Chromone as a Privileged Scaffold in Drug Discovery - ACS Publications

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Chromone as a Privileged Scaffold in Drug Discovery: Recent Advances Miniperspective Joana Reis, Alexandra Gaspar, Nuno Milhazes, and Fernanda Borges* CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto 4169-007, Portugal ABSTRACT: The use of privileged structures in drug discovery has proven to be an effective strategy, allowing the generation of innovative hits/leads and successful optimization processes. Chromone is recognized as a privileged structure and a useful template for the design of novel compounds with potential pharmacological interest, particularly in the field of neurodegenerative, inflammatory, and infectious diseases as well as diabetes and cancer. This perspective provides the reader with an update of an earlier article entitled “Chromone: A Valid Scaffold in Medicinal Chemistry” (Chem. Rev. 2014, 114, 4960−4992) and is mainly focused on chromones of biological interest, including those isolated from natural sources. Moreover, as drug repurposing is becoming an attractive drug discovery approach, recent repurposing studies of chromone-based drugs are also reported.

1. INTRODUCTION

focuses on natural and synthetic chromones. Flavonoids were not included, as they have been covered in recent reviews.

Chromones are benzoannelated γ-pyrone (4H-chromen-4-one, 4H-1-benzopyran-4-one) heterocycles that are widely distributed in nature. They have been used since ancient times in traditional medicine1 and are well-known by their diversity of pharmacological properties, such as antiallergic, anti-inflammatory, antidiabetic, antitumor, and antimicrobial.2,3 Moreover, the use of chromone-based drugs in the therapy of asthma has been extensively explored, mainly as bronchodilators.4,5 The drug discovery processes have culminated in the development of disodium cromoglycate (DSCG) and pranlukast (Figure 1), which are useful drugs for the treatment of mild to moderate asthma and allergic rhinitis, respectively.6 Focusing on the metabolism of pranlukast, the studies performed so far have shown that biotransformation reactions occur on the side chains instead of the chromone core.7 The relevance of the chromone scaffold in medicinal chemistry has been an up-and-coming area of study. Publications on chromone-based compounds have been increasingly acknowledged, a process driven by recent progress in development of chromone-based drug candidates. Chromones are excellent templates to perform structural modifications, allowing the synthesis of a wide array of compounds with diverse pharmacological profiles. Due to their synthetic accessibility and structural diversity, they play an important role in medicinal chemistry and can be considered a privileged structure for drug discovery.2,3 This report updates a previous review of chromones, published in 2014.2 Using the same approach, the current report © 2017 American Chemical Society

2. NATURALLY OCCURRING CHROMONES Chromones are a class of natural products widely distributed in the plant kingdom and present in notable amounts in several species. From the studies performed so far, thousands of chromone derivatives have been isolated and structurally elucidated, and several reviews have been published.2,8,9 For this reason, simple natural chromones isolated over the past three years are herein highlighted, along with their biological activity (Table 1). 3. SYNTHESIS OF SIMPLE CHROMONES Several scientific papers have been published describing the synthesis and biological evaluation of chromone derivatives. Following an excellent review by GP Ellis,8 several updates were published, focusing on the optimization of the synthetic processes.2,35,36 However, the development of innovative synthetic strategies has been slow, and no significant advances have been reported during the past few years. Therefore, only an overview of the most well-known methodologies is currently presented (Scheme 1). Briefly, benzopyran-4-ones can be obtained using 2-hydroxyarylalkyl ketones (Scheme 1A), phenols (Scheme 1B), and salicylic acid derivatives (Scheme 1C) as starting materials.2,35,36 The Baker−Venkatamaran rearrangement (Scheme 1), which takes place after the acylation of a Received: December 10, 2016 Published: May 24, 2017 7941

DOI: 10.1021/acs.jmedchem.6b01720 J. Med. Chem. 2017, 60, 7941−7957

Journal of Medicinal Chemistry

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Figure 1. Disodium cromoglycate (DSCG) and pranlukast drugs.

Acetylcholinesterase, the enzyme responsible for the acetylcholine catabolism, is the most well-known target in Alzheimer’s disease, and its inhibition remains the standard and first-line treatment for AD. Currently, there are three AChE inhibitors (donepezil, rivastigmine, and galantamine) used for symptomatic relief in mild-to-moderate AD.2 However, concerns about their efficacy and safety are still an open issue. For this reason, the discovery of new chemical entities that can operate as AChE inhibitors is still a subject of interest. In this context, Parveen et al.43 have synthesized 3-formylchromone derivatives, with the most promising ones (compounds 1 and 2, IC50 = 0.96 μM and 0.27 μM, respectively) depicted in Figure 2. Moreover, and following a multitarget-directed ligand (MTDL) strategy,44 the development of chromone-based derivatives possessing two or more complementary biological activities has also been performed. Liu et al.45 developed novel chromone-2-carboxamidoalkylbenzylamines and screened them toward rat AChE and rat butyrylcholinesterase (BuChE). In particular, compound 3 (Figure 2) displayed high selectivity for AChE (IC50 = 0.07 μM) over BuChE (IC50 = 51.50 μM) and also noticeable self-induced and Cu2+-induced β-amyloid (Aβ) aggregation inhibition (59.2% and 55.6%, respectively).45 This activity is of pharmacological importance in AD, given the central role of Aβ aggregates and amyloid plaques in the neurodegenerative cascade. Another important AD target is β-site APP cleaving enzyme (BACE-1), a type I membrane associated aspartyl protease.2,46 Recent work by Razzaghi-Asl et al.47 reported 2,6-dialkyl-4chromon-3-yl-1,4-dihydropyridine-3,5-dicarboxylate derivatives as BACE-1 inhibitors. The most potent chromone-based inhibitor of BACE-1 (compound 4, IC50 = 6.84 μM) is shown in Figure 2. Monoamine oxidase B (MAO-B) is a well-known target in Parkinson’s disease (PD). Currently, there are two selective and irreversible MAO-B inhibitors (selegiline and rasagiline) on the market for PD symptomatic treatment. In spite of the considerable efforts performed so far, the search for selective and reversible MAO-B inhibitors remains of high interest9,48 and has met significant advances with the recent approval of safinamide by the Food and Drug Administration. This issue has also been driven by recent findings that associate MAO-B with the neurodegenerative process in AD.2 Recently, F. Cagide et al. reported the discovery of two new classes of potent and selective MAO-B inhibitors: chromone-3-phenylcarboxamides and chromane-2,4-diones.37 The most potent derivatives were compounds 5 and 6 (IC50 = 2.9 nM and 42.3 nM, respectively), which are shown in Figure 3. Subsequent studies led to the establishment of preliminary structure−activity relationships for chromone-3-carboxamides as MAO-B inhibitors49 and yielded compound 7 (IC50 = 0.67 nM, Figure 3) a potent, selective, and reversible MAO-B inhibitor. The rational design of chromonebased MAO-B inhibitors by quantitative structure−activity relationship (QSAR) models has also been reported.50

2-hydroxyarylalkyl ketone and the formation of a 1,3-dioxophenoxy intermediate, is the most used method for the synthesis of chromones.2,35,36 Alternatively, a Claisen condensation (Scheme 1) can be used to obtain chromones from the same starting materials.2,35,36 This process usually occurs in two steps: the formation of an enolate, which subsequently reacts with a carboxylic ester, followed by ring cyclization, conventionally performed using strong heating and acidic conditions. A modified version of the Claisen condensation, the Kostanecki−Robinson reaction (Scheme 1), is also frequently used, since it precludes the acidification step needed for cyclization. Additionally, the Vilsmeier−Haack reaction (Scheme 1), which occurs between a 2-hydroxyalkylaryl ketone and (chloromethylene)dimethylammonium chloride (Vilsmeier reagent), is frequently used for the synthesis of 3-substituted chromones.2,35,36 Chromones can also be obtained from phenols by Simonis or Ruhemann reactions or from salicylic acid and its derivatives (Scheme 1).2,35,36 Interestingly, chromane-2,4-dione and chromone-3-carboxamide derivatives have been recently obtained from chromone3-carboxylic acid in a process that was dependent on the nature of the coupling agents used for the formation of the amide bond.37

4. BIOLOGICAL INTEREST OF CHROMONES Among the numerous biological activities attributed to simple chromones, a special focus will be given to the research performed in the field of neurodegenerative, inflammatory, and infectious diseases, as well as diabetes and cancer. Furthermore, we will also address recent reports focusing on new druggable targets and novel pharmacological activities. Nevertheless, it is important to acknowledge recent reports on the cardiovascular application of chromones and chromanones, mainly as vasorelaxants38 and in repolarization of cardiac tissue,39 in retinal neovascularization,40 and as alkaline phosphatase inhibitors.41,42 4.1. Neurodegenerative Diseases. Neurodegenerative diseases (NDs) encompass a variety of disorders, such as Alzheimer’s (AD) and Parkinson’s disease (PD), which are commonly associated with a slow and progressive neurological dysfunction and consequent deterioration of the neuronal function. Nevertheless, no exact causes have yet been identified and the current knowledge of ND pathology is based on a cascade of hypothesis. Furthermore, the currently available drugs to manage ND are only palliative and fail to modify disease progression. In this context, the discovery of new and effective drugs with disease modifying capacity is a pressing and unmet clinical need.2 The studies presented in this review were sustained on the development of chromone-based enzymatic inhibitors and serotonin receptor ligands. 4.1.1. Enzymatic Inhibitors. New chemical entities based on the chromone scaffold have been screened toward the following enzymatic targets: acetylcholinesterase (AChE), β-secretase-1 (BACE-1), and monoamine oxidase B (MAO-B). 7942



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Table 1. Natural Simple Chromonesa

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Table 1. continued

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Table 1. continued

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Table 1. continued

a

n.d.: not determined.

wide range of diseases, including ND. There are seven main 5-HTRs subtypes, and with the exception of ligand-gated ion channel 5-HT3 receptor, all the other 5-HTRs are G protein coupled receptors. Even though all neurotransmitter systems can be altered to some extent during the course of ND, particularly in their later stages, the levels of dopamine and serotonin (5-hydroxytryptamine, 5-HT) have been strongly correlated with cognitive dysfunctions. In the case of AD, a significant loss of serotonin-containing raphe neurons and preand postsynaptic serotonin system markers was observed.53 Receptor subtypes 5-HT4, 5-HT2B, and 5-HT6 are important regulators of memory and cognition, and as such, ligands for these receptors could be of therapeutic interest for AD.53

The chromanone scaffold has also been used in the discovery of MAO-B inhibitors,48 as shown in the recent work by Lan et al.51 The SAR studies indicated that the presence of substituents at the C7 position, particularly with a fluorbenzyloxy group, significantly increased MAO-B inhibition. The best chromanone of the series (compound 8, IC50 = 8.62 nM) is shown in Figure 3. Moreover, Desideri et al.52 have also screened a series of (E)-3-heteroarylidenechroman-4-ones, resulting in a very potent and selective MAO-B inhibitor (compound 9, IC50 = 10.58 nM, Figure 3). 4.1.2. Serotonin Receptor Ligands. Ligands targeting serotonin receptors (5-HTRs) have received renewed interest for their potential to help understand the role of 5-HTRs in a 7946



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Scheme 1. General Synthetic Strategies for the Formation of the Chromone Scaffold

synthesized a chemical library inspired on the natural compound 2-(2-phenylethyl)chromone55 (compound 10, pKi = 5.6, Figure 4) and screened it toward the 5-HT2B receptor.

Figure 4. 5-HT2B receptor ligands based on the chromone scaffold.

Accordingly, 5-hydroxy-2-(2-phenylpropyl)chromone (compound 11, pKi = 6.6 at 5-HT2B, Figure 4) emerged as a potential 5-HT2B ligand with potential therapeutic applicability on AD. 4.1.3. Repurposing of Chromone-Based Drugs. Drug repurposing, a process of discovering a new therapeutic use

Figure 2. AChE and BACE-1 inhibitors based on the chromone scaffold.

Recently, chromones were described as an important scaffold for the development of novel 5-HT2B ligands. Williams et al.54

Figure 3. MAO-B inhibitors based on the chromone and chromanone scaffolds. 7947



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(Figure 6), a chromone-based compound operating via IL-17 suppression, has been approved in China and Japan for the treatment of rheumatoid arthritis.62 Moreover, IL-5 has also been identified as a promising target to prevent or blunt eosinophil-mediated inflammation in patients with asthma,63 and several projects are currently in progress to develop anti-IL-5 inhibitors.64 For instance, Venkateswararao et al.65 successfully developed chromone-based IL-5 inhibitors (compounds 14 and 15, IC50 = 4.0 and 6.5 μM, respectively, Figure 6) as putative antiasthma agents. 4.2.2. Mast-Cell Mediator Release Inhibitors. Mast cells and basophils play a crucial role in allergic, innate, and adaptive immune responses. The activation of these cells can take place as a result of allergen-induced cross-linking of high affinity immunoglobulin E (IgE) receptors, located on the cell surface.66 Over the past years, researchers have identified several mast cell mediators and receptors, such as serine proteinases, histamine 4-receptor, 5-lipoxygenase-activating protein, 15-lipoxygenase-1, prostaglandin D2, and proinflammatory cytokines. Indeed, mediators released from activated mast cells can be pharmacologically abrogated with small molecule inhibitors, some of which are or have been in clinical trials.67 For instance, disodium cromoglycate (DSCG, Figure 1) is a chromone-based drug that can act by inhibiting the release of chemical mediators from sensitized mast cells,2,68 although the exact mechanism of action has not yet been clarified. In order to improve the potency and minimize its side effects, Velema et al.69 developed new chromone-based derivatives (compound 16, IC50 = 28 μM and compound 17, IC50 = 10 μM, Figure 7). Interestingly, these compounds outperformed commercially available DSCG (Figure 1) in terms of potency (IC50 > 1 mM). 4.3. Diabetes. Type 2 diabetes mellitus is a chronic and multifactorial metabolic disorder characterized by high blood glucose, insulin resistance, and pancreatic β-cell dysfunction.70−72 Current therapeutic approaches include life style changes (e.g., diet and exercise) and a variety of pharmacologic agents, such as insulin derivatives thereof, biguanides, sulfonylureas, and thiazolidinediones. Each drug operates via a different mechanism; for instance the biguanide metformin inhibits hepatic glucose production, and thiazolidinediones act on peroxisome proliferator-activated receptor (PPAR)-γ, a ligand-activated transcription factor of the nuclear hormone receptor superfamily.73−75 Moreover, α-glucosidase inhibitors (AGIs), oral antidiabetic drugs widely used in the treatment of patients with type 2 diabetes,76 can delay the absorption of carbohydrates from the small intestine, thus having a lowering effect on postprandial blood glucose and insulin levels. However, biguanides, sulfonylureas, and thiazolidinediones have been associated with severe side effects like hypoglycaemia, weight gain, and edema. Moreover, gastrointestinal side effects such as flatulence and diarrhea have been described for AGIs. Accordingly, there is still a pressing need for new targets and new chemical entities to treat diabetes.70 The chromone scaffold has been used to develop ligands to target PPAR-γ and α-glucosidase. Nazreen et al.77 developed a library of chromone 2,4-thiazolidinedione hybrids and screened them toward in vitro PPAR-γ activity and in vivo antidiabetic activity, along with the evaluation of their hepatotoxic risk. Two of the best chromone derivatives (compounds 18 and 19, Figure 8) are highlighted, due to their potent PPAR-γ modulating activity and absence of hepatotoxicity. Indeed, compound 18 (Figure 8) displayed an IC50 = 135 μM toward

for existing drugs or drug candidates, is an attractive drug discovery strategy. Pranlukast (Figure 1) is a chromone-based drug that acts as a selective cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, used in the prophylactic treatment of chronic bronchial asthma in pediatric and adult patients.2 Following a drug repurposing strategy, Tang et al.56 performed in vivo studies in mice using the Morris water maze (MWM) and Y-maze tests. Interestingly, pranlukast induced beneficial effects on Aβ-induced cognitive dysfunction. Additionally, the drug effectively suppressed Aβ-induced activation of the nuclear transcription factor (NF-κB) pathway, showing that the modulation of CysLT1R signaling in the brain can have a neuroprotective outcome. 4.2. Inflammatory Diseases. Inflammation and inflammatory chronic conditions may lead to a number of events, including rheumatoid arthritis, asthma, psoriasis, irritable bowel syndrome (IBS), and even cancer. Even though there are drugs available for the treatment of inflammation-associated diseases, such as steroids, antihistamines, and nonsteroidal antiinflammatory drugs, there is still an unmet therapeutic need for new and effective anti-inflammatory drugs. Accordingly, the understanding of the inflammatory signaling pathways and the discovery of new biomarkers constitute per se new challenges and opportunities for drug discovery. Several studies aimed at developing new chromone-based anti-inflammatory agents have been performed2,57,58 and are continuing. Currently, these projects are mainly focused on finding cyclooxygenase-2, interleukin 5, and mast-cell mediator release inhibitors.2,57 4.2.1. Cyclooxygenase and Interleukin Inhibitors. Cyclooxygenase (COX) is an enzyme involved in inflammatory response, catalyzing the formation of prostaglandins, thromboxane, and levuloglandins. Presently, two structural and functional human COX isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), have been described.59 The discovery that there are two COX isoforms, one prevailing at sites of inflammation (COX-2) and the other constitutively expressed in the gastrointestinal tract (COX-1), has led to great advances in the area. Both isoforms are involved in the regulation of physiological processes, such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function. COX-2 is considered a druggable target suitable for the development of anti-inflammatory drugs with fewer gastrointestinal adverse reactions. Recently, Shaveta et al.57 screened chromone−indole and chromone−pyrazole hybrids toward COX-1 and COX-2. The most promising and selective COX-2 inhibitors (compounds 12 and 13, IC50 = 20 and 29 nM, respectively) are presented in Figure 5. On the other hand, a number of inflammatory pathological conditions (e.g., asthma, colitis, hepatitis, and rheumatoid arthritis) were associated with the overexpression of cytokines, such as interleukin 1β (IL-1β), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 17 (IL-17), and tumor necrosis factor α (TNF-α).60,61 As a result, these cytokines can be considered valid targets for drug discovery.61 Interestingly, iguratimod

Figure 5. COX-2 inhibitors based on the chromone scaffold. 7948



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Figure 6. IL-5 inhibitors based on the chromone scaffold.

Figure 7. Mast-cell mediator release inhibitors based on the chromone scaffold.

of ACC inhibitors based on a chromanone-like spirocyclic core. Taking the chromanone scaffold as a starting point, further optimization studies were proposed for the development of potent ACC inhibitors with good ADME and dual-target profiles. 4.4. Cancer. The study of chromones as a useful scaffold for drug discovery in cancer has been largely focused on the discovery of novel kinase inhibitors.2 Nevertheless, other targets have been studied, including carbonic anhydrase,82 NF-κB,83 sirtuins,84 topoisomerase,85 and A3 adenosine receptors.86,87 In addition, other lines of research have been focused on the development of chromone-based modulators of apoptosis, Keap1-Nrf2,88,89 and hedgehog signaling pathways.90−92 Lastly, it is important to highlight interesting studies focused on the development of cytotoxic metal-chromone and ferrocenylchromone complexes93−97 and in the screening of a variety of chromone-based compounds toward several cancer cell lines. Although these studies are still in an embryonic stage, some of them were supported by DNA binding and/or apoptosis data. 4.4.1. Kinase Inhibitors. Protein phosphorylation plays a key role in most cellular activities. It is a reversible process mediated by protein kinases (PKs) and phosphatases: PKs catalyze the transfer of a γ phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate, and protein phosphatases catalyze the reverse process. Alterations in phosphorylation signaling are known to be deregulated in cancer and frequently associated with protein mutations. As a result, PKs have been considered promising cancer-related targets for drug discovery.98 Compound 22 (LY294002, Figure 9) is a potent (IC50 = 1.40 μM, Figure 9) and reversible chromone-based inhibitor of phosphoinositide 3-kinases (PI3Ks).98 However, several reports have shown that compound 22 is not selective for PI3Ks and could in fact act on other lipid kinases and unrelated proteins.98,99 Recent studies have shown that 22 is active against malignant osteosarcoma cells (IC50 = 62.96 μM and IC50 = 55.2 μM for U2-OS and MG-63 cell lines, respectively) by modulating the PI3K/Akt/fatty acid synthase signaling pathway.100 Indeed, these pioneering data can constitute a new

Figure 8. Antidiabetic agents based on the chromone and chromanone scaffolds.

α-glucosidase, while showing a significant PPAR-γ transactivation activity (48.72%) compared to the standard drug pioglitazone (62.48%). A different set of derivatives was explored by Takao et al.78 In this report, 3-styrylchromone derivatives were developed and screened for α-glucosidase inhibition and antioxidant activity. Compound 20 (Figure 8) was the most potent α-glucosidase inhibitor (IC50 = 16 μM), with a noteworthy antioxidant activity (EC50 = 17 μM). This bioactivity outline is of pharmacological significance, since evidence suggests a major role of oxidative stress in the pathogenesis of diabetes.70 In addition, Takao et al.79 developed a series of 3-benzylidene4-chromanone derivatives. In analogy with their previous studies, they observed that compounds containing a catechol moiety, such as compound 21 (Figure 8), displayed significant antioxidant (EC50 = 13 μM) and α-glucosidase inhibitory (IC50 = 28 μM) activities. Another target related to diabetes mellitus is acetyl-CoA carboxylase (ACC), an enzyme that catalyzes the rate-determining step in de novo lipogenesis and is involved in the regulation of fatty acid oxidation. Since lipid metabolism modifications appear to influence insulin resistance, the development of ACC inhibitors is a promising therapeutic approach for type 2 diabetes mellitus.80 Accordingly, Griffith et al.81 reported a series 7949



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the energy-dependent drug efflux mediated by ATP-binding cassette (ABC) transporters is one of the most well-recognized processes.105 Recently, an ATP-binding cassette subfamily G member 2 encoded by the ABCG2 gene has also been associated with cellular resistance in breast cancer.106 The high expression of ABCG2 protein in a variety of cells and tissues, including blood−brain and intestinal barriers, has a huge impact on pharmacokinetics, namely, in oral availability, tissue distribution, and excretion. Chromone-based derivative 24 (MBL-II-141, Figure 10) was proposed as a potent (IC50 = 0.11 μM), selective, and nontoxic inhibitor of ABCG2-mediated drug efflux.106 Indeed, compound 24 enhanced irinotecan anticancer efficiency in ABCG2positive xenografts.107 Safety and additional pharmacological data strongly support its progress toward preclinical development. Ongoing projects have focused on the SAR of chromonebased derivatives with activity against efflux proteins.108 It was observed that the 4-bromobenzyloxy substituent at position 5 and the methoxyindole ring were important moieties for the inhibition of mitoxantrone efflux and basal ATPase activity. Further structural modifications, namely, N-methylation at both nitrogen atoms and reduction of the amide function, have failed to improve potency. Recently, potent chromone-based ABCC1 modulators like compound 25 (IC50 = 11.3 μM, Figure 10) have been identified.109 This modulator showed results similar to reversan, a selective inhibitor of multidrug resistance-associated protein 1 (MDR-1) and P-glycoprotein when tested against ABCC1mediated resistance to cytostatics in MDCKII-MRP1 cells. In addition, it displayed increased selectivity toward ABCB1 and ABCG2. Another known strategy to overcome multidrug resistance is the coadministration of a MDR1 modulator with a primary chemotherapeutic agent.110 Indeed, three generations of MDR1 inhibitors were developed and clinically tested so far. Interestingly, some of the third generation inhibitors have a chromone moiety that can be converted into a fluorophore in vivo (compound 26, Figure 10) and are presently being used for in vivo imaging of multidrug resistance.110 However, their

Figure 9. Kinase inhibitors based on the chromone scaffold.

therapeutic approach for the management of osteosarcoma. Moreover, 22 effectively modulated glucocorticoid resistance in MLL-rearranged acute infant lymphoblastic leukemia,101 which can be of therapeutic value to overcome glucocorticoid resistance in cancer treatments. Compound 22 (Figure 9) has also been found to potentiate the cytotoxic effects of doxorubicin (DNA cross-linking drug), vincristine (antimicrotubule drug), and etoposide (topoisomerase II inhibitor) in cell based assays.102 Lastly, 22 has shown promising activity against hepatocellular carcinoma (HCC), a malignancy with high prevalence and poor prognosis at advanced clinical stages. Preliminary results have shown that it can significantly reduce tumor cell viability by decreasing HCC cell migration and invasion capacity and by promoting apoptosis.103 Chromone-based derivatives have been developed as kinase inhibitors. Zhu et al.104 synthesized a series of thienopyrimidine chromone derivatives and screened them toward the mammalian target of rapamycin (mTOR)/PI3K kinase. This protein kinase is involved in the PI3K-Akt-mTOR signaling pathway, which plays a key role in cell proliferation, migration, survival, and angiogenesis. Chromone derivative 23 (Figure 9) has thus emerged as a potent inhibitor of mTOR/PI3K kinase (IC50 = 0.16 μM and IC50 = 2.35 μM, respectively). Additionally, structure−activity relationships and docking studies have disclosed the importance of both the chromone core and the 6-carboxylic acid substituent for antitumor activity. 4.4.2. Transporter Inhibitors. Multidrug resistance is a major factor of chemotherapy failure. Several mechanisms can mediate cellular resistance to chemotherapeutic agents, but

Figure 10. ABC transporter inhibitors based on the chromone scaffold. 7950



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Figure 11. Anticancer chromone derivatives identified from biological screening on cancer lines.

Pioneering studies recently reported a diversity of chromonebased systems, namely, 2-styrylchromones, bis-chromones, and chromones bearing thiazolidine, thiazolidinedione, and isoxazole heterocycles,120−126 but modest to good antimicrobial activity has been reached. Chromone derivatives bearing tetrazole substituents and fluorine-containing analogs have been screened against pathogenic bacteria (Pseudomonas aeruginosa and Staphylococcus aureus), pathogenic protozoan (Entamoeba histolytica), and human fungal pathogens (Sporothrix schenckii, Candida albicans, and Candida tropicalis).127 Three chromone derivatives are highlighted (compounds 32−34, Figure 12), owing to their noteworthy activity against Gram-positive (compounds 32, 33, and 34, MIC = 40 μg/mL, MIC = 160 μg/mL, and MIC = 80 μg/mL for Staphylococcus aureus, respectively) and Gram-negative bacteria (compounds 32, 33, and 34, MIC = 160 μg/mL, MIC = 80 μg/mL, and MIC = 20 μg/mL for Pseudomonas aeruginosa, respectively). In general, an increase in antibacterial activity was observed when fluorine or iodine substituents were present. Interestingly, halogenated chromones 32 and 35 (Figure 12) were identified as potential amebicidals (IC50 = 61.7 μg/mL and IC50 = 61.7 μg/mL, respectively). In addition, a remarkable antifungal activity toward Candida tropicalis (6.25 μg/μL) has been observed for chromone 33 (Figure 12). Moreover, Cano et al.128 have described 3-tetrazolylmethyl substituted chromones as potential antiparasitic agents, especially against Giardia lamblia. A study performed by Feng et al.129 proposed the chromanone scaffold as an interesting framework for the development of antimicrobial agents. Accordingly, a series of chromanones were tested against Mycobacterium tuberculosis and a wide array of clinically relevant Gram positive and Gram negative bacteria, namely, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Although the majority of the chromanone derivatives had weak antituberculosis activity, stimulating data were obtained for the other systems. The SAR study showed that C5- and C7-hydroxyl groups, the presence of hydrogen bond donor/ acceptors at C4, and a lipophilic 2-alkyl moiety were essential for antibacterial activity. Compound 36 (Figure 12) was the

efficacy has been difficult to establish, a problem that is partly related to the lack of pharmacokinetic reporters for quantifying inhibitor localization and transport dynamics. 4.4.3. Screening toward a Panel of Cancer Lines. Several chromone derivatives have been screened toward a panel of cancer lines, namely, those bearing imidazolidinone methylamino-4-substituted-1,3-thiazoles and 4-morpholinothieno[3,2d]pyrimidine substituents.111−113 The results gathered so far led to the following conclusions: (a) Derivatives based on the 7-methoxychromone scaffold have shown relevant cytotoxic effects in several cell lines (HL-60, KB, LLC, LNCaP, LU-1, MCF7, and SW480).114 Additionally, several chromonylthiazolidines (compounds 27 and 28, IC50 = 44.1 μg/mL and IC50 = 32.8 μg/mL, respectively, Figure 11) have shown selective cytotoxic activity against human epidermoid carcinoma and breast cancer.115 (b) Bis-chromone derivatives, like 3-((5(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-methoxy-4H-chromen-4-one and 3-((5-(cyclohexylmethoxy)-4oxo-4H-chromen-3-yl)methyl)-7-hydroxy-4H-chromen-4-one (compounds 29 and 30, IC50 = 1.12−4.25 μM, Figure 11), have shown notable in vitro antiproliferative activity against human cancer cell lines (human prostate (PC-3), lung (NCI-H23), breast (MDA-MB-231), colon (HCT-15), stomach (NUGC-3), and renal (ACHN) cancer cell lines).116 Other bis-chromone derivatives have been synthesized and tested in a melanoma cell line (A375). One of the most promising chromone derivatives, compound 31 (Figure 11), induced apoptosis and cell cycle arrest and effectively reduced the adhesive potential of melanoma cells.117 4.5. Infectious Diseases. The rapid emergence of resistant microorganisms represents a major public hazard. With resistance rates rising and new resistance mechanisms emerging, the current arsenal of antibiotics is steadily losing its efficacy.118,119 On the other hand, the number of new agents being brought to the market has undergone a steep decline in the past decades.3 As a result, finding new chemical entities to supplement the pipeline is a pressing and unmet clinical need. Since chromones were recognized as a privileged scaffold,2,3 several projects focusing on innovative antimicrobial agents based on this oxygen heterocycle have been pursued. 7951



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Figure 12. Antimicrobial agents based on the chromone and chromanone scaffolds.

most potent derivative, with MIC values of 200 μg/mL for Mycobacterium tuberculosis, 6.25 μg/mL for Enterococcus faecalis, and 3.13 μg/mL for Staphylococcus aureus. 4.6. Novel Applications: Looking for Other Targets. Chromones have also been screened against other relevant biological targets and/or used as a tool to validate new targets, namely their (patho)physiological role and potential for the development of new therapeutic approaches.2 Accordingly, recent studies regarding cutting-edge topics, like orphan receptors and hormone regulators, are herein highlighted. Orphan receptors are proteins that bind and are activated by hitherto unknown signaling molecules, providing a unique resource for uncovering novel regulatory systems that impact human health. Orphan nuclear receptors represent a tremendous opportunity in drug discovery, as the identification of orphan receptor ligands can aid the understanding of its physiological role and potential as a drug target.2,130 G protein coupled receptor 35 (GPR35) is an orphan receptor discovered in 1998 that has been the subject of a growing interest as a potential target, especially considering its association with gastrointestinal, cardiovascular, and metabolic diseases.130−132 GPR35 also has increased expression in gastric cancer cells,132 cancer cell growth,133 inflammation,134,135 and antinociception.131 In this context, Funke et al.136 have identified novel GPR35 agonists based on the 8-benzamidochromen-4-one-2-carboxylic acid. The most potent and selective candidates (compounds 37 and 38, EC50 = 12.1 nM and EC50 = 11.1 nM, respectively) are depicted in Figure 13. Somatostatins, also known as somatotropin-release inhibiting factors (SRIFs), are a family of cyclopeptides that have

inhibitory effects on the secretion of hormones, such as growth hormone, insulin, and glucagon. The discovery of the five SRIF receptor subtypes belonging to the G protein coupled receptor (GPCR) superfamily has enhanced the understanding of SRIFs’ biological role(s), paving the way for the discovery of new therapeutic strategies. Indeed, it was found that SRIFs receptormediated modulation can lead to changes in hormone secretion, apoptosis, and cell growth as well as in inflammation, vascular remodeling, neurotransmission, and diabetic retinopathies related events.137 Additionally, SRIF and its analogues can inhibit hormone secretion and control the neoplastic bulk of several endocrine tumors. Somatostatin and peptide analogues have a restricted use as drugs due to their low bioavailability.138 One way to overcome this pharmacokinetic drawback is the development of peptidomimetics, such as nonpeptidic compounds containing amino acid side chains,138 non-peptide agonists and antagonists.138 Fridén-Saxin et al.139 reported the synthesis of a series of chromone and chromanone-based compounds with significant affinity for somatostatin receptor subtypes 2 and 4. For the chromone derivative 39 (Figure 14), Ki = 1.17 μM

Figure 14. Somatostatin agonists and a corticosteroid biosynthesis inhibitor based on the chromone and chromanone scaffolds.

(subtype 2) and Ki = 2.66 μM (subtype 4) were obtained. Interestingly, the chromanone analogue 40 (Figure 14) displayed Ki = 6.85 μM for somatostatin receptor subtype 2 and Ki = 7.09 μM for somatostatin receptor subtype 4. Steroid hormones are known to play an important role in the regulation of crucial physiological processes. However, their abnormal levels have been related to several hormone-related diseases, namely, those associated with the underproduction or overproduction of adrenal hormones. In particular, cortisol overproduction (hypercortisolism) can lead to several hormonerelated disorders, such as Cushing’s syndrome,140 while the deregulation of aldosterone (aldosteronism) is involved in

Figure 13. GPR35 agonists based on the chromone scaffold. 7952



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cancer and cardiovascular disorders, such as congestive heart failure or myocardial fibrosis.141 Within this context, Gobbi et al.142 developed novel chromonebased inhibitors of steroid biosynthesis. Among the promising results, a 3-substituted chromone linked to a 4-imidazolyl moiety is highlighted as a potent and selective 11 β-hydroxylase (CYP11B1) inhibitor (compound 41, IC50 = 9.7 nM, Figure 14). Compound 41 showed a lower activity toward 17α-hydroxylase/ C17,20-lyase (CYP17) and aromatase (CYP19), which are targets of hormone-dependent breast and prostate cancer. The preliminary toxicity tests performed on healthy human cells pointed toward a safe profile.142

scaffolds. Currently he is Professor of Pharmacology and Medicinal Chemistry. Fernanda Borges is Associate Professor of the Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto. She received her M.Sc. and Ph.D. (Pharmaceutical Chemistry) in Pharmaceutical Sciences from the Faculty of Pharmacy, University of Porto, Portugal. Her current research is focused on medicinal chemistry, namely, in the design and development of drugs to be used in the prevention and/or therapy of neurodegenerative diseases. She has authored more than 240 publications in peer reviewed journals, 21 international book chapters, and a number of patents.

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5. CONCLUDING REMARKS The evidence presented in this perspective supports continuing interest in the research related to the isolation and synthesis of chromone derivatives as well as the evaluation of their biological properties. The synthetic procedures used in the formation of the chromone core were discovered a long time ago and generally involve drastic conditions in terms of temperature and pH. Although these methods are still in use due to their efficiency, they urgently need to be upgraded with innovative, green, and sustainable methodologies. Overall, the development of pharmacologically active compounds based on valid scaffolds, such as the chromone core, and the development of new and improved druglike libraries are fundamental to speed up the discovery of new drugs. In the coming years, it is expected that research on chromone-based derivatives will have positive outcomes in the fields covered in this review.

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ACKNOWLEDGMENTS

This work was supported by the Foundation for Science and Technology (FCT) of Portugal (Grants UID/QUI/UI0081/ 2013 and POCI-01-0145-FEDER-006980). J.R. (Grant SFRH/ BD/96033/2013) and A.G. (Grant SFRH/BPD/93331/2013) are supported by FCT, POPH, and QREN. This article is based upon work from COST Action CA15135.

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ABBREVIATIONS USED ABC, ATP-binding cassette transporter; ACC, acetyl-CoA carboxylase; AChE, acetylcholinesterase; AD, Alzheimer’s disease; AGI, α-glucosidase inhibitor; Aβ, amyloid β peptide; BACE-1, β-secretase-1; BuChE, butyrylcholinesterase; COX, cyclooxygenase; CysLT1R, cysteinyl leukotriene receptor 1; DSCG, disodium cromoglycate; GPCR, G protein coupled receptor; HCC, hepatocellular carcinoma; IBS, irritable bowel syndrome; Ig, immunoglobulin; IL, interleukin; 5-HT, 5-hydroxytryptamine; MDR-1, multidrug resistance protein 1; MAO-B, monoamine oxidase B; MTDL, multitarget-directed ligand; ND, neurodegenerative disease; NF-κB, nuclear transcription factor; PD, Parkinson’s disease; PPAR, peroxisome proliferatoractivated receptor; PI3K, phosphoinositol 3-kinase; PK, protein kinase; QSAR, quantitative structure−activity relationship; RA, rheumatoid arthritis; SRIF, somatotropin-release inhibiting factor; TNF-α, tumour necrosis factor α

AUTHOR INFORMATION

Corresponding Author

*Phone: +351 220402560. E-mail: [email protected]. ORCID

Fernanda Borges: 0000-0003-1050-2402 Notes

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The authors declare no competing financial interest. Biographies

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