (IC50 = 200 and 45 nM, respectively).627 TAC-MC-18 could affect AChE-induced Aβ40 aggregation by 68% and bound Cu(II) in a 1:1 metal-to-ligand ratio. Administration of TAC-MC-18 to mice led to lower serum levels of aspartate aminotransferase and alanine aminotransferase, both biomarkers of liver damage, compared to an equimolar dose of tacrine, indicating lower hepatotoxicity. Resveratrol (Figure 21) has been explored in AD research for its potential beneficial antioxidant and antiamyloid aggregation properties.542,630 As such, it formed the inspiration for a sequence of tacrine-linked multifunctional molecules based on the stilbene scaffold of resveratrol and p-I-stilbene, Aβ aggregate binding compound500 employed for probing amyloids (Figure 21).631 The prime candidate, TAC-MC-19 (Figure 21), exhibited relatively ineffective IC50 values of 64 and 0.2 μM against EeAChE and BuChE, respectively.631 The compound, however, displayed other advantageous properties, including robust inhibitory action against the aggregation of Aβ42 (84% at 20 μM vs 77% for resveratrol; IC50 = 9.7 μM vs 11 μM for resveratrol) and strong antioxidant capacity in vitro (3.9 fold versus Trolox in an ORAC assay) and in SH-SY5Y neuroblastoma cells. The metal binding abilities of TAC-MC19 were spectroscopically examined where changes in absorbance were noted upon treatment with Cu(II) and Fe(II). The influence of TAC-MC-19 on Aβ42 fibrillization and AI

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Figure 22. Conjugation of tacrine with natural products, their derivatives, or antioxidants for the design of multifunctional molecules. Tacrine (chemical name indicated in Figure 19); β-carboline, pyrido[3,4-b]indole; Huperzine A, (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6azatricyclo[7.3.1.02,7]trideca-2(7),3,10-trien-5-one (2-pyridone core, highlighted in green); HBP, 5-(2-hydroxybenzoyl)pyridin-2(1H)-one (2pyridone core, highlighted in green); SAC (S-allyl cysteine), (R)-2-amino-3-prop-2-enylsulfanylpropanoic acid; SPRC (S-propargyl cysteine), 3(2-propynylthio)-alanine; TAC-MC-29, (S)-N-(6-((1,2,3,4-tetrahydroacridin-9-yl)amino)hexyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide; TAC-MC-30, 5-(2-hydroxy-5-methoxybenzoyl)-1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)pyridin-2(1H)-one; TAC-MC-31, (R)-3-(allylthio)-2-amino-N-(2-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)-ethyl)propanamide; TAC-MC-32, (R)-2-amino-N-(2-(6-chloro1,2,3,4-tetrahydroacridin-9-ylamino)ethyl)-3-(prop-2-ynylthio)propanamide.

Caffeic acid (Figure 21) containing the catechol group that binds metal ions632 has also been linked to tacrine in the preparation of multifunctional molecules targeting ChE and metal ions. Chao et al. presented that their best candidate, TAC-MC-24 (Figure 21), inhibited EeAChE and eqBuChE (0.3 and 29.5 μM, respectively), self- and AChE-induced Aβ42 aggregation (36 and 68% at 100 μM, respectively), radical scavenging properties (IC50 = 4.8 μM to scavenge DPPH radicals), and neuroprotective effects against H2O2- and glutamate-mediated death in mouse hippocampal HT22 cells.644 Digiacomo et al. examined both ferulic acid and caffeic acid conjugates with tacrine,645 additionally incorporating a moiety of amino-2-propanol previously known to inhibit BACE1.646 Among this category of compounds, the most promising one, TAC-MC-25 (Figure 21), was indicated to have inhibitory activity against AChE and BuChE (IC50 = 0.15 and 0.36 μM, respectively), Aβ42 aggregation (9.2 and 53% at 5 and 50 μM of TAC-MC-25, respectively), and could quench DPPH radicals.645 Despite incorporation of the 1,3diamino-2-propanol motif, none of the compounds possessed significant inhibitory action toward BACE1. Both TAC-MC-24 and TAC-MC-25 could bind metal ions, presumably through their catechol group; however, their influence on metal-trigged Aβ aggregation was not tested. Among a series of tacrine-ferulic acid hybrids, reported by Zhu et al., TAC-MC-26 (Figure 21) showed promising inhibitory activitives against AChE (IC50 = 37 nM against EeAChE), BuChE (IC50 = 101 nM against eqBuChE), and Aβ 42 aggregation (65% inhibition at 25 μM of the compound).647 TAC-MC-26 administration to scopolamineinduced AD mice resulted in the attenuation of cognitive impairment and presented preliminary safety in hepatotoxicity evaluation.647 Fu et al. examined potential metal binding to tacrine-ferulic acid hybrids; however, the binding was most likely to the piperazine linker and not to the phenol/methoxy groups of ferulic acid since the hydroxyl moiety was used to join the ferulic acid aromatic group to tacrine via the linker.635

Their best contender, TAC-MC-27 (Figure 21), inhibited the activities of AChE and BuChE (IC50 = 62 and 107 nM, respectively) and Aβ42 aggregation (37% at 20 μM).635 Curcumin (Figure 21) is a widely studied molecule for AD treatment648 and is known for its antiamyloid properties against the formation of Aβ aggregates and disaggregation of preformed fibrils, as well as its antioxidant and metal chelating capabilities.567,649 Already endowed with multiple features, it thus makes a good candidate for further derivatization. In this vein, Liu et al. reported on a series of tacrine-curcumin derivatives which incorporated half of the curcumin scaffold.650 The lead molecule, TAC-MC-28 (Figure 21), displayed inhibitory action against TcAChE and Torpedo californica BuChE (TcBuChE) (IC50 = 0.08 and 0.22 μM, respectively) with antioxidant capacity comparable to curcumin (Trolox equivalents of 2.4 and 3.1, respectively). The anti-Aβ aggregation activities in the absence and presence of metal ions were not reported.650 Lan et al. prepared a family of tacrine-β-carboline derivatives as multifunctional agents.651 The β-carboline core (Figure 22) appears in numerous bioactive molecules and has been investigated as an inhibitor of tau phosphorylation in AD as well as an AChEI.652 The most promising tacrine-βcarboline candidate, TAC-MC-29 (Figure 22), could inhibit ChE (IC50 = 22, 63, and 40 nM for EeAChE, hAChE, and BuChE, respectively), self-induced Aβ42 aggregation (66% at 20 μM), and displayed antioxidant activity (1.6 Trolox equivalents in an ABTS assay).651 TAC-MC-29 bound Cu(II) and consequently could control Cu(II)-triggered Aβ 42 aggregation by 64% of the sample containing Cu(II)−Aβ42. Additionally, TAC-MC-29 protected PC12 cells from H2O2induced death showing viability of 74% at 10 μM vs the compound-untreated control and was predicted to be potentially BBB permeable by PAMPA-BBB. Chand et al. linked tacrine to a 2-pyridone core,653 an important pharmacological building block, in huperzine A, a BBB-permeable AChEI and NMDAR antagonist (Figure AJ

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Figure 23. Multifunctional molecules generated via the linkage and incorporation approaches based on donepezil (AChEI), rivastigmine (ChEI), rasagiline (MAOI), and clioquinol (a metal chelator). Donepezil and rivastigmine (chemical names shown in Table 1); rasagiline (chemical name indicated in Figure 9); clioquinol (chemical name presented in Figure 2); DON-MC-1-Prochelator, 5-(4-propargylpiperazin-1-ylmethyl)quinolin-8-yl-dimethylcarbamate; DON-MC-1, 5-(4-propargylpiperazin-1-ylmethyl)-8-hydroxyquinol; DON-MC-2-Prochelator, 5-(Nmethyl-N-propargylaminomethyl)quinolin-8-yl-dimethylcarbamate; DON-MC-2 (M30 and 8-HQ-MC-3), 5-(N-methyl-N-propargylaminomethyl)-8-hydroxylquinoline; DON-MC-3, 4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-ynyl)amino)butanenitrile; DONMC-4, 4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-2-yl)methyl)(prop-2-yn-1-yl)amino)butanenitrile; DON-MC-5, 7-(((1-benzylpiperidin4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline; DON-MC-6, 7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline.

22).654,655 Specifically, they selected 2-hydroxybenzoyl-2pyridone (HBP; Figure 22), a known antioxidant, to develop tacrine-linked HBP derivatives.653 The most effective molecule, TAC-MC-30 (Figure 22) inhibited EeAChE [IC50 = 0.71 μM, which is less efficaciously by 2-fold than either tacrine or (±)-huperzine A (IC50 = 0.31 and 0.30 μM, respectively)].653 TAC-MC-30 could scavenge DPPH radicals with the EC50 value of 213 μM. Thorough metal binding and speciation studies for TAC-MC-30 were carried out using a fragment of the whole molecule. Additionally, Cu(II)-binding to TAC-MC-30 was verified by UV−Vis and MS in a 1:2 metal-to-ligand ratio.653 Quintanova et al. utilized sulfur-containing amino acids, the naturally occurring S-allyl cysteine (SAC) from garlic and a structural analog S-propargyl cysteine (SPRC), to conjugate to tacrine.656 Both SAC and SPRC (Figure 22) may possess useful properties for AD treatment, including antioxidant and neuroprotective activities.657−660 An earlier study focused mainly on speciation of metal-free and Cu(II)- and Zn(II)bound tacrine-SAC and tacrine-SPRC molecules with twocarbon linkers. The authors employed potentiometry, MS, and NMR to verify moderate metal binding ability with predominant 1:1 complex formation.656 Variation of the linker length caused variability in their ability to affect Cu(II)triggered Aβ42 aggregation, with the lead SAC candidate, TACMC-31 (Figure 22), and lead SPRC conjugate, TAC-MC-32 (Figure 22), displaying 50 and 49% inhibition, respectively, at 80 μM of the compounds. Keri et al. reported the AChEinhibiting ability of TAC-MC-31 and TAC-MC-32 with the IC50 values of 0.30 and 0.56 μM against TcAChE and

presented their antioxidant activity in a DPPH scavenging assay (EC50 = 56 μM for both compounds).660 Donepezil (Table 1) is an AChE-selective inhibitor approved by the FDA.661 The selectivity profile of donepezil, however, is different from tacrine that targets both AChE and BuChE.662 A couple of activatable multifunctional molecules targeting ChEs and metal ions were reported by Zheng et al. in multiple papers.485,486,663 The design was based on the utilization of pharmacophore fragments from donepezil and rivastigmine for ChE inhibition, coupled with clioquinol for metal chelation, and a propargyl group for MAO inhibition (Figure 23). The metal binding hydroxyl group of clioquinol was masked with a carbamyl group, which would be released upon binding to AChE, simultaneously inhibiting AChE and exposing, and thereby activating the metal chelation of clioquinol (Figure 23). The first candidate, DON-MC-1Prochelator (named HLA20A by the authors; Figure 23) possessed the IC50 values of 0.50 and 43 μM for rat AChE (rAChE) and rat BuChE (rBuChE), respectively.486 Metal chelation was not observed for DON-MC-1-Prochelator, as evidenced by the absence of spectroscopic changes upon addition of Cu(II), Zn(II), Fe(II), or Fe(III), presumably due to the masked hydroxyl group. Cleavage of the carbamyl group by AChE followed by Cu(II) or Fe(II) led to the appearance of new spectroscopic features, presumably from the formation of metal complexes. Later work further presented metal binding of activated DON-MC-1 to Zn(II).663 Activated DON-MC-1 could also inhibit Fe(II)-mediated lipid peroxidation with an IC50 of 14 μM, which was ascribed to its Fe(II)-chelating ability since inactivated DON-MC-1-ProcheAK

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Figure 24. Linkage, fusion, and incorporation of donepezil with metal binding atoms or fragments. Donepezil (chemical name presented in Table 1); lazabemide, N-(2-aminoethyl)-5-chloro-2-pyridinecarboxamide; Ro16−6491, N-(2-aminoethyl)-4-chloro-benzamide; moclobemide, 4-chloroN-(2-morpholin-4-ylethyl)benzamide; DON-MC-7, N-(2-(1-benzylpiperidin-4-yl)ethyl)-5-chloropicolinamide; DON-MC-8, 5,6-dimethoxy-2-((1((3-methylpyridin-2-yl)methyl)piperidin-4-yl)methyl)-2,3-dihydro-1H-inden-1-one; DON-MC-9, 6-[2-[1-(2-pyridylmethyl)-4-piperidyl]ethyl]spiro[[1,3]dioxolo[4,5-f ]isoindole-7,1′-cyclopropane]-5-onephosphate; DON-MC-10, (Z)-5-methoxy-6-(2-(piperidin-1-yl)propoxy)-2-(pyridin4-ylmethylene)-2,3-dihydro-1H-inden-1-one; DON-MC-11, 5,6-dihydroxy-2-(4-(methyl(propyl)amino)benzylidene)-2,3-dihydro-1H-inden-1one; DON-MC-12, N-(2-fluorophenyl)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxamide; DON-MC-13, N-(4-fluorophenyl)-5,6dimethoxy-1H-indene-2-carboxamide.

MC-3 was able to interact with Cu(II), Zn(II), and Fe(III), as indicated by optical spectral variations, and formed 1:2 metalto-ligand complexes. Moreover, a thorough ADMET (absorption, distribution, metabolism, excretion, and toxicity) study indicated the potential CNS penetration for DON-MC-3 and presented its lower toxicity to HepG2 liver carcinoma cells compared to donepezil.664 In a follow-up study, the linkage position between clioquinol and the donepezil fragment was altered, along with variation of the linker length, in order to prepare new molecules.664,665 The most promising multifunctional molecule, DON-MC-4 (Figure 23), inhibited hAChE, hBuChE, and hMAO-A with the IC50 values of 0.029, 0.039, and 10 μM, respectively, but did not prevent the activity of MAO-B for which IC50 was determined to be >100 μM.665 Like its predecessor,664 DON-MC-4 was bound to Cu(II) or Zn(II) in a 1:2 metal-to-ligand ratio.664,665 It was additionally found to have antioxidant abilities showing prevention of Cu(II)induced H2O2 production, with its ability to quench DPPH radicals and indicated an ADMET profile similar to that of DON-MC-3 showing predicted BBB permeability.664,665 Prati et al. reported another series of donepezil-clioquinol derivatives for devising multifunctional molecules able to inhibit AChE and chelate metal ions.44 Their ChE inhibiting properties were not very active, but their selectivity was reversed compared to the parent AChE-selective donepezil inhibitor. DON-MC-5 (Figure 23) showed 56 and 64%

lator was ineffective in this assay. Both DON-MC-1Prochelator and its activated form have biologically applicable properties, including potential BBB permeability.663 Despite the presence of a propargyl group, neither DONMC-1-Prochelator nor its activated form was effective MAOIs (only ca. 9 and 5% inhibition for MAO-A and MAO-B, respectively, at 10 μM of the compound).663 Thus, a new prochelator agent, DON-MC-2-Prochelator, was devised to bring the propargyl group from rasagiline (Figure 9)485 and was an activatable carbamyl protected derivative of the previously reported DON-MC-2 (Figure 23).483 This new entity, DON-MC-2-Prochelator, better inhibited MAO compared to DON-MC-2 (IC50 = 7.7 nM and 7.9 μM for DON-MC-2-Prochelator against rMAO-A and rMAO-B, respectively) while simultaneously retaining activity against ChEs (IC50 = 0.52 and 45 μM for rAChE and rBuChE, respectively).485 Like DON-MC-1-Prochelator, DON-MC-2Prochelator did not chelate metal ions until activated by exposure to AChE.485 In another study, the essential features (i.e., clioquinol and propargyl moiety) of DON-MC-2 (Figure 23) were combined with those from donepezil (Figure 23) to construct a series of hybrids that varied in linker length.664 The top performer, DON-MC-3 (Figure 23), showed the IC50 values of 1.8, 1.6, 6.2, and 10 μM for EeAChE, eqBuChE, rMAO-A, and rMAOB, respectively, and indicated a mixed-type AChE inhibition profile with irreversible MAO-A/MAO-B inhibition. DONAL

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metal binding sites directly into the donepezil backbone.671 While DON-MC-9 (IC50 = 793 nM and 31 μM for AChE and BuChE, respectively; SI = 40) was not as potent or selective as donepezil (IC50 = 93 nM and 6.7 μM for AChE and BuChE, respectively; SI = 73), it possessed other useful properties. The optical features of DON-MC-9 intensified upon addition of Cu(II) and Fe(III), and it prevented Aβ aggregation in a test of Cu(II)-induced Aβ42 aggregation or disaggregation of preformed Aβ42 fibrils, as measured by a fluorescence-based assay. DON-MC-9 was not a regular ionophore and, in contrast to PBT2 (Figure 5, vide supra),479,480 did not increase intracellular Zn and Fe contents in SH-SY5Y neuroblastoma cells, and only marginally affected Cu content. DON-MC-9 improved memory deficits in Aβ25−35 intracerebroventricularally injected mice, as assessed by spatial learning in a MWM test, and decreased neuroinflammation in the hippocampus, as gauged by levels of TNFα and interleukin-1β (IL-1β).671 Some research groups that have focused on the indanone portion of donepezil have also presented multifunctional molecules for ChE inhibition and metal binding.672−675 Meng et al. employed the indanone portion of donepezil and substituted the methoxy with various amine functional groups.672 They reported DON-MC-10 (Figure 24) displaying particularly interesting properties, with the IC50 values of 1.8 nM and 9.5 μM for EeAChE and eqBuChE, respectively, corresponding to a SI of 5249, far exceeding donepezil under their experimental setup (IC50 = 26 nM and 4.7 μM for EeAChE and eqBuChE, respectively; SI = 180).672 The authors reported metal binding based on shifts in UV−Vis spectral peaks. Huang et al. also highlighted the indanone moiety of donepezil which they functionalized with diversely substituted aryl and arylamines (Figure 24).673 Despite the inclusion of the indanone from donepezil and the possibility for action against AChE, this property was not tested. The most promising candidate to show alternative properties, DON-MC-11 (Figure 24), was assessed for inhibition of MAOs (IC50 = 38 and 7.5 μM for MAO-A and MAO-B, respectively; SI = 5.0) and attenuation of metal-free and Cu(II)-induced Aβ42 aggregation. Additionally, it could disassemble preformed Cu(II)-treated Aβ42 fibrils. Moreover, DON-MC-11 possessed significantly noticeable antioxidant activity (5.6 Trolox equivalents) and behaved as a metal binder toward Cu(II).673 Yerdelen et al. similarly emphasized the indanone part of donepezil in their design strategy, combining it with various ortho-, meta-, and para-substituted secondary aromatic amides.674 Their most promising agent, DON-MC12 (Figure 24), inhibited AChE preferentially over BuChE (IC50 = 80 nM and 3.2 μM, respectively) and self-induced Aβ42 aggregation (55% at 25 μM of the compound). In addition, DON-MC-12 could scavenge DPPH radicals but not as effectively as Trolox (IC50 = 76 and 21 μM, respectively). A bathochromic shift in DON-MC-12’s spectrum was observed upon incubation with Zn(II).674 Koca et al. also conducted their design based on the indanone from donepezil, and they fused it to carboxamides (Figure 24).675 One candidate that arose, DON-MC-13 (Figure 24), only demonstrated modest inhibition of EeAChE and eqBuChE (IC50 = 2.3 and 1.1 μM, respectively) compared to donepezil (IC50 = 0.042 and 0.54 μM, respectively). DONMC-13 fared better at attenuation of self-induced Aβ42 aggregation (50% inhibition at 25 μM of the compound) versus curcumin (42% inhibition at the same concentration; structure shown in Figure 18).675 In UV−Vis studies, a

inhibition of hAChE and hBuChE, respectively, at a concentration of 40 μM, while another candidate, DONMC-6 (Figure 23), did not affect the activity of hAChE and inhibited hBuChE by 89% at the same concentration. Their reported IC50 values for hBuChE were 23 and 5.7 μM for DON-MC-5 and DON-MC-6, respectively, and they were presented to affect the self-aggregation of Aβ42 by 65 and 44%, respectively at equimolar concentrations (50 μM). DON-MC5 and DON-MC-6 bound Cu(II) and Zn(II) by UV−Vis, but their ability to regulate metal-triggered Aβ aggregation was not gauged. Furthermore, DON-MC-5 was endowed with stronger antioxidant capability compared to Trolox, while DON-MC-6 was less toxic to T67 glioma and primary human umbilical vein endothelial cells.44 Donepezil hybrids with metal binding moieties other than clioquinol have also been reported. To invent a family of differently substituted dual AChE and MAO inhibiting molecules, Li et al. combined the common structural elements from lazabemide and its analog (i.e., Ro16−6491)-known reversible, potent, and selective MAO-B inhibitors,666,667 and moclobemide, a reversible, short-acting preferential MAO-A inhibitor,668 with a donepezil fragment via linkers of different lengths (Figure 24).669 The metal chelating moiety arose from the structural features from the MAO-inhibiting molecules. The prime agent, embodying the most equitable distribution of multifunctional properties, was DON-MC-7 (Figure 24), which possessed the activity against both AChE and MAO. Its IC50 values were 0.22, 1.2, 13, and 3.1 μM against EeAChE, eqBuChE, hMAO-A, and hMAO-B, respectively, suggesting a compromised selectivity for AChE compared to donepezil (SI = 5.6 and 66 for DON-MC-7 and donepezil, respectively).669 Small perturbations in UV−Vis features were observed upon addition of Cu(II) to DON-MC-7, but an in-depth analysis or elucidation of metal-to-ligand ratio was not performed. PAMPA-BBB predicted the potential availability of DONMC-7 in the CNS, while cell viability in rat adrenal PC12 cells indicated relatively low toxicity.669 Wang et al. designed and prepared a new class of donepezil derivatives with metal binding properties via (i) the incorporation approach by installing an N donor atom into the donepezil aryl group and (ii) the linkage approach by conjugation to clioquinol.670 The foremost candidate with the best balance of multifunctional properties was DON-MC-8 (Figure 24) that exhibited noticeable inhibition against AChE (IC50 = 85 and 73 nM for EeAChE and hAChE, respectively), which was ca. 2-fold less potent than donepezil (IC50 = 51 and 48 nM for EeAChE and hAChE, respectively).670 DON-MC-8 (IC50 = 21 and 66 μM for eqBuChE and hBuChE, respectively) was less active against BuChE than donepezil (IC50 = 2.5 and 3.2 μM for EeBuChE and hBuChE, respectively).670 UV−Vis studies demonstrated that DONMC-8 bound Cu(II), Zn(II), and Fe(III), forming 1:1 metalto-ligand complexes.670 The inhibitory impact of DON-MC-8 on Cu(II)-triggered and metal-free Aβ42 aggregation and AChE-induced Aβ40 aggregation was investigated, which were limited to 46, 19, and 72%, respectively, at 20 μM of the compound. It displayed moderate antioxidant capacity (0.92 Trolox equivalents in an ORAC assay), could control H2O2 formation in a Cu(II)/ascorbate-mediated H2O2-generating reaction, and was predicted to be potentially available in the CNS by PAMPA-BBB.670 Very recently, Li et al. reported the properties of DON-MC9 (named AD-35 by the authors; Figure 24) built by installing AM

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Figure 25. Linkage and incorporation of donepezil fragments with natural products, genistein and scuterllarein. Donepezil and genistein (chemical names shown in Table 1 and Figure 17, respectively); thioxanthone, 9H-thioxanthen-9-one; memoquin, 2,5-bis(6-(ethyl-(2methoxybenzyl)-amino)-hexylamino)-[1,4]benzoquinone; scutellarein, 5,6,7-trihydroxy-2-(4-hydroxyphenyl)chromen-4-one; DON-MC-14, 7-(4(ethyl(2-methoxybenzyl)amino)butoxy)-3-(4-(4-(ethyl(2-methoxybenzyl)amino)butoxy)phenyl)-5-hydroxy-4H-chromen-4-one; DON-MC-15, 3((6-((2-(dimethylamino)benzyl)(ethyl)amino)hexyl)oxy)-1-hydroxy-9H-thioxanthen- 9-one; DON-MC-16, 5-hydroxy-40-(3-((ethyl)(2methoxybenzyl)amino)butoxy)-6,7-dimethoxyflavone; DON-MC-17, N-(4-(ethyl(2-methoxybenzyl)amino)butyl)-2-(4-(5-hydroxy-6,7-dimethoxy-4-oxo-4H-chromen-2-yl)phenoxy)acetamide.

observed in its spectrum upon addition of Zn(II) and Fe(II). Finally, it increased the latency time in a passive avoidance task in a mouse model of scopolamine-induced memory deficits.676 Luo et al. followed up the study of genistein by replacing it with thioxanthone, a bioisostere of xanthone, a widely occurring scaffold in natural products (Figure 25).682 Specifically, for metal binding, 1,3-dihydroxy-9H-thioxanthen9-one was the selected thioxanthone, where binding could be possible at the 1-hydroxyl and 9-one positions, which was conjugated to donepezil or memoquin-like fragments (Figure 25). Of all the resulting molecules, DON-MC-15 (Figure 25) displayed inhibitory action against EeAChE (IC50 = 0.59 μM) and rBuChE (only 29% at 50 μM), which was limited compared to donepezil (IC50 = 0.023 and 21 μM for EeAChE and rBuChE, respectively).682 DON-MC-15 also exhibited a balanced hMAO-A and hMAO-B profile (IC50 = 1.0 and 0.90 μM, respectively) versus rasagiline (IC50 = 2.6 μM and 10 nM for hMAO-A and hMAO-B, respectively; structure shown in Figure 9), which favored inhibition of MAO-B. DON-MC-15 efficiently blocked both self- and Cu(II)-promoted Aβ42 aggregation (75 and 88% at 25 μM of the compound, respectively), with metal-induced shifts in UV−Vis spectra. It exhibited potential BBB permeability in PAMPA-BBB and was relatively nontoxic to SH-SY5Y neuroblastoma cells (10 μM), but it was a less potent antioxidant than Trolox.

decrease in the peak intensity at ca. 340 nm was taken to indicate possible binding to Cu(II), Fe(II), and Zn(II). The ability of DON-MC-13 to regulate metal-triggered Aβ was not reported. As with the tacrine-natural product derivatives, similar studies have been taken up with donepezil. Qiang et al. conjugated natural products or their derivatives to donepezil to produce donepezil-genistein hybrids (Figure 25).676 The same research group later reported on donepezil-scutellarein hybrids (Figure 25).677 Genistein (Figure 25), the most abundant isoflavone in soybeans, has been investigated as antioxidants and neuroprotective agents in the context of AD.678−680 Genistein has the ability to interact with metal ions.681 The main candidate to emerge from the study, DONMC-14 (Figure 25), embodied a series of useful properties for a multifunctional molecule.676 Although not as effective as donepezil against hAChE, DON-MC-14 still maintained a relatively comparable potency (IC50 = 0.09, 0.14, and 0.35 μM for rAChE, EeAChE, and hAChE for DON-MC-14, respectively; IC50 = 0.015, 0.12, and 0.011 μM for rAChE, EeAChE, and hAChE for donepezil, respectively). Moreover, DON-MC-14 could significantly control self- and Cu(II)induced Aβ42 aggregation by 35 and 78%, respectively, at 25 μM of the compound.676 At a higher concentration of 100 μM, it inhibited hAChE-induced Aβ40 aggregation by 36%. DONMC-14 bound to Cu(II), but no significant effects were AN

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Figure 26. Linkage, fusion, and incorporation of donepezil fragments with natural products. Donepezil and rivastigmine (chemical names indicated in Table 1); homoisoflavonoid, 3-benzylidene-4-chromanones; paeonol, 2-hydroxy-4-methoxyacetophenone; aurone, 2benzylidenebenzofuran-3(2H)-one; curcumin (chemical name indicated in Figure 8); DON-MC-18-Prochelator, 2-methoxy-4-(piperidin-1ylmethyl)phenyldimethylcarbamate; DON-MC-19, 4-(1-benzylpiperidin-4-yl)-1-(3-hydroxy-4-methoxyphenyl)butane-1,3-dione; DON-MC-20, 1(2-hydroxy-4-methoxyphenyl)-2-(4-(4-methylbenzyl)piperazin-1-yl)ethanone; DON-MC-21, (Z)-2-(3-hydroxy-4-(piperidin-1-ylmethyl)benzylidene)-5,6-dimethoxybenzofuran-3(2H)-one; DON-MC-22, (E)-3-(3-hydroxy-4-(piperidin-1-ylmethyl)benzylidene)-6,7-dimethoxychroman-4-one.

25) is a veteran of multitargeted molecules and is observed to affect Aβ processing and aggregation, the activity of AChE, and formation of ROS.685 The preeminent candidate from the family of molecules was DON-MC-17 (Figure 25) that exhibited high selectivity for AChE over BuChE (SI > 9804), far exceeding that of donepezil (SI = 1380) (IC50 = 0.051 and >500 μM for rAChE and rBuChE for DON-MC-17, respectively; IC50 = 0.015 and 21 μM for rAChE and rBuChE for donepezil, respectively).684 The influence of DON-MC-17 (25 μM; Figure 25) on Aβ42 under various conditions was examined. Inhibition was 57% for both self-induced and hAChE-triggered Aβ aggregation, by DON-MC-17, significantly better than for donepezil (<5.0 and 19%, respectively).684 Under metal-containing conditions, DON-MC-17 prevented Cu(II)-added Aβ42 aggregation and promoted disaggregation of Cu(II)-preformed Aβ42 aggregates by 43 and 66%, respectively, while donepezil scored less than 5.0% inhibition of Cu(II)-induced Aβ42 aggregation. DONMC-17 bound Cu(II), showing 1:1 metal-to-ligand stoichiometry, as demonstrated by UV−Vis; however, spectroscopic changes were minimal upon addition of Fe(II) or Zn(II). It had the antioxidant capacity of 1.1 Trolox equivalents in an ORAC assay, displayed no apparent toxicity by an MTT assay to SH-SY5Y neuroblastoma cells (10 μM of the compound), and indicated a protective effect against H2O2-mediated toxicity to PC12 cells (1 μM of the compound). Finally, the in vivo assessment of DON-MC-17 in scopolamine-impaired mice in a step-down passive avoidance task was similar to that of donepezil. Donepezil derivatives with other natural products and naturally occurring core structures have also been widely presented. Li et al. prepared the combined derivatives of donepezil with rivastigmine and curcumin (the 4-hydroxy-3methoxyphenyl portion) via the incorporation approach to

In a report by the same laboratory, Sang et al. synthesized donepezil-scutellarein conjugates.677 Scutellarein (Figure 25) is an aglycone derivative of scutellarin, the principle active component from the Chinese herb Erigeron breviscapus, which has pharmacological properties that have made it useful for AD research,683 and metal chelation observed from similar flavones.681 Scutellarein served as the inspiration for the design of multifunctional molecules for AChE inhibition, antiAβ aggregation, and metal chelation.677 The selected choice, DON-MC-16 (Figure 25), possessed the IC50 values of 0.62, 62, 0.85, and 0.25 μM for rAChE, rBuChE, EeAChE, and hAChE, respectively.677 DON-MC-16 fared less well against hAChE and rAChE than donepezil (IC50 = 0.015, 21, 0.11, and 0.012 μM for rAChE, rBuChE, EeAChE, and hAChE, respectively). DON-MC-16 inhibited self-induced Aβ 42 aggregation in a dose-dependent manner (44, 69, and 87% at 12.5, 25, and 50 μM of the compound) and Cu(II)-triggered Aβ42 aggregation (47, 65, and 86% at 12.5, 25, and 50 μM of the compound). Influence of DON-MC-16 on hAChEtriggered Aβ40 aggregation was less pronounced and only achieved 62% inhibition at 100 μM of the compound, while it was capable of disaggregating Cu(II)-mediated Aβ42 aggregation by 81% at compound’s concentration of 25 μM. UV−Vis studies confirmed its preferential binding to Cu(II), and an ORAC assay found its antioxidant capacity of 0.84 of Trolox equivalents. It was nontoxic to SH-SY5Y neuroblastoma cells at 10 μM and resulted in a viability of 81% at its concentration of 100 μM. DON-MC-16 (10 μM) was observed to protect PC12 cells from H2O2-involved insult and increased latency time at a passive avoidance task in scopolamine-induced memory deficits in mice.677 Sang et al. reported on a different scutellarein conjugate with donepezil fragments, which can also be thought of as scutellarein-memoquin derivatives.684 Memoquin (Figure AO

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Figure 27. Linkage, fusion, and incorporation of rivastigmine with natural products or imaging molecules for Aβ species. Rivastigmine, rasagiline, and scutellarein (chemical names presented in Table 1 and Figures 9 and 25, respectively); cinnamic acid, (2E)-3-phenylprop-2-enoic acid; caffeic acid, ThT, and 125I-chalcone derivative (chemical names presented in Figures 21, 10, and 14, respectively); RIV-MC-1, (S)-ethyl-methyl-carbamic acid 3-[1-(methyl-prop-2-ynyl-amino)-ethyl]-phenyl ester; RIV-MC-2, 4-(5-hydroxy-6,7-dimethoxy-4-oxo-4H-chromen-2-yl)phenyl-N,N-diethylcarbamate; RIV-MC-3, (E)-3-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenyl(N-ethyl(methyl))carbamate; RIV-MC-4, (E)-4-(3-(4(dimethylamino)phenyl)acryloyl)-3-hydroxyphenylpyrrolidine-1-carboxylate; RIV-MC-5, 2-(1,3-benzoxazol-2-yl)phenyl-N,N-dimethylcarbamate.

engineer compact multifunctional small molecules.686 Their main contender, DON-MC-18-Prochelator (Figure 26), could inhibit both AChE (rat cortex homogenate) and BuChE (serum) (IC50 = 0.097 and 0.024 μM for rAChE and rBuChE, respectively) and fared well compared to either donepezil (IC50 = 11 nM and 1.3 μM for rAChE and rBuChE, respectively) or rivastigmine (IC50 = 2.1 and 0.37 μM for rAChE and rBuChE, respectively).686 DON-MC-18-Prochelator was decarbamated to the active chelator, DON-MC-18, over incubation for 24 h with cortex homogenate, as determined by MS. DON-18-Prochelator and DON-MC-18 could impact metal-free and Cu(II)-triggered Aβ40 aggregation, respectively, as visualized by TEM. Optical shifts upon treatment of Cu(II) to DON-MC-18 were more significant compared to either Zn(II) or Fe(II) addition but were generally small.686 Finally, DON-MC-18 could quench radicals in an ABTS assay [IC50 = 2.9 and 1.9 μM for DON-MC-18 and melatonin (structure shown in Figure 21), respectively]. Yan et al. fashioned hybrids composed of donepezil and curcumin to invent multifunctional molecules targeting AChE, metals, and metal-free Aβ.687 Their lead molecule, DON-MC19 (Figure 26), was selective for EeAChE (IC50 = 0.19 μM) over eqBuChE (IC50 = 12 μM) with the SI value of 66, retaining preference for AChE, similar to donepezil (IC50 = 37 nM and 3.1 μM for EeAChE and eqBuChE, respectively, with SI = 85).687 Inhibition of DON-MC-19 toward self-Aβ42 aggregation was tested (45% vs 55% for 20 μM of DONMC-19 and curcumin, respectively) as was antioxidant capacity (3.1 and 2.5 Trolox equivalents for DON-MC-19 and curcumin, respectively, in an ORAC assay). Potential BBB permeability was predicted for DON-MC-19 based on PAMPA-BBB. Metal binding to DON-MC-19 was examined by UV−Vis, indicating the spectral shifts upon addition of Cu(II) and Fe(II).687 The stoichiometry of Cu(II) complexes with DON-MC-19 was determined to be 1:1.

Zhou et al. employed paeonol, a natural phenolic antioxidant molecule isolated from the root bark of Moutan Cortex (Paeonia suffruticosa), which they integrated with donepezil to create paeonol-donepezil hybrids (Figure 26).688 Previously, paeonol was shown to improve cognitive impairment in galactose-induced aged mice.689 The best reported hybrid, DON-MC-20 (Figure 26), inhibited AChE (IC50 = 0.61 μM vs 0.053 μM for donepezil) and could scavenge DPPH radicals (IC50 = 158 μM).688 In PC12 cells, DON-MC-20 exhibited protective effects against H2O2mediated oxidative damage, as determined by an MTT assay and phase-contrast microscopy. Addition of Cu(II) induced spectral changes in DON-MC-20, indicating a 1:1 Cu(II)-toligand stoichiometry.668 Li et al. focused on the aurone scaffold (Figure 26), naturally occurring and isomeric to flavones, whose derivatives possess high affinity for Aβ aggregates690,691 and MAO and AChE inhibitory action.692,693 Aurone was incorporated with a donepezil fragment, and the best choice produced from the study was DON-MC-21 (Figure 26) that displayed inhibition against rAChE, EeAChE, and hAChE (IC50 = 8.8, 21, and 37 nM, respectively), similar to donepezil (IC50 = 19, 27, and 36 nM for rAChE, EeAChE, and hAChE, respectively).692 DONMC-21 had relatively high selectivity for AChE with only 13% inhibition of eqBuChE at 50 μM. Inhibition of hMAO by DON-MC-21 was tested but was not found to be strong. DON-MC-21 modulated self- and Cu(II)-prompted Aβ42 aggregation (58 and 45%, respectively).692 Modest optical shifts were seen upon incubation of DON-MC-21 with Cu(II) and Fe(II). DON-MC-21 indicated some antioxidant activity (1.7 Trolox equivalents in an ORAC assay), conferred significant neuroprotective effect against H2O2-mediated injury to PC12 cells by an MTT assay, and was anticipated to be potentially BBB permeable by PAMPA-BBB. AP

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Figure 28. Multifunctional ChE- and metal-targeting molecules based on scaffolds, designed via the linkage, fusion, and incorporation approches. Bis-(−)-nor-meptazinol, 3,3'-[1,9-nonanediylbis[(3S)-3-ethylhexahydro-1H-azepine-1,3-diyl]]bis-phenol; rivastigmine (chemical name indicated in Table 1); memoquin, ferulic acid, and cinnamic acid (chemical names presented in Figures 25, 21, and 27, respectively); deoxyvasicinone, 2,3dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one; DFP, ThT, and resveratrol (chemical names presented in Figures 2, 10, and 15, respectively); pyridoxine, 5-hydroxy-6-methyl-3,4-pyridinedimethanol; ChEI-MC-1, N1,N2-bis(3-((S)-3-ethyl-3-(3-hydroxyphenyl)azepan-1-yl)propyl)oxalamide; ChEI-MC-2, N1,N2-bis(3-((S)-3-ethyl-3-(3-hydroxyphenyl)azepan-1-yl)propyl)-ethane-1,2-diamine; ChEI-MC-3, (E)-N-(6-(ethyl(2methoxybenzyl)amino)hexyl)-3-(4-hydroxy-3-methoxyphenyl)acrylamide; ChEI-MC-4, (E)-4-(3-(3,4-dimethoxyphenyl)acrylamido)-1-(4fluorobenzyl)pyridin-1-ium; ChEI-MC-5, 3-(2-(3-fluoropyrid-1-yl)-acetamino)-7,8-dehydrorutaecarpine; ChEI-MC-6, 2-((3,5-difluorobenzyl)amino)-N-(9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-7-yl)acetamide; ChEI-MC-7, 1-(4-(2-(benzo[d]thiazol-2-yl)pyrrolidin-1-yl)-4-oxobutyl)-3-hydroxy2-methylpyridin-4(1H)-one; ChEI-MC-8, (E)-5-(4-(5-(dimethylamino)-2-hydroxybenzylamino)styryl)-benzene-1,3-diol; ChEIMC-9, (E)-2-((4-(3,5-dimethoxystyryl)phenylamino)methyl)-4-(dimethylamino)phenol; ChEI-MC-10, (E)-5-(3-hydroxy-4-(piperidin-1ylmethyl)styryl)-4-(hydroxymethyl)-2-methylpyridin-3-ol.

equivalents in an ORAC assay) and was predicted to be possibly available in the CNS by PAMPA-BBB. Rivastigmine (Figure 27) has also been considered as a scaffold in the design of multifunctional, metal-targeting molecules, although not as frequently as tacrine or donepezil. RIV-MC-1 (Figure 27) is a hybrid molecule of rasagiline and rivastigmine.699 Reported as a multifunctional molecule, RIVMC-1 exhibited inhibitory activities against MAO-A, AChE, and BuChE as well as neuroprotective properties against H2O2induced toxicity in SH-SY5Y cells. In vivo studies demonstrated that the daily chronic administration of the compound (5−10 mg/kg) reduced memory and cognitive impairments, displayed brain-selective MAO-A and ChE inhibition, and increased the levels of essential neurotransmitters (i.e., dopamine, serotonin, and norepinephrine).699 Sang et al. prepared scutellarin-rivastigmine hybrids to generate multifunctional molecules targeting AChE, metals, and ROS.700 Among the compounds, the best resultant

Li et al. selected the homoisoflavonoid structure, which they integrated with a donepezil fragment to produce a large series of molecules.694 Homoisoflavonoids (Figure 26) were chosen for their affinity for Aβ aggregates,695 MAO-B inhibitory profile,696 antioxidant qualities,697 and anti-inflammatory properties.698 The primary compound tested, DONMC-22 (Figure 26), exhibited a preference for AChE inhibition (IC50 = 2.5 nM for EeAChE, inhibition of rBuChE by 20% at 50 μM of the compound), greater than donepezil (IC50 = 23 nM and 21 μM for EeAChE and rBuChE, respectively).694 Like earlier reports of MAO inhibition of homoisoflavonoids, DON-MC-22 was preferential for MAOB (25% inhibition of hMAO-A at 20 μM of the compound; IC50 = 1.7 μM for hMAO-B). It attenuated self- and Cu(II)induced Aβ42 aggregation (39 and 47%, respectively), and subtle changes in UV−Vis spectra of DON-MC-22 were found upon treatment of either Cu(II) or Fe(II).694 DON-MC-22 showed relatively good antioxidant capability (2.3 Trolox AQ

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molecule, RIV-MC-2 (Figure 27), preferentially inhibited ratderived AChE (IC50 = 0.57 and 23 μM for rAChE and rBuChE, respectively, SI = 40 for RIV-MC-2; IC50 = 5.6 and 1.4 μM for rAChE and rBuChE, respectively, SI = 0.25 for rivastigmine), and exhibited antioxidant capacity (1.3 Trolox equivalents in an ORAC assay).700 Metal binding was investigated by UV−Vis, which indicated changes upon Cu(II) addition but not with Fe(II) or Zn(II) and formation of a 1:1 Cu(II)-to-ligand ratio. RIV-MC-2 presented a neuroprotective effect toward H2O2-induced damage to PC12 cells with 79% viability at 10 μM of the compound (versus 58% viability from the H2O2-only control).700 It was predicted to be potentially BBB permeable via PAMPA-BBB, which was supported by a decrease in brain AChE activity ex vivo upon RIV-MC-2 administration to mice. In addition, it improved short-term working memory in scopolamine-induced cognitively impaired mice in a Y-maze spontaneous alternation test.700 Extending studies on the conjugation of ferulic acid- or caffeic acid-like molecules to AChE inhibiting scaffolds, such as tacrine,633−637,644,645 Chen et al. produced a series of rivastigmine-hydroxycinnamic acid hybrids (Figure 27).701 The best candidate, RIV-MC-3 (Figure 27), at a concentration of 1 μM, prevented the activity of AChE and BuChE by 23 and 76%, respectively, which was opposite in selectivity to donepezil, whose inhibition was 95 and 15% of the activity of AChE and BuChE, respectively, at the same concentration.701 RIV-MC-3 (10 μM) scavenged DPPH radicals by 52% and controlled Aβ42 self-aggregation by 85% and was nontoxic to HT22 cells. Moreover, it afforded some neuroprotective effects against glutamate- and H2O2-induced toxicity to HT22 cells, although the impact was more perceptible in H2O2-triggered toxicity.701 UV−Vis studies presented binding of RIV-MC-3 to Cu(II), but its influence on Cu(II)-generated Aβ aggregation was not tested. Xiao et al. utilized the chalcone scaffold, a known imaging agent for Aβ aggregates534 with ChE702 and MAO inhibiting profiles703 for their integration with rivastigmine via the incorporation approach (Figure 27).704 The main reported molecule, RIV-MC-4, exhibited moderate but selective EeAChE inhibition (IC50 = 4.9 μM), without activity registered against rBuChE. AChE inhibition was comparable to rivastigmine (IC50 = 9.9 and 2.9 μM for EeAChE and rBuChE, respectively).704 RIV-MC-4 was also preferential for MAO-B over MAO-A (13% inhibition of hMAO-A at 10 μM; IC50 = 0.29 μM for hMAO-B; SI > 35), which is less potent but more selective than rasagiline (structure shown in Figure 27; IC50 = 1.4 and 0.083 μM for hMAO-A and hMAO-B, respectively; SI = 17).704 RIV-MC-4 modified self- and Cu(II)-activated Aβ42 aggregation (90 and 80% at 25 μM, respectively). RIV-MC-4 bound Cu(II) in a 1:1 metal-toligand stoichiometry and indicated 2.8-fold antioxidant capacity of Trolox. Telpoukhovskaia et al. employed the ThT backbone, an imaging agent with an affinity for amyloids,705 where metal chelating sites were directly installed via the incorporation approach.706 The metal chelating group was masked by a carbamate similar to rivastigmine leading to the molecule, RIV-MC-5 (named BXc by the authors; Figure 27), with an IC50 value of 58 μM against EeAChE. The carbamate could be removed upon exposure to EeAChE, and the resultant molecule, known as HBX (structure shown in Figure 46), was observed to have metal chelating properties capable of attenuating metal-induced Aβ aggregation.508,706

Scaffolds other than tacrine, donepezil, and rivastigmine have been used to engineer multifunctional ChE-/metaltargeting molecules. Zheng et al. employed bis(−)-normeptazinol (Figure 28), an inhibitor against AChE and AChE-induced Aβ aggregation inhibitor,707 as the framework to invent multifunctional molecules.708 Similar to the scheme adopted by Bolognesi et al. where metal donor atoms were introduced into the linker joining two tacrine units,600 Zheng et al. prepared derivatives of bis(−)-nor-meptazinol, where metal donor atoms were installed onto the linker.708 ChEIMC-1 and ChEI-MC-2 (named ZLA and ZLB by the authors; Figure 28) could inhibit both AChE and BuChE [IC50 = 9.6, 1.8, and 1.3 μM for hAChE, mouse AChE (mAChE), and mouse BuChE (mBuChE), respectively, for ChEI-MC-1; IC50 = 8.6, 1.5, and 1.7 μM for hAChE, mAChE, and mBuChE, respectively, for ChEI-MC-2] on par with rivastigmine (Figure 28; IC50 = 8.5, 5.4, and 2.1 μM for hAChE, mAChE, and mBuChE, respectively).708 ChEI-MC-1 and ChEI-MC-2 were also efficacious at controlling Aβ40 aggregation but not as potently as propidium iodide (IC50 = 49, 55, and 12 μM, respectively). Metal chelation was probed by UV−Vis, which indicated intensifying bands upon addition of Cu(II) with a suggested 1:1 metal-to-ligand complex ratio. Both ChEI-MC-1 and ChEI-MC-2 could affect Cu(II)- and Zn(II)-triggered Aβ40 aggregation. Neither compounds displayed any obvious toxicity toward SH-SY5Y neuroblastoma cells up to 100 μM.708 Pan et al. favored memoquin,685 an AChE-inhibiting scaffold for their design to combine it with ferulic acid (Figure 28).709 The prime candidate, ChEI-MC-3 (Figure 28), was a moderate but selective AChEI (IC50 = 3.2 μM for EeAChE; 36% inhibition of eqBuChE at 50 μM). It inhibited self-induced Aβ42 aggregation and induced the disassembly of preformed fibrils (38 and 46% at 25 μM), was nontoxic to SHSY5Y neuroblastoma cells (10 μM), and afforded some protection to PC12 cells from H2O2-mediated insults.709 Metal binding was not tested. Lan et al. devised variously substituted cinnamic acid derivatives bearing the N-benzylpyridinium moiety (Figure 28).710 N-benzylpyridinium molecules had been shown previously to be dual AChE inhibitors capable of binding to both the CAS and PAS sites.711,712 The prime candidate, ChEI-MC-4 (Figure 28), was disubstituted at the 3 and 4 positions of the cinnamic acid ring with methoxy groups and was consequently similar to a ferulic acid derivative.710 It preferentially inhibited the activity of AChE (IC50 = 12 and 8.6 nM for EeAChE and hAChE, respectively; IC50 = 2.6 and 4.4 μM for eqBuChE and hBuChE, respectively), bound Cu(II) and Fe(II), formed 1:1 Cu(II)-to-ligand complexes, and inhibited Cu(II)-induced Aβ42 aggregation (65% at 20 μM of the compound).710 ChEI-MC-4 offered neuroprotection to PC12 cells from Aβ42-mediated toxicity, confirmed by an MTT assay, and was predicted to be possibly available in the CNS by PAMPA-BBB. The brain AChE activity of sacrificed OF1 mice that had been administered with ChEI-MC-4 by intraperitoneal injection was lower than in the controls.710 He et al. designed and synthesized multifunctional AChEand metal-targeting compounds employing 7,8-dehydrorutaecarpine (Figure 28),713 previously reported as a selective AChE inhibitor.714 They were appended with 3-aminoalkanamido substituents to construct a series of derivatized 7,8-dehydrorutaecarpines.713 The lead compound from the broad arsenal of multifunctional molecules was ChEI-MC-5 AR

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Figure 29. Multifunctional ChE- and metal-targeting molecules designed based on scaffolds other than tacrine or donepezil via the fusion, incorporation, and FBDD approaches. Clioquinol (chemical name presented in Figure 2); ChEI-11, N-((1-(2,3-dihydro-1H-inden-2-yl)piperidin3-yl)-methyl)-N-(2-methoxyethyl)-2-naphthamide; curcumin (chemical name shown in Figure 8); ferulic acid and caffeic acid (chemical names shown in Figure 21); donepezil and coumarin (chemical names indicated in Table 1 and Figure 20); ChEI-MC-11, N-((1-(2,3-dihydro-1H-inden2-yl)piperidin-3-yl)methyl)-8-hydroxy-N-(2-methoxyethyl)-5-nitroquinoline-7-carboxamide; ChEI-MC-12, bis[2-(3,4-dimethoxy-phenyl)ethenyl]dithioperoxyanhydride; ChEI-MC-13, bis[2-(4-hydroxy-3-methoxy-phenyl)-ethenyl]dithioperoxyanhydride; ChEI-MC-14, (S)-allyl(E)3-(3,4-dihydroxyphenyl)prop-2-enethioate; ChEI-MC-15, (E)-1-(4-benzylpiperidin-1-yl)-3-(4-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butoxy)-3methoxyphenyl)prop-2-en-1-one; ChEI-MC-16, 4-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)butyl piperidine-1-carbodithioate; ChEI-MC-17, 1(6-(4-((dipropylamino)methyl)-1H-imidazol-1-yl)-pyrimidin-4-yl)-3-ethylthiourea; ChEI-MC-18, 1-ethyl-3-(6-(4-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)-pyrimidin-4-yl)thiourea.

metal-to-ligand ratio) and possibly to Fe(II) and Fe(III).717 Other biological properties, such as antioxidant capacity, BBB permeability, and cytotoxicity, along with activity toward Cu(II)-promoted Aβ aggregation were not addressed. Nunes et al. fashioned multifunctional molecules based on the structure of 3-hydroxy-4-pyridinone, specifically the known Fe-chelating drug, DFP,718 with the benzothiazole moiety of ThT (Figure 28).719 The lead compound, ChEI-MC-7 (Figure 28), inhibited EeAChE (IC50 = 15 μM), self-induced Aβ42 aggregation (59% at 100 μM of the compound), and scavenge DPPH radicals (EC50 = 148 μM).719 A speciation investigation of the ligand with and without Fe(III) was reported, showing strong Fe-chelating ability. Additionally, ChEI-MC-7 could control Zn(II)-added Aβ42 aggregation by 32% (at 40 μM of the compound) and was predicted to possess drug-likeness.719 Lu et al. engaged the resveratrol backbone to devise multifunctional metal chelating molecules (Figure 28).720 The main candidate, ChEI-MC-8 (Figure 28), and its methoxy derivative, ChEI-MC-9 (Figure 28), displayed relatively similar properties to one another. The IC50 values recorded for ChEIMC-8 were 6.3, 21, 7.1, and 14 μM for EeAChE, eqBuChE, hMAO-A, and hMAO-B, respectively, while ChEI-MC-9 displayed the values of 36, > 50, 8.2, and 12 μM, respectively. Both were able to inhibit self-induced Aβ42 aggregation (IC50 =

(Figure 28). It exhibited the IC50 values of 0.60 nM and 1.9 μM for EeAChE and eqBuChE, respectively, corresponding to SI = 3092, as opposed to tacrine (IC50 = 108 and 33 nM for EeAChE and eqBuChE, respectively). ChEI-MC-5 additionally prevented self- and AChE-induced Aβ42 (46 and 91%, respectively) at 25 μM, more effective even than propidium iodide that inhibited 85% of AChE-induced Aβ42 aggregation at the same concentration. The antioxidant activity of ChEIMC-5 was registered at 2.3 Trolox equivalents, and it was bound to Cu(II), Zn(II), and Fe(II) in a 1:1 metal-to-ligand ratio. Finally, ChEI-MC-5 was nontoxic to SH-SY5Y cells (IC50 > 100 μM).713 Ma et al. utilized deoxyvasicinone, a naturally occurring alkaloid with a known ChE inhibition profile,715 structurally similar to tacrine (Figure 19),716 to generate multifunctional compounds.717 The principal multifunctional molecule from the study was ChEI-MC-6 (Figure 28), which proved to be a potent ChEI (IC50 = 7.6 and 2.4 nM for hAChE and hBuChE, respectively) compared to its structurally related tacrine (IC50 = 77 and 11 nM for hAChE and hBuChE, respectively).717 Additionally, ChEI-MC-6 (10 μM) inhibited self-induced Aβ42 aggregation of 64% versus 52% for curcumin (structure shown in Figure 17). Binding to biometals was investigated by both UV−Vis and fluorescence, indicating binding to Cu(II) (1:1 AS

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6.5 and 7.6 μM for ChEI-MC-8 and ChEI-MC-9, respectively) and Cu(II)-added Aβ42 aggregation and disaggregation as anticipated based on their ability to bind Cu(II).720 ChEI-MC8 and ChEI-MC-9 were antioxidants (4.7 Trolox equivalents for both compounds). ChEI-MC-9 was predicted to be potentially BBB permeable as assessed by PAMPA-BBB and appeared to be devoid of acute toxicity to mice up to a dose of 2 g/kg.720 Yang et al. also combined the resveratrol scaffold with pyridoxine to prepare a series of resveratrol-pyridoxine hybrids (Figure 28).721 All candidates were tested for ChEand MAO-inhibiting activities. The product with the most balanced profile, ChEI-MC-10 (Figure 28), was found to exhibit the IC50 values of 2.1, 17, 13, and 12 μM, respectively, for EeAChE, BuChE, hMAO-A, and hMAO-B. ChEI-MC-10 was shown to be a good antioxidant (2.6 Trolox equivalents) and bound to Cu(II) and Fe(II).721 In contrast to the majority of prior literature, Knez et al. chose a hBuChEI, ChEI-11 (Figure 29), identified in an earlier work, for the design of their multifunctional metal chelating molecules.722 ChEI-11 exhibited an IC50 value of 21 nM against hBuChE with the ability to modify self-induced Aβ42 aggregation by 62% at its concentration of 10 μM.370 Metal chelation was introduced into ChEI-11 by rational design via incorporation of clioquinol into the naphthalene moiety.722 The lead derivative, ChEI-MC-11 (Figure 29), retained selectivity for hBuChE, albeit with relatively lower potency (IC50 = 215 nM) and diminished the ability to inhibit Aβ42 self-induced aggregation (20% at 10 μM of the compound). Metal binding studies by UV−Vis showed spectral shifts upon addition of Cu(II), Zn(II), Co(II), Mg(II), Ca(II), and Fe(II) but preferential binding to Cu(II) with the 1:2 Cu(II)-to-ligand ratio.722 Unfortunately, the influence of ChEI-MC-11 on Cu(II)dependent Aβ aggregation was not investigated. Manral et al. integrated diallyl disulfide, a naturally occurring compound from garlic already examined in AD research,657,723 into a curcumin-like motif (Figure 29).724 The authors utilized in silico computation to predict aryl ring substituents for optimal CNS penetration and other crucial pharmacokinetic criteria to yield 40 candidates that were further filtered by docking to the structure of Aβ42 (PDB 1IYT) obtained by NMR.725 This led to the identification of 21 possible compounds which were synthesized and experimentally screened.724 Their inhibitory activity toward EeAChE and eqBuChE were evaluated, and the top candidates, ChEI-MC-12 and ChEI-MC-13 (Figure 29), fared well compared to donepezil (structure shown in Table 1) (for EeAChE and eqBuChE, IC50 = 56 nM and 14 μM, respectively, for ChEI-MC-12; 0.12 and 13 μM, respectively, for ChEI-MC-13; 49 nM and 8.7 μM, respectively, for donepezil).724 The multifunctional compounds also inhibited self-induced Aβ42 aggregation (74 and 71%, respectively, for 25 μM of ChEI-MC-12 and ChEI-MC-13), along with antioxidant capacity (5.2 and 5.9 Trolox equivalents for ChEI-MC-12 and ChEI-MC-13, respectively) and binding to Cu(II) and Fe(II) in a 1:1 metal-to-ligand ratio. Their ability to lessen Cu(II)-elicited Aβ42 aggregation was examined by TEM and a fluorescence-based assay, which exhibited fewer fibrils and lower fluorescence, respectively. ChEI-MC-12 and ChEI-MC-13 were relatively nontoxic to human embryonic kidney (HEK) cells at 100 μM (89 and 81% viability, respectively).724 Simoni et al. presented ChEI-MC-14 (Figure 29), a caffeic acid derivative containing a diallyl disulfide functionality.726

The highlighted molecule was observed to prevent ROS generation and Aβ-induced alteration in the conformation and activity of p53, a protein associated with apoptosis. ChEI-MC14 was also capable of inhibiting the self-aggregation of Aβ42 (>90% at 50 μM of the compound).726 In vitro evaluation of ChEI-MC-15 (Figure 29), a ferulic acid derivative with multifunctionality, indicated its ability to target various pathological factors in AD: (i) cholinesterases (IC50 = 2.1, 1.8, 3.8 μM for EeAChE, rAChE, and hAChE, respectively; IC50 = 0.021, 8.6, 0.07 μM for eqBuChE, rBuChE, and hBuChE, respectively); (ii) Aβ42 (51% inhibition of selfinduced aggregation and 39% disaggregation of preformed aggregates at 25 μM of Aβ42 and 25 μM of the compound); (iii) ROS (0.55 Trolox equivalents).727 The PAMPA-BBB assay suggested the molecule’s potential capacity to cross the BBB. In addition, scopolamine-induced mice treated with ChEI-MC-15 showed significant improvements in cognitive function.727 Jiang et al. reported ChEI-MC-16 (Figure 29), a multifunctional coumarin-dithiocarbamate derivative.728 ChEI-MC-16 displayed the inhibitory activities against Aβ42 aggregation (40% at 25 μM of the compound), AChE (IC50 = 0.027 μM), and BuChE (15% inhibition of BuChE activity at 10 μM), interacted with metal ions, and reversed scopolamine-induced memory deficits in mice.728 Furthermore, the PAMPA-BBB results suggested the molecules’s potential BBB permeability.728 Li et al. adopted a screening approach on 630 low molecular weight fragments729 that hone in on the pyrimidine framework, a recurring motif in AD (Figure 29).730 The initial hit was further refined by variation of the ethylamino group, which identified the ethylthiourea analog as a lead.729 The ethylthiourea moiety is known to chelate metal ions and have antioxidant properties,731−733 and thus proved to expand on the AChE inhibiting qualities of the initial pyrimidine hit. The pyrazolyl group was diversified, and the derivatives were tested for the AChE inhibitory effect to filter results down to an imidazolyl group.729 Substitution at the 2 and 4 positions of the imidazolyl group led to the final series of candidates, of which ChEI-MC-17 and ChEI-MC-18 (Figure 29) were ultimately tested for AChE inhibition, anti-Aβ aggregation, metal chelation, and antioxidant capacity.ChEI-MC-17 and ChEI-MC-18 potently and preferentially inhibited rAChE over rBuChE (IC50 = 0.20 μM and 67 nM, respectively; SI > 196 and > 597, respectively), but their effect on metal-free Aβ aggregation was not significant.729 Metal binding was tested by UV−Vis, which presented a decrease in the peak intensity only upon the addition of Cu(II). ChEI-MC-17 and ChEI-MC-18 could attenuate Cu(II)-promoted Aβ42 fibrillization, as measured by TEM and dot blot, control Cu(II)-induced H2O2 production, and were marginally stronger antioxidants than Trolox. In addition, they offered modest protection to SH-SY5Y neuroblastoma cells from Cu(II)−Aβ42-induced toxicity and, in the absence of Aβ, were less toxic than donepezil (structure presented in Table 1) at compounds’ concentration of 100 μM. PAMPA-BBB predicted the potential brain uptake of ChEI-MC-17, and thus it was further investigated in mice with scopolamine-induced cognitive deficits, where it could decrease escape latency in passageway water maze.729 Metal chelation is increasingly becoming an important facet of the design of multifunctional molecules, as evidenced by the increasing number of reports examining this aspect. In order to AT

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design the best candidates and develop them into compounds most likely to provide therapeutic benefit, several factors need to be taken into consideration. Many candidates reported in the literature that inhibit AChE and/or BuChE also possess potential metal binding sites, but this feature is often overlooked. While multiple designs include known inhibitors, such as tacrine and donepezil (structures shown in Figure 19 and Table 1, respectively), some have moved toward new AChEI and/or BuChEI frameworks. Since these molecules are tested primarily on their AChE-inhibiting properties, less consideration has been given to potentially toxic off-target effects. Thus, in vivo safety profiles as well as in vivo efficacy are valuable and need to be further evaluated. Taken together, the efforts on engineering small molecules with multifunctionality, including AChE/BuChE inhibition, metal chelation, and/or amyloid peptides’ aggregation control (for example, modulation of Aβ aggregation) have been and will be advancing our understanding in this area. 2.6.3. Molecules Targeting Tau. Based on the lack of effective therapeutics targeting Aβ in clinical trials and increasing evidence in support of tau’s role in AD pathology (e.g., correlation between tau load and neurodegeneration, tau’s direct role in microtubule stabilization, and Aβ-mediated toxicity), tau has been considered as a therapeutic target.734−736 Various aspects of tau pathology offer several potential treatment strategies: (i) modification of tau aggregation;737−739 (ii) alteration of post-translational modifications (PTMs) of tau (e.g., phosphorylation,414,740 acetylation,741 and cleavage742,743); (iii) regulation of tau levels;744 (iv) stabilization of microtubules.745 Tau aggregation contributes toward both the loss-of-function in microtubule stabilization and gain-of-toxic function via the formation of PHFs, SFs, and tau oligomers.152,746,747 Similar to Aβ oligomers,132 the notion of tau oligomers as potential toxic species has been gaining traction.152,746 For these reasons, the strategy to alter tau aggregation has been widely viewed as a potential therapeutic avenue and numerous small molecule inhibitors have been reported. 737−739,748 Although the mechanisms of tau aggregation are not as well-understood as those of Aβ, research suggests that the microtubule binding repeats (MTBRs) may be responsible for the intermolecular interactions between tau monomers.749,750 Furthermore, specific sequences among the MTBRs (e.g., VQIVYK and VQIINK) have been indicated as core structures in tau aggregation.751 As for Aβ, tau aggregation is driven by a transition to β-sheet structure.752 The shared cross-β structure of the proteopathic amyloids (e.g., Aβ fibrils, tau PHFs, and SFs) presents a common feature between Aβ and tau fibrils, which may lead to structural similarities between molecular scaffolds capable of targeting the aggregates of Aβ and tau. In fact, probes currently under development for imaging NFTs (Figure 30) are structurally similar to those used to image Aβ fibrils (e.g., 11C-BF-227 and 11C-PIB; Figure 6).461,753,754 Although numerous imaging agents for SPs have been developed and some have been in active commercial use, no clinical imaging tool selectively assesses tau pathology in ADaffected brains at present.753 Currently, tau aggregation inhibitors (TAIs) dominate the domain of therapeutics targeting tau and only a few multifunctional molecules have been reported. Phosphorylation of tau is also a prominent aspect of tau research that has been gaining interest as a potential therapeutic target.414,740 Known to affect tau’s ability to stabilize microtubules and aggregates, abnormal phosphor-

Figure 30. Some radiolabeled imaging probes for NFTs. 11C-BF-158, 2-[(4-methylamino)phenyl]quinoline; 123I-TH2, (Z)-3-(2-(1H-imidazol-4-yl)ethyl)-5-((5-(3-iodophenyl)furan-2-yl)-methylene)-2-thioxoimidazolidin-4-one; 18 F-THK523, 2-(4-aminophenyl)-6-(2fluoroethoxy)quinoline); 18F-AV1451, 7-(6-fluoropyridin-3-yl)-5Hpyrido[4,3-b]indole; 123I-PDB-3, (E)-4-((6-iodobenzo[d]thiazol-2yl)diazenyl)-N,N-dimethylaniline.

ylation of tau has been implicated as a pathological feature in several tauopathies.755 The exact definition regarding the degree of hyperphosphorylation and its variable impact on tau aggregation remain elusive, however.756 The influence of phosphorylation at specific sites of tau contributes to the complexity of tau pathology.756 In this section, we provide a brief overview of structural frameworks that target the pathology of tau. MB (Figure 31), a phenothiazine, is a representative TAI (IC50 = 1.9 μM).604,757 Wischik et al. reported that MB reversed the proteolytic stability of protease-resistant PHFs isolated from the brain by blocking tau-tau binding (inhibitory constant Ki = 3.4 μM) via MTBRs without disrupting tautubulin interactions.757 In addition, MB was shown to attenuate Aβ pathology by controlling its aggregation (IC50 = 2.3 μM)604,758 and promoting the clearance of soluble Aβ.759 A study indicated that MB modified the aggregation of full-length tau constructs containing two N-terminal domains and four MTBRs (2N4R) through cysteine oxidation.760 Preclinical studies have suggested the potential therapeutic benefits of MB. When orally administered to 8 to 11 month old P301L tau Tg mice over a period of 5 months, MB reduced the levels of detergent-resistant ptau.761 Clinical studies of MB, however, revealed limited efficacy and bioavailability in the brain.738 The therapeutic potential of MB from preclinical studies encouraged further investigations of derivatives with improved pharmacological properties.762,763 TAI-1 (Figure 31) was developed to stabilize the reduced form of MB and demonstrated improved absorption.762,763 The results of the phase III trials of TAI-1 in 2016 have been controversial,764 and a second phase III study proposed its effectiveness as a monotherapy for AD at dosages as low as 4 mg.765 Further studies to confirm its efficacy are necessary and ongoing. Various thiacarbocyanine dyes [for example, 123I-PDB-3 (Figure 31)], which embody the benzothiazole functionality, have been investigated as TAIs.766−768 Chirita et al. presented TAI-2 (named N744 by the authors; Figure 31), a thiacarbocyanine capable of selectively inhibiting arachidonic acid-induced aggregation of recombinant human tau (htau) (i.e., htau23 and htau40) at a substoichiometric concentration AU

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Figure 31. Examples of TAIs fashioned based on the backbones of MB, benzothiazole (e.g., 123I-PDB-3), rhodanine, and thiazolyl-hydrazine. MB (methylene blue) and 123I-PDB-3 (chemical names shown in Figures 19 and 30, respectively); rhodanine, 2-thioxothiazolidin-4-one; epalrestat, 2-[(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]acetic acid; TAI-1, N3,N3,N7,N7-tetramethyl-10H-phenothiazine-3,7-diaminium; TAI-2, 3-(2-hydroxyethyl)-2-[2-[[3-(2-hydroxyethyl)-5-methoxy-2-benzothiazolylidene]methyl]-1-butenyl]-5-methoxybenzothiazolium; TAI-3, 5,16,17,18,34,35,36,37-octahydro-[1,6,12,17]tetraazacyclodocosino[7,6-b:11,12-b′:18,17-b″:22,1-b‴]tetrakisbenzothiazole-14,33-diium; TAI-4, (Z)-2-(5-((5-(3-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid; TAI-5, (Z)-3-((1H-benzo[d]imidazol-2-yl)methyl)-5-((5-(3-chlorophenyl)furan-2-yl)methylene)-2-thioxothiazolidin-4-one; TAI-6, N′-(5-(4nitrophenyl)thiazol-2-yl)-1H-benzo[d]imidazole-6-carbohydrazide.

(IC50 = ca. 300 nM).769 At a stoichiometric level, TAI-2 promoted the disaggregation of mature synthetic tau filaments. A notable feature of TAI-2 is its structural similarity to the probe, 123I-PDB3 (Figure 31). Cyclic thiacarbocyanines (e.g., TAI-3; Figure 31) composed of carbocyanines connected via linkers to complete the ring, have been developed as TAIs.766 Schafer et al. investigated the impact of the linker length on the molecules’ ability to influence htau with 2N4R aggregation, which led to the discovery that a linker length of four methylene units was optimal. At 1 μM, the representative compound, TAI-3 (called bis-thiacarbocyanine 2b by the authors; Figure 31), significantly controlled octadecyl sulfateinduced fibrillization of full-length tau.766 Rhodanine (Figure 31) is a 5-membered heterocyclic compound with a thioxothiazolidine core, similar to the molecular structure of 123I-TH2, an imaging probe for NFTs (Figure 30), whose scaffold researchers have utilized to develop potential TAIs. Epalrestat (Figure 31), an aldose reductase inhibitor used to treat diabetic neuropathy,770 has also been reported for its bioavailability, tolerability, and ability to inhibit β-sheet formation.771 On the basis of the rhodanine scaffold of epalrestat, Bulic et al. synthesized a number of rhodanine-based inhibitors. Among them, TAI-4 (Figure 31) exhibited notable inhibitory activity against the aggregation of a fetal isoform htau23 [IC50 = 0.82 μM; disassembly inducing half-maximal concentration (DC50) = 0.10 μM; 20% inhibition at 15 μM in N2a neuroblastoma cells].772 When another

rhodanine derivative, TAI-5 (known as bb14; Figure 31), was added to detergent-insoluble aggregates of an aggregationprone tau isoform, the level of detergent-soluble tau was increased by ca. 25%.773 TAI-5 was able to reduce the level of tau aggregates in brain slices from mice expressing the aggregation-prone four repeat domain fragment with mutation ΔK280 (deletion of K280 in the R2 repeat domain) and partially prevented the loss of spines and neurons.774 HTS studies have identified diverse molecular scaffolds capable of inhibiting the aggregation of tau.775 Among the various phenylthiazolyl-hydrazide derivatives, TAI-6 (described as BSc3094 by the investigators; Figure 31), showed inhibitory activities against the aggregation of K19, a truncated three repeat tau segment (IC50 = 1.6 μM; DC50 = 0.70 μM; 82% inhibition in N2a neuroblastoma cells at 10 μM).776 The low cytotoxicity of TAI-6 was another feature implicating its potential applicability as an AD therapeutic.776 Aminothienopyridazines (ATPZs; Figure 32) are another novel class of TAIs discovered through quantitative HTS.777 On the basis of the inhibitory activity of ATPZs, Ballatore et al. designed and synthesized a series of new analogs as TAIs to investigate their SAR.778 Using a heparin-induced tau K18PL fibrillization assay, the authors determined the efficacy of ATPZ analogs as TAIs. Among them, TAI-7 (Figure 32) (IC50 = 2.5 μM) presented desirable ADME-PK properties.778 Further studies demonstrated its ability to penetrate the BBB and in vivo tolerability.778 Mechanistic studies proposed that, AV

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Figure 32. TAIs developed based on the frameworks of ATPZ, curcumin, and rosamine. APTZ (aminothienopyridazine), thieno[3,4d]pyridazin-1(2H)-one; curcumin (chemical name shown in Figure 8); rosamine, 6-amino-9-phenyl-3H-xanthen-3-iminium; crystal violet, tris(4(dimethylamino)phenyl)methylium; TAI-7, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide; TAI-8, 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]ethenyl]-1H-pyrazole; TAI-9, 3-[[6-[(2chloroacetyl)amino]hexyl]amino]-6-(dimethylamino)-9- (4-methoxy-3,5-dimethylphenyl)-xanthylium.

properties were tested against K18ΔK280, a truncated fourrepeat fragment of tau missing the K280 residue. Myricetin (Figure 33), another flavonoid presented as a redox-active metal chelator and Aβ aggregation inhibitor,60,787 is a TAI with an IC50 value of 1.2 μM against recombinant htau46.604 A wellknown Aβ aggregation inhibitor and antioxidant, curcumin (Figure 32) has been noted for its ability to modify tau aggregation.788 In addition, the metal binding properties of curcumin allow the compound to modulate the aggregation pathways of metal−Aβ (described in section 2.6.1).568 Ma et al. reported that curcumin selectively reduced the level of tau dimers in Tg mice expressing htau, implying its ability to modify tau aggregation pathways.788 TAI-8 (also identified as PE859; Figure 32), a curcumin derivative, inhibited the aggregation of both Aβ and tau.789 Oral administration of TAI8 significantly diminished sarkosyl-insoluble aggregated tau and prevented the onset and progression of motor dysfunction in JNPL3 P301L-mutated htau Tg mice.790 The IC50 values for TAI-8’s inhibiting activity against tau aggregation were 0.81 and 2.23 μM against full length 3R and 4R tau proteins, respectively.790 The studies of tau treated with TAI-8 by CD showed that the inhibitory activities of the compound stemmed from its ability to hinder the transition toward the β-sheet conformation.790 Crystal violet (Figure 32), a triarylmethane dye used as a histological stain, exhibits several biological properties, including antimicrobial and antitumoral activities.791 Aggregation of amyloidogenic peptides was observed to be hindered in the presence of crystal violet (IC50 = 0.18, 0.15, and 0.15 μM for recombinant htau40, recombinant α-Syn, and human Aβ42, respectively).792 TAI-9 (also named TR-2; Figure 32), a rosamine derivative bearing mild thiol reactivity, labeled

like MB, ATPZs inhibited tau aggregation through cysteine oxidation.760 Numerous reports have investigated various natural products as potential TAIs.604,779 EGCG (Figure 33), a polyphenolic

Figure 33. Natural products as TAIs (EGCG, myricetin, and PcTS) and tideglusib (a kinase inhibitor). EGCG and myricetin (chemical names in Figure 16); PcTS (phthalocyanine tetrasulfaonate), 29H,29H,31H-phthalocyanine-2,9,16,23-tetrasulfonic acid; tideglusib, 4-benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione.

flavonoid known for its wide range of biological activities (e.g., inhibition of Aβ production, aggregation, and toxicity,780,781 antioxidant,782,783 metal binding784) inhibited tau phosphorylation and aggregation by reducing formation of tau oligomers via binding to its phosphorylation region and modifying its 3D conformation.785,786 Studies regarding EGCG’s antiaggregation AW

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Figure 34. Multifunctional molecules devised based on DFP, rasagiline, coumarin, and selegiline. DFP, rasagiline, and coumarin (chemical names in Figures 2, 9, and 20, respectively); selegiline, (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-1-yn-3-amine; MAOI-MC-1, 1-(3′-(di(prop-2ynyl)amino)propyl)-3-hydroxy-2-methylpyridin-4(1H)-one; MAOI-MC-2, 3-hydroxy-2-methyl-1-(2-(4-(prop-2-inyl)piperazin-1-yl)ethyl)pyridin4-one; MAOI-MC-3, N,N-diethyl-N′-[1-(prop-2-yn-1-yl)-1H-indol-6-yl]urea; MAOI-MC-4, (E)-7-((2-hydroxybenzylidene)amino)-3,4-cyclopentylcoumarin; MAOI-MC-5, (E)-4-hydroxy-3-((2,3,4-trihydroxybenzylidene)amino)-2H-chromen-2-one; MAOI-MC-6, (R)-2-(((4-(2-(methyl(prop-2-yn-1-yl)amino)propyl)phenyl)amino)methyl)phenol.

our comprehension regarding the inhibitory mechanisms against tau aggregation, which is inherently complicated by its multiple isoforms and PTMs, may impede the rational design and development of more effective TAIs. Uncovering these mechanistic details would consolidate tau aggregation as an effective therapeutic strategy for AD. In addition, the practicality of targeting PTMs of tau to treat AD needs to be further examined. Tau has been increasingly utilized as a potential therapeutic target based on the past and current ongoing clinical trials for AD. This trend may be based on improved approaches in tau experimentation, the dual aspect of loss-of-function and gainof-toxic function potentially involved in neuronal degradation, and technological advancement allowing the clinical imaging of tau, implicating the correlation between neurodegeneration and tau load. Oligomers of tau and ptau are implicated in toxicity; however, these species are not clearly defined. Investigating the properties of tau and determining its toxic forms would foster the efforts to clarify its role in AD pathology as a standalone factor as well as a component of the interconnected network of AD pathology. In addition to tau itself, its interrelation with other pathological factors, such as Aβ and metal ions may be a contributing feature to AD pathology. High levels of metal ions [e.g., Fe(II/III), Cu(II) and Zn(II)] are observed to be associated with NFTs.806,807 Although their proximity likely points to a connection between the two pathological factors, research regarding the direct interaction between metals and tau/ptau are preliminary. Yamamoto et al. presented that the presence and the oxidation state of Fe(II/III) influenced the aggregation of tau.808 ROS generation by tau fragments in the presence of Cu(II) was reported.809 A study regarding the interactions between Cu(II) and tau depending on the phosphorylation state of tau revealed that Cu(II) exhibited stronger interactions with phosphorylated tau over nonphosphorylated tau.810 The interconnection of tau with other pathological AD features indicates that multifunctional molecules may be a promising avenue. Numerous studies thus far have identified several TAIs or modifiers against PTMs, whose scaffolds may serve as starting points for the design of multifunctional molecules able to target and regulate

recombinant four repeat tau segment K18 and prevented its aggregation (IC50 = 3.7 μM) by disrupting the generation of disulfide cross-linked tau oligomers.793 Porphyrins, another class of naturally occurring molecules, were first observed to weakly affect tau aggregation.604 Akoury et al. determined that phthalocyanine tetrasulfonate (PcTS) (Figure 33) could suppress the fibrillization of htau40 in vitro by a thioflavin-S (ThS) assay (IC50 = 1.3 μM) and in living cells by 97% at 50 μM.794 An interesting aspect of this research was the promotion of tau oligomerization in favor of fibrillization by PcTS. In contrast, Park et al. reported that PcTS transformed Fe-induced oligomeric species of Aβ40 into fibrils, potentially suppressing toxicity by reducing the levels of ROS generation and Fe(II/III)−Aβ oligomers.795 The quinone and catechol functionalities appear to be a recurring motif of natural products in TAIs, as they are for molecules that modify Aβ aggregation.61,559,796 SAR studies of both synthetic and naturally occurring TAIs would be beneficial to verify the specific structural backbones capable of interacting with different species of tau and metal-associated tau/ptau. In addition to inhibition of tau aggregation, other areas of tau research have examined the influence of PTMs of tau. The phosphorylation state of tau alters its charge and properties that impact its ability to bind and stabilize microtubules and alter its aggregation (discussed in section 2.1).8,742,797,798 Tau’s phosphorylation state is dictated by the activities of various kinases and phosphatases. GSK and cdk are implicated in AD pathology for their role in tau phosphorylation.151 Tideglusib (Figure 33) is an irreversible GSK3β inhibitor with an IC50 value of 60 nM.799 A phase II trial of tideglusib failed to demonstrate clinical efficacy in AD patients.800 Regardless of the lack of clinical success, the strategy of controlling multiple kinases [e.g., GSK3β, cdk5, and protein kinase C (PKC)] involved in AD pathology has been continuing to be sought after as a potential strategy to treat AD.799,801,802 In recent years, other PTMs, such as acetylation741,797 and cleavage743,803−805 of tau, have been increasingly supported as potential contributors toward tau pathogenesis of AD. Utilization of tau-targeted molecules toward modulation of aggregation and PTMs have shown promise in preclinical models and have been undergoing development. Limitations in AX

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Another report by the same group (Wang et al.) extended the family of coumarin-fused metal chelating molecules but joined the scaffolds at a different position on the coumarin ring.823 They observed that their prime candidate, MAOI-MC5 (Figure 34), inhibited hMAO-A and hMAO-B (IC50 = 0.67 and 0.71 μM; SI = 0.95) more potently compared to iproniazid (IC50 = 7.1 and 8.5 μM; SI = 0.84).823 An ABTS assay revealed an antioxidant capacity of 1.3 Trolox equivalents for MAOI-MC-5 versus 1.5 Trolox equivalents for curcumin; a DPPH radical scavenging assay determined an IC50 value of 45.8 μM for MAOI-MC-5 compared to 39.6 μM for curcumin. MAOI-MC-5 modified self-induced Aβ42 aggregation (60% at 20 μM of the compound), which is on par with curcumin (50% at 20 μM).823 In this instance, the effect of MAOI-MC-5 on Cu(II)promoted Aβ42 aggregation was tested, and it was found to decrease the extent of aggregation as monitored by ThT fluorescence. Cu(II) binding to MAOI-MC-5 was confirmed by UV−Vis, which indicated a 1:1 Cu(II)-to-MAOI-MC-5 stoichiometry.823 Additionally, MAOI-MC-5 could control H2O2 production in the presence of Cu(II) and Aβ42 as detected by a HRP/Amplex red assay. MAOI-MC-5 was relatively nontoxic to PC12 cells and protected them from H2O2-induced toxicity at a concentration as low as 5−10 μM.823 PAMPA-BBB predicted possible BBB penetration of MAOI-MC-5. Xie et al. deployed selegiline (Figure 34), a known MAOI,824 which they fused to metal chelating groups to fashion a family of multifunctional molecules.825 The lead molecule, MAOI-MC-6 (Figure 34), inhibited hMAO-A and hMAO-B (IC50 = 5.4 and 0.21 μM, respectively), faring better against hMAO-A, but not against hMAO-B, compared to selegiline (IC50 = 70 and 0.019 μM, respectively). MAOI-MC6 demonstrated antioxidant capacity (4.2 Trolox equivalents in an ORAC assay), and metal binding capability by UV−Vis upon Cu(II) addition, with the 1:2 Cu(II)-to-MAOI-MC-6 stoichiometry.825 The impact of MAOI-MC-6 on Cu(II)activated Aβ42 aggregation was observed (69% of the control at 50 μM of the compound), and PAMPA-BBB predicted its potential CNS availability.825 Li et al. adopted the aurone scaffold in their design of multifunctional molecules, onto which they directly installed metal chelating groups via the incorporation strategy.826 Aurones (Figure 35) have been shown to bind to Aβ and possess MAO inhibitory action.690−693 The primary molecule, MAOI-MC-7 (Figure 35), inhibited hMAO-A and hMAO-B (IC50 = 0.27 and 0.39 μM, respectively), comparable to rasagiline (IC50 = 1.4 and 0.083 μM, respectively; structure shown in Figure 34).826 It also attenuated both self- and Cu(II)-induced Aβ42 aggregation by 99 and 84%, respectively, at a concentration of 25 μM, greater than curcumin (41 and 67% inhibition of self- and Cu(II)-induced aggregation, respectively).826 An ORAC assay determined 1.9 Trolox equivalents antioxidant capacity for MAOI-MC-7, and shifts in UV−Vis were seen upon treatment with Cu(II) and Zn(II), with a 1:1 Cu(II)-to-ligand stoichiometry. PAMPA-BBB forecasted possible BBB permeability by PAMPA-BBB.826 Li et al. utilized the chromone scaffold (Figure 35), from which they appended metal-chelating moieties.98 The chromone scaffold was selected due to its prior success in the design of MAOIs.827,828 MAOI-MC-8 (Figure 35) inhibited hMAO-A and hMAO-B (IC50 = 5.1 and 0.82 μM, respectively) and self-induced Aβ42 aggregation by 75% (at a

other aspects, including Aβ, metal ions, ChEs, and oxidative stress, in addition to tau. 2.6.4. Multifunctional Molecules Directed at Metal Ions and Other Targets. The activity of MAOs results in the breakdown of serotonin and dopamine neurotransmitters with the concomitant production of H2O2.400 Consequently, inhibition of MAOs has been seen as an approach to manage psychiatric and neurological disorders, including depression, PD, and AD. Clinical trials of AD or PD with MAOIs, particularly MAO-B selective inhibitors, have yielded mixed or negative results;811,812 therefore, the potential benefit from MAO inhibition for AD treatment remains to be definitively clarified. In addition, there is the possibility of improving benefits by integration of MAO inhibition with other therapies targeting alternative AD pathological features. As a result, numerous multifunctional molecules have emerged regulating MAO, metals, Aβ, and AChE. Arduino et al. prepared a series of DFP derivatives with propargylamino groups similar to the MAOI, rasagiline, to produce MAOI-MC-1 and MAOI-MC-2, which were tested in animal models of AD and PD (Figure 34).813 The authors employed 1-methyl-4-phenylpyridinium (MPP+), a toxic molecule that interferes with mitochondrial oxidative phosphorylation, leading to ATP depletion and cell death.814 MPP+ causes death of dopaminergic neurons in PD models.815 Although primarily a PD model, MPP+ was combined with Aβ40 or Aβ42 to induce damage to human teratocarcinoma NT2 cells.813 They found that MAOI-MC-1 and MAOI-MC-2 could protect NT2 cells from toxicity induced by MPP+ and Aβ42.813 Albeit slated as a MAOI, their MAO inhibitory properties was not experimentally tested nor was the metal binding abilities of MAOI-MC-1 and MAOI-MC-2 or their influence on metal-triggered Aβ aggregation. MAOI-MC-3 (Figure 34) was highlighted as a potent multifunctional agent with inhibitory activities against hMAO-A (IC50 = 4.3 μM), hMAO-B (IC50 = 2.6 μM), EeAChE (IC50 = 3.7 μM), and eqBuChE (IC50 = 2.8 μM).816 Additionally, MAOI-MC-3 exerted neuroprotection (53% at 1 μM of the compound) against MPP+ toxicity in SH-SY5Y cells.816 Huang et al. designed multifunctional molecules based on the ring system from the natural product, coumarin (Figure 34), fused to a metal binding moiety.817 Coumarin derivatives have been previously known as selective MAO-B inhibitors,818−820 although some studies have noted MAO-A preference.821 Coumarin derivatives have also been reported as inhibitors of Aβ aggregation.822 The best molecule from the Huang et al. investigation was MAOI-MC-4 (Figure 34) that selectively inhibited hMAO-B (IC50 = 81 nM) with only 3.5% inhibition of hMAO-A at 100 μM of the compound, compared to iproniazid (N-isopropylisonicotinohydrazide), a nonpropargylamino irreversible MAOI (IC50 = 6.6 and 7.8 μM for hMAO-A and hMAO-B, respectively).817 MAOI-MC-4 also modulated metal-free Aβ 42 aggregation at 53% at a concentration of 20 μM versus 50 and 64% at 20 μM of curcumin and resveratrol (structures shown in Figures 17 and 15, respectively), respectively. Binding to Cu(II) was demonstrated by UV−Vis, with moderately intensifying peaks at ca. 250, 300, and 400 nm.817 MAOI-MC-4 was nontoxic to PC12 and SH-SY5Y neuroblastoma cells up to 100 μM and was predicted to be possibly BBB permeable by PAMPA-BBB.817 The influence of MAOI-MC-4 on metaltriggered Aβ aggregation was not tested. AY

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Figure 35. Multifunctional compounds fashioned on the rings of aurone and chromone. Aurone (chemical name shown in Figure 26); chromone, (4H)-1-benzopyran-4-one; MAOI-MC-7, (Z)-4,6-dihydroxy-2-(4-(piperidin-1-yl)benzylidene)benzofuran-3(2H)-one; MAOI-MC-8, (E)-3-(((2-hydroxy-5-methylphenyl)imino)methyl)-6methyl-4H-chromen-4-one.

concentration of 20 μM of the compound). 98 ThT fluorescence of Cu(II)-triggered Aβ42 aggregation in the presence of MAOI-MC-8 was 60% of the control sample; visualization of the resultant Cu(II)−Aβ42 aggregates by TEM revealed fewer fibrils when MAOI-MC-8 was present.98 Antioxidant capacity for MAOI-MC-8 was assessed by an ORAC assay and found to be 3.6 Trolox equivalents, and it could decrease ROS in H2O2-treated PC12 cells. UV−Vis and fluorescence spectra indicated an interaction between MAOIMC-8 and Cu(II), Fe(II), Fe(III), and Zn(II), and a Cu(II)to-ligand ratio of 1:1 was verified for MAOI-MC-8.98 MAOIMC-8 was nontoxic to PC12 cells at 20 μM and protected them from H2O2-triggered toxicity at a concentration as low as 1 μM. PAMPA-BBB predicted it could be available in the CNS.98 Sheng et al. integrated the structural elements from three scaffolds in their design scheme.829 As depicted in Figure 36, the motifs from the Aβ aggregation inhibitor (SKF-64346),830 the metal chelator (DFP), and the aminopropoxyphenyl pharmacophore of the histamine H3 receptor (H3R) inverse agonist831 were combined to generate a collection of small molecules. H3R antagonists were reported to raise the levels of neurotransmitters in the brain and improve cognitive performance in AD preclinical models.832,833 The main molecule reported, H3RA-MC-1 (H3R inverse agonist with metal binding), expressed selective human H3R (hH3R) antagonistic activity (IC50 = 0.32 nM) over hH1R, hH2R, and hH4R (IC50, all >10 μM).829 H3RA-MC-1 controlled self-induced Aβ42 aggregation (IC50 = 2.9 μM, 80% inhibition at 20 μM of the compound) and exhibited a value of 1.5 in a TEAC assay. Inhibition of Cu(II)-mediated Aβ42 aggregation and disaggregation of preformed fibrils were demonstrated by TEM, whereupon fewer fibrils were observed in the presence of H3RA-MC-1.829 UV−Vis shifts were observed when Cu(II) or Fe(II) was incubated with H3RA-MC-1, and a 1:2 Cu(II)-toH3RA-MC-1 stoichiometry was determined.829 Among the presented multifunctional molecules, certain compounds have shown promising in vivo results as potential AD therapeutics. DFO, a metal chelator, demonstrated its ability to enhance the performance of P301L tau Tg mice in a radial arm water maze test through its inhibitory activity

Figure 36. Design of a multifunctional compound based on an Aβ aggregation inhibitor (SKF-64346), a metal chelator (DFP), and an inverse agonist of H3R. SKF-64346, (2-(4-(3-(diethylamino)propoxy)phenyl)-1-benzofuran-3-yl)-(4-methylphenyl)methanone; DFP (chemical name shown in Figure 2); H3R inverse agonist, 2methyl-3-[4-[3-(1-pyrrolidinyl)propoxy]phenyl]-5-(trifluoromethyl)4(3H)-quinazolinone; H3RA-MC-1, 3-hydroxy-2-methyl-1-(4-(3(pyrrolidin-1-yl)propoxy)phenyl)pyridin-4(1H)-one.

against GSK3β and decrease memory loss in APP/PS1 mice, while reducing Aβ load in the brain.456 DFP was observed to lower the levels of Aβ and tau phosphorylation in a cholesterolinduced rabbit AD model.457 Administration of ThT-MC-1, a compound capable of interacting with metal ions and Aβ, to APP/PS1 mice exhibited a decrease in cortical Aβ load by 32%.504 Treatment of pISTIB-MC-2, a compound specific for metal−Aβ, in 5xFAD mice resulted in noticeable cognitive improvements compared to the control mice according to the MWM test.612 EGCG was reported to diminish Aβ plaque load in APPswe mice by promoting α-secretase cleavage.549 On the basis of the positive in vivo effects reported, further evaluation or optimization of these molecules may pose an advantageous strategy for producing effective AD treatments. While the number of small molecules targeting metal ions and pathological features other than AChE, Aβ, and tau is at present rather small, it may be an area of expanding interest. MAOs are an alternative therapeutic target; thus, the development of multifunctional molecules capable of inhibiting both MAOs and AChE, along with metal chelation, would be valuable. Moving forward, the integration of scaffolds inhibiting other brain receptors or enzymes central to AD pathology into multifunctional molecules could be a path forward (e.g., alternative targets outlined in section 2.5, such as NMDAR, kinases, phosphatases, and PDEs).

3. PARKINSON’S DISEASE (PD) The second most prevalent neurodegenerative disease, PD is an idiopathic motor system disorder, characterized by the loss of dopaminergic neurons.2 The number of people affected by AZ

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PD in 2015 was estimated to be ca. 6 million worldwide.834 Like other neurodegenerative disorders, the incidence rate of PD exhibits a positive correlation with age. With the aging population and increase in life expectancy, the incidence rate of PD is expected to rise.834 The onset of PD is genderdependent as males are more likely to be affected by PD with a male-to-female ratio of 3:2.835 A reported, 83% of PD patients are simultaneously affected by dementia.836 Currently, no cure is available for PD. The most notable characteristics of PD are its motor symptoms, collectively known as Parkinsonism, which include bradykinesia (slowness of movement), muscular rigidity, rest tremor, and postural and gait impairment.837 In addition, autonomic symptoms (e.g., urinary incontinence, chronic constipation, and postural hypotension) are observed during the later stages of PD.836,838,839 Disease progression and symptoms differ from case to case. Two major subtypes of PD have been proposed based on the observed motor symptoms: tremor-dominant and nontremor dominant PD. Tremor dominant PD is often characterized by a slower rate of progression and less functional disability relative to nontremordominant PD.840 Apart from its motor symptoms, nonmotor features of PD include olfactory dysfunction, cognitive impairment, psychiatric symptoms, sleep disorders, autonomic dysfunction, and fatigue.2 These nonmotor symptoms often precede the onset of the classical motor symptoms.841 Experts have suggested that the initial pathogenic progression of PD could occur during the premotor stages of PD. The late stage of PD is marked by treatment-resistant motor and nonmotor features leading to postural instability, freezing of gait, dysphagia, and speech dysfunction. The selective degeneration of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy pathology are the main criteria for the diagnosis of PD.2 Currently, there are no definitive methods of diagnosing PD at the early stage.842 Initial diagnosis of PD is largely based on the manifestation of characteristic motor symptoms.842 Subsequent tests eliminate alternate diagnoses based on the presence of auxiliary clinical, physiological, and histological characteristics (e.g., presence of Lewy bodies).2,842 Lastly, the prospective positive criteria for PD is reviewed to finalize the diagnosis. Supplementary imaging tests, such as magnetic resonance imaging (MRI), ultrasound, SPECT, and positron emission tomography (PET), are often utilized to improve the accuracy of the diagnosis. Due to its complexity, the diagnosis of PD has been a subject of intensive research and numerous articles examine the relevant diagnostic methods and their accuracy.842−844 The precise etiology of PD remains elusive. Research dedicated toward identifying the principle causative factors in PD has led to the belief that the interplay of both genetic and environmental factors may be involved in the pathogenesis of the disease.2 At the physiological level, mood disorders and constipation have been reported to nearly double the likelihood of developing PD.845 A meta-analysis has identified environmental factors that could considerably increase the risk for PD: exposure to metals and pesticides, head injury, rural living conditions, usage of β-blockers, agricultural occupation, and water source.845 On the other hand, smoking tobacco, coffee and alcohol consumption, and usage of nonsteroidal anti-inflammatory drugs and calcium channel blockers have been reported to be correlated with a lower chance of developing PD.845 Epidemiologic studies have proposed that

the intake of antipsychotics and exposure to solvents, especially trichloroethylene, may enhance the risk of PD.846,847 The genetic facet was first suggested by the increased risk of PD with a family history of the disease or tremor.845 The strongest genetic indicators for PD are the monogenic forms of the disease (e.g., SNCA, LRRK2, VPS35, EIF4G1, DNAJC13, CHCHD2, parkin, PINK1, and DJ-1), characterized by mutations to a single gene. Mutations in LRRK2 and parkin are the most common causes of dominantly and recessively inherited PD, respectively.848 Genetic association tests and a multicenter study have implicated the involvement of mutations in GBA as a genetic factor for PD.849−851 GBA encodes glucocerebrosidase, known to affect the expression and aggregation of α-Syn.852,853 The intersection of diverse genetic and environmental elements portray the complexity of PD pathology, and further research regarding their interplay would prove helpful in understanding the inner workings of the disease and discovering treatments capable of halting its progression. Loss of dopaminergic neurons, the key histopathological feature of PD, is responsible for the characteristic Parkinsonism. This cellular attrition can be observed at the early stage of the disease at moderate levels, implying the progression of the disease at premotor stages and the importance of detecting the disease early.854 The loss of neurons is accompanied by the death of astrocytes and a significant increase in the number of microglia in the substantia nigra.855,856 Although the main focus regarding neuronal degradation in PD is directed toward the substantia nigra, other regions of the brain (e.g., amygdala and hypothalamus) are also affected.857 The principal sources of neuronal loss observed in PD have not been revealed; however, research in this subject area has led to the proposal of several potential pathological factors. Lewy bodies, composed of α-Syn, are considered a hallmark of PD. Thus, α-Syn has been implicated as a pertinent pathological factor and regarded as a possible therapeutic target.858−864 Additionally, oxidative stress,865 metal ion dyshomeostasis,10,866 mitochondrial dysfunction,865,867 defects in metabolism, aberrant axonal transport,868 and chronic inflammation869 have been investigated for their roles in the pathology of PD. To date, there are no treatments capable of effectively preventing the progression of PD. Current therapeutic strategies for PD include the administration of a dopamine precursor [e.g., L-DOPA (L-3,4-dihydroxyphenylalanine)], dopamine agonists (DAs), MAOIs, catechol-O-methyltransferase inhibitors (COMTIs), and anticholinergics. L-DOPA (Figure 37) has been shown to only temporarily elevate

Figure 37. Dopamine and L-DOPA. Dopamine, 3,4-dihydroxyphenethylamine; L-DOPA: L-3,4-dihydroxyphenylalanine.

neurotransmitters’ levels to relieve the motor and nonmotor PD symptoms.870,871 Advancements in our understanding of the interconnected network of pathological features, and the development of multifunctional compounds capable of concurrently targeting and regulating multiple pathogenic factors of PD may offer a prospective direction in formulating BA

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Rodriguez et al. through cryo-EM.894 Oligomeric forms of αSyn, composed of 2 to 100 monomers, are considered as potential toxic species.861 Cryo-EM analysis revealed α-Syn oligomers with hollow cylindrical architectures, similar to its fibrillar species, suggesting that the oligomers may be kinetically trapped during the self-assembly process.895 Larger oligomeric α-Syn species have been reported to impair protein degradation, accelerate the aggregation kinetics via a seeding effect, and interrupt crucial cellular functions.860,895 Studies indicated that α-Syn oligomers could disrupt lipid membranes through pore formation as observed with annular Aβ oligomers,896 more effectively than both monomers and fibrils.895,897 In vivo experiments further supported the toxicity of α-Syn oligomers. Rat brains injected with lentivirus expressing oligomer-prone α-Syn mutants demonstrated the presence of oligomers and the loss of dopaminergic neurons within 3 weeks, whereas other mutants, more inclined to form fibrils, were significantly less toxic.898 The proposed pathways regarding α-Syn-triggered toxicity were indicated to be associated with several organelles (e.g., synaptic vesicles, mitochondria, ER, Golgi, lysosomes, autophagosomes, and nucleus). Binding of large oligomeric α-Syn species to vesicle-associated membrane protein 2 disturbed SNARE complex formation, release of dopamine, and synaptic-vesicle motility, leading to neuronal degradation.899,900 Although α-Syn is mainly found in the presynaptic terminal, its aggregates can be observed in multiple locations of the cell, suggesting that its toxic effects may extend to cellular components other than the presynaptic terminal.883 α-Syn has also been suggested to induce mitochondrial dysfunction by enhancing calcium uptake and impairing mitochondrial protein transport.901,902 Prion-like transmission of α-Syn has been proposed through in vivo studies: the injection of synthetic αSyn into different cerebral regions in Tg and wild-type (wt) mice led to the formation of Lewy body-like structures with a widespread distribution.903−905 Additionally, the injection of Lewy body extracts from the brains of PD patients into the substantia nigra of macaque monkeys induced substantial nigrostriatal neurodegeneration.864 Although significant effort has been made to confirm the toxic nature of α-Syn oligomers, further research would be necessary to pinpoint the species responsible for the neurodegeneration observed in PD and determine their pathogenic mechanisms. On the basis of these observations, Lewy pathology has been proposed as a primary causative factor in the neuronal loss observed in PD.2 Braak et al. have proposed six stages representing the progression of Lewy pathology throughout the CNS.906,907 The Braak model has been increasingly accepted as it appropriately parallels the clinical development of PD.2 A positive correlation between the onset of PD and the development of Lewy pathology in the brain has been supported by several studies.908−910 Additionally, characteristic abnormal protein aggregates (i.e., Aβ and tau) observed in AD can also be found in the PD-affected brain, indicating the potential conjunction among proteopathies and a relationship between AD and PD. Furthermore, α-Syn, Aβ, and tau could influence the aggregation of one another in vitro in a synergistic manner that may lead to accelerated cognitive dysfunction.883,911 The susceptibility of the amygdala against different neurodegenerative disorders may serve as confirmation of the synergistic pathological relation between α-Syn and tau since it contains colocalized Lewy bodies and NFTs.912 Apart from its independent proteopathic indications, the

therapeutics effective in halting PD progression. This section illustrates the current knowledge of multiple pathological factors found in PD and discusses some examples of multifunctional molecules discovered and investigated as potential therapeutics investigated as potential therapeutics. 3.1. α-Synuclein (α-Syn)

α-Syn is a 14 kDa protein and the main component of the aberrant neuronal aggregates called Lewy bodies.872 As an intrinsically disordered protein, α-Syn lacks a defined 3D structure and is known to adopt multiple conformations, including α-helices, β-sheets, and random coils, depending on its environmental factors.858,873,874 Three specific components of α-Syn have been identified: (i) an N-terminal lipid-binding region; (ii) a central non-Aβ component in the hydrophobic region;875−877 (iii) an intrinsically disordered C-terminus.874 Under physiological conditions, α-Syn is highly soluble and exists at higher concentrations at presynaptic terminals, where it binds to membranes to promote the synaptic-vesicle fusion at the presynaptic terminal and may also regulate synapticvesicle trafficking.858,863,878 Previous studies suggest that α-Syn controls the release of synaptic vesicles by its interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to the SNARE protein synaptobrevin-2 and vesicle-associated membrane protein 2.858,879 α-Syn is also involved in the biosynthesis and regulation of dopamine.880 Overexpression of α-Syn in Tg mice is associated with dopaminergic terminal loss, deficient release of dopamine, and altered distribution of synaptic vesicles.881,882 Point mutations in α-Syn (A30P, E46K, H50Q G51D, A53E, and A53T) and genomic duplications or triplications containing the α-Syn locus have been implicated in autosomal dominant forms of familial PD.883 Single-nucleotide polymorphisms in α-Syn have been identified as factors that could increase susceptibility to sporadic PD through genome-wide association investigations.851,884 Changes in the concentration of α-Syn are shown to be linked to familial PD, and its accumulation leads to various synucleinopathies (e.g., PD, Lewy body dementia, and multiple system atrophy).883 Misfolded aggregates of α-Syn form intracellular inclusions within the cell body and neurites.885 The aggregation pathway of α-Syn, similar to that of Aβ, is composed of the nucleationdependent lag phase, exponential growth (elongation) phase, and steady state.886 Like many amyloidogenic peptides, transition to a β-sheet-enriched conformation drives the aggregation of α-Syn. In recent years, increasing evidence has indicated that PTMs (e.g., phosphorylation, ubiquitination, nitration, glycation, and truncation) of α-Syn as pathological features in PD, which could alter its propensity to aggregate into soluble oligomers and insoluble fibrils.887−890 For example, the phosphorylation of α-Syn at S129 has been implicated as a predominant modification in the PD-affected brain.891 In addition, the kinetics of α-Syn aggregation have been observed to be affected by metal ions, C-terminal proline residues, peptide concentration, molecular crowding, physical agitation, temperature, pH, ionic strength, and other exogenous factors.886 α-Syn, like Aβ and tau, is capable of existing in diverse forms (e.g., soluble oligomers and insoluble fibrils) throughout its aggregation pathway.892,893 The key structural contributor of α-Syn toward its aggregation is an 11-residue segment in the central hydrophobic region (NACore),875 confirmed by BB

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interconnected role of α-Syn with other pathological factors, such as metal ions, oxidative stress,913 dopamine,859,914−916 and MAOs,917,918 has been increasingly supported by evidence in recent years.

range.938 The pivotal role of M1 in Cu(II) binding to α-Syn was further confirmed a year later when Jackson et al. published the studies identifying a minimal Cu(II) binding αSynF4W sequence (MDVW) by analyzing metal binding properties of a modified α-Syn N-terminal fragment.939 In another study, H50 residue was suggested to serve as a “coordination switch” among three Cu(II) binding modes of α-Syn depending on the pH and a ratio of Cu(II) to α-Syn: (i) at pH 6.5, Cu(II) could be bound to the peptide via the Nterminal amine, the deprotonated amide and carboxylate groups of D2, and one water molecule; (ii) at physiological pH, the imidazole group of H50 occupied the fourth labile equatorial position at the Cu(II) center; (iii) at a high ratio of Cu(II) to α-Syn, H50 could be dissociated from the coordination sphere centered at the N-terminus.940 A cryoEM study visualized the formation of spherical, chainlike, and annular α-Syn oligomers in the presence of Cu(II).941 Cu(I) could bind to α-Syn, and two binding sites have been identified: (i) the first five N-terminal residues (MDVFM) and (ii) the residues 116−127 (MPVDPDNEAYEM).942,943 Interestingly, Cu(I) was observed to oxidize α-Syn at M1 under physiological conditions, which may alter its aggregation pathway.943 The interconnected pathological roles between Cu(I/II) and α-Syn have been supported by evidence as shown above. Although different types and sizes of oligomeric species have been observed, further research may be necessary to confirm the identity of metal-associated α-Syn oligomers contributing to neurodegeneration in PD and characterize their morphological, structural, and chemical properties in detail. Such experimental information may advance our understanding of the interrelated pathological roles between α-Syn and metal ions in PD and foster the development of effective therapeutics targeting pathologically relevant metal−α-Syn species. Binding of α-Syn to other metal ions [e.g., Zn(II), Al(III), Cd(II), and Co(II)] implicated in PD pathology has not been explored in detail, relative to Fe(II/III) and Cu(I/II). Although only limited information is available regarding Zn(II)’s role in PD proteopathy, it has been suggested that Zn(II) could facilitate α-Syn aggregation.944−946 Further investigations into the interactions between α-Syn and Zn(II) could represent an intriguing aspect of PD research that may open up new directions for discovering effective therapeutics. To further complicate the matter, PTMs of α-Syn are known to influence its metal binding properties. For example, the phosphorylation of α-Syn at S129 or Y125 was reported to alter the specificity and the affinity for metal binding. The phosphorylation at these residues increased the binding affinity for Cu(II), Pb(II), and Fe(II), but did not affect Fe(III) binding affinity.947 The complexity regarding the role of metal ions in relation to other pathological factors (e.g., α-Syn and oxidative stress) manifests the need for further investigations. PTMs of α-Syn, such as phosphorylation, could modify its charge and metal binding properties. Studies clarifying how PTMs of α-Syn could affect its binding affinity toward diverse metal ions [e.g., Fe(II/III), Cu(I/II), and Zn(II)] could be helpful in understanding a pathological relationship between α-Syn and metal ions and the impact of metal ion dyshomeostasis in PD at a molecular level.

3.2. Metal Ions

Research regarding the pathogenesis of PD has implicated metal ion dyshomeostasis as a contributing feature. Epidemiological studies of PD indicate that long-term exposure to heavy metals is associated with the onset of the disease.919−921 The potential involvement of Fe(II/III) in the pathology of PD has been speculated since the 1920’s, when Fe(II/III) was found to be colocalized with Lewy bodies.922 Post-mortem analysis of the brain tissue from PD patients has demonstrated noticeable changes in the levels of metal ions in the substantia nigra.923−925 Reports presented the elevated amounts of Zn(II) and Fe(III) in the substantia nigra of the PD affected-brain, while the level of Cu(II) was lowered.866 Technological advancements have since allowed researchers to more accurately quantify the contents of metal ions in the brain.926 Synchrotron X-ray fluorescence confirmed the increased total Fe(II/III) contents and decreased Cu(I/II) levels in the substantia nigra of the PD-affected brain.927,928 A pathogenic aspect of metal ions in PD is their relation with α-Syn.866 Recent studies exhibited α-Syn’s ability to interact with Fe(II/III), Cu(I/II), and Zn(II), which could alter its aggregation and induce its cross-linking via metal-catalyzed oxidation.866,929 Cole et al. indicated that metal-catalyzed oxidation of α-Syn inhibited the formation of α-Syn fibrils and instead observed the accumulation of β-sheet-enriched oligomers.929 The presence of metal ions [e.g., Al(III), Cu(II), Cd(II), and Fe(III)] was reported to trigger the aggregation of α-Syn through conformational changes.930,931 Biophysical studies of binding between α-Syn and Fe(II) through tyrosine fluorescence quenching determined the binding affinity to be ca. 173 μM.932 NMR titration studies showed a binding affinity of ca. 1 mM and suggested a potential C-terminal Fe(II) binding site (D121, N122, and E123).933 The binding constant between Fe(II) and α-Syn was deduced to be 1.7 × 10−4 M by a combination of MS and cyclic voltammetry.934 In the same study, the authors proposed a mechanism for metal-mediated oxidation of α-Syn whereby Fe(II) within the Fe(II)−α-Syn complex could be oxidized in the presence of O2 followed by dissociation from the complex despite a relatively high binding affinity (0.8 × 10−13 M) due to the propensity of Fe(III) to form Fe(OH)3.934 Addition of Fe(III) to preformed α-Syn oligomers in vitro yielded larger detergent-resistant oligomers capable of pore formation in lipid bilayers.935 These findings suggested that Fe(II/III) and α-Syn might be cooperatively associated with toxicity. Cu(I/II), present in lower levels in the PD-affected brain, is known to interact with α-Syn and promote its aggregation in favor of more compact conformations, generating toxic oligomers.936 NMR studies revealed two specific binding sites centered around M1 and H50, respectively, for Cu(II).937 Binolfi et al. presented three Cu(II) binding modes of α-Syn via the combined application of NMR, EPR, UV−Vis, CD, and matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS): (i) N-terminal M1 and amide bond between M1 and D2 with two water molecules (Kd = ca. 2 × 10−7 M); (ii) binding centered around H50 with a weaker Cu(II) binding affinity (Kd = ca. 5 × 10−5 M); (iii) C-terminal binding with very low selectivity and binding affinity in the milimolar BC

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3.3. Oxidative Stress

observed as a common theme among several neurodegenerative diseases and a connective element among pathological factors in PD, directly targeting oxidative stress solely through antioxidant approaches has proven ineffective thus far.982−984 Regardless, research related to oxidative stress is crucial to elucidating the underlying mechanisms that lead to neurodegeneration. In addition, antioxidant capacity could prove useful in combination with other functions to formulate multifunctional molecules.

Oxidative stress contributes to the pathogenic cascade that leads to the degradation of dopaminergic neurons in PD.948 The pathological role of oxidative stress in PD is closely linked to an array of pathogenic factors (e.g., mitochondrial dysfunction, dopamine metabolism, metal ion dyshomeostasis, and inflammation).948−952 Under pathological conditions, a number of signs (e.g., oxidation of proteins,953 lipids,954 and DNA955 as well as decreased levels of reduced glutathione956) indicate the exacerbation of the imbalance between production and removal of ROS throughout PD progression. Furthermore, PD animal models exhibiting motor symptoms triggered through oxidative stress by 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), rotenone, 1,1′-dimethyl-4,4′-bipyridinium dichloride (paraquat), and 6-OHDA support the pertinence of ROS to PD pathology.957−960 Mitochondrial dysfunction and dopamine metabolism are major sources of ROS in the brain.913 Oxidative phosphorylation in mitochondria, responsible for energy generation for neural activity, is the main source of O2•− and H2O2.961,962 Deficiencies of complex I in the respiratory chain are suggested to be associated with the bulk of the detrimental effects stemming from ROS production in PD.963 Inhibition of complex I followed by aggravation of ROS production creates a deleterious cycle that contributes to oxidative stress.963 The preferential neurotoxicity of MPTP, a well-known complex I inhibitor, against dopaminergic neurons has supported a role of complex I in the pathology of PD.964 Accumulation of α-Syn was also shown to disrupt the activity of complex I, leading to elevated ROS formation and oxidative stress in dopaminergic neurons.965,966 Under normal conditions, the level of dopamine is regulated by oxidative metabolism via MAO-A.913 Alternatively, the balance in the enzymatic activity between MAO-A and MAO-B shifts with age, leading to an increased generation of H2O2 as a byproduct of MAO-mediated dopamine degradation.967,968 The contribution of MAO-B in the pathology of PD through oxidative stress is further supported by the selective and progressive neurodegeneration of dopaminergic neurons in the substantia nigra.969 Oxidation of dopamine and the pathological implications brought by its byproducts are discussed in section 3.4. Other sources of ROS implicated in PD pathology include Ca(II) homeostasis,965,970 lipid peroxidation in the presence of Fe(II/III),913 and the actions of 4-hydroxyl-2nonenal, a toxic end-product of free radical-stimulated peroxidation of phospholipid-bound arachidonic acid.971,972 Neuronal degradation is induced by the elevated production of ROS and their disrupted removal. Among them, the ubiquitin-proteasome system (UPS) is responsible for multiple processes that reduce oxidative stress, including the degradation of α-Syn973,974 and defective mitochondria.975 Conversely, oxidized and aggregated α-Syn and inhibited complex I activity are known to disrupt proteasomal function.976,977 Neuroinflammation, mainly mediated by microglia, is another aspect of PD pathogenesis associated with oxidative stress.978 Reports have exhibited the activation of microglia with the release of oxidatively modified proteins, lipids, and DNA as a result of cell death.978 Activated microglia could produce O2•−, NO, glutamate, and TNFα, leading to neurodegradation.978−980 Interactions between ROS could also present important molecular pathways toward PD pathogenesis.981 The pathological role of oxidative stress in PD renders a highly complex map of interrelated factors. Although oxidative stress can be

3.4. Additional Targets

The selective degeneration of dopaminergic neurons in the substantia nigra is considered a hallmark of PD.985 Dopamine (Figure 37), deficient in the PD-affected brain,986 is a major neurotransmitter responsible for a wide range of physiological functions (e.g., motor control, emotion, and reward mechanisms).987,988 Dopamine is synthesized from tyrosine by tyrosine hydroxylase and stored in synaptic vesicles after uptake by the vesicular monoamine transporter 2.989,990 Current PD treatments attend to the deficiency of dopamine through the utilization of dopamine precursors and agonists. Metabolism of dopamine is a critical part of PD pathology and can be divided into enzymatic and nonenzymatic pathways.917 Enzymatic degradation of dopamine is catalyzed by MAO (section 3.4.2), generating H2O2 as a byproduct. For example, MAO-mediated oxidative deamination of dopamine yields 3,4dihydroxyphenylacetaldehyde (DOPAL) and H2O2.917,991 DOPAL exhibited greater toxicities in vitro and in vivo than dopamine by reacting with proteins to form Schiff bases.992 The production of O2•− during the oxidation of DOPAL to its quinone derivative has been indicated as a possible alternative pathway for its toxicity.917 On the other hand, nonenzymatic oxidation of dopamine results in the formation of semiquinone radicals and dopamine-o-quinone.993 Dopamine-o-quinone also induces modifications in PD-related proteins: α-Syn, parkin, DJ-1, superoxide dismutase 2 (SOD2), and ubiquitin carboxyterminal hydrolase L1.963,993 In addition, dopamine-o-quinone inactivates tyrosine hydroxylase994 and inhibits mitochondrial function.995 Further oxidation of dopamine-o-quinone can yield aminochrome that is capable of generating O2•− and depleting cellular NADPH through redox cycling.963 Oxidation of dopamine-o-quinone can also yield neuromelanin, a complex polymeric molecule associated with aging and PD.996 The role of neuromelanin in PD pathogenesis is unclear, but its metal binding ability and affinity for lipids, pesticides, and MPP+, a metabolite of MPTP, present potential contributions.997 Masoud et al. demonstrated that increased uptake of dopamine through dopamine transporter over-expression resulted in oxidative damage, neuronal cell death, and motor deficits.998 The dopamine pathology is connected to other PD pathological factors reported to be involved in disease progression. The oxidative conjugation of dopamine with αSyn has been suggested to lead to accumulation of α-Syn species in dopaminergic neurons. MAOs are mitochondria-bound enzymes that catalyze the oxidative deamination of dietary amines, hormones, and monoamine neurotransmitters (e.g., dopamine, serotonin, and tryptamine).400 Two different types of MAO, MAO-A and MAO-B, differ in their substrate and inhibitor specificity.400 In humans, MAO-B is responsible for the majority of dopamine metabolism under pathological conditions.400 An increased level of MAO-B in neuronal tissue has been observed with aging and PD.968 On the basis of the current BD

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understanding of MAOs’ role in dopaminergic neurodegeneration of the substantia nigra, MAO inhibition has been considered a potential therapeutic tactic for PD. Reversible and irreversible MAO-A and MAO-B inhibitors have been studied for their efficacy in treating PD and other neurodegenerative disorders.999−1002 Clinical evidence has demonstrated that MAO-B inhibitors are effective PD therapeutics, suggesting that the inhibitory selectivity toward MAO-B is an essential parameter to consider in drug design.1003 Unfortunately, MAO inhibition cannot stop or recover the progression of PD. This therapeutic strategy, however, could manage the symptoms of PD and may be able to slow the progression of the disease. Therefore, this enzymatic regulation could be a crucial facet for the design of multifunctional molecules to treat PD.1004,1005 In recent years, AChE, mainly known for its involvement in AD, has been suggested to be associated with PD pathogenesis since cholinergic deficits have been observed, along with dopaminergic alterations.1006 This idea has been supported by the irregular activity of AChE exhibited in the brains of PD patients.1007−1009 Furthermore, previous research has implicated a link between neuronal cell death and AChE expression.1010 Zhang et al. investigated this notion by monitoring a MPTP-induced PD mouse model, in which they revealed that the deficiency of AChE led to a decrease in expression of apoptotic proteins, such as caspase-3.1010 Multiple studies investigating the clinical effects of AChEIs in PD patients further reported the involvement of AChE in PD pathology.1011−1014 A randomized, double-blind efficacy study indicated that the administration of donepezil (Table 1), an AChEI, showed dose-dependent efficacy in the patients with PD.1006 Apart from the potential therapeutic targets of PD presented above, a multitude of biological features has been proposed to participate in the pathological progression of the disease. These include COMT,1015,1016 glutamate receptors,1017 membrane lipids,862 PPARγ,1018 and T-type calcium channels.1019 Despite the efforts to identify the specific roles of principle pathological factors in PD, researchers have not been able to clearly pinpoint the direct cause of PD. In fact, these failures indicate the complexity of the disease’s pathology and that the effective treatment of PD may require the simultaneous targeting of multiple features, as we have presented to be the case in AD.1005,1020 In this section, we summarize some examples of the molecules targeting the pathogenic factors implicated in PD with a focus on multifunctionality and the ability to interact with metal ions.

Figure 38. PcTS and natural products reported to alter the aggregation of α-Syn and exhibit beneficial biological functions, such as antioxidant activity and neuroprotection. PcTS and EGCG (chemical names reported in Figures 33 and 16, respectively); baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one; quercetin (chemical name presented in Figure 17); exifone, (2,3,4trihydroxyphenyl)(3,4,5-trihydroxyphenyl)methanone; ginsenoside Rb1, (2R,3R,4S,5S,6R)-2-[[(2R,3S,4S,5R,6S)-6-[(2S)-2[(3S,5R,8R,9R,10R,12R,13R,14R,17S)-3-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-12-hydroxy-4,4,8,10,14pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1Hcyclopenta[a]phenanthren-17-yl]-6-methylhept-5-en-2-yl]oxy-3,4,5trihydroxyoxan-2-yl]methoxy]-6-(hydroxymethyl)oxane-3,4,5-triol; curcumin (chemical name indicated in Figure 8).

morphologies and low toxicity in the presence of PcTS (50 μM).1023 A specific aromatic interaction between PcTS and αSyn was demonstrated by trapping prefibrillar α-Syn by anchoring to Y39.1021,1024 Fibril formation was inhibited at a 5:1 ratio of α-Syn to PcTS, which yielded negligible ThT fluorescence, even after incubation for 10 days.1024 FonsecaOrnelas et al. showed that PcTS stabilized the helical formation of vesicle-associated α-Syn and consequently hindered its pathogenic misfolding and aggregation.1024 Flavonoids (e.g., EGCG and baicalein; Figure 38) reported for their useful properties (e.g., antioxidant and neuroprotective properties) have been studied for their ability to modulate the aggregation of α-Syn. Equimolar concentrations of EGCG promoted the dissociation of α-Syn fibrils into smaller and nontoxic aggregates by reordering the fibrillar architecture.1025 Under the conditions of this study, smaller less structured α-Syn aggregates were detected upon incubation with EGCG for 24−72 h. Lorenzen et al. proposed that EGCG reduced the toxicity of α-Syn oligomers by inhibiting their ability to permeabilize vesicles.1026 The molar ratio of EGCG to α-Syn oligomers needed to prevent 50% of calcein release from the membrane was determined to be ca. 7:1. Furthermore, EGCG immobilized the C-terminal region of α-Syn oligomers and, as a result, slightly weakened its

3.5. Molecules

3.5.1. Molecules Targeting α-Syn. A variety of molecules has been reported for their ability to modify the aggregation of α-Syn. Although evidence supports that the presence of metal ions affects the aggregation and toxicity of α-Syn, there is a shortage of multifunctional molecules capable of interacting with both α-Syn and metal ions [e.g., Cu(I/II) and Fe(II/III)]. In this section, we describe examples of the compounds known to modulate the aggregation of α-Syn. PcTS (Figure 38), reported for its ability to inhibit tau aggregation (section 2.6.3), also acts as an α-Syn aggregation inhibitor (ASI).1021−1024 The binding affinity between PcTS and α-Syn is within a low micromolar range.1023 Lee et al. reported the altered aggregation of α-Syn (0.2 and 1 mg/mL), resulting in the formation of aggregates with different BE

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Figure 39. Representative inhibitors against the aggregation of α-Syn (ASIs). ASI-1, (1E,6E)-1,7-bis(4-(benzyloxy)-3-methoxyphenyl)hepta-1,6diene-3,5-dione; ASI-2, 4,4′-(5-ethyl-6,6′-dihydroxy-5′-methoxy-(1,1′-biphenyl)-3,3′-diyl)bis(butan-2-one); ASI-3 (rifampicin), 5,6,9,17,19,21hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)-dione-21-acetate; ASI-4 (ceftriaxone), (6S,7S)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3(((2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylic acid; ASI-5, (5R,7R,9S,11S,16R,18R,20S,22S)-5,22:7,20:9,18:11,16-tetramethanononacene-8,19-diol,5,7,9,11,16,18,20,22-octahydro-8,19-bis(dihydrogen phosphate); ASI-6 (entacapone), (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide; ASI-7 (tolcapone), (3,4-dihydroxy-5nitrophenyl)(p-tolyl)methanone.

propensity to bind to membranes.1026 In vivo studies utilizing a MPTP-induced mouse model of PD indicated that the oral administration of EGCG (2 mg/kg/day) significantly controlled the accumulation of α-Syn and Fe(II/III) in the substantia nigra pars compacta.1027 Furthermore, EGCG inhibited the loss of tyrosine hydroxylase-positive neurons and abnormalities in the expression of mitochondrial apoptosis regulating proteins (e.g., Bcl-2 and BAX) as well as PKC isoenzyme α, an enzyme involved in controlling cell survival and apoptosis.1027,1028 Baicalein (Figure 38), a flavonoid originally isolated from the roots of Scutellaria baicalensis and Scutellaria laterflora, is a multifunctional molecule able to modify α-Syn aggregation,1029,1030 attenuate neuroinflammation, and inhibit the production of cathepsin B in the substantia nigra of MPP+-treated rat models of PD.1031 Other natural products with antiaggregation properties toward α-Syn include quercetin,1032,1033 exifone,1034 and ginsenoside Rb1 (Figure 38).1035 The inhibitory activities of these molecules were not tested against metal-induced α-Syn aggregation. Natural products (e.g., curcumin, exifone, ginsenoside Rb1, and various flavonoids; Figure 38) known to alter the aggregation of amyloidogenic peptides have also been investigated for their effects on the aggregation of α-Syn. Curcumin could inhibit in vitro aggregation of α-Syn1036,1037 and reduce the toxicity of its oligomers.1034,1038 Singh et al. presented that curcumin (3 μM) could recover the viability of SH-SY5Y neuroblastoma cells treated with α-Syn oligomers (5 μM) purified via size exclusion chromatography by 20%, compared to that without the compound, potentially through morphological alterations of α-Syn oligomers.1039 A compara-

tive analysis of the effects of curcumin analogs on the aggregation and toxicity of α-Syn led to the discovery of ASI-1 (Figure 39) that exhibited improved binding to α-Syn and suppressed its aggregation and toxicity better than curcumin.1040 ASI-1 (5 μM) diminished α-Syn (10 μM)-induced toxicity to SH-SY5Y neuroblastoma cells by 93%. Premised on the rapid degradation of curcumin at physiological pH, Marchiani et al. investigated the effects of curcumin metabolites and their analogs on the pathology of α-Syn.1041 ASI-2 (biphenyl zingerone derivative; Figure 39) exhibited a relatively high affinity (Kd = 0.11 μM) for α-Syn and antioxidant activity (IC50 = 23 μM in a DPPH assay; 1.8 equiv in a TEAC assay). Lastly, cell viability studies displayed that ASI-2 could attenuate the toxicity induced by MnCl2 in PC12 cells.1041 Note that the effects of ASI-1 and ASI-2 on metal-induced aggregation of α-Syn were not reported. Several antibiotic compounds have been shown to control the aggregation pathway of α-Syn. ASI-3 (rifampicin; Figure 39) is a commercially available antibiotic used for tuberculosis treatment.1042 Apart from its original usage, this antibiotic has been found to stabilize monomeric forms of α-Syn in vitro, affect the fibrillization process, and destabilize preformed aggregates.1043 Li et al. presented that ASI-3 (50 μM) was able to inhibit the fibrillization of α-Syn and modulate α-Syn aggregation (at 100 μM of the compound).1043 Prevention of the conformational changes of α-Syn may be the MoA for ASI3’s inhibitory activities. ASI-3 reduced MPP+-induced toxicity in PC12 cells in a dose-dependent manner, resulting in 92% viability (at a concentration of 100 μM) compared to 77% in the MPP+-treated control.1044 ASI-4 (ceftriaxone; Figure 39), a well-tolerated and brain-permeable β-lactam antibiotic, has BF

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been suggested as a potential therapeutic agent for several neurodegenerative diseases due to its multifunctionality.1045 Known for its ability to counteract glutamate-mediated toxicity and boost the degradation of misfolded proteins, in vivo studies with ASI-4 demonstrated its potential in ameliorating the loss of dopaminergic neurons in MPTP-induced rat models of PD.1046 Daily intraperitoneal administration of ASI-4 (200 mg/kg/day) for 14 days lowered dopaminergic neurodegeneration in the nigrostriatal system and microglial activation, increased the expression of glutamate transporter 1, and improved cognitive deficits, relative to the compound-free control.1046 The impact of ASI-3 and ASI-4 on the aggregation of α-Syn in the presence of metal ions was not investigated. ASI-5 (CLR01; Figure 39) is a “molecular tweezer” with an affinity for lysine (Kd = ca. 2 × 10−4 M).1047 It is reported to modulate the aggregation of several amyloidogenic proteins, including α-Syn, and its neuroprotective properties in vitro and in vivo have been studied.1048,1049 An equimolar concentration of ASI-5 almost completely inhibited the aggregation of α-Syn in vitro and an excess amount of ASI-5 dissociated preformed fibrils.1049 A cell proliferation assay using bromodeoxyuridine (BrdU) incorporation showed that ASI-5 attenuated α-Syninduced toxicity in HEK cells (IC50 = 4 μM). Lastly, this study reported the neuroprotective properties of ASI-5 against α-Syn toxicity in zebrafish embryos.1049 There are no reports regarding ASI-5’s ability to modify metal-induced aggregation of α-Syn. Two nitrocatechols as COMTIs, ASI-6 (entacapone) and ASI-7 (tolcapone) (Figure 39), were observed to control the aggregation of α-Syn and Aβ.1050 At an equimolar concentration, both compounds prevented the aggregation of α-Syn by ca. 90% as well as the seeding effect of α-Syn fibrils. ASI-6 (5 μM; structure shown in Figure 39) was especially effective in reducing the toxicity of preaggregated α-Syn (40 μM) in PC12 cells. Cell viability of the control was ca. 60% versus treatment with ASI-6 and ASI-7 (cell survival, ca. 100 and 75%, respectively).1050 On the basis of their results, the structural significance of the nitrocatechol group was suggested as the potential therapeutic functionality. Additional novel molecules discovered or designed as ASIs include BIOD303,1051 FN075,1052 ELN484228,1053 scyllo-inositol,1054 mannitol,1055 lovastatin,1056 and fasudil1057 (Figure 40). These molecules have not been subjected to studies regarding their effects on metal-induced α-Syn aggregation. Research efforts thus far indicate that the α-Syn-associated pathology is a major contributing factor in PD; however, therapeutics solely targeting α-Syn have not been clinically successful. It may be that modification of α-Syn aggregation may not suffice to halt the onset and progression of PD. On the basis of the complexity of PD involving α-Syn, the development of multifunctional molecules capable of simultaneously targeting proteopathic aggregation and other pathological features, such as metal ions, in the disease may pose a potential therapeutic approach. 3.5.2. Molecules Targeting Metal Ions. The accumulation of Fe(II/III) in the substantia nigra of the PD-affected brain garnered the attention of scientists as a pathological feature for the disease. Thus, efforts to control the levels of Fe(II/III) to combat its dyshomeostasis make up a large portion of research targeting metal ions in PD. Intracerebroventricular administration of DFO (130 ng; Figure 41), a clinically available Fe(II/III)-chelator used to treat Fepoisoning, was shown to prevent the loss of dopaminergic

Figure 40. Molecular structures of additional ASIs. BIOD303, 3-(1pyrrolidinylmethyl)-benzenemethanamine; FN075, (3R)-2,3-dihydro7-(1-naphthalenylmethyl)-5-oxo-8-[3-(trifluoromethyl)phenyl]-5Hthiazolo[3,2-a]pyridine-3-carboxylic acid; ELN484228, N-(4-fluorophenyl)-benzenesulfonamide; scyllo-inositol, (1r,2r,3r,4r,5r,6r)-cyclohexane-1,2,3,4,5,6-hexol; mannitol, (2R,3R,4R,5R)-hexane1,2,3,4,5,6-hexaol; lovastatin, (2S)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8ahexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo2H-pyran-2-yl]ethyl]-1-naphthalenyl-ester-2-methyl-butanoic acid; fasudil, 5-[(hexahydro-1H-1,4-diazepin-1-yl)sulfonyl]-isoquinoline.

Figure 41. Compounds able to chelate metal ions and have supplementary properties, such as MAO inhibition. DFO and DFP (chemical names presented in Figures 5 and 2, respectively); VK28 (8-HQ-MC-5), M30 (8-HQ-MC-3), and HLA20 (8-HQ-MC-4) (chemical names reported in Figure 9); M30D, 5-((methyl(prop-2yn-1-yl)amino)methyl)quinolin-8-yl dimethylcarbamate; HLA20A, 5((4-(prop-2-yn-1-yl)piperazin-1-yl)methyl)quinolin-8-yl dimethylcarbamate.

neurons induced by 6-OHDA in male adult rats.1058 A separate study showed that intramuscular injections of DFO (250 mg/ kg/day) for 10 days inhibited the accumulation of Fe(II/III) in MPTP-treated C57BL/6 mice.1059 Youdim et al. further BG

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Figure 42. Multifunctional MAOIs. MAOI-1, (E)-4-(((4-(benzyloxy)phenyl)imino)methyl)benzene-1,2,3-triol; MAOI-2, 1-ethyl-3-(6-(4((methyl(prop-2-yn-1-yl)amino)methyl)-1H-imidazol-1-yl)pyrimidin-4-yl)thiourea; MAOI-3, 1-(4-(3-(4-benzylpiperazin-1-yl)propoxy)-2hydroxyphenyl)ethan-1-one; MAOI-4, 3-((6-((2-(dimethylamino)benzyl)(ethyl)amino)hexyl)oxy)-1-hydroxy-9H-thioxanthen-9-one; MAOI-5, N-(3,4-dichlorophenyl)-1H-indazole-5-carboxamide; MAOI-6, N-(3-chloro-4-fluorophenyl)-1H-indazole-5-carboxamide; MAOI-7, N-(3-chloro-4fluorophenyl)-1-methyl-1H-indazole-5-carboxamide; MAOI-8, (E)-5-(3-hydroxy-4-(piperidin-1-ylmethyl)styryl)-4-(hydroxymethyl)-2-methylpyridin-3-ol.

confirmed the in vivo efficacy of DFO (lowest neuroprotective dose = 1.3 μg), showing the suppression of 6-OHDA-induced drops in the level of dopamine in mouse models of PD.1060 DFO has also been reported to downregulate the mRNA expression of α-Syn.1061 A comparative in vivo study regarding the effects of several Fe-chelators displayed that the administration of DFO (30 mg/kg) and DFP (10 mg/kg; Figure 41) in a 6-OHDA rat model of PD significantly attenuated the loss of dopaminergic neurons and the amount of dopamine.1062 DFP, which binds Fe(III) in a 1:3 metal-toligand ratio,1063 showed noticeable neuroprotective properties in neurons treated with Fe(III) nitrilotriacetate (10 μM) with a calculated EC50 value of ca. 20 μM.1064 Furthermore, DFP protected neuronal cells from H2O2. VK-28 (Figure 41; 8-HQ-MC-5 in Figure 9, vide supra) is a BBB-permeable Fe(II/III) chelator. In 6-OHDA-induced PD rat models, VK-28 suppressed basal and Fe(II/III)/ascorbateinduced mitochondrial membrane lipid peroxidation (IC50 = 13 μM).1065 Daily intraperitoneal injections of VK-28 (5 mg/ kg/day) to 6-OHDA-treated rats for 10 days were able to recover 68% of the loss of dopamine in comparison to the controls.1065 VK-28 does not indicate other biological activities, such as MAO inhibition. Thus, the derivatives of VK-28 (e.g., M30 and HLA20; Figure 41) were constructed to impart additional therapeutic benefits.482,1066 M30 (Figure 41; 8-HQ-MC-3 in Figure 9) is a potent multifunctional Fe(II/III) chelator designed via combination of an N-propargylamine moiety from rasagiline (structure shown in Figure 9) with a metal chelating agent, 8-HQ (Figure 9). Effects of M30 include MAO inhibition (IC50 = 37 and 57 nM for MAO-A and MAO-B, respectively), prevention and recovery of striatal dopamine depletion,1066 neuroprotection of tyrosine hydroxylase-positive neurons, reduction of microglial activation, and regulation of Fe(II/III). In vivo studies indicated that M30 could induce major antioxidant defense systems comprised of catalase, SOD, and glutathione peroxidase in the brain.1067

Zheng et al. developed M30D (Figure 41), a derivative of M30 containing the pharmacophore of rivastigmine (structure shown in Table 1).485,1068 M30D was reported to be a potent MAO-A inhibitor (IC50 = 7.7 nM) and a moderate MAO-B inhibitor (IC50 = 7.9 μM). Incorporation of the AChEinhibiting pharmacophore imparted an AChE-inhibitory activity to M30D, a prochelator (IC50 = 0.52 μM).1068 Although rivastigmine could inhibit the activity of BuChE, the corresponding inhibitory activities of M30D (IC50 = 43 μM) were much weaker than its parent molecule, M30.1068 The cytotoxicity of M30 and M30D was compared in SH-SY5Y neuroblastoma cells. The viability of SH-SY5Y cells treated with M30 was determined to be 71%, 25%, and 1% at 10, 25, and 50 μM of the compound, respectively. M30D-added cells demonstrated 87%, 50%, and 16% viabilities at the same concentrations as M30, respectively. These results showed that cells were more tolerant of M30D.485 HLA20 (Figure 41; 8-HQ-MC-4 in Figure 9) is a multifunctional molecule fashioned as a potential therapeutic for PD with Fe(III) chelating, MAO-B inhibitory (IC50 = 110 μM), and antioxidant properties.482 Zheng et al. reported that HLA20 could permeate chronic myelogenous leukemia K562 cells, known for their Fe(II/III) regulatory properties, at 80% relative to the control.482 EPR studies indicated HLA20’s ability to scavenge •OH. HLA20A (Figure 41), a derivative of HLA20, was designed by incorporating the pharmacophores of rasagiline and rivastigmine (structures shown in Figure 9 and Table 1, respectively).486,1068 Thus, HLA20A’s structure contains a carbamate moiety (for AChE inhibition) and a propargylamine group (for neuroprotective activity).1068 HLA20A presented moderate rAChE inhibition (IC50 = 0.50 μM) and weaker rBuChE inhibition (IC50 = 43 μM).486 In a manner similar to M30, the weak metal binding affinity of HLA20A was significantly enhanced in the presence of AChE via the release of HLA20.1068 HLA20A also displayed lower cytotoxicity compared to that of its parent molecule, HLA20.1068 BH

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Figure 43. Multifunctional molecules designed based on the molecular scaffolds of pramipexole and 5-OH-DPAT, previously reported DAs. Pramipexole, N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine; 5-OH-DPAT, 6-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol; DA-1, N6-(2-(4-([2,2′-bipyridin]-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine; DA-2, (S)-4-(4-(4-(2-((2amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperazin-1-yl)phenyl)quinolin-8-ol; DA-3, (S)-4′-(4-(2-((2-amino-4,5,6,7tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperazin-1-yl)-[1,1′-biphenyl]-3,4-diol; DA-4, (S)-4′-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)piperazin-1-yl)-[1,1′-biphenyl]-3,4-diol.

hybrid designed to inhibit MAOs and ChEs.721 The enzymatic inhibition studies determined the IC50 values of MAOI-8 to be 2.1 and 12 μM against EeAChE and MAO-B, respectively. The ORAC value was observed to be 2.6.721 3.5.4. Molecules Targeting Dopamine Receptors. Several DAs have been designed and reported as multifunctional molecules exhibiting a range of properties (e.g., metal chelation and antioxidant activity). Diverse multifunctional molecules have been developed based on pramipexole (Figure 43),1073,1074 a potent dopamine receptor agonist that has been clinically used for PD therapy.1075 DA-1 (dopamine agonist-1; named D-607 by the authors; Figure 43) is a multifunctional brain-penetrating dopamine D2/D3 receptor agonist with binding preference for Fe(II).1076 EC50 values of the aforementioned molecule were determined to be 51 and 14 nM for dopamine D2 and D3 receptors, respectively.1077 Metal binding studies determined that DA-1 could interact with both Fe(II) and Fe(III) (Kd = 1.6 × 10−13 and 2.4 × 10−4 M, respectively).1077 In vivo studies using Drosophila melanogaster fly and MPTP-induced mouse models demonstrated DA-1’s neuroprotective properties against α-Syn and MPTP.1076 The protective mechanisms for such activities were suggested to be involved in mitochondrial stabilization and inhibition of prolyl hydroxylase. A study tested the neuroprotective properties of another dopamine D2/D3 receptor agonist, DA-2 (named D-390 by the authors; Figure 43) developed employing the framework of pramipexole, with metal chelating and antioxidant properties.1078 The agonist activity of the molecule was determined as EC50 = 34 and 6.8 nM for dopamine D2 and D3 receptors, respectively.1078 DA-2 prevented MPTP-mediated dopaminergic cell loss in the substantia nigra in mice. The observed neuroprotective effects were proposed to stem from the synergistic effects of the molecule’s functionalities (e.g., dopamine agonist activity, Fe(II/III) chelation, and antioxidant capacity). Yedlapudi et al. presented two multifunctional DAs, DA-3 and DA-4 (called D-519 and D-520, respectively by the authors; Figure 43),1029 which were constructed based on the structures of pramipexole and 5-OH-DPAT (another dopamine receptor agonist),1079 respectively (Figure 43). Both

3.5.3. Molecules Targeting Monoamine Oxidases (MAOs). MAOI-1 (monoamine oxidase inhibitor-1; Figure 42) is a salicyladimine derivative with MAO-B inhibitory (IC50 = 1.7 μM), antioxidant (IC50 = 43 μM and 0.67 Trolox equivalent in DPPH and TEAC assays, respectively), and metal chelating properties.1069 The design strategy for MAOI-1 was to utilize the pharmacophores of a MAO-B inhibitor, 7-(3chlorobenzyloxy)-4-formylcoumarin and a metal chelator, clioquinol (Figure 2). MAOI-2 (propargylamine-modified 4aminoalkyl imidazole substituted pyrimidinylthiourea derivative; Figure 42), a multifunctional MAO-B inhibitor (IC50 = 1.4 μM for hMAO-B), presented AChE inhibition (IC50 = 0.32 μM against rAChE), moderate antioxidant capacity, Cu(II) chelating ability, and low cytotoxicity.1070 The molecule’s ability to alter α-Syn aggregation was not investigated; however, it effectively controlled Cu(II)-induced Aβ 42 aggregation. In vivo studies revealed that MAOI-2 ameliorated scopolamine-induced cognitive impairment in mice.1070 MAOI-3 (Figure 42), a 2-acetyl-5-O-(amino-alkyl)phenol derivative, presented relatively selective MAO-B inhibition (IC50 = 6.8 μM).1071 Additionally, MAOI-3 could inhibit AChE (IC50 = 0.69 μM for EeAChE), act as an antioxidant (ORAC value = ca. 1.5), chelate metal ions, and potentially cross the BBB.1071 A study reported a series of 1-hydroxyl-3aminoalkoxy-thioxanthone derivatives as multifunctional agents.682 Among them, MAOI-4 (Figure 42) potently inhibited the activities of MAO-A and MAO-B (IC50 = 1.0 and 0.9 μM, respectively) and AChE (IC50 = 0.59 μM) and chelated metal ions. Further studies revealed that the molecule showed low cytotoxicity in SH-SY5Y neuroblastoma cells and BBB permeability.682 Tzvetkov et al. published a subclass of N-unsubstituted indazole-5-carboxamides and their N-methylated analogs, fashioned as candidates for diagnostic and therapeutic agents for PD.1072 Three representative MAO-B inhibitors [i.e., MAOI-5, MAOI-6, and MAOI-7 (Figure 42); named NTZ1006, NTZ-1032, and NTZ-1441, respectively, by the authors; IC50 = 0.59, 0.68, and 0.66 nM against hMAO-B, respectively] displayed the ability to bind to Fe(II) and Fe(III) via UV−Vis. MAOI-8 (Figure 42) is a pyridoxine-resveratrol BI

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FALS genes are C9ORF721084,1085 and SOD11086 followed by TARDBP (TAR DNA-binding protein 43 that encodes the DNA and RNA binding protein TDP-43)1087,1088 and FUS.1089,1090 All four mutated genes also occur in SALS.9 Outward ALS symptoms depend on whether it is limb or bulbar onset. Limb onset is initially manifested by muscle weakness and awkwardness in walking, and by difficulty eating or talking in bulbar onset. As ALS progresses, muscle denervation leads to muscle atrophy.9 Histopathologically, ALS is characterized by loss of motor neurons in the motor cortex and spinal cord.9 Similar to most neurodegenerative diseases, ALS is characterized by multiple pathological features that include: (i) intraneuronal, protein-rich inclusions (generally, but not exclusively) within motor neurons;1091 (ii) metal ion dyshomeostasis and oxidative stress;10 (iii) neuroinflammation and proliferation of glial cells.1092−1095 There is currently a paucity of pharmacological treatment options for ALS. Riluzole (Figure 44),1096 a possible glutamate

of these molecules could bind to dopamine receptors (i.e., D2L and D3 isoforms) expressed in HEK-293 cells (Ki = 233 and 1.4 nM against D2L and D3 receptors for DA-3, respectively; Ki = 42 and 0.35 nM against D2L and D3 receptors for DA-4, respectively),1080 modify α-Syn aggregation, and exhibit neuroprotective properties against α-Syn-induced toxicity in PC12 cells and in a Drosophila model of synucleinopathy.1029 The currently available dopaminergic therapies have limitations in stopping the progression of PD and plausibility of developing complications following long-term administration.2 Resistance against symptomatic treatment in the later stages of PD shows the need for novel approaches to treat the chronic symptoms and halt the progression of the disease.2 On the basis of the complexity of PD pathogenesis, the design concept of multifunctionality may be an essential component in developing effective treatments for the disease. The increase in the number of compounds targeting multiple factors found or designed represents the growing interest in multifunctional molecules as potential therapeutic candidates for the motor system disorder, PD. In vivo studies of multifunctional molecules may present promising therapeutics with possible applicability. EGCG in PD mouse models reduced the levels of α-Syn and accumulated Fe(II/III), as well as the loss of tyrosine hydroxylase-positive neuron, while exhibiting neuroprotective properties against oxidative neuronal death in the hippocampus.1027,1081 Several in vivo studies have suggested ASI-4’s potential as a PD therapeutic. ASI-4 was capable of counteracting glutamate-mediated toxicity, preventing the loss of dopaminergic neurons in MPTP-induced PD models, decreasing microglial activation, increasing the expression of glutamate transporter 1, and improving cognitive deficits in animal PD models.1046 Such in vivo data indicate promising potential PD therapeutic candidates, which could serve as a basis for further development of applicable clinical treatments in the future.

Figure 44. Current FDA-approved molecules for ALS (riluzole and edaravone) and PD (rasagiline). Riluzole, 6-(trifluoromethoxy)benzothiazol-2-amine; edaravone, 5-methyl-2-phenyl-4H-pyrazol-3one; rasagiline (chemical name shown in Figure 9).

receptor antagonist that addresses abnormal excitatory amino acid metabolism in ALS,1097 and edaravone (Figure 44),1098 a possible radical scavenger, are approved by the FDA; however, they only provide a modest survival benefit. A significant hurdle to the discovery of ALS drugs is the heterogeneous nature of the disease, which can be caused by a number of mutations for which a unifying underlying pathogenesis is at present not known.1099 In addition, the multifactorial nature of the disease, encompassing proteopathy, metal ion dyshomeostasis, oxidative stress, and inflammation, adds another layer of complexity for the discovery of appropriate therapeutics. As a consequence, researchers have turned their attention to multifunctional molecules as a possible solution.

4. AMYOTROPHIC LATERAL SCLEROSIS (ALS) ALS is a progressive neurodegenerative disease characterized by the loss of motor neurons in the brain and spinal cord.9 Relatively rare compared to AD and PD, ALS affects approximately 1 to 3 individuals per 100000 globally.3,9 Certain subpopulations, however, suffer higher-than-average incidences.3 ALS is classified based on the initially affected area: (i) limb onset with loss of motor capability in arms and legs or (ii) bulbar onset associated with loss of motor neurons that enervate facial and throat muscles, leading to difficulty chewing, swallowing, or speaking.9 In both instances, the progressive nature of the disease spreads to all motor neuron populations, although it is slower in limb versus bulbar onset. Both types of ALS patients, however, ultimately succumb to respiratory failure from the loss of diaphragm function and intercostal muscle enervation. Most ALS cases are sporadic (ca. 90%) with later onset of the disease (midlife to middle-to-late 50’s). The remaining cases are familial forms inherited as a dominant trait with earlier onset (teenage to early adulthood).9 Approximately 15−20% of ALS cases are also linked to neurodegeneration of the frontal and temporal lobes of the cortex in FTD, which is more prevalent in familial ALS (FALS).1082 The number of genes and mutant variants associated with both FALS and sporadic ALS (SALS) has grown since the discovery of the first ALS gene in SOD1 in 1993.1083 The most commonly mutated

4.1. Superoxide Dismutase 1 (SOD1) and TAR DNA Binding Protein 43 (TDP-43)

Similar to other neurodegenerative diseases, ALS is characterized by protein aggregation, which in ALS occurs in the form of protein-rich cytoplasmic inclusions and Bunina bodies.1091,1100 As in AD, both wt and mutant proteins (e.g., TDP-43 and SOD1) have a propensity to aggregate. Intracytoplasmic deposits of the DNA and RNA binding protein wt TDP-43 occur, in which it may be cleaved, ubiquitinated, hyperphosphorylated, or mislocalized from the nucleus to the cytoplasm, in addition to aggregates of mutant TDP-43 in patients with a TARDBP mutation.1087,1088 Similarly, although mutant SOD1 proteins possess a greater tendency to aggregate,1101 wt SOD1 deposits are also common in many types of ALS.1102 In general, the scope of mutated genes implicated in ALS is believed to fall into three principle classes of the genes BJ

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influencing:1103 (i) protein homeostasis (e.g., SOD1); (ii) RNA homeostasis and trafficking (e.g., C9ORF72,1084,1085 TARDBP,1087,1088 and FUS1089,1090); (iii) cytoskeletal dynamics [e.g., tubulin 4A (TUBA4A)].1104 Proteins that disrupt protein homeostasis aggregate into prionlike assemblies resistant to clearance, which can overwhelm the cellular protein degradation machinery and cause ER stress.1103 RNA binding proteins are the fastest growing collection of ALSassociated mutations.9 These proteins are translocated from the nucleus to the cytoplasm where they aggregate and form inclusions. C9ORF72, the most commonly mutated gene in ALS, is an RNA binding protein linked to an elevated risk of FTD.1084,1085 In ALS, mutant C9ORF72 is composed of multiple additional copies of a noncoding 6-nucleotide repeat. mRNA transcripts of C9ORF72 accumulate and sequester nuclear proteins within the nucleus, forming potentially toxic RNA foci.1103 C9ORF72 mRNA transcripts translocated to the cytoplasm may be noncanonically translated into various toxic dipeptides. Finally, the genes that disrupt cytoskeletal dynamics destabilize microtubules leading to impaired axonal transport and neurite growth, a scenario reminiscent of tau pathology.7,8,1105 Ultimately, the cumulative effect of these diverse pathological mechanisms is the deposition of intranuclear and cytosolic protein and RNA aggregates, disruption of protein degradation, ER stress, mitochondrial dysfunction, defective nucleocytoplasmic and axonal transport, and altered neuronal function. The design of small molecules to target the aggregation of proteins (e.g., SOD1 and TDP-43) is facilitated by an understanding of aggregates’ structures. Although under study, fewer reports have been made on the structure of ALS aggregates compared to that of Aβ aggregates found in AD. The conformation and energy landscape of soluble monomeric and dimeric ALS-associated SOD1 mutants have been compared to those of wt SOD1 in efforts to identify the factors that contribute to their folding, oligomerization, and interactions with membranes and organelles.1101,1106−1111 A variety of SOD1 aggregates are generated in vitro, including nanometer-sized amyloid fibers and larger interwoven bundles, amyloid-like tubular arrays, nanosized annular aggregates, and spherical aggregates.1101 The relevance of aggregates formed in vitro to aggregates in vivo is uncertain; however, microaggregates from mutant SOD1 mice react with ThS, which suggests an amyloid-like structure.1112 Recently, solid-state NMR spectra of monomeric apo SODΔIV−VII, a variant that lacks the loops IV and VII but still fibrillizes like the full-length SOD1, were reported.1113 The simplified, smaller-sized apo SODΔIV−VII facilitated the peak assignment, while still possessing the β-barrel structural core that fibrillizes. The in vitro formation of ThT-reactive, amyloid-like aggregates of wt and mutant SOD1 has also been observed by TEM,1114−1116 along with the interaction of structurally disordered SOD1 with membranes, a possible mechanism of toxicity.1117,1118 As with Aβ in AD, soluble, prefibrillar oligomers of mutant SOD1 are believed to be neurotoxic.1119 They interact with C4F6, an antibody with an unidentified epitope that only recognizes SOD1 from the ALS-affected tissue; thus, they are associated with ALS pathology.1119,1120 A report correlating mutant SOD1 trimers with toxicity to motor neurons provided a link between genetic mutations and ALS pathology,1121 while another recently communicated the relation of a structured SOD1 segment oligomer to cytotoxicity toward primary motor neurons.1122

The structure of TDP-43 has also received some attention; however, due to its large size, many studies have focused on TDP-43 domains.1123−1129 A high-resolution NMR structure of the N-terminal domain was reported,1123 and mutations to this region were shown to destabilize the structure and function of TDP-43.1124 NMR monitoring of the RNA recognition motif 1 of TDP-43 demonstrated its propensity to aggregate and the importance of cysteine residues to this property.1125 A minimal segment at the C-terminus (wt TDP43 residues 343−366) has also been structurally characterized by NMR and interacted with ThT when aggregating,1126 and another minimal segment [wt and mutant TDP-43 segment D1 (residues 287−322)] was shown to form twisted amyloid fibrils by TEM.1127 Aggregates of the C-terminal TDP-43 fragment spanning the residues 341−357 have been examined by antibody binding, TEM, solid-state NMR, and X-ray diffraction, which cumulatively supported a cross-β configuration.1128 A recent report has proposed a model wherein the folded, thermodynamically stable N-terminal TDP-43 domain reversibly oligomerizes, facilitating aggregation of the intrinsically disordered C-terminal domain.1129 Recombinant fulllength human TDP-43 can aggregate into spherical oligomers with exposed hydrophobic surfaces that are reactive to the A11 oligomer-specific antibody able to recognize structured Aβ oligomers.80,1130 Oligomerized TDP-43 suffers from diminished DNA-binding capacity and is cytotoxic, with the ability to seed Aβ oligomers, possibly suggesting its participation in the pathogenesis of ALS.1130 The possible recurrence of amyloid-like aggregates and exposed hydrophobic surfaces of mutant SOD1 or TDP-43 segments suggest that targeting strategies for Aβ in AD, such as intercalation and hydrophobic interactions, may be effective against ALS SOD1 and TDP-43 aggregates. In addition, targeting soluble oligomers and redirecting them into unstructured, amorphous states may be a tactic to subdue the pathogenicity associated with potentially toxic SOD1 or TDP-43 oligomers as for Aβ oligomers.78,1119,1121,1130 4.2. Metal Ions

Transition metals, including Fe, Cu, and Zn, that play pivotal roles in AD are also thought to participate in ALS pathology, although this aspect has been investigated to a lesser extent. One significant relationship between metal ion dyshomeostasis and ALS is the association with mutant SOD1, which is a Cu/ Zn metalloprotein.1101 Therefore, a link between ALS and metal ions (particularly, Cu and Zn) has been anticipated; thus, it has been the focus of multiple studies (vide infra). The overall level of metal ions in the CNS has been examined in some detail.10 ALS is principally a neurodegeneration of motor neurons in the spinal cord and motor cortex. Most investigations have focused on the amount of metals in the spinal cord. A significant portion of ALS patients, however, also exhibits FTD (ca. 15−20%) and therefore additionally suffers from neurodegeneration of the frontotemporal lobes.1082 In this subpopulation of patients, the level of metal ions in the brain may be as pertinent as their levels in the spinal cord. This highlights the heterogeneity in ALS patients and advises caution in interpreting the findings in mouse models with specific transgenic mutations to translate to all ALS patients. Due to the multitude of known SOD1 mutations and the link of SOD1 to metals, especially Cu and Zn, several studies on the spinal cord metal level in mutant SOD1 Tg mice have BK

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been performed.10 Early work on SOD1G93A Tg mice revealed an elevated Cu amount in the spinal cord, concurrent with the increased expression of metallothionein isoform I and II (MT-I and MT-II) and a diminished Zn level.1131 Further research has demonstrated that disrupted Cu homeostasis in the spinal cord is not a unique feature of SOD1G93A Tg mice and does not necessarily correlate to Cu binding affinity of the mutant protein. In a study of Tg mice with multiple mutants, SOD1G93A, SOD1G127insTGGG (an insertion of TGGG after the codon for G127, leading to five new amino acids after G127 followed by premature termination), SOD1 G85R , and SOD1D90A, all exhibited the accumulation of Cu in the spinal cord despite their varying Cu binding affinity.1132 This was accompanied by an increase in Zn, although no changes were discernible in the levels of Mg, Ca, Al, Mn, and Fe.1132 In the examination of a mutant TDP-43A315T Tg mouse model that exhibits both FTD and ALS, the extent of metals was unaltered in the brain, but the concentrations of Cu, Zn, and Mn were elevated in the spinal cord.1133 Although a measure of the net level of metal ions provides the support regarding their role in the pathogenesis, these observations may be strengthened by functional studies that intentionally alter the Cu level in mice to rescue the disease phenotype. In one study, MT-I, a Cu regulator, was pharmacologically overexpressed in SOD1G93A Tg mice, which reestablished Cu homeostasis within the spinal cord.1134 Consequently, lifespan increased, disease progression slowed, and ALS symptoms (e.g., motor coordination) improved. Histologically, the extent of motor neuron and ventral root axon death was lowered, as was the deposition of SOD1 aggregates in the spinal cord. In another experiment, Cu levels were genetically decreased by mating SOD1G86R Tg mice to mottled/brindled (Mobr) mice.1135 This X-linked mutation inhibits the activity of ATP7A, an ATPase Cu transporter, and leads to severe Cu deficiency that can be lethal. Despite this, these double mutant mice displayed improved survival rates compared to SOD1G86R Tg progeny without the Mobr allele, and they also presented a 60% reduction in the spinal cord Cu level. The improved lifespan was ascribed to the reduction of the Cu content, which ameliorated the pathology. Overall, these findings provide evidence supporting a role for Cu in the pathogenesis of ALS linked to SOD1 mutations. At the molecular level, studies have been conducted on the correlation between SOD1 mutation, active site Cu/Zn occupancy,1101 and aggregation state.1136 Active site SOD1 mutations decrease Cu/Zn affinity, but not all ALS mutations occur within the active site or diminish SOD1’s affinity for Cu and Zn. Insoluble mutant SOD1 aggregates isolated from the spinal cords of Tg mice (G37R, G93A, and H46R/H48Q), however, are devoid of metal ions, even when the soluble mutant SOD1 fraction retains metal ions.1136 This is also the case for aggregates of mutant SOD1 (A4 V, G37R, H80R, and D125H) overexpressed in CHO cells.1137 Since metalated SOD1 mutants are relatively stable despite the mutation, they are not anticipated to aggregate in vivo. This suggests that if SOD1 aggregates are lacking metal ions, the aggregates may arise from immature nascent apo-SOD1 that has a propensity to aggregate, and not from wt or mutant metal-bound SOD1.1136 Although the impact of metal ions on protein aggregation has been a subject of intense research, this avenue has been much less explored in ALS research. Cu/Zn SOD1 is more stable than apo-SOD1; therefore, the metal-free form is likely

to aggregate.1101,1115,1138 Nevertheless, recent studies have started to examine a possible role for aberrant Zn binding on SOD1 aggregation1139 and the influence of Ca.1116,1140 The effect of Zn on TDP-43 aggregate formation has also been examined in vitro in SH-SY5Y neuroblastoma cells expressing endogenous TDP-43. Addition of Zn prompted the formation of TDP-43 inclusions, but addition of Cu, Fe, or H2O2 had no impact.1141 Overall, the studies on the influence of metal ions on protein aggregation in ALS are not numerous and could be an area to explore further. Several investigations support a role of Fe in ALS pathogenesis. A genetic link to mutations in the human hemochromatosis gene (HFE), which codes a protein involved in Fe homeostasis, is associated with SALS.1142,1143 Dysregulation of Fe metabolism is also apparent from serum biomarkers.1144 A retrospective study found that ALS patients exhibited lower transferrin serum and higher ferritin levels, related to shorter life expectancy compared to healthy controls.1144 In the studies on human-derived ALS spinal cord tissue, transferrin was colocalized with TDP-43 in Bunina bodies, histopathological intraneuronal inclusion bodies in lower motor neurons.1145−1147 A role of Fe in ALS is also supported in studies of SOD1G93A Tg mice that indicate the elevated serum Fe level and increased expression of transferrin and heme oxygenase-1 (HO-1), a biomarker of oxidative stress, in the spinal cord.1148 Dysregulation of Fe was observed in another ALS mouse model, Tg SOD1G37R, which accumulated Fe within ventral motor neurons, overexpressed ferritin in ventral motor neuron mitochondria, and enhanced expression of proteins involved in Fe homeostasis in the spinal cord.1149 A possible link between SOD1 and Fe metabolism was suggested by a study in cultured cells that compared transferrin receptor and ferritin levels in response to intracellular activity of SOD1 and SOD1G93A.1150 The findings implied that SOD1 activity affected Fe metabolism. Overall, studies support the involvement of Cu, Zn, and Fe in ALS pathogenesis, suggesting that targeting these metal ions may constitute a therapeutic avenue. In fact, several research groups have examined metal chelation therapy as a possible treatment for ALS in mutant SOD1 mouse models (vide infra). Multifunctional metal chelators (e.g., dual functions: metal chelation and MAO inhibition) have also been explored in ALS mouse models, though to a lesser extent in ALS than in AD and PD (vide inf ra). 4.3. Oxidative Stress and Mitochondrial Dysfunction

Oxidative stress is another pathological aspect of ALS,1092,1151 an association strengthened by mutation to SOD1, a protein involved in the defense against oxidative stress but also in nonSOD1 mutant ALS.1152 Whether mutant SOD1 definitively contributes to oxidative stress in ALS, and if so, by what mechanisms, is not completely understood. Histological evidence for elevated oxidative stress in both SALS and FALS patients compared to healthy individuals was obtained by early studies on post mortem spinal cord tissue.1153−1155 The tissue showed increased protein carbonyl levels, a marker of oxidative stress, in SALS,1153 nuclear DNA 8-hydroxy-2′deoxyguanosine, HO-1, and malondialdehyde-modified protein in SALS and FALS spinal cord,1154 as well as reactive microglia and glial proliferation.1093−1095 In addition, elevated lipid peroxidation has been detected in a SOD1G93A Tg ALS mouse model.1131 Oxidative stress can also impact SOD1 BL

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survival was relatively modest (ca. 10%), it had a significant influence on motor function and histological markers of disease progression, including reduced motor neuron loss, gliosis, and markers of oxidative damage. Early intervention with another lipophilic metal chelator, SIH (salicylaldehyde isonicotinoyl hydrazine; Figure 45), yielded similar results, with an approximate 10% increase in mean survival and ameliorated locomotion and histopathology.1149 Another metal chelator, WN1316 (Figure 45), has been tested for ALS treatment is in SOD1G93A mice.1173 In this instance, oral treatment began after the onset of symptoms, which boosted lifespan and motor function and attenuated oxidative damage and neuroinflammation. These results were especially interesting since WN1316 administration took place after the onset of disease, a scenario more akin to human ALS patients where treatment would commence after symptom onset and ALS diagnosis. 4.4.2. Multifunctional Molecules Targeting Metal Ions and Oxidative Stress. Another widely studied molecule for AD treatment and neurodegenerative diseases, EGCG (Figure 46),62 has also received attention for ALS treat-

aggregate formation through oxidation-induced misfolding.1111,1156−1158 Mitochondrial dysfunction is another aspect of ALS, but as for oxidative stress, the precise mechanism of the pathogenesis is unknown due to a multitude of potential contributing factors.1159 The question whether mitochondrial dysfunction is a cause or a consequence of neurodegeneration remains unanswered with evidence implying both.1160 SOD1 has been implicated in mitochondrial dysfunction since aggregates form within mitochondria1161−1163 and SOD1 mutants are translocated to mitochondria,1164 providing a link between genetic mutations and pathogenesis related to mitochondrial dysfunction. In addition, SOD1 mutants have been shown to interact with and modify motor neuron mitochondrial shape and distribution within axons.1165 4.4. Molecules

Although not as widely studied in ALS, the concept of multifunctional small molecules to simultaneously target two or more pathological features has been employed in ALS research, in some instances employing the same molecules that demonstrated promise in AD and other neurodegenerative diseases. Candidate molecules may be tested in ALS mouse models106 or simpler organisms, such as nematode, zebrafish, and fruit fly.71,1166 Some tested compounds are not multifunctional, but their efficacy in ALS mouse models and human patients and their FDA-approved status make them promising candidates as potential scaffolds for multifunctional drug design. Riluzole (Figure 44), an FDA-approved possible glutamate receptor antagonist for ALS treatment,1096 was effective in ALS mouse models and exerted a synergistic effect when coadministered with rasagiline (Figure 44), a MAOI.1167 Edaravone,1098 a possible radical scavenger and recently FDAapproved treatment for ALS, demonstrated promising results in SALS-like “wobbler”1168−1170 and FALS1171 mouse models. Although riluzole and edaravone only provided modest benefits for ALS patients, their efficacy may be augmented in combination with other moieties to target other pathological factors of the disease. 4.4.1. Metal Chelators. DP-109 (Figure 45), a lipophilic metal chelator, previously showed the efficacy in an AD mouse model where it decreased Aβ burden and inflammation.459 Due to its neuroprotective effects in AD, DP-109 was tested for treatment of ALS and were found to offer neuroprotection in a SOD1G93A mouse model.1172 Although its impact on

Figure 46. Multifunctional molecules tested in ALS mouse models. EGCG and curcumin (chemical names shown in Figures 16 and 8, respectively); HBX, 2-(benzo[d]oxazol-2-yl)phenol; M30 (8-HQMC-3) and HLA20 (8-HQ-MC-4) (chemical names reported in Figure 9); VAR10303, 5-(2-(methyl(prop-2-yn-1-yl)amino)ethyl)quinolin-8-ol.

ment.1174−1176 In a model of ventral spinal cord 4.1 (VSC 4.1) cells, EGCG could protect both wt and SOD1G93A ALS VSC 4.1 motor neuron cells from H2O2-induced oxidative stress.1174 Western blot analysis showed increased PI3K/Akt signaling and decreased GSK3β signaling in response to EGCG in both wt and SOD1G93A motor neuron cells. These results were recapitulated in vivo, in SOD1G93A ALS mice whose treatment with EGCG extended life and delayed time of disease onset, while activating PI3K/Akt signaling and deactivating GSK3β signaling.1175 Similar observations were made in another study of oral EGCG administration to SOD1G93A mice before appearance of symptoms.1176 The results supported the postponement of disease onset and lifespan extension of EGCG-treated mice versus control vehicle mice. Histological

Figure 45. Metal chelators investigated in ALS mouse models. DP109 (chemical name indicated in Figure 5); SIH, (E)-N′-(2hydroxybenzylidene)isonicotinohydrazide; WN1316, 2-(mesityl(methyl)amino)-N-(4-(pyridin-2-yl)-1H-imidazol-2-yl)acetamide. BM

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(i.e., Cu(II)(gtsm) and Cu(II)(atsm); Figure 47) were tested as possible MPACs to potentiate this effect.1184 The complexes

analysis revealed features indicative of an amelioration of disease in the EGCG cohort, namely a greater number of motor neurons, lower microglial activation, and diminished apoptosis. Another notable molecule, which has also been explored in AD, is curcumin (Figure 46), which has been shown to inhibit metal-free and metal-induced Aβ fibril formation.568 This antiamyloid aggregation property was also active against the aggregation of wt SOD1 reduced by dithiothreitol (DTT) as confirmed by ThT, TEM, and AFM.1177 Curcumin redirected SOD1 aggregation into less toxic disordered aggregates. Tryptophan fluorescence quenching indicated a direct interaction between curcumin and SOD1 aggregates and stronger propensity to interact with soluble oligomers, suspected to be toxic, than with fibrils. Curcumin mitigated the toxicity of SOD1 aggregates in THP-1 cells. Curcumin is a bifunctional molecule with both antioxidant and metal chelating properties. Unfortunately, however, the authors did not examine the neuroprotective effects of curcumin in the presence of metal ions to assess potential utility for tackling ALS pathogenesis related to metal ions. HBX (Figure 46) is a metal chelating, potential antioxidant, and antiaggregation agent, structurally related to the amyloid binding molecule, ThT. HBX has been tested for AD treatment508 and was selected for the same properties (metal chelation, antioxidant activity, and antiaggregation) to address multiple pathologies for ALS therapy in Tg SOD1G93A mice.1178 HBX did not affect median survival, although it exerted a small influence on maximum lifespan and onset of disease. HBX decreased neuromuscular denervation and the extent of mutant SOD1 deposition in the spinal cord. 4.4.3. Multifunctional Molecules Targeting Metal Ions and MAOs. PD and AD drug candidates, M30 and HLA20 (Figure 46; 8-HQ-MC-3 and 8-HQ-MC-4 in Figure 9),38,99 have been investigated for potential utility in ALS models.1179,1180 M30 and HLA20 exhibited profound neuroprotective abilities that impacted multiple signaling pathways. In mouse motor-neuron-like NSC-34 cells, M30 and HLA20 afforded cell protection against oxidative stress induced by H2O2 and 3-morpholinosydnonimine (liberates NO) and promoted differentiation, neurite growth, and expression of growth factors via mitogen-activated protein kinase (MAPK) and PKC pathways.1179 In vivo, M30 was also effective for improving survival outcome and delaying the onset of disease in ALS SOD1G93A mice.1180 Histologically, a decrease in motor neuron loss and TDP-43 protein aggregation in the spinal cord were observed, concurrently with decreases in Fe levels, transferrin receptor expression, and amounts of ROS, along with suppression of glial activation. Another PD candidate and M30 analog, VAR10303 (Figure 46),1181 was also tested for efficacy in ALS mouse models. 1182 Administration of VAR10303 together with high-calorie feed to SOD1G93A mice produced a favorable effect on survival and motor function, while limiting motor neuron loss and iron accumulation. 4.4.4. Metal Protein Attenuating Compounds (MPACs). MPACs that have proved efficacious in AD mouse models1183 have also been tested in ALS murine models.1184 In AD, they function by redistributing sequestered Cu from Aβ aggregates into intracellular bioavailable Cu which institutes a kinase signaling cascade that ultimately results in Aβ clearance.10 Due to evidence supporting a role of kinaseinduced accumulation of TDP-43 in ALS, Cu(II) complexes

Figure 47. Cu(II)bis(thiosemicarbazonato) complexes, Cu(II)(gtsm) and Cu(II)(atsm), that act as MPACs [gtsm, glyoxalbis(N4-methyl-3-thiosemicarbazonato); atsm, diacetylbis(N4-methyl-3thiosemicarbazonato)].

prevented formation of paraquat-induced stress granules of TDP-43 and protected cells from paraquat-induced death, effects mediated by blocking phosphorylation of extracellular signal-regulated kinase. Cu(II)(atsm) inhibited abnormal phosphorylation and truncation of TDP-43 and improved survival prospects and locomotion in a SOD1G93A ALS mouse model.1185 Tardiff et al. employed a yeast system expressing TDP-43 tagged with green fluorescent protein (GFP) to screen a vast library of ca. 200,000 small molecules.1186 Among the top hits identified, which were selected based on mitigation of TDP-43induced toxicity, 8-HQ (Figure 48) was a recurrent motif. In

Figure 48. HQ-415, identified in a screen of TDP-43-induced toxicity in yeast, which includes the framework of 8-HQ. HQ-415, 7-((3ethoxy-4-methoxyphenyl)((4-methylpyridin-2-yl)amino)methyl)quinolin-8-ol; 8-HQ (chemical name reported in Figure 9).

particular, the study pursued HQ-415 (Figure 48), which, in addition to rescuing yeast from toxic expression of TDP-43 (EC50 = ca. 15 μM), also protected them from PD-associated α-Syn (EC50 = ca. 20 μM). Treatment of yeast cells with HQ415 decreased the number of TDP-43 foci and increased membrane localization of α-Syn.1186 Finally, to confirm the bifunctional nature of HQ-415, metal chelation was observed by UV−Vis upon addition of Cu(II), Fe(II), and Zn(II). Furthermore, metal chelation was found to be the principal protective mechanism in yeast cells since treatment with HQ415 upregulated expression of copper transport CTR1, ferric reductase FRE3, and Zn-regulated transporter ZTR1 mRNA.1186 4.4.5. Molecules for Antiaggregation. One mode by which small molecules can interfere with amyloid formation is by intercalation. Although the precise structural features of ALS aggregates are uncertain, an amyloid-like configuration is supported for both SOD1 and TDP-43 oligomers and fibrils (see refs 1112, 1114, 1115, 1127, 1128, and 1130). A series of acridine derivatives (Figure 49) with varying side arms were tested for their ability to control TDP-43 aggregation.1187 One candidate, AIM4 (Figure 49), hindered in vitro aggregation of BN

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process, and until now, there are no feasible, successful diseasemodifying drug treatment options for ALS. Multifunctional molecules are beginning to reveal the benefit of simultaneously targeting multiple pathologies and spurring our understanding of the multifactorial nature of the disease. It is anticipated that a better comprehension of the pathology will aid the design of multifunctional molecules better capable of targeting and treating ALS in a disease-modifying manner. The development of ALS models has attributed significantly toward ALS research, and in vivo studies have identified multifunctional molecules exhibiting their potential as ALS therapeutics. EGCG-treated ALS mouse models showed extended life expectancy and delayed time of disease onset. Compared to vehicle-controls, the mice treated with EGCG retained a greater number of motor neurons and exhibited lower microglial activation.1175,1176 Researchers reported that EGCG activated the PI3K/Akt signaling pathway while deactivating GSK3β signaling. M30 also demonstrated its neuroprotective ability in ALS SOD1G93A mice, in which it improved their survival outcome and postponed the onset of ALS.1180 Furthermore, the decrease in loss of motor neurons, TDP-43 aggregation, Fe(II/III) levels, transferrin receptor expression, and oxidative stress was observed in M30administrated ALS mice. Together, these in vivo data suggest the possibility of discovering or creating potential ALS therapeutics in the future.

Figure 49. An acridine derivative that inhibits TDP-43 aggregation in vitro and in a yeast model. Acridine, dibenzo[b,e]pyridine; AIM4, 4,5-bis((N-carboxy-methyl-imidazolium)methyl)acridine.

an aggregation-prone C-terminal segment of TDP-43 as determined by ThT and AFM. In yeast cells, AIM4 was able to inhibit TDP-43-YFP aggregation, reinforcing its potential utility as an antiaggregation molecule for ALS. Further functionalization could extend its utility by integrating it into multifunctional molecules. 4.4.6. Antioxidants. Due to the presence of oxidative stress in ALS, one line of treatment has been to administer antioxidants. In one study, TEMPOL (Figure 50), a radical

5. CONCLUDING REMARKS AND OUTLOOK With the prevalence of neurodegenerative diseases expected to rise alongside the aging world population, the need for treatments capable of effectively halting the progression of the disease is becoming increasingly urgent. Not only are there no effective therapeutics available but also the current understanding of AD, PD, and ALS is not conclusive since the fundamental causes of the observed neurodegeneration are not identified. The trends in research regarding their pathologies point to the concurrent involvement of multiple pathological factors. As a consequence, multifunctionality is demonstrated to be a key component in designing molecules as potential therapeutics. As presented above, a wide range of multifunctional molecules have been discovered, designed, and investigated for their ability to manipulate multiple pathogenic factors of AD, PD, and ALS. A variety of molecules has been reported to target both metal ions and Aβ found in AD. There is, however, a shortage of multifunctional molecules capable of influencing tau pathology. Development of molecules equipped with relevant multifunctionality (e.g., modulation of proteopathic pathways of Aβ and tau, inhibition of detrimental post-translational protein modifications, chelation of metal ions, and antioxidant properties) could provide a new direction in potential therapeutic strategies and further our understanding of AD pathogenesis. In the case of PD, most multifunctional molecules focus on metal chelation and either MAO inhibition or dopamine receptor interaction. Most ASIs have not been evaluated for their ability to interact with metal ions or modulate metal-induced α-Syn aggregation. Only a small number of multifunctional molecules has been developed and studied for ALS. Previous research has implicated several drug candidates for AD and PD as prospective ALS treatments. Proper validation of potential multifunctional molecules necessitates careful selection of in vitro and in vivo tests that are relevant to AD, PD, and ALS. The pathologically relevant

Figure 50. Antioxidant molecules, TEMPOL and Fe(TCPP), studied in ALS animal models. TEMPOL, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; TCPP, 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin.

scavenger, was tested in a Tg rat model of SOD1G93A.1188 Although the compound exerted only a modest effect on the severity of disease onset, it decreased the rate of disease progression with a small effect on survival. In addition, favorable effects were observed on the density of motor neurons and the level of carbonylated proteins. The studies demonstrated that antioxidants may be useful for ALS symptoms, but since the effects were small, they may benefit from combination with moieties for targeting other ALS pathological features. Another avenue for antioxidant treatment is the catalytic deactivation of ROS by metalloporphyrins. This scheme was implemented in Tg SOD1G93A mice that were treated with Fe(TCPP) (Figure 50).1189 Fe(TCPP) improved the survival rate of mice and ameliorated motor function, a property that extended to ALS mice that were treated after the onset of disease. Markers of oxidative damage, malondialdehyde, and protein carbonyl level were also inhibited by Fe(TCPP), as was motor neuron death. A major challenge in ALS is the heterogeneity of the patient population in terms of the diversity in ALS-associated mutations. In addition, the multifactorial nature and the complexity of the disease have thus far hampered efforts to discover a unifying and underlying etiology for all types of ALS. Consequently, this has challenged the drug design BO

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protein species (for example, their oligomeric state) are yet to be clearly characterized. Oligomeric species of misfolded proteins (e.g., Aβ, tau, α-Syn, SOD1, and TDP-43) have been implicated as a source of toxicity in AD, PD, and ALS; however, specific conformations of proteins are yet to be clarified. In addition, PTMs of proteins could also affect their pathological properties, but they are not always taken into account when designing molecules targeting such proteins. Rational construction of molecules as potential therapeutics for AD, PD, and ALS based on pathologically relevant factors could improve their success rate. The development of AD, PD, and ALS animal models has allowed researchers to investigate in vivo efficacy of potential molecules; however, the experimental applicability of these models need to be cautiously evaluated. Potential side effects of multifunctional therapeutics could arise from various aspects of the molecules. As for metal binding compounds, their potential interactions with metal ions in metalloenzymes could disrupt the proper functioning of enzymes.1190 Specificity and selectivity issues involving unwanted interactions or reactivities with biological components and signaling pathways could also present unforeseen problems, such as ADME and PK of the compounds. Our limited understanding of complex pathologies of AD, PD, and ALS is a major obstacle for the development of effective therapeutics. A clear comprehension of pathogenic factors directly and indirectly involved in the neurodegeneration found in AD, PD, and ALS by identifying the specific molecular and histological culprits, such as pathologically relevant proteins, may greatly foster the process for discovering therapeutics. Apart from their therapeutic potential, multifunctional molecules can be used as chemical tools to advance our understanding of interrelated networks among multiple pathological factors. Taken together, through this review, the significance and implications of multifunctionality in originating compounds as potential therapeutics for AD, PD, and ALS, along with examples of multifunctional compounds, are overviewed and discussed.

cofounder of SciGency Science Communications (scigency.com). She continues to enjoy collaborating with her previous advisors.

AUTHOR INFORMATION

Misun Lee received her B.S. degree in 2017 from the Department of Chemistry at UNIST, Ulsan, Republic of Korea. She is currently a graduate student in the laboratory of Professor Mi Hee Lim in the Department of Chemistry at UNIST. Her recent research focuses on the development of small molecules as potential therapeutic agents for human neurodegenerative disorders.

Geewoo Nam is a doctoral student in the Department of Chemistry at UNIST, Ulsan, Republic of Korea, under the guidance of Professor Mi Hee Lim. He received his B.S. in Chemistry at Virginia Polytechnic Institute and State University, Blacksburg, VA, USA, and then obtained his M.Sc. in Pharmacology at Seoul National University, Seoul, Republic of Korea in 2016. During his master’s program, Geewoo worked with photodynamic therapy and liposomal drug delivery systems. His current research focuses on developing multifunctional molecules against multiple pathological factors in neurodegenerative diseases. Juhye Kang is a doctoral student as a Global Ph.D. Fellow from the National Research Foundation of Korea (NRF) in the Department of Chemistry at UNIST, Ulsan, Republic of Korea, under the guidance of Professor Mi Hee Lim. She received her M.Sc. degree in 2014 in Chemistry from Seoul National University of Science and Technology, Seoul, Republic of Korea, under the supervision of Professor Cheal Kim. During her master’s program, she conducted research as a visiting scholar at the University of Michigan, Ann Arbor, MI, USA, under the direction of Professors Mi Hee Lim and Gabrielle Rudenko. Her current research interests include the design of chemical reagents capable of targeting amyloidogenic peptides and modifying their aggregation and toxicity. Hyuck Jin Lee is currently a postdoctoral scholar in the laboratory of Professor Mi Hee Lim at KAIST, Daejeon, Republic of Korea. He received his B.S. degree in Biochemistry jointly from Minnesota State University, Mankato, MN, USA, and Catholic University of Daegu, Daegu, Republic of Korea, in 2011. He completed his Ph.D. in Chemistry in 2015 from the University of Michigan, Ann Arbor, MI, USA, under the supervision of Professor Mi Hee Lim. After his Ph.D., Dr. Lee continued the research with Professor Mi Hee Lim at UNIST, Ulsan, Republic of Korea, as a postdoctoral scholar. His research interests include the investigation of protein−protein interactions and the development of small molecules able to control the aggregation of amyloidogenic peptides found in neurodegenerative diseases.

Corresponding Author

*E-mail: [email protected] ORCID

Mi Hee Lim: 0000-0003-3377-4996

Mi Hee Lim is an Associate Professor in the Department of Chemistry at KAIST. In 2001, Professor Lim obtained her M.Sc. under Professor Wonwoo Nam at Ewha Womans University, Seoul, Republic of Korea. Professor Lim moved to MIT in 2002 where she received her Ph.D. under the supervision of Professor Stephen J. Lippard. She then pursued her postdoctoral research as a TRDRP postdoctoral fellow in the laboratory of Professor Jacqueline K. Barton at Caltech. In the summer of 2008, she began her independent career as an Assistant Professor of Chemistry and Research Assistant Professor in the Life Sciences Institute at the University of Michigan, Ann Arbor, MI, USA. In the fall of 2013, Professor Lim moved to UNIST, Ulsan, Republic of Korea, as an Associate Professor with tenure. Very recently, Professor Lim joined the Department of Chemistry at KAIST as an Associate Professor with tenure. Her current research interests lie on elucidating the individual and mutual roles of metals, proteins, oxidative stress, and inflammation in human diseases.

Author Contributions ∥

M.G.S., G.N., and J.K. contributed equally to this work.

Notes

The authors declare no competing financial interest. Biographies Masha Savelieff began her science career in Chemistry at the American University of Beirut, Beirut, Lebanon, where she earned her B.S. and M.Sc. under the guidance of Professor Ulrich Kortz. She then received her Ph.D. in Chemistry in 2008 at the University of Illinois at Urbana−Champaign, Champaign, IL, USA, with Professor Yi Lu before undertaking postdoctoral studies in AD research at the University of Michigan, Ann Arbor, MI, USA, with Professors Mi Hee Lim and Bing Ye. She widened her biology experience with her next appointment in cancer research at the Castro-Lowenstein lab, also in Michigan. She is currently a full-time professional science writer and BP

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DOI: 10.1021/acs.chemrev.8b00138 Chem. Rev. XXXX, XXX, XXX−XXX