Rational Design of Multitarget-Directed Ligands ... - ACS Publications

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Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms Junting Zhou,†,‡ Xueyang Jiang,†,‡ Siyu He,† Hongli Jiang,†,‡ Feng Feng,‡,§ Wenyuan Liu,⊥ Wei Qu,*,‡ and Haopeng Sun*,† †

Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, People’s Republic of China Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China § Jiangsu Food and Pharmaceutical Science College, Huaian 223003, People’s Republic of China ⊥ Department of Analytical Chemistry, China Pharmaceutical University, Nanjing 210009, People’s Republic of China

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S Supporting Information *

ABSTRACT: Due to the complexity of multifactorial diseases, single-target drugs do not always exhibit satisfactory efficacy. Recently, increasing evidence indicates that simultaneous modulation of multiple targets may improve both therapeutic safety and efficacy, compared with single-target drugs. However, few multitarget drugs are on market or in clinical trials, despite the best efforts of medicinal chemists. This article discusses the systematic establishment of target combination, lead generation, and optimization of multitargetdirected ligands (MTDLs). Moreover, we analyze some MTDLs research cases for several complex diseases in recent years and the physicochemical properties of 117 clinical multitarget drugs, with the aim to reveal the trends and insights of the potential use of MTDLs.

1. INTRODUCTION The doctrine of “one molecule, one target, one disease” dominated the pharmaceutical industry in the 20th century.1 Plenty of successful selective drugs have been developed from this doctrine, which will predominate for certain diseases in the future.2 However, for multifactorial diseases such as cancer,3−6 neurodegenerative disease,7,8 cardiovascular disease9,10 and infection,11 the initiation and progression involve multiple receptors or signaling pathways. For multifactorial diseases, manipulating a single target does not always lead to satisfactory efficacy, despite the best research efforts.12 Hence, there is an increasing interest in developing therapeutics which simultaneously manipulate multiple targets for improving therapeutic efficacy and (or) safety.13 There are two approaches of multitarget therapeutics: the first approach is a mixture of monotherapies, including drug cocktail (combinations of drugs with a single active ingredient, respectively) and combination drug (one formula includes multiple active ingredients), whereas the second approach is multitarget-directed ligands (MTDLs, one tablet, one active ingredient).14 The former approach may provide better dose flexibility and lower treatment cost. However, it often suffered from adverse effects and poor patient compliance.15 For instance, the combination of venlafaxine and fluoxetine for depression therapy may cause severe anticholinergic adverse effects.16 Furthermore, it often leads to undesired effects such as dose-limiting toxicities, drug−drug interactions, and © XXXX American Chemical Society

complex and unpredictable pharmacokinetic (PK)/pharmacodynamic (PD) profiles.17 Since 2004, Morphy et al. started to systematically review strategies for multifunctional ligands development.18−22 MTDLs are agents that treat multifactorial diseases by interacting with multiple targets involved in pathogenesis.23 This strategy could avoid many pitfalls.24−26 In Table 1, the advantages and disadvantages of the above two approaches are discussed. To date, some outstanding MTDLs have been in clinical trial stage or approved by regulatory agencies.12 However, many of them were found by serendipity, such as imatinib (a multitarget kinase inhibitor).27 The “simple” strategy of making MTDLs by linking two active ligands together usually resulted in very large molecular weight (MW).7 For example, many research studies have published about hybrids of tacrine and other active ligands, which were obtained in linked pharmacophore approach.28,29 Moreover, some lead compounds discovered through phenotypic screening lack definite targets, with high promiscuity and severe adverse effects.30 These problems explain the failures of many MTDLs. Thus, we believe that multitarget drugs should be designed in a more rational and holistic view of target combination, ligands selection, and the balance of desired activities to maximize developability, efficacy, and safety. In this review, we Received: January 4, 2019 Published: May 13, 2019 A

DOI: 10.1021/acs.jmedchem.9b00017 J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

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Table 1. Comparison of the Advantages and Disadvantages of Two Multitarget Therapeutics14 mixture of monotherapies

multiple ligands

Advantages 1. Can offer better dose flexibility by directly adjust ratio of drugs in mixture. 1. They are new chemical entity. 2. Can achieve sequenced administration or adjusting target exposure. 2. The programs of development and regulatory approval are standard, same as the single target drugs. 3. Clinical trials may be faster due to clinical experience, and the treatment 3. As a single active component, the PK/PD properties are easier to formulate cost may be lower. compared with a mixture. 4. Therapeutic efficacy may increase through synergies even at low dosages. 5. Reduced adverse effects enable wider therapeutic windows. Disadvantages 1. “Combination versus parts” factorial trial might be conducted. 1. Achieving balanced and multiselective potency toward multiple targets is challenging. 2. Should align PK/PD properties of the multiple components. 2. Difficult to achieve sequenced administration at the targets. 3. More likely to cause drug−drug interaction.

reduced adverse effects, and antipsychotic drugs such as cariprazine and aripiprazole are the successful examples.44−46 2.2. Target Combination Based on Phenotypic Screening. Phenotypic screening is another approach for target combination.47,48 Cellular, tissue, and animal models can all be used for screening large numbers of compound combinations for synergies.49 But high throughput of putative compounds or target combination requires tremendous animal experiments. Although only a few compounds are tested, different dose combinations would require large animal sample sizes. Therefore, genetic knockdown or knockout of one target is a feasible approach to reduce animal usage, due to the absence of dose combinations.17 For instance, a study used diclofenac (a COX inhibitor) in an inflammatory model using FAAH (−/−) mice to validate the synergistic effect of these two targets.50 Biological assays that generate multidimensional readouts are usually known as high-content screening, which are valuable approaches for MTDLs discovery.51 If the screening systems are more complex, entire animals may be employed, enabling sophisticated readouts including even behavioral changes.52 For example, fruit fly or zebrafish can be used for the complex screening system.53 2.3. Target Combination Based on in Silico Technique. In silico technique is also a feasible approach for screening suitable target combination.54 Many in silico methods55 are available, such as analysis of biological target networks via machine learning.56 The network pharmacology method by analyzing signaling networks is especially valuable.57 However, the hypothetic target combination predicted by computational approaches needs wet-lab validation to confirm its biological foundation and feasibility. For example, the target combination of insulin-like growth factor 1 receptor (IGF1R) and cyclin-dependent kinase 4 (CDK4) was predicted by computational modeling and validated to be synergistic drug targets for DDL in dedifferentiated liposarcoma (DDL)-derived cells.58

discuss the above critical issues, analyze the physicochemical properties of 117 clinical multitarget drugs, and go over important references about MTDLs published in recent years to provide a comprehensive compendium of the rational design of MTDLs.

2. RATIONAL COMBINATION OF MULTIPLE TARGETS FOR MTDLS The design and validation of target combination is crucial for MTDLs discovery; ideal target combination may provide superior therapeutic efficacy through synergies. It is generally easier to design multitarget ligands for highly related targets in the same superfamily.31,32 If targets belong to different superfamilies, their endogenous ligand had better be similar or even identical (often a monoamine or an eicosanoid).19 If so, the binding sites of multiple targets are more likely to accommodate a shared ligand frame.19 Interestingly, there are also some rare examples whose targets come from different superfamilies, and endogenous ligands are also unrelated.33,34 In this case, the realistic method could be combining pharmacophores via exploiting the tolerant positions of each component. Nonetheless, for highly similar targets, achieving multiple activities is easy, but formulating optimized selectivity at closely related but undesired targets is the challenge.35 Theoretically, undesired but relevant targets had better be as few as possible. But a few examples showed that it was not impossible.36,37 2.1. Target Combination Based on Clinical Observations. Combination therapies such as drug cocktails are common topics of clinical studies, but the issues of complex PK profiles, drug−drug interaction often limit their clinical applications. 14 However, the increasing knowledge of enhanced efficacy suggests that the target combination (validated by drug cocktails) may be possible.26,38,39 A typical example of target combination based on clinical observations is antipsychotic. Initially, the antipsychotics targeting dopamine D2-like receptors often cause considerable adverse effects, for example, the extrapyramidal motor symptoms.40 The following clinical research found that additional inclusion of antiserotonergic 5-HT2A led to improved treatment effect and reduced adverse effects.41 Subsequently, the adjustment of potencies toward multiple targets, including agonism on one receptor and partial agonism on another was achieved.42,43 Such multitarget design driven by clinical observation significantly improved efficacy and

3. LEAD GENERATION For exploring MTDL lead compounds, there are generally two approaches: screening approaches and knowledge-based approaches.19,20,59 They usually analyze information in the literature or patent. 3.1. Knowledge-Based Approach. Knowledge-based approach is also known as pharmacophore-based approach, which is currently the predominant method for generating MTDLs.59 This approach combines pharmacophores of B



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Figure 1. Multitarget drug design strategy based on pharmacophore.22 In linked MTDLs, the pharmacophores are connected by stable or biodegradable linkers. In fused MTDLs, the pharmacophores are attached directly. In merged MTDLs, the pharmacophores are merged together.

Scheme 1. Two Categories of Linked MTDLs: Cleavable MTDLs and Noncleavable MTDLsa

a

(A) Compound 3 is a cleavable MTDL, with an ester linker that can be hydrolyzed in vivo.62 (B) Compound 6 is a noncleavable MTDL, the linker of which is stable in vivo.64

ligands.17 Recently, linked pharmacophores become a popular concept: a targeting ligand (e.g., the antibody) is linked to an active molecule, then the targeting ligand delivers the active ligand to a desired target to exert efficacy.61 The cleavable MTDLs employ a linker that can be degraded to release ligands for corresponding targets, respectively.19 In most cases, cleavable MTDLs have an ester linker that can be degraded by plasma esterase, as shown in the example in Scheme 1A. Although cleavage might make the PK/PD relationship complex, cleavable MTDLs are regarded as a single active ingredient in the stage of administration. This is one advantage compared with cocktails and multicomponent drugs. Compound 3 was reported as a new multitarget therapeutic candidate, which incorporated the pharmacophores of cinnamic acids 1 (lipoxygenase inhibitors, antioxidants, and anti-inflammatories)62 and paracetamol 2 (a nonsteroidal antiinflammatory drug)63 via an ester linker. Compound 3 showed high analgesic activity (91%) suggesting the application in treating peripheral nerve injuries62 (Scheme 1A). This kind of MTDL may be referred to as “mutual prodrug”: after degradation of ester linker, the released ligands will elicit therapeutic effects in distinct pathways. Most reported linked MTDLs are actually noncleavable MTDLs, whose linker is stable in vivo. As single active

selective ligands for multiple targets into a single compound, which integrates the activities of these ligands. In the order of pharmacophore overlap incrementation, the MTDLs are classified into linked, fused, and merged types (Figure 1).22 Actually, the level of overlap of the pharmacophores forms a continuum: one extreme is the linked MTDLs with high MW and lengthy linker, whereas the other extreme is the merged MTDLs, which is the result of a high degree of overlap of pharmacophores and obtains smaller MW and simpler structure.22 3.1.1. Linked Pharmacophores. A linked MTDL typically contains underlying pharmacophores separated by a linker that does not exist in any one of the original ligands.22 Although this is a straightforward strategy, the position, length, and composition of linkers can be designed to retain the activity of the template scaffolds.60 For instance, the linker should not join a ligand at the position with steric effect. Sometimes, the linker itself works as a pharmacophore by interacting with the target. Therefore, linkers should be tailored so as to enhance interactions between the targets and linkers.60 According to the property of linkers, the linked MTDLs are further divided into two categories: cleavable or noncleavable.19 However, linked MTDLs are usually too large for favorable bioavailability or accessing intracellular compartments. Moreover, the linker may hinder the interaction between targets and C



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Scheme 2. Representative Structures of Fused Pharmacophoresa

a

The two pharmacophores are in blue and red; purple illustrates the fused/merged pharmacophore from two selective ligands. (A) Dual cholinesterase/MAO-B inhibitor (9).65 (B) Neuroprotection/antioxidative bisfunctional agent (12).66 Both compounds 9 and 12 are the products of fused pharmacophores approach.

Scheme 3. Representative Structures of Merged Pharmacophoresa

a

(A) Multifunctional agent (16) is designed by merging the pharmacophores of the aminopropoxyphenyl scaffolds from compounds 13, 14, and 15.67 (B) Bisfunctional compound 19 is designed via merging the pharmacophores from chelator HLA20 (17), rivastigmine (7), and donepezil (18).68

(Scheme 2A).65 Compound 12 is a hybrid of curcumin 10 and melatonin 11, two well-studied natural products in Alzheimer’s disease (AD) models. Hybrid 12 was discovered to exhibit significant neuroprotection and antioxidative activities66 (Scheme 2B). 3.1.3. Merged Pharmacophores. The MTDLs with merged pharmacophores have the highest level of pharmacophore overlapping. By identification of the “tolerant region” for each receptor and taking advantage of commonalities in each framework of the template ligands, the pharmacophores are highly integrated to obtain smaller MW and simpler structures with optimized physicochemical profiles. Through incorporating the pharmacophore of 3-hydroxy-4pydinone (for metal chelation) from deferiprone and aminopropoxyphenyl scaffold from a H3R antagonist into one molecule, compound 16 was designed, synthesized, and biologically characterized.67 It shows excellent selective H3R

ingredients, noncleavable MTDLs are able to interact multiple targets and responsible for corresponding activity. Compound 6 is a pharmacological hybrid combining H1 receptor (H1R) and H2R antagonistic activities. It was designed through linking roxatidine-type H2R antagonist (5) pharmacophore with mepyramine-type H1R antagonist (4) motif.64 The N-desmethylmepyramine was linked by a polymethylene linker to form the cyanoguanidine motif that was the “urea equivalent” of the H2R antagonist moiety. Compound 6 was the most potent hybrid with pKb values of 8.42 for H1R and 6.43 for H2R64 (Scheme 1B). 3.1.2. Fused Pharmacophores. The MTDLs with partially overlapped pharmacophores are classified as fused MTDLs. Compound 9 was designed by fusing the phenyl from rivastigming (7) and the dihydroindene ring from rasagiline (8). Compound 9 exhibited both acetylcholinesterase (AChE) and monoamine oxidases (MAOs) activities simultaneously D



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modeled.71 The SAR data of selective template ligands may provide many hints for the optimization of the hybrid, e.g., whether scaffold hopping is workable and whether substituents are feasible, etc. Of note, instead of two distinctly separated approaches, the rational generation of merged pharmacophores and the design-in approach can be referred to as a common strategy.20 Using design-in approach, Woo et al.72−77 designed a phenol sulfamate moiety from compound 21 into the scaffold of compound 20. The phenol sulfamate moiety of compound 21 is responsible for irreversible steroid sulfatase (STS) inhibition, and the scaffold of 20 is for aromatase inhibition. The initial optimization relied on molecular docking and cocrystals studies that created the hybrid compound 22. Further SAR research and scaffold hopping developed several chemotypes of MTDLs, among which the compound 23 targeted both enzymes with activities down to picomolar values (Scheme 4). 4.2. Design-Out Approach. Generally, design-out approach begins with a compound that simultaneously acts on all targets of interest, involving undesired ones. By reduction of the affinity to undesired targets, selectivity to the targets of interest will be improved.78 Compared with design-in and merged pharmacophores approaches, this approach may benefit more from X-ray structure analysis because it starts from a single ligand which already modulates with all desired targets.18 The binding mode of the lead compound toward undesired targets can be characterized via cocrystal structures analysis. The identification of the binding mode differences between desired and undesired targets paves the way for the disruption of the potency on the “off-target(s)”. Such approach is less common due to the rarity of available leads with multitarget activities. However, it is still attractive if the number of targets of interest exceeds two because every additional target may exponentially increase the challenges of design-in approach.17 The design-out approach has been applied successfully to develop MTDLs. For instance, Reichard et al.79 designed a neurokinin 1 (NK1)/NK2 dual antagonist in this approach. Compound 24 is a broad-spectrum NK antagonist. Its Ki values are 1.3 nM, 0.4 nM, and 0.3 nM for NK1, NK2, and NK3, respectively. However, NK3 receptor may have a critical impact on androgen/secretion/gonadotrophin production. Targeting NK3 may lead to an anti-androgen therapy, but their intention was to develop a NK1/NK2 dual antagonist for asthma. Therefore, they minimized NK3 binding affinity of the lead to avoid potential NK3-mediated effects. By application of a stereosimplification strategy, a strict SAR study of piperidine pharmacophore from 24 was carried out via an efficient synthesis of substituted cyclic urea, which resulted in the development of compound 25, which showed selective NK1/ NK2 affinity (the Ki values were 1.9, 4.1, and 945 nM for NK1, NK2, and NK3, respectively) (Scheme 5). 4.3. Balancing of Activities. Establishing the optimal ratio of affinities to multiple targets via in vitro assays is critical: ideally, each target should be modulated to a suitable level in vivo at similar brain or plasma concentrations to maximize clinical relevance.19 For a MTDL with large difference in affinities in vitro toward multiple targets, it may well only exert multiple effects at high doses. However, it often causes side effects that limit the dosage upper limit.80,81 However, recent examples showed the feasibility of balancing activities through synergistic effect with differences in in vitro activities.82 So the phenotypic experiments in vivo activity validations are

antagonism (from compound 13), amyloid-β (Aβ) aggregation inhibition (from compound 14), metal ion chelation, and radical scavenging (from compound 15)67 (Scheme 3A). A site-activated multifunctional candidate for treating AD was reported.68 This research integrated their newly developed bifunctional chelator HLA20 (17) and two marketed drugs, rivastigmine (7) and donepezil (18, an AChE inhibitor). Three moieties (phenyl, carbamyl, and ethylmethylamino moieties) of rivastigmine bound to the active site of AChE; meanwhile, the pharmacophore [(5, 6-dimethoxy-1-indanon-2-yl)methylpiperidine] from donepezil interacted with the middle of AChE gorge and the PAS. The above moieties were merged into the scaffold of 17. Compound 19 showed less cytotoxicity than 17 and negligible affinity to metal ions, unless it inhibited BuChE and AChE (Scheme 3B). 3.2. Screening Approach. The screening approach is another commonly reported strategy for MTDL lead generation.69 Actually, focused screening is the main-stream screening strategy instead of “irrational” high throughput screening (HTS). In focused screening, compound classes already identified to be effective toward one of the targets of interest are subsequently screened for another one. It is a favorable approach for targets that are kinases: MTDLs are often identified via cross-screening of compounds in kinase panel profiling.70 MTDLs produced by screening methods may obtain all activities toward both targets of interest (A and B).20 But the resulting MTDLs are highly unlikely to possess the balanced affinity to multiple targets; therefore, the affinity would need to be optimized on all targets (cf. section 4.3). Moreover, the lead may also have activity toward undesired targets, which must be “design-out” during optimization (cf. section 4.2) (Figure 2).

Figure 2. The screening of compounds libraries may generate a lead compound that obtains all activities toward both targets of interest (A and B). (a) But a single compound may be unlikely to have balanced affinity to all targets; therefore its activities should be optimized. (b) In another case, the lead compound also has activity toward undesired targets, which must be “designed out” during optimization.20

4. LEAD OPTIMIZATION After the lead generation phase, the next challenge is to optimize the lead ligand for balanced activities and better physicochemical profiles. In this lead optimization phase, there are mainly two approaches: the design-in and design-out approaches.17 4.1. Design-In Approach. In design-in approach, the pharmacophore of one ligand is designed into the other according to molecular architecture and functional groups important for interacting with the biological targets.19 Preferably, the two selective lead compounds share sufficient similarity. The challenge of this approach lies in enhancing affinity to one target while retaining the affinity to the other target. Therefore, systematic structure−activity relationship (SAR) of substitution for multiple potencies should be E



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Scheme 4. Representative Example of Design-In Strategya

a

Based on design-in approach, the pharmacophore of 20 is designed into that of 21, according to molecular docking and cocrystals information.75,76

Scheme 5. Representative Example of Design-Out Approacha

a In the design-out approach, compound 25 is obtained by reducing the affinity to the undesired target NK3, meanwhile retaining the affinities on NK1 and NK2.79

necessary.22 In most cases, the goal is to balance in vitro activities within an order of magnitude for multiple targets, under the presumption that it may achieve similar degrees of in vivo receptor occupancy. However, the biodistribution of compound, the level of receptor occupancy for each target, receptor and (or) enzyme densities are different in various tissues.20 Therefore, clinical knowledge and input are very important for optimizing in vitro activities. If clinical knowledge or input is insufficient, animal pathological models may be helpful to find the optimal balanced ratio.22 Ideally, the template ligands to be integrated should contain similar physicochemical profiles and in vivo activities at the same order of magnitude because it is hard to obtain a workable MTDL if the template ligands are completely different from each other in terms of PK/PD profiles and activities.20

nature of template ligands, linkage site, linker length, etc. Therefore, developing efficient synthetic strategies for MTDLs is crucial for MTDLs development. For linked MTDLs, the linker may be the key in designing leads because the length, position, and structure of linkers may influence the activity. In some cases, linkers can participate in target binding and even work as pharmacophores.83 The click chemistry paradigm84 has been quickly applied to medicinal chemistry because it meets three important criteria to be an ideal reaction: versatility, selectivity, and efficiency. Recent application of click chemistry mainly focused on copper-catalyzed azide−alkyne cycloaddition (CuAAC), the thiol−yne click reaction (TYC)/thiol−ene click reaction (TEC), and the Diels−Alder (DA) reaction.84 Among them, CuAAC reactions are most widely applied in MTDLs synthesis (Scheme 6A). The simplicity and tolerance of CuAAC reaction, with the relatively inertial triazole ring, suggested its capability of linking two or more ligands. For instance, a “click chemistry” method was described for the efficient synthesis of proteosis-targeting chimera (PROTAC).85 This reaction was applied in linking the bromodomain and extra-terminal domain 4 (BRD4) ligand, and ligase

5. MTDL SYNTHESIS Since MTDLs are often hybrids integrated by two or more selective ligands, their synthesis will be undoubtedly be more difficult than traditional small molecule drugs. Moreover, the generation of effective molecules as MTDLs relies on the F



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Scheme 6. General Scheme and Representative Example of CuAAC Reactiona

a

(A) 1,3-Dipolar cycloaddition between alkynes and azides; (B) representative example of CuAAC reaction.85

Scheme 7. General Schemes and Representative Example of DA and Thiol−Ene/Yne Click Reactiona

a

(A) Diels−Alder (DA) reaction; (B) TEC reaction (top) and the TYC reaction (bottom); (C) representative example of DA reaction.92

substituted cyclohexene derivative (Scheme 7A). On the basis of merged pharmacophores approach, Arepalli et al.92 designed a series of novel 1,3-diphenylbenzo[f ][1,7]benzonaphthyrdines as potent cytotoxic agents and topoisomerase IIα inhibitors, through one-pot intermolecular imino DA reaction (Scheme 7C). This reaction has many advantages, such as being economical, having atom-economy, being a multicomponent reaction, being region-selective, and having broad substrate scope.92 TEC/TYC reaction only has a few applications in the synthesis of MTDLs (Scheme 7B). Apart from the click chemistry, cross-coupling reactions are emerging as an effective method of organic transformations with diverse applications in the systhesis of carbon−carbon (or carbon−heteroatom) bonds.93 They have enabled synthesizing complex organic molecules, with extensive applications in the

binders targeting Von Hippel−Lindau (VHL) and cereblon (CRBN) proteins (Scheme 6B). Furthermore, the structures of 1,2,3-triazoles formed through CuAAC reaction not only contribute to linking entities but also work as biologically active pharmacophores in treating cancer,86 acquired immune deficiency syndrome epidemic,87 tuberculosis,88 fungal infections.89,90 However, few 1,2,3-triazole-bearing therapeutics are on market or in clinical trials. Hopefully, we will witness the emergence of them on market as the click reactions are used more and more widely. Compared with CuAAC reaction, TEC/TYC and DA reactions are less applied in the synthesis of MTDLs. DA reaction can be applied between a substituted alkene (usually termed the dienophile) and a conjugated diene,91 to form a G



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Scheme 8. General Scheme and Representative Example of Suzuki Reactiona

(A) Aryl Suzuki reaction: C(sp2−sp2) cross-coupling. (B) Acyl Suzuki reaction: C(acyl-sp2) cross-coupling. (C) Representative example of Suzuki reaction.97

a

Scheme 9. General Scheme and Representative Example of Stille Reactiona

a

(A) Stille reaction; (B) representative example of Stille reaction.100

preparation of MTDLs.94 Such reactions have several advantages: (i) mild conditions; (ii) high yields; (iii) easy application under both aqueous and heterogeneous conditions; (iv) toleration of a broad range of functional groups; (v) robustness to steric hindrance.95 The high predictability, operational-simplicity, and superb functional group tolerance of cross-coupling reactions may contribute to efficient strategies development for MTDLs synthesis. The Suzuki cross-coupling represents the most powerful C− C bond forming reaction in organic synthesis.96 Traditional Suzuki cross-coupling contains the coupling of an aryl halide (pseudohalide) and an organoboron reagent and is most commonly employed for the synthesis of biaryls by a C(sp2)− C(sp2) disconnection using a nickel or palladium catalyst (Scheme 8A). Acyl Suzuki cross-coupling contains the coupling of an acyl electrophile (acyl halide, anhydride, ester, amide) and an organoboron reagent (Scheme 8B). Hou et al.97 developed an efficient and convenient protocol for synthesizing ABT-869 (a MTDL for receptor tyrosine kinases), and the Suzuki coupling reaction was applied in the key step of ABT-

869 synthesis (Scheme 8C). The synthetic process was more suitable for industrial production due to the advantages of simplicity, high yield, and purity.97 The cross-coupling reaction of organic electrophiles with organostannanes is usually referred to as the Stille reaction (Scheme 9A). The process of Stille reaction is mild, and it can tolerate of a broad range of functional groups, which is therefore widely applied in the synthesis of complex molecules.98 Further, organostannanes are generally insensitive to oxygen and moisture, are tolerant to harsher conditions, and can be achieved through various methods.98 The R1 group attached to the trialkyltin is generally sp2-hybridized, involving aryl and alkenes groups, but conditions have been designed to incorporate both sp3-hybridized groups, such as benzylic and allylic substituents, and sp-hybridized alkynes. X is generally a halide (such as Cl, Br, or I), but pseudo-halides (such as triflates), sulfonates, and phosphates can also be used.99 Rasolofonjatovo et al.100 designed a series of hybrids through merging combretastatin A-4 and isocombretastatin A-4 cores. H



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Scheme 10. General Scheme and Representative Example of Sonogashira Reactiona

a

(A) Sonogashira reaction; (B) representative example of Sonogashira reaction.102

Scheme 11. General Scheme and Representative Example of Heck Reactiona

a

(A) Heck reaction; (B) representative example of Heck reaction.105

Table 2. Physicochemical Properties Data of MTDLs on Market or in Clinical Trailsa therapeutic field MW cLogP HBA HBD PSA RB heteroatom approved drug number sample number

cancer

nervous system disease

cardiovascular disease

infectious disease

full MTDL set

476.51 (471.26) 3.81 (4.43) 6.18 (6.00) 1.95 (2.00) 99.06 (94.00) 6.32 (6.00) 9.36 (9.50) 14 22

335.06 (314.91) 3.16 (3.51) 3.75 (3.00) 1.35 (1.00) 62.27 (54.64) 5.46 (5.00) 5.41 (5.00) 13 56

408.08 (391.98) 3.27 (3.29) 5.20 (5.00) 2.50 (2.00) 102.11 (93.89) 8.20 (7.50) 7.25 (6.50) 10 20

407.90 (324.34) 2.58 (2.48) 5.95 (4.00) 3.00 (3.00) 115.91 (96.79) 6.84 (5.00) 8.68 (8.00) 12 19

385.96 (371.54) 3.22 (3.39) 4.81 (4.00) 1.93 (2.00) 84.70 (77.23) 6.32 (5.00) 7.00 (6.00) 49 117

a

The values outside the parentheses represent the mean values, and the inside ones represent the median values.

The Stille reaction was applied in the key synthesis progress (Scheme 9B). The palladium catalyzed C−C bond formation, which couples a sps carbon of an aryl or vinyl halide (or triflate) with a terminal sp hybridized carbon (from an alkyne), is generally referred to as Sonogashira cross-coupling reaction (Scheme 10A). It is one of the most frequently used for sp2−sp C−C bond construction, widely applied in natural products synthesis, dendrimers, heterocycles, and conjugated polymers.101 Khatyr et al.102 obtained the multitarget ligands through chemioselective palladium-catalyzed Sonogashira reaction (Scheme 10B). The main advantage of this method is adaptability and synthetic versatility for synthesizing multitopic metal-binding ligands with various bridging units and phenyl substituents.102

The Heck reaction is the reaction of an alkene with an unsaturated halide (or triflate), which was catalyzed by a palladium or palladium nanomaterial, to create a substituted alkene (Scheme 11A).103 It is attractive in terms of synthesis because high chemoselectivity and mild conditions are associated with low cost of the reagents and low toxicity.104 On the basis of fused pharmacophores approach, Palem et al.105 reported a novel quinazolinones with allylphenylquinoxaline hybrid designed for antiproliferative activity, utilizing palladium-catalyzed Heck reaction in the final synthesis step (Scheme 11B). The synthesis of MTDLs is generally more difficult than single-target ligands. The synthetic reactions discussed above are all efficient and mild methods for MTDLs synthesis. What is more, they all have high product yields and are tolerant of a I



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them were originally designed as multitarget drugs, such as axitinib109 and lapatinib,110 whereas the rest are just serendipity:27 the multiple activities were discovered during kinase activity profiling, or they were designed for other therapeutic areas. In other words, they were designed for single targets but actually act on multiple targets. The discovery of imatinib is a typical example.27 From the successful case of imatinib, high throughput in vitro screening may facilitate discovering more MTDLs ever considered as single-target drug candidate. Regarding the MTDLs in the fields of cardiovascular and infectious diseases, the mean (median) values are generally higher than that of full MTDL set (except for the cLogP median values of cardiovascular disease). This also indicates to some extent the complexity of the multitarget drugs for cardiovascular disease and infectious disease. Therefore, as a general principle of MTDL design, the complexity and size of the template ligands had better be minimized, and the pharmacophores overlap had better be maximized. Removing functionality and rotatable bonds to simplify structures has often been required in lead optimization.111 If the pharmacophores are completely different, it may be impossible to integrate into a compact compound, and a high MW may be unavoidable. In this case, the high MW will be one of the main reasons for failure in clinical settings. Therefore, similar targets, in terms of possessing identical or highly similar endogenous ligand or being from the same superfamily, are preferred to rationally design multiple ligands. On the other hand, where possible, the template ligands are highly desirable with favorable physicochemical profiles because it is hard to obtain a worthy MTDL if the template ligands suffer physicochemical liabilities. Moreover, it is easier to discover high-quality lead compounds by taking screening and pharmacophore combination approaches simultaneously because the lead compounds obtained by screening usually have small molecular size and more favorable physicochemical profiles. If a drug candidate is given via intravenous administration or the aim is to discover pharmacological tools to explore the feasibility of novel target combination, the oral bioavailability is less of an issue.112

broad range of functional groups. Thus, these efficient reactions may enable convenient synthesis of MTDLs.

6. DEVELOPABILITY AND PHYSICOCHEMICAL CHALLENGES Many factors contribute to the developability of MTDLs, particularly the physicochemical properties relevant to the molecular size and complexity.12 Physicochemical properties will further influence the PK profiles and oral bioavailability, which is the most favorable route of administration.20 In general, optimizing the PK profiles while keeping a balanced activity is the most difficult challenge in the lead optimizing phase. As a result of a combination of selective ligands, MTDLs may be more lipophilic and have higher molecular weight than approved drugs on market.20 Many MTDLs have MW > 500 and cLogP > 5,22 which are major challenges to developability. A database of 117 MTDLs on market or in clinical trials was compiled by searching the Web site https://integrity.thomsonpharma.com. According to the classification on this Web site, the full database was divided into subsets by therapeutic fields. For each MTDL, seven physicochemical properties were calculated: MW, cLogP, the number of hydrogen bond acceptors (HBA), the number of hydrogen bond donors (HBD), polar surface area (PSA), the number of rotatable bonds (RB), and the number of heteroatoms.106,107 The mean and median values of the above seven properties for the full set and each subset are shown in Table 2. We found significant differences in physicochemical properties among the MTDLs in the four therapeutic fields. For instance, the mean (median) values of MW are 335.06 (314.91) for MTDLs in the field of nervous system disease and 476.51 (471.26) for MTDLs in the field of cancer. It is remarkable that nervous system disease cluster occupied the lowest mean (median) values of all seven properties, especially the MW and lipophilicity, which are critical for blood−brain barrier (BBB) permeability. It is consistent with the fact that few MTDLs in the field of neurodegenerative diseases (especially for AD) reached clinical trial stage or on market, though many research studies have been conducted. Through a literature search, we found that the MTDLs for AD in basic research had significant different targets (such as AChE and Aβ aggregation inhibition). Most of these MTDLs have MW > 500 Da, which may raise concerns on their oral bioavailability and the ability to cross BBB. For instance, many research studies have been published about hybrids generated simply via linking active pharmacophore to tacrine.108 Except for a few exceptions, most of MTDLs in basic research studies for AD have never been tested for the ability to cross the BBB or oral bioavailability. If tests to address these problems were conducted, they were confined to in vitro experiments by the parallel artificial membrane permeability assay (PAMPA). However, PAMPA which is based on an artificial membranemimic system is just a passive model for testing BBB permeability, whose results may not agree with actual in vivo situation. Conversely, the mean (median) values for MTDLs in the field of cancer are all higher than or equal to that of full MTDL set. Furthermore, the MTDLs in the field of cancer have the highest MW, cLogP, HBA, and heteroatom mean (median) values, consistent with the structure complexity of targets involved in cancers. So far, many MTDLs for cancer treatment are on market or in clinical trial stage; however, only a few of

7. RECENT PROGRESS OF MTDLS IN DRUG DISCOVERY CAMPAIGN A full description of recently discovered MTDLs is beyond the scope of this article. So we just discuss the MTDLs’ application in some common multifactorial diseases to provide better insights of translational research. 7.1. MTDLs for Cancer. Currently, cancer is the focus of MTDL discovery because of the multifactorial nature and frequently developed resistance to chemotherapy.113 The synergistic activities of MTDLs may contribute to higher therapeutic efficacy and delayed resistance development.3−6 7.1.1. MTDLs Targeting Histone Deacetylase and Other Targets. Histone deacetylase (HDAC) is an epigenetic enzyme associated with tumorigenesis and development. HDAC is therefore regarded as an important target for cancer therapy.114,115 Generally, HDAC inhibitors (HDACi) consist of three parts: (i) a zinc binding group (ZBG) to chelate the catalytic zinc ion; (ii) a hydrophobic linker to occupy the tunnel of the active site; (iii) a surface cap to recognize the amino acid residues around the entrance of the active site.116 J



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Scheme 12. MTDLs Targeting HDAC and Other Targetsa

a

Most HDACi consist of three parts: a ZBG, a hydrophobic linker, and a surface cognition cap.138 The HDACi pharmacophores can tolerate diverse cap groups, enabling MTDLs strategies. K



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Table 3. Biological Activities of MTDLs Targeting HDAC and Proteasome127 compd 28 bortezomib ricolinostat vornostat

HDAC6

HL60

SEM

SUP-B15r

IC50 (μM)

IC50 (nM)

IC50 (nM)

IC50 (nM)

0.27 ± 0.01

260.70 ± 3.12 6.67 ± 0.16 >25000 >25000

394.20 ± 9.85 4.43 ± 0.13 >25000 >25000

820.50 ± 13.94 28.09 ± 1.15 >25000 >25000

MDM2 can reactivate the function of p53 and is therefore believed to be a promising strategy for cancer therapy. By analyzing the binding models of known MDM2 inhibitors and HDACs, they found that three functional groups on the imidazole scaffold of compound 29 can mimick Phe19, Leu26, and Trp23 residues in p53, which stretched into the binding pocket of MDM2. Therefore, they used the SAHA (30) and 29 as templates to design and synthesize MDM2-HDAC dual inhibitors. The N3 substitution of 29 exposed to the solvent was designed to introduce a linker (Scheme 12B). The resulting compound 31 showed remarkable selectivity for HDAC6 and high affinity to MDM2 (Table 4). Moreover, it exhibited superb in vivo antitumor efficacy in A549 xenograft model (tumor growth inhibition (TGI) = 74.5%) and was orally available.

So far, four HDACi have been approved, including vorinostat (SAHA),117 belinostat (PXD101),118 romidepsin (FK228),119 and panobinostat (LBH589).120 However, HDACi only demonstrated the efficacy in hematologic malignancies but not solid tumors.121 Hopefully, combination therapies would lead to more clinical applications of HDACi, and emerging interest was drawn to this field.122 Moreover, the HDACi pharmacophores can tolerate diverse cap groups to enable MTDLs strategies. Currently, HDACi have been combined with a variety of anticancer drugs in clinical studies, and the target combination selection of HDACi-based multitarget drug candidates was mainly based on these clinical experience.123−126 Proteasome inhibitor (PI) bortezomib123 was applied in combination with HDACi panobinostat in clinical studies to induce simultaneous blockage of the aggresome pathways and ubiquitin degradation. Bhatia et al.127 reported a first-in-class dual HDAC-proteasome inhibitor. Rather than covalent binders, they focused on noncovalent scaffolds of PIs in order to avoid the pitfalls of insufficient specificity, insufficient stability, excessive reactivity, as well as chemical incompatibilities due to highly reactive electrophilic warheads.128 The high affinity of compound 26 was mainly due to a P3-neopentyl-Asn residue (Scheme 12A).129 Moreover, the available crystal structures of proteasome and corresponding peptidic ligands reveal that the bulky residue, as an excellent side chain, can occupy the whole S3 specificity pocket in the chymotrypsinlike site of the 20S core particle. So they utilized compound 26 as template to design and synthesize dual-HDAC-PIs. The Xray structure of 26 revealed the exposure of P4 residue to the solvent. So they decided to incorporate the HDACi part in the P4 position (Scheme 12A). On the other hand, the most effective synergy was derived from the combination of PIs and HDAC6. Compound 27 is a representative selective HDAC6 inhibitor on the basis of an N-dydroxybenzamide scaffold which provided HDAC6 selectivity. They replaced the solventexposed 4-picolyl scaffold by a methyl group in the P2 position to reduce MW. The above hybridization strategy led to the HDAC-proteasome inhibitor compound 28. Biochemical assays, cellular assays, and X-ray crystal structures analysis (HDAC6 and 20S proteasome complexed with compound 28) confirmed that compound 28 inhibited both targets simultaneously. Compound 28 was tested for the activity of proteasome inhibition. While ricolinostat (HDAC6 inhibitor) and vorinostat (pan-HDAC inhibitor) were the negative controls, bortezomib was the positive control. Furthermore, compound 28 can block the activity of chymotrypsin-like proteasome in selected leukemic cell lines (HL-60, SUP-B15r, and SEM), while vorinostat and ricolinostat cannot (Table 3). Regarding to the fused-pharmacophores strategy, He et al.130 have reported novel HDACs and p53-human murine double minute 2 (MDM2) interaction dual-inhibitors (Scheme 12B). The interaction with MDM2 protein is a major inhibitory mechanism of of p53.131 Blocking the interaction of p53 and

Table 4. Biological Activities of MTDLs Targeting HDAC and MDM2130 compd 29, nutlin-3 30, SAHA 31

MDM2

HDAC1

HDAC6

Ki (μM)

IC50 (nM)

IC50 (nM)

0.14 ± 0.04 >20 0.11 ± 0.03

45.0 ± 3.1 821 ± 12

16.3 ± 1.6 17.5 ± 1.5

The combination of pazopanib124 (a multiple vascular endothelial growth factor receptor (VEGFR) inhibitor for advanced renal cell carcinoma treatment) and HDACi exhibited good preclinical results.125 Therefore, another series of dual HDAC-VEGFR inhibitor were designed down the road.132 Zang et al.132 incorporated pazopanib (32) into the surface recognition cap of HDACi pharmacophore from MS275 (33, an HDACi) (Scheme 12C) to overcome developed drug resistance in almost all patients treated with VEGFR inhibitors.133,134 Vascular endothelial growth factor (VEGF)/ VEGFR signaling pathway is regarded as the main antiangiogenesis target for cancer therapy.135 They selected pazopanib as a template based on promising preclinical study results of combination of pazopanib and HDACi.124,125 To decide which site of compound 32 can be substituted without losing the affinity to VEGFR-2, they analyzed the binding pattern of compound 32 within the ATP pocket of VEGFR-2. They found that the 2-aminopyrimidine scaffold of 32 formed two critical hydrogen bonds with the Cys917 residue in the hinge region, and the indazole moiety inserted into the inner pocket of VEGFR-2. Therefore, they kept these two important scaffolds without modification. They figured out that the solvent-exposed benzenesulfonamide moiety could be modified with the HDACi motif without compromising the VEGFR-2 inhibition. Therefore, they conjugated two privileged ZBGs (ortho-aminoanilide and hydroxamic acid) to the solvent-exposed phenyl group straightway or by diverse linkers, resulting in a series of dual HDAC-VEGFR-2 inhibitors. The resulting compound 34 showed HDACs inhibition comparable L



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mutations can be treated with MEK inhibitor (trametinib) for melanoma in clinical trials.142 There is a need to apply combination therapies to improve the clinical response.143 Recent clinical research showed that the simultaneous inhibition of MEK and Src led to improved efficacy in cancer patients.144 In previous work, Cui et al.145 found that acridine derivatives OA (37) exhibited inhibition on Src. But the inhibition of 37 on Src is weak, likely because there is merely one hydrogenbond interaction between 37 and the hinge of Src protein. In addition, studies have shown that molecules that bear a moiety can improve the affinity of kinase inhibition obviously, such as urea bonds which had the ability to bind the DFG-out conformation of c-Src.146 For examples, some kinase inhibitors approved or in clinical trial stage, such as imatinib,147 ponatinib,148 and regorafenib,149 all have amido or urea moieties capable of forming hydrogen bonds with the amino acid residues of the DFG-out pocket of kinases.150 Taking these into considerations, they introduced the phenylurea moieties to the 9-anilinoacridine substituents by fusedpharmacophores approach (Scheme 13). Among the derivatives, compound 39 inhibited 59.67% of Src activity and exhibited inhibition rates on MEK and PI3K of 43.23% and 44.41% at 10 μM, respectively. The antiproliferative activity of 39 was determined on HepG-2 and K562 cells using MTT assay, and imatinib was the positive control. For compounds 37 and 39, the IC50 of antiproliferative activities on HepG-2 and K562 cells were shown in Table 7. Compound 39 is a novel MTDL for dual Src and MEK inhibition and can induce cancer cell apoptosis.150 7.1.3. MTDLs Targeting ERα and VEGFR-2. In breast cancer, estrogen receptor α (ERα) is charge of estrogeninduced proliferation.151 VEGFR-2 is also considered as a dominant receptor in the angiogenesis pathway.152 However, VEGFR-2 inhibitors have limited efficacy as monotherapy.152,153 A combination of tamoxifen (41, a selective estrogen receptor modulator (SERM)) and only low doses of brivanib alaninate (a VEGFR-2 inhibitor) was able to improve therapeutic efficacy and at the same time prevent SERM resistant tumor growth.154 Furthermore, VEGFR-2 inhibitors that contain an indol-2-one scaffold share some structural similarities with SERMs, such as YM231146 (42) and sunitinib. Hereby, Tang et al.155 designed and synthesized a series of dual-target inhibitors toward VEGFR-2 and ERα through linked-pharmacophore approach. They integrated the 2H-1benzopyran pharmacophore form acolbifene (40) with functional groups capable of inhibiting VEGFR-2 selectively (Scheme 14). Among the ERα/VEGFR-2 dual inhibitors, compound 43 had the highest level of inhibitory activities for ERα and VEGFR-2 (Table 8). Following studies demonstrated potential antiproliferation activity of compound 43 on MCF-7 breast cancer cells, as well as good in vivo antiangiogenesis activity. In pursuit of diverse scaffolds as MTDLs for ERα and VEGFR-2 inhibition, they further designed a series of 6arylindenoisoquinolone analogues containing side chains.156 Compound 44 contained two hydroxyl groups, which mimicked estradiol to form two hydrogen-bond interactions with ERα. Compound 44 was also tested for inhibitory activity of human breast cancer cell lines MCF-7 (ER+). Compound 44 proved to be an ERα/VEGFR-2 dual inhibitor, and its IC50 values are shown in Table 8. This work identified a novel

to entinostat (an HDACi in phase III) and uncompromised antiangiogenic activities compared with pazopanib (Table 5). Moreover, compound 34 has ideal PK profiles, up to 72% oral bioavailability in SD rats, and desirable in vivo antitumor efficacy in HT-29 xenograft model (TGI = 40%). Table 5. Biological Activities of MTDLs Targeting HDAC and VEGFR-2132 compd

VEGFR-2

HDAC

Inh % (0.2 μM)

IC50 (μM)

32, pazopanib 33, MS-275 34 SAHA

95 1.8 4.6 0.13

100

The combination of Janus kinases 2 (JAK2) and HDAC inhibitors has been reported in clinical studies.126 On this basis, Huang et al.136 reported designing dual JAK2-HDAC inhibitors for invasive fungal infections (IFIs) and leukemia treatment simultaneously (Scheme 12D). JAK2 is a validated target for multiple cancers, including hematological malignancies.137 But the application of JAK2 inhibitors has been in compliance with drug resistance and the complication of IFIs.138 In general, a JAK2 inhibitor consists of three parts: two hydrophobic groups, hinge-region binder (typically an aminopyrimidine), and a solvent-exposed motif. The aminopyrimidine proved to be an important motif for JAK2 inhibition. The first series were designed via merging of the central motif of the template compound 35 with the ZBG group from compound 30 (benzamide or hydroxamic acid) by diverse linkers. Since N-phenylmethanesulfonamide derivatives of compound 35 showed similar activity for JAK2 inhibition, the second series were designed and synthesized with the Ncyanomethylbenzamide/N-phenylmethanesulfonamide substitution. A minor substitution in the hydrophobic area of compound 35 could be tolerated; thus benzamide or hydroxamic acid was introduced in this position. The optimized compound 36 in the second series showed highly selective JAK2/HDAC6 inhibition (Table 6). Importantly, compound 36 had shown efficacy in several in vivo models, such as human embryonic lung fibroblasts (HEL) xenograft model. Table 6. Biological Activities of MTDLs Targeting HDAC and JAK2136 compd 30, SAHA 35 36

JAK2

HDAC1

HDAC6

IC50 (nM)

IC50 (nM)

IC50 (nM)

40 ± 9 41 ± 5 8.4 ± 0.7

250 ± 25

46 ± 1.7

7.1.2. MTDLs Targeting Src and MEK Kinases. As a nonreceptor type tyrosine kinase, Src regulates many activities of cancer cells, such as proliferation, migration, and invasion.139,140 Therefore, Src is believed to be a valuable target to treat cancer. On the other hand, MEK kinase can influence mitogen-activated protein kinase (MAPK) signaling pathway and regulate apoptosis and oncogenic transformation141 and is therefore another important anticancer target. Unfortunately, merely 22% patients in the presence of the BRAF gene M



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Scheme 13. MTDLs Targeting Src and MEK Kinases145

Table 7. Biological Activities of MTDLs Targeting Src and MEK Kinases145 compd 37 39 imatinib

Src

MEK

K562

HepG-2

Inh %

Inh %

IC50 (μM)

IC50 (μM)

8.02 at 50 μM 59.67 at 10 μM

44.03 at 50 μM 43.23 at 10 μM

5.8 4.08 0.53

>50 9.41 >25

Table 8. Biological Activities of MTDLs Targeting ERα and VEGFR-2155 compd 43 44 41, tamoxifen sunitinib

ERα

MCF-7

VEGFR-2

Inh % (0.1 mg/mL)

IC50 (μM)

Inh % (0.1 mg/mL)

99.89 7.2 μMa 100

2.73 1.2 1.89

100.26 0.099 μMb 100 (0.14 μMb)

a

The value represents the IC50 values for ERα inhibition. bThe value represents the IC50 values for VEGFR-2 inhibition.

approach to design multitarget drugs with pharmacophores from two families’ targets. 7.1.4. MTDLs Targeting Microtubule and Tyrosine Kinase (RTK). Combination chemotherapy with cytotoxic and antiangiogenic drug (especially RTK inhibitors) has shown promising results in clinical studies.157−159 Compound 46 is a dual inhibitor for VEGFR-2 and platelet-derived growth factor receptor β (PDGFR-β), with furo[2,3-d]pyrimidine scaffold.160,161 Furthermore, 6-methylcyclopenta fused pyrimidines 45 showed strong tubulin depolymerization activity, as well as both in vitro and in vivo anticancer activities.162−164 As an initial research study, Zhang et al.165 tried to integrate tubulin inhibitory activity of compound 45 into the existing RTK inhibitor compound 46. They replaced the 5-substitution onto the 4-NH moiety of compound 48 and placed a 6-CH3 group on compound 46 to generate a hybrid furo[2,3d]pyrimidine scaffold (Scheme 15). This scaffold has

antitubulin activity compared to compound 45, and it can also access the hydrophobic region on the basic pharmacophore for RTKs (VEGFR-2 and PDGFR-β). Among the derivatives generated by the 2-substitution, the 2-methylgroup-substituted compound 47 showed EC50 value of 3.9 μM for angiogenesis inhibition. The inhibitory efficiency of compound 47 was 9-fold higher than erlotinib and approximately equals half of sunitinib. Moreover, 47 was the most active compound as tubulin depolymerizer and for EGFR, VEGFR-2, and PDGFR-β inhibition (Table 9). SAR analysis of this compound series indicated that the N-alkyl group is the key for microtubule depolymerization activity. In order to explore the bioactive conformation, they further designed a series of 4-substituted 2,6-dimethylfuro[2,3-d]-

Scheme 14. MTDLs Targeting ERα and VEGFR-2155

N



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Scheme 15. MTDLs Targeting Tyrosine Kinase and Microtubule165

different molecules in one small molecule could be very challenging for PK optimization.171 Initially, they found some known GSK-3β inhibitors had common five-membered heterocyclic fragments with hydrogen bond donor and acceptor functionalities.172,173 Thiadiazolidinedione (TDZD) is the first class reported non-ATP competitive inhibitor of GSK-3β,174 and tideglusib (49) is currently under clinical development.175 Interestingly, thiohydantoin, hydantoin, and rhodanine were discovered as effective scaffolds to inhibit tau antiaggregation.176 Thus, they speculated that the cross-talk of the above scaffolds may be applied for the two selected targets. They did not select rhodanine as lead due to the pan-assay interference compounds (PAINS) behavior.177 Conversely, they selected the 2,4-thiazolidinedione (TZD) fragment without PAINS (Scheme 12),178,179 even though TZD scaffold has never been explored as either GSK-3β or tau antiaggregation fragment. Previous works showed that (i) 5-arylidene substitution could improve efficacy of the 2-iminothiazolidin-4-one GSK-3β inhibitors and (ii) their volume and size did not fit in similar regions of homologous kinases, suggesting that selectivity for GSK-3β could be optimized.173 Thus, they modified position 5 using diverse heteroaromatic and aromatic substituents and obtained series of 5-arylidene-2,4-thiazolidinediones. The resulting compounds 50 and 51 exhibited (i) micromolar IC50 values for GSK-3β (Table 10) and increased the cell viability in cell model induced by okadaic acid, (ii) PAMPABBB permeability and suitable cellular safety profile, and (iii)

Table 9. Biological Activities of MTDLs Targeting RTKs and Microtubule165 compd 47 48 sunitinib combretastatin A-4

PDGFR-β

VEGFR-2

microtubule depolymerization

IC50 (nM)

IC50 (nM)

EC50 (nM)

22.8 ± 4.9 58.2 ± 8.0 83.1 ± 10.1

19.1 ± 3.0 33.2 ± 5.0 18.9 ± 2.7

103 21 9.8

pyrimidines that were conformationally restricted. Compared with compound 47, optimized compound 48 exhibited a remarkable improved inhibitory efficiency on RTKs and microtubule assembly.166 7.2. MTDLs for Central Nervous System Diseases. Owing to the complex etiology of central nervous system diseases, development of new multifunctional drugs in this therapeutic field has become more attractive in recent years.167,168 7.2.1. MTDLs Targeting Glycogen Synthase Kinase 3β and Tau-Aggregation for AD. In 2018, Gandini et al.169 developed 2,4-thiazolidinedione derivatives with dual inhibitory activities on the glycogen synthase kinase 3β (GSK-3β, a phosphorylating tau kinase) and tau aggregation process (Scheme 16). It is not easy to design a ligand binding two targets which shared no binding site similarity, as in the cases of tau protein and GSK3β.170 Moreover, combining molecular skeletons from two

Scheme 16. MTDLs Targeting GSK-3β and Tau-Aggregation for AD169

O



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indicated that compound 54 effectively improved the learning and memory of scopolamine-treated ICR mice; (iii) it had lower hepatotoxicity compared with tacrine. The research identified a novel approach for developing dual GSK-3β/AChE inhibitors as drug candidates for AD therapy (Scheme 17). Melatonin (55) is a pineal neurohormone, and its level decreases with age, notably in AD patients. Studies have shown that melatonin had strong antioxidant activities and could eliminate various reactive oxygen species.184 Furthermore, it can protect microglial cells from Aβ-induced apoptosis and improve cognitive disorders in rats.185,186 Rodriguez-Franco et al.187 developed novel melatonin-tacrine hybrids based on the linked-pharmacophore approach. They linked the two pharmacophores with different length of linkers, which can be stretched into the enzyme cavity (Scheme 17). Compound 56 was the strongest inhibitor for hAChE with 40 000-fold inhibitory efficiency of tacrine. Interestingly, it showed high selectivity of 1000-fold on AChE over hBuChE. Moreover, compound 56 had 2.5-fold higher oxygen radical absorbance capacity than trolox (a vitamin E analogue) (Table 12).

Table 10. Biological Activities of MTDLs Targeting GSK-3β and Tau Aggregation169 compd 50 51 49, tideglusib

GSK-3β

tau K18 self-aggregation

IC50 (μM)

Inh % (10 μM)

4.93 ± 0.66 0.89 ± 0.21 0.69 ± 0.09

35a

a

Compared to tau K18 self-aggregation alone.

satisfactory PK properties and balanced activities with low MW. 7.2.2. MTDLs Targeting ChE and Other Targets for AD. Tacrine is an acetylcholinesterase inhibitor (AChEI) approved by the FDA,180 but its hepatotoxicity limited further clinical applications. Nowadays, tacrine is widely used as a template for designing MTDLs for AD therapy.181,182 It is worth mentioning that many of tacrine hybrids have decreased toxicity. Neurofibrillary tangles (NFTs) represent one of the most relevant histopathological hallmarks of AD. According to the tau hypothesis, GSK-3β is a multifunctional serine/threonine kinase that regulates tau phosphorylation and precipitation as NFTs. On the basis of linked-pharmacophore strategy, our group designed a series of GSK-3β/AChE dual inhibitors.183 The hybrid compound 54 exhibited the promising profile: (i) the IC50 values for hAChE and hGSK-3β inhibition are 6.5 nM and 66 nM, respectively (Table 11); (ii) in vivo studies

Table 12. Biological Activities of MTDLs Targeting ChE and Oxidation187 compd 52, tacrine 55 56

Table 11. Biological Activities of MTDLs Targeting GSK-3β and ChE183 compd 52, tacrine 53 54

hGSK-3β

hAChE

hBuChE

IC50 (nM)

IC50 (nM)

IC50 (nM)

230 ± 31

40 ± 3.7

6.4 ± 0.3

260 ± 32

1.1 66 ± 6.2

hAChE

hBuChE

trolox

IC50 (nM)

IC50 (nM)

equiva

350 ± 10

40 ± 2

0.008 ± 0.0004

7.8 ± 0.4

10000 101 14

>1000 >1000 180 42 6

donor atoms, as well as a hydroxyl group, were introduced to form a tetradentate hybrid to increase metal binding ability. In this conformation, the ligand can inhibit ROS generation by disrupting the favorable tetrahedral geometry of Cu(I). Substituents (such as phenolic and quinoline groups)202 as validated antioxidants were introduced into hybrid for antioxidation. Finally, polar groups (such as amino and hydroxyl groups) were added to improve water solubility. Series of chemical studies indicated that hybrid 65 targeted metal free and metal-Aβ, inhibited in vitro Aβ aggregation, as well as reduced the toxicity caused by Aβ. Moreover, compound 65 was water-soluble with potential BBB permeability and regulated the formation and presence of free radicals (Table 15). 7.2.4. MTDLs Targeting MAO-B and Other Targets for Parkinson’s Disease. Parkinson’s disease (PD) is a well-known nervous system disease. MAOs plays an important role in neurotransmitter degradation. In the human brain, the MAO-B mainly degrades dopamine and therefore serves as a target for PD.203 The human histamine H3 receptor (hH3R) is mainly expressed in the central nervous system (CNS). The activation of presynaptic H3R might reduce the release neurotransmitters including dopamine,204,205 indicating its value as a promising target for PD. Compounds 68 and 69 are potent and selective reversible MAO-B inhibitors. Ciproxifan (66) is a H3R inverse agonist with simultaneous MAO-B inhibitory activity. In the linked-pharmacophore approach, Affini et al.206 designed and synthesized MAO-B/H3R dual-target ligands for PD therapy. The alkyloxyphenyl linker of compound 66 was kept, whereas the imidazole moiety was replaced by Q



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Scheme 19. MTDLs Targeting Metal Chelation, Aβ, Metal-Aβ, and ROS for AD197

group of compound 71 was substituted by diverse aromatic groups, and there substituent groups were introduced directly or through various linkers to the N8 of the pyrazinopurine scaffold (Scheme 21). Among these compounds, compound 73 showed comparable inhibitory activities on A1, A2AARs, and MAO-B (Table 17). 7.2.5. MTDLs Targeting SERT/5-HT1A/5-HT7 for Depression. Depression is one of the leading causes of disability in the world.212 However, there are still significant challenges for depression treatment, such as limited patient response rate and tremendous adverse effects.213,214 The combination of SERT and 5-HT receptor inhibition may be an effective strategy for treating depression.215 Recent research indicated that pindolol could enhance selective serotonin reuptake inhibitors (SSRIs) effects and simultaneously target 5-HT1A.216 Additionally, the combination of selective 5-HT7 receptor antagonist with even a low dose of SSRI was effective in depression models. Hence, MTDLs toward SERT/5-HT1A/5-HT7 may be valuable for treating depression. The benzofuran derivative 77 showed high binding affinity to the 5-HT1A receptor and SERT.217 2-Biphenylpiperazine derivatives 74−76 exhibited high affinity to 5-HT1A as well as 5-HT7 receptors.218−220 On the basis of the knowledge above, Gu et al.221 reported a series of novel aralkylpiperazine compounds in a merged-pharmacophore approach. To explore the affinity to 5-HT1A and 5-HT7 receptors, the N1 position was introduced by diverse aromatic groups. And they tested if replacing the benzofuran scaffold with indole scaffold could enhance serotonin reuptake inhibition (Scheme 22). Among the series of compounds, compound 78 exhibited high affinity to 5-HT1A/5-HT7 and strong serotonin reuptake inhibition (RUI) (Table 18). 7.2.6. MTDLs Targeting Dopamine D2 Receptor and Serotonin Reuptake for Schizophrenia. Schizophrenia is an overwhelming mental disease.222 Though typical antipsychotics show improvement in mitigating positive symptoms by blocking dopamine D2 receptors (D2Rs),223 they may also lead to extrapyramidal symptoms (EPS) like PD and tardive dyskinesia.224 The combination of a neuroleptic together with a SSRI showed improved efficacy for schizophrenia, at the same time a decrease in depression, without exacerbating EPS.225 Therefore, Smid et al.226 designed hybrids based on the templates of a well-known dopamine D2 receptor inhibitor (eltoprazine,227 80) and a serotonin reuptake (SR) inhibitor (indalpine, 79) (Scheme 23). They took some factors into consideration for receptor affinity: (i) the length of the alkyl

Table 15. Biological Activities of MTDLs Targeting Metal Chelation, Aβ, Metal-Aβ, and ROS197 target Aβ and metal-Aβ

Aβ42 fibers Metal Early oligomerization of Aβ Metal-associated Aβ-induced toxicity ROS formation Oxidation BBB permeability

multiple activities of 65 65 can bind to Aβ40 and Aβ42. 65 stoichiometry and can bind to metal-Aβ42 and chelate Cu(II) from Aβ42 competitively. 65 can interact with Aβ42 fibers and bind to Zn(II)-Aβ42 fibers. 65 can bind to Cu(II) and Zn(II) selectively and chelate metal ions surrounded by soluble Aβ. 65 can inhibit the formation of dodecamer and hexamer. 65 may regulate Aβ/metal-Aβ-induced toxicity. 65 may control Cu-triggered formation of hydroxyl radicals. 65 can scavenge free radicals more effectively than trolox (1.41 ± 0.15 for 65; 1.00 ± 0.08 for trolox) by the TEAC assay. 65 may cross the BBB in PAMPA assay.

piperidine (from UCL2190, 67) which fits the H 3 R pharmacophore more favorably. Series I was designed by introduction of the H3R pharmacophore to the C5 or C6 position of the indanone scaffold of compound 68. Series II was designed by introducing the H3R motif to the C5 or C6 position of the more lipophilic 2-benzylideneindanone derivative 69. Series III was designed by introducing the H3R motif to the benzylidene ring B at the C4′ position (Scheme 20). Extensive SAR studies generated various chemotypes of dual MAO-B/hH3R inhibitors. Compound 70 (from series III) showed strong activities on MAO-B and hH3R, as well as selectivity on MAO-B over A (SI > 36) (Table 16). Thus, indanone-substituted derivatives are potent lead compounds for MAO-B/hH3R dual-target candidates for the treatment of PD. Among the validated targets for PD treatment, A 2A adenosine receptor (AR) and MAO-B are two most important ones.207 Combined with levodopa, MAO-B inhibitors can inhibit dopamine metabolism in the brain and therefore increase the levels of dopamine. Compound 71 is a strong A2A antagonist.208 Caffeine (72) is a nonselective AR antagonists with cognitive enhancer efficacy in treating PD and AD.209 In 2014, the first compound is reported to inhibit all three targets of interest, A1, A2AARs, and MAO-B.210 In 2016, Brunschweiger et al.211 further developed a series of novel derivatives based on compound 71 via SAR investigation. The benzyl R



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Scheme 20. MTDLs Targeting MAO-B and H3R for PD206

Table 16. Biological Activities of MTDLs Targeting MAO-B and H3R206 compd 66, ciproxifan 67, UCL2190 68 69 70

MAO-A

MAO-B

IC50 (nM)

IC50 (nM)

2100 39 >1000000 >10000

11000 3 9.2 276

SIa

Table 17. Biological Activities of MTDLs Targeting MAO-B and A1/A2A AR211

H3R

compd

Ki (nM)

0.19 11 13

46−180

36

10

71 72 73

a

Selectivity index (SI) = IC50(MAO-A)/IC50(MAO-B).

A1AR

A2AAR

hMAO-A

hMAO-B

Ki (μM)

Ki (μM)

IC50 (μM)

IC50 (μM)

0.265 ± 0.068 44.9 0.393 ± 0.101

1.06 ± 0.30 23.4 0.595 ± 0.051

>50.0 >10.0

>10.0 >50.0 0.210 ± 0.041

heteroaryl structure. Some key candidates showed potent in vitro and in vivo pharmacological activities, especially compound 81. Molecular docking also indicated that compound 81 can adopt two different conformations, which

linker between the aryl and indole piperazine groups; (ii) the substitution pattern of the indole scaffold; (iii) the bicyclic

Scheme 21. MTDLs Targeting MAO-B and A1/A2A AR for PD211

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Scheme 22. MTDLs Targeting SERT/5-HT1A/5-HT7 for Depression221

Table 18. Biological Activities of MTDLs Targeting SERT/ 5-HT1A/5-HT7221 compd 74 75 76 77 78

5-HT1A

5-HT7

SERT

Ki (nM)

Ki (nM)

IC50 (nM)

60.9 188 99 1.94 28

0.13 0.58 1.4 3.3

Table 19. Biological Activities of MTDLs Targeting Dopamine D2 Receptor and Serotonin Reuptake226 in vitro

in vivo

hD2

rSR

APOa

5-HTPb

Ki (μM)

Ki (μM)

EC50 (mg/kg)

EC50 (mg/kg)

compd 79, indalpine 80, eltoprazine 81

25.3 25

2.0 ± 0.1 6.9 ± 1.8

0.1 2.0 ± 0.1 0.2 ± 0.1

0.08

0.15

a

Antagonizing apomorphine induced climbing behavior in mice (po). b 5-HTP induced serotonin syndrome like behavior in mice (po).

fit the SR pharmacophore and dopamine D2 receptor pharmacophore, respectively (Table 19). 7.3. MTDLs for Cardiovascular Diseases. Cardiovascular diseases are the leading causes of death in humans,228 the pathological process of which is multifactorial.228 The development of MTDLs may bring great benefits for cardiovascular disease patients.229 7.3.1. MTDLs Targeting AT1 and ETA for Hypertension. In the renin−angiotensin−aldosterone system (RAAS), angiotensin II (Ang II) binds to two G-protein-coupled receptors (GPCRs), angiotensin II type 1 (AT1) and AT2, leading to vasoconstriction and the release of vasopressin and aldosterone.230,231 Therefore, an antagonist for AT1 and AT2 might be useful for treating cardiovascular diseases.9,232 The endothelin receptors ETA and ETB are also potential targets for cardiovascular diseases.233,234 ETA regulates vasoconstriction, whereas ETB counteracts these effects by facilitating the synthesis of vasodilators prostacycline and nitric oxide.235,236 In merged-pharmacophore approach, Murugesan et al.37 reported a dual-target AT1 and ETA antagonist. Compound 82 (a known ETA antagonist) was selected as the template.

Irbesartan (compound 83) is an AT1 antagonist approved by many regulatory agencies. They merged the pharmacophores of 82 (a biphenylsulfonamide attached to a 5-isoxazole) and 83 (a biphenylimidazolone). Moreover, the 5-isoxazole was replaced by a 3-isoxazole to improve the metabolic stability (Scheme 24). The resulting compound 84 exhibited balanced activities for the two targets (Table 20). PK profiles such as oral bioavailability, Cmax/Tmax and half-life in plasma were also tested. Compared to 82 and 83, 84 exhibited further decreased blood pressure in rats and more durable effects. 7.3.2. MTDLs Targeting PPARγ and AT2 for Cardiovascular Disease. The peroxisome proliferator-activated receptor γ (PPARγ), as a critical target for the prevention of diabetes, is an intracellular nuclear hormone receptor regulating insulin and glucose metabolism.237 The American Heart Association indicated that there’s a strong association between cardiovascular diseases and diabetes; patients with one disease are prone to suffer from the other.238 Therefore, a drug candidate with dual activities to AT1 and PPARγ may potentially treat

Scheme 23. MTDLs Targeting Dopamine D2 Receptor and Serotonin Reuptake for Schizophrenia226

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Scheme 24. MTDLs Targeting AT1 and ETA for Hypertension37

Table 20. Biological Activities of MTDLs Targeting AT1 and ETA37,a compd 82 83, irbesartan 84

ETA

AT1

Ki (nM)

Ki (nM)

1.4 >10000 9.3

>10000 0.8 0.8

Table 21. Biological Activities of MTDLs Targeting PPARγ and AT1239 compd 85, telmisartan pioglitazone 87

AT1

hPPARγ

Ki (nM)

EC50 (nM) (% max)a

0.49

1520 1280 212

1.6

a

The maximal efficacy of darglitazone in the PPARγ activation assay was defined as 100%.

a

symptoms that are cardiovascular risk factors, e.g., hypertension, insulin resistance, and hypertriglyceridemia.239 In merged-pharmacophore approach, Casimiro-Garcia et al.239 developed a dual-active PPARγ agonist and AT1 antagonist. Telmisartan (compound 85) is an approved AT1 antagonist, and compound 86 is a PPARγ agonist. A general pharmacophore to address two targets was identified by crossscreening: an acidic head group, a hydrophobic tail, and a nonpolar phenyl linker (Scheme 25). The carboxylic acid was substituted with bioisostere tetrazole ring with a large size to fully occupy the binding pocket and keep the favorable interactions. Further, they complemented the biphenyl linker of compound 85 with a cyclopentyl group to reduce polarity. The template benzimidazole was substituted with a pyridine imidazole to enhance the interactions with the charged binding site (Scheme 25). Among the 15 synthesized molecules, compound 87 has optimal activity profile on both targets (Table 21). In two in vivo models, compound 87 also reduced blood pressure for a longer duration compared with the approved drug telmisartan. 7.3.3. MTDLs Targeting ACE and DPP4 for Hypertension and Diabetes, Respectively. It has been estimated that about 70% of patients with type 2 diabetes are hypertensive.240 On the other hand, the risk of suffering from type 2 diabetes is far

higher in patients with hypertension.241 For the patients with both hypertension and diabetes, taking angiotensin converting enzyme (ACE) inhibitors and dipeptidyl peptidase 4 (DPP4) inhibitors is the common practice. However, the combinations of multiple prescription drugs could be challenging for patient compliance. Therefore, dual-target inhibitors for ACE and DPP4 may further improve the treatment of cardiovascular disease. In 2017, Sattigeri et al.242 reported a new series of dual inhibitors for ACE and DPP4. Initially, they analyzed ligandACE and ligand-DPP4 cocrystal structures to orient the design of dual inhibitors.243−246 Thus, ACE inhibitors need a carboxy group, a zinc chelating group (SH or COOH), and a hydrophobic group to occupy the pocket of ACE. DPP4 inhibitors typically need a hydrophobic moiety (such as trifluorophenyl to interact with a serine) and a basic amine (such as amino to form a salt bridge with glutamic acid). The structure analysis of fosinoprilat (89) and zofenopril (90) suggested that the proline ring of enalaprilat (88) can be further substituted. A similar analysis of DPP4 inhibitors (91 and 92) suggested that the pocket of DDP4 was large enough to accommodate certain substitutions, and ACE ligand can be merged at the triazolopiperidine ring of compound 91 (Scheme 26A). Thus, they removed the triazolopiperidine

The maximal efficacy of darglitazone in the PPARγ activation assay was defined as 100%.

Scheme 25. Design of Multitargeted Agents Targeting PPARγ and AT1 for Hypertension239

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Scheme 26. MTDLs Targeting ACE and DPP4 for Hypertension and Diabetesa

a

(A) Representative scaffold of ACE and DPP4 inhibitors.242 (B) ACE/DPP4 dual inhibitors merged by enalaprilat 82 and sitagliptin 85.

7.4. MTDLs for Infectious Disease. 7.4.1. MTDLs Targeting Integrase and Reverse Transcriptase for AIDS. Human immunodeficiency virus (HIV) is the pathogen of acquired immunodeficiency syndrome (AIDS). Integrase (IN) and reverse transcriptase (RT) are two enzymes for indispensable HIV-1 replication.247 IN integrates viral DNA into the host genome, whereas RT transcribes single-stranded RNA viral genome into double-stranded DNA.248 Recently, designing MTDLs for IN and RT dual inhibition is emerging for anti-HIV research.248 Wang et al.249 provided the first IN/RT dual inhibitors. TNK-651 (94) is a strong non-nucleoside RT inhibitor, whose N-1 substituent group stretches from the NNRTI binding site to the protein/solvent interface250 (Scheme 27). It would tolerate the integration of another pharmacophore for IN.251 GS-9137 (95)252 is a very strong IN inhibitor with a quinolone carboxylic acid core. Therefore, linking quinolone pharmaco-

motif of compound 91 and incorporated all necessary scaffolds for ACE and DPP4 inhibitionvia an amide (Scheme 26B). Among the hybrids, compound 93 was the strongest dual inhibitor of DPP4 and ACE (Table 22) and showed good PK properties in plasma (AUC = 23.49 μg·h/mL, Cmax = 2.51 μg/ mL). Table 22. Biological Activities of MTDLs Targeting ACE and DPP4242 ACE inhibiton,a IC50 (nM) compd 88, enalaprilat 91, sitagliptin 93

mouse

human

9.6

rat

11.5

2800

2210

2.5 11 μM 51

DPP4 inhibiton,a IC50 (nM) rat 33 1230

mouse

human

46 7170

>100 μM 20 102

a

Plasma from Wistar rat, ob/ob mouse, and human was used as source of ACE and DPP4 enzymes.

Scheme 27. MTDLs Targeting IN and RT for AIDS249

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phore and pyrimidine generated IN/RT dual inhibitors, e.g., compound 96 (Table 23).

Table 24. Biological Activities of MTDLs Targeting IN and RT247

Table 23. Biological Activities of MTDLs Targeting IN and RT249 compd 94, TNK-651 95, GS-9137 96

IN

RT

HIV

IC50 (μM)

IC50 (μM)

EC50 (μM)

2.4 0.0072 35

0.057

0.033 0.0009 0.22

0.19

compd 97 98, delavirdine 99

IN

RT

HIV

IC50 (μM)

IC50 (μM)

EC50 (μM)

0.093 >100 11

>100 0.036 0.059

0.16 0.021 0.52

production of 15(S)-hydroxyeicosatetraenoic acid (15-HETE) and eoxins.260 As for COX, it has two isoforms: COX-1 and COX-2.261 COX-1 participates in the prostaglandins synthesis, which is important for normal physiology of some organs, such as gastrointestinal tract and kidney, whereas COX-2 mainly participates in the process of inflammation.262 Omar et al.36 reported an anti-inflammatory MTDL for 15LOX and COX-2 dual inhibition. They surmised that the hybridization of the pharmacophores 4-thiazolidinone (from 103, a 15-LOX inhibitor) and 1,3,4-thiadiazole (from 104, a COX-2 inhibitor) could strongly inhibit inflammation with minimal adverse effects. Merging both scaffolds was expected to provide better selectivity on COX-2 over COX-1 because the large size of the hybrid compound may not fit in the COX1 binding pocket, which is smaller than COX-2 (Scheme 30).263 Adopting a fused-pharmacophore approach, compound 105 showed activities against COX-2 and 15-LOX (Table 26). Additionally, it showed in vitro inhibitory activity on LOX significantly higher than zileuton and was well tolerated in animal models (Table 26).

Subsequently, they reported another IN/RT inhibitor247 (Scheme 28). In a similar way, through crystallographic analysis, they found that the methylsulfonamide motif at position C-5 of delavirdine (98, an RT inhibitor)253 was located on the protein/solvent interface, which can tolerate functional substituent groups. Therefore, they substituted the sulfonamide group with a diketoacid (DKA) group (from compound 97 ) and obtained IN/RTdual inhibitors. Except for a DKA type of metal-chelating functionality, IN binding also needs a hydrophobic aromatic ring adjacent to the chelator that can be satisfied by the indole ring of the hybrid. These hybrids all strongly inhibited both IN and RT enzymatic activities and HIV proliferation in a cell assay. Compound 99 had the strongest activities among these hybrids (Table 24). 7.4.2. MTDLs Targeting PfATP6 and Host Hemoglobin Digestion for Malaria. Malaria is a severe disease that leads to over one million deaths per year. More seriously, the parasite has developed resistance to the majority of monotherapy.254 For this reason, combination chemotherapy of artemisinin (100) with other antimalarials like quinine (101)255 is recommended.256 Quinine can effectively inhibit the asexual erythrocytic forms of malaria, possibly due to the interference with host hemoglobin digestion.257 A Fe2+-activated artemisinin has strong PfATP6 (a critical parasite Ca2+ transporter) inhibitory activity.256 On the basis of the knowledge above, Walsh et al.256 designed a artemisinin−quinine hybrid that was linked covalently (102) (Scheme 29). The vinyl group from quinine was modified for the introduction from artemisinin. This novel hybrid had strong in vitro activity on the (drugresistant) FcB1 and 3D7 strains of Plasmodium falciparum. The activity was better than quinine alone, artemisinin alone, or a 1:1 mixture of quinine and artemisinin (Table 25). 7.5. MTDLs Targeting 15-LOX and COX-2 for Inflammation. MTDLs comprising various targets for inflammation exhibited good therapeutic potentials.258 The activation of lipoxygenases (LOXs) and cyclooxygenases (COXs) are both crucial for generating multiple downstream mediators for inflammation.259 Overexpression of 15-LOX is related to some inflammatory diseases due to downstream

8. CONCLUSION In the past few decades, the “one molecule, one target, one disease” paradigm dominated the pharmaceutical industry. But the increasing research studies indicate that perhaps we are entering an exciting new era of systematic discovery of MTDLs.60 So far, the major challenges for rational design of MTDLs are target selection, achieving appropriate ratio of desired activities, and optimizing the PK profiles. Thus, future rational, successful MTDLs discovery calls for a holistic view rather than the reductionistic approach.12 This review provided an overview of recent development of MTDLs for the treatment of multifactorial diseases. The identification and validation of novel target combination in disease relevance and developability perspectives will be critical for success. Balancing the multitarget activities, optimizing the physicochemical and PK profiles, and achieving high selectivity over undesired targets are the most challenging aspects. In addition to the methods discussed above, there are many other computational methods for rational drug design, e.g., the field of quantitative systems pharmacology, a computer-based methodology that combines preclinical neurophysiology,

Scheme 28. MTDLs Targeting IN and RT for AIDS247

W



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Scheme 29. MTDLs Targeting PfATP6 and Host Hemoglobin Digestion for Malaria

Table 25. Biological Activities of MTDLs Targeting PfATP6 and Host Haemoglobin Digestion256 compd 100, artemisinin 101, quinine 102 quinine + artemisinina

Table 26. Biological Activities of MTDLs Targeting 15-LOX and COX-236

3D7 (48 h) 3D7 (72 h) FcB1 (48 h) FcB1 (72 h) IC50 (nM)

IC50 (nM)

IC50 (nM)

IC50 (nM)

49.4 149 8.95 31.8

45.5 73.5 10.4 28.6

50.0 96.8 9.59 27.9

55.0 75.3 10.2 26.3

compd 103 104 105 a

15-LOX

COX-1

COX-2

IC50 (μM)

IC50 (μM)

IC50 (μM)

8.94 15.42

0.33 0.07

SIa

8.24 11.87

27 220.29

Selectivity index (SI) = IC50(COX-1)/IC50(COX-2).

a

Values represent concentrations of each of quinine and artemisinin in a 1:1 ratio.

misfolded protein conformation. The synthetic hydrophobic groups (such as adamantane, a bulky hydrocarbon) form a covalent bond to the surface of target proteins, inducing their degradation via the proteasomes.272 An example is fluvestrant273 approved by the FDA in 2002. Moreover, the PROTAC technology is another strategy for protein degradation. PROTAC is a special kind of MTDL that integrates a target-binding ligand and an E3 ligase ligand into one molecule via a linker. By accessing rather than inhibiting active E3 ligases, PROTAC induces ubiquitination and degradation of the target protein by the proteasome.274,275 Therefore, we can see that the future application of MTDL will become even more diversified. Therefore, we foresee that the new generation of MTDLs, characterized by the chemical, biological, and theoretical level, provides a road to treat complex diseases effectively.

neuropharmacology, and available clinical information, enabling testing of combinations in virtual patients.264 QSAR methodology has been used to identify molecular factors for target interaction and to propose the best molecules for the following studies.265 Virtual screening methods have been applied to identify leads in huge in silico libraries of compounds.266 On the basis of molecular docking, dynamic studies may evaluate the stability of the ligand−protein complexes and determine important interactions in the binding patterns of the ligands.267 Apart from the typical MTDLs inhibiting or activating two or more targets simultaneously, it may be possible to further develop dual functional molecules targeting different systems of the body. For instance, the antibody−drug conjugates (ADCs), hydrophobic tag (HyT), PROTAC are emerging technologies, which are structurally characterized by bifunctionality. For a typical MTDL, it acts on two (or more) different targets to exert additive or synergistic effects. Different from typical MTDLs, molecules designed with the above three technologies can recruit protein of interest (POI), then induce protein−protein interaction (PPI) and POI degradation. ADCs consist of recombinant monoclonal antibodies (mAbs) and cytotoxic chemicals (known as payloads) by linkers.268 The mAb binds to specific antigens or receptors on cancer cell, then the whole ADC is internalized into the cancer cell, where the payloads exert cytotoxic effects.269 After about 50 years of research, several ADCs have been approved: trastuzumab emtansine270 and brentuximab vedotin271 have paved the way for clinical trials of more ADCs. Hydrophobic tags technology is a small molecule that mimics a

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00017. Name, indication, MW, cLogP, PSA, HBA, HBD, RB, number of heteroatoms, and clinical phase of 117 MTDLs on market or in clinical trails (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*W.Q.: e-mail, [email protected]; phone, +86-13852294378. *H.S.: e-mail, [email protected]; phone, +8613951934235.

Scheme 30. MTDLs Targeting 15-LOX and COX-2 for Inflammation36

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ORCID

at China Pharmaceutical University. Her current research interests are focused on design, synthesis, and biological evaluation of natural compounds and active chemical constituents from natural medicines, in particular, agents targeting neurodegenerative diseases and cancer.

Haopeng Sun: 0000-0002-5109-0304 Author Contributions

H.S., W.Q., and J.Z. were responsible for writing this manuscript. All authors have participated in the checking and revision of the manuscript.

Haopeng Sun graduated in Pharmacy at the China Pharmaceutical University in 2006. He received his Ph.D. in 2011 in Medicinal Chemistry, with a thesis about the structural optimization and mechanism study of the natural product, with Advisor Prof. Q. D. You. In 2014, he was promoted to Associate Professor of Medicinal Chemistry at China Pharmaceutical University. So far, he has published more than 110 papers in peer-review journals indexed by Science Citation Index. His major research interests include the design, synthesis, and biological evaluation of small molecule bioactive compounds, in particular, agents targeting neurodegenerative diseases. In addition, he is focusing in the field of anticancer and antiinflammatory agents.

Notes

The authors declare no competing financial interest. Biographies Junting Zhou received her Bachelor’s degree from China Pharmaceutical University in 2016. She is currently a postgraduate student at the Department of Natural Medicinal Chemistry (China Pharmaceutical University) under the supervision of Prof. Feng Feng. Her main research focuses on the discovery, synthesis, and biological evaluation of designed multiple ligands targeting Alzheimer’s disease.

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Xueyang Jiang studied Pharmacy at Anhui University of Chinese Medicine and received his Bachelor’s degree in 2013. He is pursuing his doctorate in nature medicinal chemistry at China Pharmaceutical University under the supervision of Prof. Feng Feng. His research is focused on the structural optimization and mechanism study of the natural product in the field of Alzheimer disease.

ACKNOWLEDGMENTS We gratefully thank the support from National Natural Science Foundation of China (Grants 81573281 and 81830105). We also thank the support from “Double First-Class” initiative innovation team project of China Pharmaceutical University (Grants CPU2018GF11 and CPU2018GY34). We also appreciate the support from the Joint Laboratory of China Pharmaceutical University and Taian City Central Hospital.

Siyu He received her Bachelor’s degree from China Pharmaceutical University in 2016. She is currently a postgraduate student at the Department of Medicinal Chemistry (China Pharmaceutical University) under the supervision of Associate Prof. Haopeng Sun. Her research mainly focuses on the discovery, synthesis, and biological evaluation of small molecules targeting autophagy machinery.

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ABBREVIATIONS USED AD, Alzheimer’s disease; MTDL, multitarget-directed ligand; PK, pharmacokinetic; PD, pharmacodynamics; MW, molecular weight; AChE, acetylcholinesterase; BBB, blood−brain barrier; DDL, dedifferentiated liposarcoma; H1R, H1 receptor; IGF1R, insulin-like growth factor 1 receptor; CDK4, cyclin-dependent kinase 4; MAO, monoamine oxidase; SAR, structure−activity relationship; NK, neurokinin; CuAAC, cycloaddition; TEC, thiol−ene click reaction; TYC, thiol−yne click reaction; DA, Diels−Alder reaction; BRD4, extra-terminal domain 4; VHL, Von Hippel−Lindau; CRBN, cereblon; PSA, polar surface area; RB, rotatable bond; HBD, hydrogen bond donor; HBA, hydrogen bond acceptor; HDAC, histone deacetylase; HDACi, histone deacetylases inhibitor; ZBG, zinc binding group; PI, proteasome inhibitor; MDM2, murine double minute 2; VEGFR, vascular endothelial growth factor receptor; VEGF, vascular endothelial growth factor; IFI, invasive fungal infection; MAPK, mitogen-activated protein kinase; JAK, Janus kinase; ERα, estrogen receptor α; SERM, selective estrogen receptor modulator; PDGFR-β, platelet-derived growth factor receptor β; TDZD, thiadiazolidinedione; PAINS, pan assay interference compounds; TZD, thiazolidinedione; Aβ, amyloid-β; NFT, neurofibrillary tangle; ACh, acetylcholine; AChEI, acetylcholinesterase inhibitor; GSK-3β, glycogen synthase kinase 3β; SERT, serotonin transporter; CNS, central nervous system; PD, Parkinson’s disease; hH3R, human histamine H3 receptor; AR, adenosine receptor; SSRI, selective serotonin reuptake inhibitor; RUI, reuptake inhibition; D2R, dopamine D2 receptor; Ang II, angiotensin II; GPCR, G-protein-coupled receptor; PPARγ, proliferatoractivated receptor γ; DPP4, dipeptidyl peptidase 4; ACE, angiotensin converting enzyme; COX, cyclooxygenase; LOX, lipoxygenase; 15-HETE, 15(S)-hydroxyeicosatetraenoic acid; ADC, antibody−drug conjugate; HyT, hydrophobic tag; PROTAC, proteosis-targeting chimera; PPI, protein−protein interaction; POI, protein of interest; mAbs, monoclonal

Hongli Jiang received her Bachelor’s degree from China Pharmaceutical University in 2017. She is currently a postgraduate student at the Department of Natural Medicinal Chemistry (China Pharmaceutical University) under the supervision of Associate Prof. Wei Qu. Her research mainly focuses on the design, synthesis, and biological evaluation of small molecules for AD therapy. Feng Feng graduated in Chemistry at Shaanxi Normal University in 1991. He received his Ph.D. in 2001 in Pharmacy, with a thesis about natural products with antitumor activities supervised by Prof. S. X. Zhao. He studied at the University of California, Irvine as Visiting Scholar in 2005. In 2010, he was promoted to Professor of Natural Medicinal Chemistry at China Pharmaceutical University. So far, he has published more than 70 papers in journals indexed by Science Citation Index. His major research interests include extraction and isolation of chemical constituents from natural medicines, structural modification of active compositions, and drug analysis in vivo. In addition, he is focusing on the prevention and treatment of cancer and neurodegenerative agents. Wenyuan Liu graduated in Chemistry at Shaanxi Normal University in 1991. She received her Ph.D. in 2004 in Pharmaceutical Analysis, supervised by Prof. Z. X. Zhang. She studied in the University of California, San Diego as Visiting Scholar in 2008. In 2010, she was promoted to Professor of Pharmaceutical Analysis at China Pharmaceutical University. So far, she has published more than 50 research papers in Journal of Chromatography A, Journal of Chromatography B, Journal of Pharmaceutical and Biomedical Analysis, and others. Her major research interests include the analysis of pharmaceutical instruments. Wei Qu graduated in Traditional Chinese Pharmacy at the China Pharmaceutical University in 2004. She received her Ph.D. in 2009 in Natural Medicinal Chemistry, with a thesis about natural products with antitumor activities supervised by Prof. J. Y. Liang. In 2016, she was promoted to Associate Professor of Natural Medicinal Chemistry Y



Perspective

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antibodies; BED4, bromodomain and extra-terminal domain 4; TGI, tumor growth inhibition; STS, steroid sulfatase; EPS, extrapyramidal symptom; SR, serotonin reuptake; AT1, angiotensin II type 1; HEL, human embryonic lung fibroblast

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REFERENCES

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