Chromone: A Valid Scaffold in Medicinal Chemistry - Chemical

Feb 21, 2014 - She received her MSc in Pharmaceutical Sciences from the Faculty of Pharmacy, University of Porto, Portugal. Her professional interests...
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Chromone: A Valid Scaffold in Medicinal Chemistry Alexandra Gaspar,†,‡ Maria Joaõ Matos,†,‡ Jorge Garrido,†,§ Eugenio Uriarte,‡ and Fernanda Borges*,† †

CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua Campo Alegre 687, 4169-007 Porto, Portugal ‡ Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago of Compostela, 15782 Santiago de Compostela, Spain § Department of Chemical Engineering, School of Engineering (ISEP), Polytechnic of Porto, 4200-072 Porto, Portugal 4.3.7. Aromatase Inhibitors and Estrogen-Receptor Modulators 4.3.8. Screening toward a Panel of Cancer Lines 4.4. Antimicrobial Drugs 4.4.1. Antibacterial and Antifungal Drugs 4.4.2. Antiviral Drugs 4.5. Drugs for Neurodegenerative Diseases 4.5.1. Acetylcholinesterase Inhibitors 4.5.2. Monoamine Oxidase-B Inhibitors 4.5.3. Dopamine D2 Receptor Agonists 4.5.4. Sirtuin Inhibitors 4.5.5. Imaging Probes 4.6. Antiobesity Drugs 4.7. Novel Applications: Development of Adenosine Receptors Antagonists 5. Concluding Remarks Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Natural Occurrence of Simple Chromones 3. Methods of Synthesis of Simple Chromones 3.1. Synthesis of Chromones by Bicyclic Construction 3.1.1. Synthesis of Chromones from orthoHydroxyarylalkylketones 3.1.2. Synthesis of Chromones from Phenols 3.1.3. Synthesis of Chromones from Salicylic Acid and Derivatives 3.1.4. Synthesis of Chromones via C−C Cross Coupling Reactions 3.2. Synthesis of Chromones from Chromanones 3.3. Synthesis of Chromones from Chromones 3.3.1. Heterocyclic-Substituted Chromones 3.3.2. Vinyl-Substituted Chromones 3.3.3. Other Type of Functionalized Chromones 4. Biological Interest of Simple Chromones 4.1. Anti-inflammatory Drugs 4.1.1. Cyclooxygenase Inhibitors 4.1.2. Leukotriene Receptor Antagonists 4.1.3. Mast Cell-Targeted Drugs 4.1.4. Interleukin-5 Inhibitors 4.1.5. Intercellular Adhesion Molecule Inhibitors 4.2. Antiplatelet Drugs 4.3. Anticancer Drugs 4.3.1. Kinase Inhibitors 4.3.2. Protein Tyrosine Phosphatases Inhibitors 4.3.3. Thymidine Phosphorylase Inhibitors 4.3.4. Apoptotic Inhibitors 4.3.5. Topoisomerases Inhibitors 4.3.6. Drug Transporter Inhibitors © 2014 American Chemical Society

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1. INTRODUCTION Chromones are a group of naturally occurring compounds that are ubiquitous in nature, especially in plants. The word chromone is derived from the Greek word chroma, meaning “color”, which point out that many chromone derivatives can exhibit a diversity of colors.1 Chromones are oxygen-containing heterocyclic compounds with a benzoannelated γ-pyrone ring being chromone (4Hchromen-4-one, 4H-1-benzopyran-4-one) the parent compound (Figure 1). The chromone ring system is the core

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Figure 1. Chromone core and flavonoids (flavone and isoflavone). Received: May 14, 2013 Published: February 21, 2014 4960

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Table 1. Natural Simple Chromones

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Table 1. continued

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Table 1. continued

a

Biological activity described as anti-inflammatory. bBiological activity described as cytotoxic. cBiological activity described as antiviral. dBiological activity described as neurotoxic. eAlthough referred in literature as new chromones they present the same structural formula. fRevised structure of a previously described chromone. gFirst report on the isolation of the chromone from a natural source.

fragment of several flavonoids, such as flavones and isoflavones (Figure 1). Although flavonoids (C6−C3−C6) have a chromone unit in their backbone and have been from time to time included in this family they were not included in the present work as they have been extensively revised in the past decade.2 The structural diversity found in chromone family led to their roughly division into different categories: simple chromones and fused chromones (pyrano and furanochromones). Yet, the present revision will be only focused in simple chromones as they are a large class of compounds that have attracted interest for a long time either from a biosynthetic and synthetic point of view or because of their interesting biological activities, especially when used in folk medicine. Until now, simple chromones have been an up-and-coming area of exploration, and the literature in the area is diffuse. So, the purpose of this Review is to analyze and summarize aspects related to the medicinal chemistry artwork performed with simple chromones to look at their potential therapeutic applications. In addition, information concerning the development of innovative synthetic strategies and biological applications, with particular emphasis on structure−activity relationships (SAR) will be also included.

such as phenols and ortho-substituted phenols (Figure 2). Yet, other building blocks, such as ortho-hydroxyarylalkynyl ketones

Figure 2. Retrosynthetic analysis of simple chromones.

and salicylic aldehydes have been used. Despite the advances performed in synthetic processes they are still the most cited in the literature. As microwave assisted-synthesis is nowadays a valuable tool in the area of heterocyclic compounds efforts were performed to include this type of methodology along the topic. 3.1.1. Synthesis of Chromones from ortho-Hydroxyarylalkylketones. The main classic routes for the obtention of simple chromones from ortho-hydroxyarylalkylketones are depicted in Scheme 1. They enclose three synthetic approaches: synthesis via Claisen condensation (classic Claisen condensation, Baker−Venkatamaran, and Kostanecki−Robinson recation), synthesis via benzopyrylium salts and via Vilsmeier−Haack reaction. 3.1.1.1. Synthesis via Claisen Condensation. 3.1.1.1.1. Synthesis via Classic Claisen Condensation. The Claisen condensation is a well-known synthetic method that was first applied for the synthesis of chromones, namely, of 7ethoxychromone-2-carboxylic acid, by Kostanecki, Paul, and Tambor.33b In this type of reaction the construction of the chromone core from ortho-hydroxyarylalkylketones occurs in two steps. The first encompasses the use of a strong base, traditionally sodium ethoxide in ethanol, to generate an enolate that react with a carboxylic ester leading to the formation of a 1,3-dioxophenoxy intermediate (Scheme 1). The second step encloses a subsequent cyclization of the intermediate under acidic conditions using conventional heating.34 Several type of acidic catalysts have been used over the time, such as mineral (sulphuric, hydrochloric, hydriodic, polyphosphoric and perchloric acids) and organic acids (acetic and p-toluenesulfonic (PTS) acids) and other type of dehydrating agents

2. NATURAL OCCURRENCE OF SIMPLE CHROMONES Chromones are secondary metabolites widely distributed in the plant kingdom and are present in notable amounts in several species. However, the specific role of these compounds is not well understood and has been the topic of some debate. Natural chromones have been extensively studied and some reviews have been published containing relevant information on this subject.3 Accordingly, this review will report only simple chromones that were isolated from different sources, including the data related with biologic activity, and described for the first time in the last 5 years (Table 1). 3. METHODS OF SYNTHESIS OF SIMPLE CHROMONES 3.1. Synthesis of Chromones by Bicyclic Construction

An overview of the general methodologies used in the synthesis of simple chromones is presented in the review. For deep information in the field it is advised to access the excellent review published by GP Ellis in 1977.33 Generally, the total synthesis of simple chromones can be attained using starting materials that do not possess a pyran ring in their structure, 4965

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Scheme 1. Synthesis of Chromones from ortho-Hydroxyarylalkylketones

Scheme 2. Synthesis of Chromones by Kostanecki Reaction

An important group of simple chromones, chromone-2carboxylic acid or its ester derivatives, have been synthetized by a variation of the Claisen condensation that was called the Kostanecki reaction.40 The synthetic strategy has involved the condensation of an ortho-hydroxyacetophenone with a particular ester, diethyl oxalate, in the presence of sodium ethoxide in EtOH, followed by the cyclization, under acidic conditions, of the 1,3-dioxophenoxy intermediate (Scheme 2).35d,41 Over the years other modifications on the Claisen condensation have been reported, namely through the use of other type of esters. Several chromones have been obtained by the condensation of ortho-hydroxyacetophenones with tertbutylethyl oxalate, followed by a cyclodehydration in the presence of concentrated HCl.42 It was stated that the use of tert-butylethyl oxalate led to a shorter reaction time and better yields. Other authors have synthetized several chromone derivatives by performing the condensation of different 2hydroxyphenones with ethyl chlorooxoacetate and in situ cyclization in the presence of pyridine,41b,43 without the requirement of the acidification step for ring closure. 3.1.1.1.2. Synthesis via Baker−Venkatamaran Rearrangement. The Baker−Venkatamaran rearrangement can be considered as a variation of the Claisen condensation previously described for the synthesis of chromones. This methodology involves the acylation of ortho-hydroxyarylalkylketones with acyl chlorides that in basic medium undergo a Baker−

(methanesulfonylchloride, triflic anhydride, and phosphorus oxychloride).35 Over the years a number of variants were described for the synthesis of the 1,3-dioxophenoxy intermediate that were essentially focused in finding mild reaction conditions. The employment of triethylamine as solvent and base36 and other type catalysts, such as LiH,35b NaH in THF,35c and NaH in pyridine,33a,37 have been reported. More recently, several chromone derivatives, namely, 2,6dimethylchromone and 2-methyl-6-chlorochromone, were synthesized taking advantage of microwave irradiation. The synthetic strategy encompasses a Claisen condensation and a two-step procedure: the obtention of the 1,3-dioxophenoxy intermediate that after isolation was cyclized under acidic conditions.38 The major asset of the synthesis is related with the use of microwave irradiation to obtain the intermediate at a reduced reaction time. Mozingo et al.39 reported a modification of the Claisen condensation to synthetize alkylchromones, such as 2-ethylchromone. In their work, the 1,3-diketone intermediate was obtained from the condensation of an appropriate orthohydroxyacetophenone with an ester, using as catalyst metallic sodium instead of sodium etoxide in ethanol. The desired chromones were obtained by promoting the intramolecular cyclization of the intermediate using an inorganic acid, such as HCl. 4966

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Scheme 3. Synthesis of 3-Alkyl or 3-Formylchromones by Vilsmeier−Haack Reaction

Scheme 4. Synthesis of Chromones through Modified Vilsmeier−Haack Reactions

Claisen condensation reaction to obtain a diversity of chromones.33b In this type of reaction the chromone is obtained by the reaction of an ortho-hydroxyarylketone with an aliphatic acid anhydride, in the presence of its corresponding sodium or potassium salts, without the need of the acidification step for ring closure (Scheme 1). After the ortho-acylation of the starting material the arylketone suffers an enolization process affording the corresponding enolacetate. The chromone is obtained after the subsequent aldol intramolecular cyclization.53 Typically, the Kostanecki−Robinson reaction occurs at temperatures that often exceed 160 °C, although mild reaction conditions have been already described and with K2CO3 in acetone under reflux for 24 h.46a,54 The pioneer work on this reaction was realted to the conversion of 2′,4′dihydroxyacetophenone and 4-ethoxy-2-hydroxyacetophenone, in a mixture of acetic anhydride and sodium acetate, into their corresponding chromones.33b Efforts have also been focused in the modification of electrophile, namely in the work of Yamaguchi et al.55 that uses a stoichiometric amount of DBU instead of sodium acetate. The Kostanecki−Robinson reaction has been applied over the years for the synthesis of a large number of chromones.49,56 Despite the success, the methodology has some drawbacks, mainly related with the formation of side-products, for instance coumarins.33b Moreover, the Baker−Venkatamaran rearrangement can take place with the formation of 3-substituted chromones. This contingency has been explored and tailored for the obtention of 3-substituted chromones.57 The work of Lacova et al.50 is an example of the synthesis of 3-acyl-2methylchromones by the classic Kostanecki−Robinson involving the Baker−Venkatamaran rearrangement. 3.1.1.2. Synthesis via Benzopyrylium Salts. The synthesis of 2-nonsubstituted chromones can be attained via benzopyrylium salt intermediates. In this condition, the 2-hydroxyacetophe-

Venkatamaran rearrangement with the formation of a 1,3dioxophenoxy salt intermediate (Scheme 1). The subsequent cyclization step take place usually under severe acidic conditions, for instance in the presence of sulfuric acid. The Baker−Venkatamaran rearrangement44 was originally described for the synthesis of a flavone using as starting material an ortho-benzoyloxyacetophenone that in presence of a base, for example potassium carbonate, suffer an intramolecular rearrangement with the formation of a ortho-hydroxydibenzoylmethane intermediate.44 The cyclization process is performed, after the isolation of the intermediate, in the presence of strong acids. It is important to remark that 2-styrylchromones are classically obtained through Baker−Venkatamaran rearrangement.45 Several modifications have been proposed to this method. One is related with the possibility to perform the cyclization process in situ avoiding the step related with the isolation of the intermediate, using pyridine as a catalyst.46 An example of this type of approach is related to the synthesis of 2,8-disubstituted chromone derivatives and the use of diazabicyclo[5.4.0]undec7-ene (DBU) and pyridine to promote the cyclization step.47 Another variation of the method is related to adjustments performed in the acylation step: instead of the use of the conventional acyl chlorides some works report the direct application of carboxylic acids48 or acid anhydrides49 as starting materials. In addition, the use of other type of bases, such as sodium metallic,50 sodium alkoxide,35e,37a,51 sodium hydride,37a and potassium or sodium hydroxide,52 have also been reported. Recently it has been reported by Dyrager et al.52 the synthesis of 3-(4-fluorophenyl)-2-(4-pyridyl)chromone derivatives through a microwave-assisted Baker−Venkatamaran rearrangement. 3.1.1.1.3. Synthesis via Kostanecki−Robinson Reaction. Kostanecki, Robinson, and their co-workers modified the 4967

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Scheme 5. Synthesis of Chromones from Phenols by (A) Simonis and (B) Ruhemann Reactions

Scheme 6. Synthesis of Chromones from Salicylic Acids and Derivatives

type of ortho-hydroxyalkylarylketone used as starting material (Scheme 3). However, some reaction drawbacks have been mentioned, such as long reaction time, unexpected side-reactions and unsatisfactory yields. In fact, the obtention of formylchromone derivatives from ortho-hydroxyacetophenones bearing a methoxyl group at the C-4 or C-5 position (e.g., 4-methoxy or 5methoxy-2-hydroxyacetophenone) take place with poor yields. To overcome some of the reaction problems some modifications of the method has been proposed, namely, the use of a boron trifluoride diethyl etherate with the formation of a dioxoborin intermediate,61a,62 and variants of the Vilsmeier− Haack reagent (formylating reagent), such as triphosgene (bis(trichloromethyl)carbonate)/DMF, phosgene iminium chlorides, or DMF−dimethyl acetal (DMF−DMA)63 (Scheme 4). In this context, one can mention the synthesis of 2-aminochromones64 and 3-halochromones.65 A sucessuful example of a modified Vilsmeier−Haack reaction is related with the employment of 2-hydroxyacetophenones and DMF−DMA that, after cyclization and in the presence of iodine, gave 3iodochromones.66 The use of commercially available enaminoketones have been also described for the synthesis of 3substituted chromones (Scheme 4).67 In recent years, the synthesis of 3-formylchromones by Vilsmeier−Haack reaction has been improved by the

nones used as starting materials react with triethyl ortho formate and a strong mineral acid, like perchloric acid (Scheme 1).58 Subsequently, the obtained benzopyrylium salt is converted to the chromone by heating the crude material in water. This method has been applied to the synthesis of 3substituted chromones, such as 3-hydroxychromones33b and 3methylchromones.59 3.1.1.3. Synthesis via Vilsmeier−Haack Reaction. In the Vilsmeier−Haack reaction (also called Vilsmeier reaction),33b the synthesis of chromones was performed between an orthohydroxyalkylarylketone and a formylating reagent, known as the Vilsmeier−Haack reagent. Accordingly, the chloroiminium ion formed in situ from the reaction of a N,N-disubstituted formamide, such as dimethylformamide (DMF), with phosphorus oxychloride reacts with the ketone enolate generated from the ortho-hydroxyalkylarylketone. In general, the reaction mechanism encompasses the formation of an unsubstituted chromone as intermediate that suffer a second attack from the chloroiminium ion giving rise typically to 3-substituted chromones (Scheme 1). This one-pot procedure was applied to the synthesis of chromones for the first time in 197360 and has been widely used since then for the synthesis of 3-alkyl or 3formylchromones,60,61 a processs that is dependent on the 4968

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3.1.4. Synthesis of Chromones via C−C Cross Coupling Reactions. 3.1.4.1. Synthesis via PalladiumMediated Catalysis. Transition-metal-catalyzed reactions provide nowadays one of the most attractive methodologies for the formation of C−C and C-heteroatom bonds. The application of these reactions has increased tremendously during the last decades and cross-coupling reactions became an important tool for synthetic chemists. Following this tendency an attractive synthetic method has been developed for the obtention of chromones involving a one-pot Sonogashiracarbonylation-annulation reaction that involves the reaction of an ortho-iodophenol with a terminal acetylene, in the presence of a palladium complex, and the formation of an orthohydroxyarylalkynylketone intermediate. The processs avoid the harsh reaction conditions (strong bases and acids or high temperature) used in the reactions previously mentioned. The obtention of a chromone encompasses a cyclocarbonylation process which occurs in situ in the presence of carbon monoxide (Scheme 7A).78 The reaction proceeds in a short

expenditure of microwave-promoted synthesis and solidsupported methods.68 3.1.2. Synthesis of Chromones from Phenols. 3.1.2.1. Synthesis via Simonis Reaction. In 1913, Simonis33b reported a reaction by which phenol or its derivatives were condensed with β-ketoesters (e.g., ethyl acetoacetate) in the presence of phosphorus pentoxide (P2O5) to obtain chromones, instead of the corresponding coumarins, as a final product. This acid-catalyzed condensation become known over the world as Simonis reaction (Scheme 5A).33a Classically, phosphorus pentoxide is used as the condensing agent but sulfuric acid69 or polyphosphoric acid70 have also been employed. The synthesis of chromones by Simonis reaction is usually operative when the phenol used as starting material has electron-withdrawing substituents, such as halogens or nitro groups. It was also found that the presence of alkyl substituents on the α-position of the β-ketoester can favor the formation of chromone. More recently, Eric Fillion et al.71 described a successful synthetic strategy for obtention of 2-methylchromones by promoting the condensation of the appropriated phenol with 5-(1-methoxyethylidene) Meldrum’s acid in the presence of trifluoroacetic acid. 3.1.2.2. Synthesis via Ruhemann Reaction. Chromones can be obtained by the reaction of a phenol with acetylenic dicarboxylic acids or esters or with chlorofumaric acid, or other analogues, in basic conditions, such as metallic sodium or K2CO3. After the formation of the intermediate a subsequent cyclization process must occur, in presence of sulphuric acid, perchloric acid or hydrogen fluoride, to afford chromone. (Scheme 5B) This method, known as Ruhemann reaction, was largely applied to the synthesis of chromone-2-carboxylic acids and derivatives.40 In 1977, Lee and co-workers proposed a modification of the process using polyphosphoric acid as a catalyst.33b Ruhemann reaction was also used, with slight modifications, for the synthesis of flavones and styrylchromones.72 3.1.3. Synthesis of Chromones from Salicylic Acid and Derivatives. Salicylic acid or its derivatives have been used as starting materials for the obtention of chromones. Throughout the reaction O-acyl(aroyl) derivatives were attained and converted to the corresponding silyl esters, in the presence of tert-butyldimethylsilyl chloride and imidazole. Chromones were then obtained via intramolecular Wittig ester carbonyl olefination, using (trimethylsilyl)methylenetriphenylphosphorane (Scheme 6A).73 Another interesting approach comprise the reaction of activated salicylic derivatives with diethyl malonate and the obtention of intermediates that after subsequent hydrolysis and decarboxylation processes led to the formation of 2methylchromones.74 This type of chromones have also been obtained by the reaction of methyl salicylate with dimethylpenta-2,3-dienedioate, in presence of KOtBu/BuOH (Scheme 6B).75 The synthesis of chromones via the condensation of methyl salicylate with bromocrotononitrile derivatives, and subsequent cyclization of the vinyl ether intermediate in basic (NaH) medium, has been also described (Scheme 6C).76 Functionalized 2-amino-3-cyano-4-chromones have also been obtained by a one-pot procedure by which acetylsalicylic acid derivatives react with N-hydroxybenzotriazole (HOBt) and malononitrile under basic conditions (NaH). The cyclization step was attained with acid catalysis (HCl) (Scheme 6D).77

Scheme 7. Synthesis of Chromones via Palladium-Mediated Catalysis

time and with very good yields. The use of a microwave-assisted reaction can speed up the process and increase substantially the yields.78c However, in particular situations a mixture of chromones and aurones can be obtained. This drawback was reported to be minimized by the use of ionic liquids.78c The chromone formation by Sonogashira coupling with palladium catalysis was also performed using an orthomethoxybenzoyl chloride with a terminal acetylene (Scheme 7B) or an ortho-methoxybenzaldehyde with a lithium acetylide (Scheme 7C).79 In all the cases, the cyclization of the intermediates (2-methoxyarylalkynylketones), carried out by ICl, afford 3-iodochromones.80 In summary, the obtention of chromones via palladiummediated catalys is considered to be a simple and high efficient approach. The type of chromones obtained depend on the starting material and the method used for ring closure. 3.1.4.2. Synthesis via Organo-Mediated Catalysis. An interesting alternative to the metal-catalyzed C−C cross coupling reactions are the organocatalyzed reactions. These 4969

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important to emphasize in this Review the work done on this subject and in accordance several examples of the functionalization of these building blocks will be described in the sections below. 3.3.1. Heterocyclic-Substituted Chromones. Heterocyclic-substituted chromones are probably one of the most representative derivatives as these types of entities are very important as ligands in the medicinal chemistry artwork. Thus, the different approaches used so far will be pointed out in this part of the review with special emphasis on the new and more efficient ones, namely, related with the microwave-assisted synthesis as it corresponds to an expeditious technique.93 3.3.1.1. Azaheterocyclic-Chromone Derivatives. Chromone-3-carbaldehyde is a highly reactive and well-studied benzopyran compound that was applied as starting material for the synthesis of a diversity of compounds and targeted libraries because of the presence of three electrophilic centers. However, the generation of chemical diversity based on heterocyclic decoration with azoles, such as indoles and pyrroles, was found to be scarce yet. Chromones presenting a pyrrole ring substituent have been synthesized from chromone-3-carbaldehydes under diverse experimental conditions (Scheme 9).

reactions are eco-friendly, as they are metal free and costeffective and are currently one of the most significant green chemistry research areas. In this context, N-heterocyclic carbenes (NHCs) have recently gained importance as catalysts for carbon−carbon bond formation. The use of NHCs catalysts was recently proposed for the synthesis of 3-aminochromones and other 3-substituted chromones (Scheme 8).81 NHCs Scheme 8. Synthesis of Chromones via Organo-Mediated Catalysis

Scheme 9. Azaheterocyclic-Chromone Derivatives

catalysts were used with the purpose of promoting the intramolecular cross coupling between the aldehyde and the nitrile function (Scheme 8A) or to enhance the intramolecular reaction of the aldehyde with an activated alkyne (Scheme 8B). This latter reaction is a modification of the known intramolecular Stetter reaction.81 3.2. Synthesis of Chromones from Chromanones

The formation of chromones from chromanones is not a procedure as common as the methodologies described earlier as the starting material is not readily available and the overall yields are often low.33b In the last three decades, few studies have reported on the topic and in for the most part of the cases the reactions enclose oxidation or dehydrogenation processes. To achieve the goal several oxidants, such as iodide,82 vanadium pentoxide,83 and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)84 were used. The reaction is often conducted in acidic medium.85 However, other catalysts, such as diethoxymethyl acetate,86 thallium(III),87 and the Lewis acids AlCl388 and BF3-Et2O89 have also been described. Furthermore, chromones can be obtained by dehydration of 2-hydroxychromanones, through treatment with HCl in EtOH90 or by dehydrobromination of the starting chromanone.91 The last reaction is usually carried out in basic medium and can be performed with microwave irradiation.92

Some examples have been found in the literature: (a) (chromon-3-yl)bis(indol-3-yl)methanes and (E)-2-hydroxy-3(1-methylpyrrol-2-ylmethylene)chromones have been obtained on reaction with indoles and N-methylpyrroles, respectively, under solvent-free conditions94 and (b) chromonylpyrrolidines have been synthetized from 3- and 4-(2-hydroxybenzoyl)pyrroles. They have been synthesized from azomethine ylides generated from the reaction of the chromone derivative with αamino acids.95 Dispirochromonepyrrolidines have been obtained by an efficient one-pot synthesis by which sarcosine and ninhydrin were used as source of azomethine ylides.96 (c) Chromones with diverse pyrroles substituents were synthesized by an in situ deformylation reaction using tosylmethylisocyanide (TOSMIC) in the presence of potassium carbonate.97 3.3.1.2. Diazaheterocyclic-Chromone Derivatives. Substituted chromone derivatives containing diazaheterocycles (Scheme 10) have been synthesized either under conventional heating or microwave irradiation employing 3-formylchro-

3.3. Synthesis of Chromones from Chromones

As described before efficient chemical strategies have been developed for the synthesis of simple chromones. However, in recent years a modification on the synthetic approaches has been observed a reality that is mainly related with the need to speed-up the drug discovery process, namely, for establishing structure−activity relationships studies, in medicinal chemistry programs. In consequence, several functionalized simple chromones are by now commercially available and used as starting materials. The most common chromones used as starting materials have been found to be 6/7-hydroxy, halo, methyl, or cyano chromone derivatives, chromone-3-carbaldehyde and chromone carboxylic acids. So, it was found

Scheme 10. Diazaheterocyclic-Chromone Derivatives

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mones and 5-acetyl-1,3-dimethylbarbituric acid and other hydrazine type bases as starting materials.98,99 3.3.1.3. Dithiazole-Chromone Derivatives. Biological active chromones have been synthesized by a condensation reaction of chromone-3-carbaldehyde with different type of amino derivatives, such as aminobenzothiazoles and aminothiobenzothiazoles. For instance, substituted-3-(5-phenyl-3H-[1,2,4]dithiazol-3-yl)chromone have been prepared using 6/6,7substituted-3-formylchromones as starting materials (Scheme 11).100

Scheme 13. Alkyl/Alkoxycarbonylvinyl-Chromone Derivatives

Scheme 11. Dithiazole-Chromone Derivatives

materials. The processes embrace in common the formation of a carbon−carbon bond as the key step (Scheme 14).106 3.3.1.4. Oxadiazole-Chromone Derivatives. Chromones functionalized with oxadiazole groups are other important derivatives in medicinal chemistry (Scheme 12). Starting from

Scheme 14. Styrylchromone Derivatives

Scheme 12. Oxadiazole-Chromone Derivatives

chromone-3-carbaldehyde diverse compounds have been synthesized, such as 3-(3-acetyl-5-aroyl-1,3,4-oxadiazol-2-yl)-, 3-(5-aryl-1,3,4-oxadiazol-2-yl)-, and 3-(3-acetyl-5-aryl-2,3-dihydro-1,3,4-oxadiazol-2-yl)chromones, from a heterocyclization reaction via hydrazone intermediates.101 Reaction of 3formylchromone-N-benzoylhydrazone with ketenes, prepared in situ from the corresponding acid chlorides and the mixed anhydride, allows the synthesis of chromone-1,3,4-oxadiazolines.102 This type of compounds has also been obtained by a convergent synthesis process based on the condensation of pnitrophenylacetonitrile with chromone-3-carbaldehyde in acetic anhydride and with sodium acetate. The treatment of the nitrile derivative with hydroxylamine hydrochloride/NaHCO3 in methanol under reflux afforded the desired amidoxime.103 3.3.2. Vinyl-Substituted Chromones. Vinyl-substituted chromones located in different positions of the chromone scaffold have been obtained from appropriate substituted benzopyrones. Alkylcarbonylvinyl, alkoxycarbonylvinyl, or styrylchromones derivatives will be emphasized as they are the most frequently mentioned in the literature. 3.3.2.1. Alkyl/Alkoxycarbonylvinyl-Chromone Derivatives. A series of chromone derivatives having the alkyl/alkoxycarbonylvinyl unit at the C-3 position have been synthesized (Scheme 13). In this process, the benzopyranonyl acrylic acids were obtained by a condensation reaction between different types of chromone aldehydes and malonic acid.104 A facile and ecofriendly synthesis of a series of chromonyl chalcones from 3formylchromones derivatives, employing Zn(L-proline)2 as a recyclable Lewis acid catalyst and water as the reaction medium, was also reported.105 3.3.2.2. Styrylchromone Derivatives. Several synthetic strategies have been developed for the obtention of 2- and 3styrylchromones from diverse substituted chromones as starting

3-Styrylchromones were efficiently synthesized from different types of simple chromones, namely, from diverse chromone-3carboxaldehydes by a Wittig reaction using benzylic ylides with electron-withdrawing or electron-donating substituents107 or from a condensation reactionwith phenylacetic acids followed by a decarboxylation process (Scheme 14A).108 In the second case a diastereomeric mixture of (E)- and (Z)-3-styrylchromones, predominantly (Z) isomers, is obtained and in the first one the reaction is stereoselective giving (E)-3-styrylchromones. The direct reaction of chromone with vinyllithium or vinyl magnesium bromide gave complex mixtures, due to competing 1,2- and 1,4-additions and decomposition. However, it was reported that the reaction of vinyl magnesisum bromide with benzopyrylium triflate, generated in situ with Me3SiOTf, gave rise in a regioselective conjugate addition to the desired 2vinylchromone (Scheme 14B).109 2-Alkenylchromones, 2alkenylthiochroman-4-ones, and 2-alkenylquinol-4-ones were also prepared with very good regioselectivity by Me3SiOTfmediated conjugate addition of alkenylmagnesium bromides and alkenyllithium compounds to chromones and thiochromones.110 4971

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A new efficient method for the direct alkenylation of chromones via a palladium(II)-catalyzed C−H functionalization reaction was reported (Scheme 14B). The use of pivalic acid with Cu(OAc)3/Ag2CO3 provided superior reactivity. This synthetic approach represents a significant advance for the obtention of 3-vinylchromone derivatives as the classic two-step reactions have been circumvented.111 2-Styrylchromone derivatives can be synthesized from diverse 2-methylchromones by a condensation reaction with different types of benzaldehydes in the presence of sodium methoxide (Scheme 14C).112 On the other hand styrylchromones have frequently been used as starting materials for the synthesis of more elaborated scaffolds (Figure 3).

Scheme 15. Ether- and Thioetherchromone Derivatives

Scheme 16. Ester-Chromone Derivatives

3.3.3.3. Amine-Chromone Derivatives. Amino- and aminomethyl-chromone derivatives are important bioactive compounds that can be obtained throughout the use of different building blocks and diverse methodologies (Scheme 17): (a) a diversity of aminomethylchromones has been synthesized from 2-chloromethylchromones (Scheme 17A). Substituted chromone-2-carboxylic acids used as precursors were esterified with linear alcohols that after a subsequent reduction reaction gave 2-hydroxymethylchromones that in turn react with thionyl chloride affording the activated chromone.119 (b) 2-[(3Aminoalkyl or 3-bromoalkyl)amino]chromone derivatives have been synthesized from 2-(dialkylamino)chromones by amine exchange using 1,3-diaminopropane (or 1-amino-3bromopropane).120 (c) Ethylenediiminobis(6-hydroxychromone-3-carbaldehyde) have been prepared by condensation of 6-hydroxy-3-carbaldehydechromone with ethylenediamine (Scheme 17B),121 and (d) N-(Chromone-3-ylmethyl)-Nmethylglycine and N,N-di(chromone-3-ylmethyl)glycine have been obtained from chromone-3-carbaldehyde in the presence of excess formaldehyde by a deformylative Mannich type reaction (other type of amino acids, such as alanine, leucine, or methionine can be used in the reaction). 122 (e) 2Arylmethylaminomethyl-5,6-dihydroxychromone derivatives have been synthesized from substituted methylchromones that were first converted to key bromomethyl intermediates and then conjugated, by Gabriel synthesis, with different type of arylmethylamines (R-PhCH2NH2);123 (f) chromone sulfonamides have been prepared by the reaction of (un)substituted chromone-3-carbaldehydes with 3-aminobenzenesulfonamide or 4-aminobenzenesulfonamide.124 A series of chromone-based lavendustin analogs, which are hybrids of hormothamnione (2-styrylchromone) and lavendustin A, have been synthesized by the reductive-amination of formylchromone with various amines (Scheme 17C).125 Hydrazone derivatives were also synthesized using as starting materials other type of chromones (Scheme 18), namely,

Figure 3. Chromone scaffolds obtained from styrylchromones.

Actually, 2-styrylchromones can afford (a) 4-aryl-3-(2chromonyl)-2-pyrazolines with diazomethane by 1,3-dipolar cycloaddition reactions, using microwave-assisted conditions (Figure 3A),113 (b) 2-(3-aryl-1,2,3,4-tetrahydronaphth-2-yl)chromones by a Diels−Alder reaction with ortho-benzoquinodimethane and subsequent dehydrogenation (Figure 3B),114 and (c) 2-(7-aryl-4-methoxy-2-methyl-5,6,7,8-tetrahydroquinazolin6-yl)chromone derivatives by Diels−Alder reaction with a pyrimidine ortho-quinodimethane (Figure 3C).115 3.3.3. Other Type of Functionalized Chromones. 3.3.3.1. Ether and Thioetherchromone Derivatives. Etherification is an interesting approach for functionalization of chromones because of the simplicity of the synthetic methodologies and the broad chemical diversity that they can provide. 3/6/7-Hydroxy- or mercaptochromone derivatives have been often used as starting materials to obtain alkoxy/aryloxy, benzyloxychromones, or the corresponding thio derivatives, through a nucleophilic substitution reaction using halides under different basic conditions (Scheme 15A).116 Ether triazole derivatives have been synthesized from 7-(prop-2-yn-1-yloxy)chromone using substituted benzyl bromides (Scheme 15B).117 3.3.3.2. Ester-Chromone Derivatives. The esterification reaction has been used for the functionalization of the chromone scaffold. Some examples are described in Scheme 16. This type of derivatives has been synthesized from (a) 3hydroxy or 3-hydroxymethyl substituted chromones (Scheme 16A) or (b) chromone-3-carbaldehyde that was transformed in the corresponding carboxylic acid by oxidation with sodium chlorite in the presence of aminosulfonic acid (Scheme 16B).118 4972

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Scheme 17. Amine-Chromone Derivatives

3.3.3.4. Amide-Chromone Derivatives. An important family of chromone derivatives is the one containing the amide function (Scheme 19). This type of derivatives can be prepared from (a) chromone 2-ethyl esters (Scheme 19A) or chromone carboxylic acids previously activated via acylchloride, for instance with PCl5, with subsequent condensation with different type of amines (Scheme 19A);129 (b) chromone-3carbaldehyde using Meldrum’s acid, isocyanides and primary aromatic amines leading to a diversity-oriented library of chromones;130 and (c) chromone carboxylic acids via carboxylic acid activation with organophosphoric (Scheme 19B)131 or phosphonium salts as coupling reagents132 or by reaction with a hydroxylamine using an ethyldimethylaminopropyl carbodiimide/hydroxybenzotriazole (EDC/HOBt) system, and subsequent oxidation with Desse−Martin periodinane reagent.133 A new microwave-assisted method for the synthesis of chromone carboxamides from chromone carboxylic acids via POCl3 was developed (Scheme 19B). The method present several advantages, including operational simplicity, good performance, significant reduction in reaction time, less formation of byproducts, and easier workup.134 3.3.3.5. Dithiocarbamate-Chromone Derivatives. A series of chromone derivatives bearing dithiocarbamate moieties have been synthesized from methylchromone derivatives. After their

Scheme 18. Hydrazone- and PhosphorohydrazideChromone Derivatives

chromone-3-carbaldehyde or chromone-2-amino-3-carbaldehyde, and aromatic or aliphatic hydrazines.126,127 Similarly, phosphorohydrazide derivatives have been obtained from the reaction of methylchromone-3-carboxylate, chromone-3-carbaldehyde and chromone-3-carbonyl chloride with diverse phosphorus hydrazines (Scheme 18).128 Chromone-3-carbaldehydes can also react with aromatic amino carboxylic acids yielding 2-hydroxy(alkoxy)chromones or 3-(aryliminomethyl)chromones, depending on the reaction conditions.128 Scheme 19. Amide-Chromone Derivatives

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subsequent transformation in bromomethylchromones, by a bromination reaction with N-bromosuccinimide (NBS), a three-component reaction was performed, using the pretended amine and carbon disulfide in basic medium, and the desired compounds obtained (Scheme 20).135 Scheme 20. Dithiocarbamate-Chromone Derivatives

4. BIOLOGICAL INTEREST OF SIMPLE CHROMONES Numerous biological activities have been attributed to simple chromones and analogues. Among them, anti-inflammatory, antiplatelet, anticancer, and antimicrobial activities, including those related with central nervous system and obesity will be discussed in particular. However, other interesting studies have been reported along the years, such as the application of chromones as antidiabetics and cardiovascular agents,136 carbonic anhydrase,52,137 NADH:ubiquinonereductase (complex I),138 aldose reductase and calpain inhibitors,43a,133,139 calcium antagonists,140 and as ligands for orphan nuclear receptors, such as retinoid receptors.141 In addition their application as diuretics,142 hypoglycemic, hypolipidemic,119,143 antiarrhythmic and hypotensive agents,144 and antioxidants145 have been also described in the literature.

Figure 4. Metabolic pathway of arachidonic acid. Arachidonic acid is released in response to stimuli, such as tissue injury, from phospholipids by the action of phospholipases. It can be metabolized by either cyclooxygenases 1 and 2 or by 5-lipoxygenase. The cyclooxygenase (COX) pathway produces prostanoids, like prostaglandins and thromboxanes and the lipoxygenase (LOX) pathway produce leukotrienes. The mentioned enzymatic pathways can be stimulated by pro-inflammatory factors.146 Abbreviations: cyclooxygenases 1 and 2 (COX-1 and COX-2); 5-lipoxygenase (5-LOX); interleukin 1 family (IL-1), tumor necrosis factor-alpha (TNF-α); interleukin-5 (IL-5); intercellular adhesion molecules (ICAMs).

arachidonic acid into inflammatory prostaglandins (Figure 4).147 COX exists in two isoforms, COX-1 and COX-2. COX-1 is known as a housekeeping enzyme and constitutively expressed in all tissues, while COX-2 is constitutively expressed only in kidney, brain and ovaries. COX-2 is increasingly expressed during inflammatory conditions by pro-inflammatory molecules, such as interleukin 1 family (IL-1 family) and tumor necrosis factor-alpha (TNF-α).148 Adverse drug reactions have been associated to NSAIDs, mainly related to gastrointestinal and renal effects. These effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding and death, limiting the use of NSAID therapy. Since then, structural modifications at enhancing its anti-inflammatory activity and reducing the toxicity have been carried out with the obtention of more potent selective COX-2 inhibitors. However, the ulcerogenic liability is still a problematic issue.149 In this context several studies aimed at developing novel antiinflammatory agents were designed based on chromone scaffold. A group of derivatives of 7-methanesulfonylamino-6phenoxychromone (1) (Figure 5), obtained by the introduction of substituents at the pyrone and aromatic rings, were synthesized and evaluated against acute and chronic inflammation.58c The chromone-based library was tested in rat models of carrageenan-induced edema and adjuvant-induced arthritis,

4.1. Anti-inflammatory Drugs

Inflammation is a beneficial host response to a challenge by foreign bodies or to tissue injury and is characterized by redness, warmth, swelling, and pain. When this normal physiological process becomes deregulated it can become harmful and destructive leading to inflammatory events.146 The well-known inflammatory diseases are related with rheumatoid (arthritis), respiratory (asthma), cutaneous (psoriasis), and irritable bowel syndrome (IBS) events. In recent years, it has become clear that inflammation also plays a key role in other prevalent diseases, not previously considered to have inflammatory etiologies, such as atherosclerosis, diabetes, cardiovascular, Alzheimer’s and Parkinson’s diseases, and cancer.146 Despite some notable successes there are still major unmet medical needs in the treatment of inflammatory diseases. Over the past 20 years in the modern era of target-based drug discovery, a relatively small number of pivotal targets have been identified. Most of these are antagonists of endogenous proinflammatory mediators such as prostaglandins, leukotrienes and histamine. These targets include the enzymes cyclooxygenases 1 and 2 (COX-1 and COX-2) and the leukotrienes (LTs) receptors (Figure 4). However with a significant increase in knowledge about immunology, both in terms of molecular targets and molecular mechanisms, new targets such as the proinflammatory factors have appeared (Figure 4). In turn, the number of targets being pursued for drug discovery and development has increased. 4.1.1. Cyclooxygenase Inhibitors. The majority of the currently marketed anti-inflammatory drugs are nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ibuprofen, piroxicam, or nimesulide, which target cyclooxygenase (COX), a rate-limiting enzyme that converts

Figure 5. Structures of 7-methanesulfonylamino-6-phenoxychromone (1) and the drug candidate T-614 (2). 4974

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inhibitory activity and a significant anti-inflammatory outline in a TPA-induced mouse ear edema model (Figure 6).149a 4.1.2. Leukotriene Receptor Antagonists. Leukotrienes (LTs) are arachidonic acid-derived lipid mediators of inflammation. The initial catalytic step in the formation of leukotrienes is catalyzed by 5-lipoxygenase (5-LOX) (Figure 4), in conjunction with its activating partner protein FLAP (arachidonate 5-lipoxygenase-activating protein). Evidence has been accumulated that LTs are involved in the mediation of various inflammatory disorders, in particular in the etiology of asthma, although they can have effects on many parameters of airway function, including the development and regulation of inflammation.150 These features have prompted extensive research efforts to search for drugs that can either block LT biosynthesis or antagonize LT actions either for the treatment of allergy and asthma or for the treatment of various inflammatory diseases. Several leukotriene receptor antagonists have been developed during the 1980s and 1990s and are currently on the market for the management of asthma symptoms. Pranlukast is a chromone derivative (Figure 7) that was originally intended for bronchial asthma management and later on (2000) approved for use in allergic rhinitis. One of the most significant works performed in this area is related to the discovery of RG 12553 (Figure 7A), a compound that is one of the most potent leukotriene D4 (LTD4) antagonists reported so far.151 The structural modifications performed, wich were based on Pranlukast and the prototype leukotriene antagonist FPL55712 structures, allow concluding that the combination of the chromone ring with the (2quinolinylmethoxy)phenyl group led to a significant increase in leukotriene receptor binding affinity. In addition, is important to mention that a (piperidinylalkoxy)chromone (Figure 7B)

including gastro-ulcerogenic liability, and from the data obtained a 3-formylamino derivative (T-614) (2) (Figure 5), has emerged as a prospective disease-modifying antirheumatic agent.58c The potent arthritic activity in chronic inflammatory disease models and low gastro-ulcerogenic liability in oral administration of the chromone derivative allow proposing it as a drug candidate. Clinical evaluations of T-614 as slow-acting disease-modifying antirheumatic agent are currently in progress. Stellatin (Figure 6), isolated from Dysophylla stellatais, was described as a cyclooxygenase (COX) inhibitor.149a Inspired in

Figure 6. Stellatin and Derivatives.

the reported data new stellatin derivatives were synthesized and the anti-inflammatory inhibitory activity toward COX-1 and COX-2 was evaluated. Eight derivatives have exhibited a more pronounced COX-2 inhibition than stellatin and indomethacin (a NSAID drug used in therapy). The SAR study revealed that a chromone skeleton with a OH at 5-position is an essential feature for COX inhibition and that the methoxyl groups at position 6 and 7 of stellatin cand be replaced by hydroxyl or isoprenyl substituents (Figure 6). Two chromones (3 and 5) exhibited greater anti-inflammatory activity than indomethacin and two compounds (3 and 4) exhibited the highest COX-2

Figure 7. Leukotriene receptor antagonists. Design of RG 12553 from pranlukast and FPL 55712 (A) and (piperidinylalkoxy)chromone scaffold (B). 4975

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have been also described as an important scaffold for the development of antihistaminic compounds with additional antagonist receptor activity against LTD4.152 4.1.3. Mast Cell-Targeted Drugs. Mast cells and basophils are well-known critical participants in several biological processes related with allergic diseases. These cells express surface membrane receptors with high affinity and specificity for immunoglobulin E (IgE). The interaction of antigen-bound IgE in surface membrane receptors causes the release of histamine, prostaglandins, leukotrienes and cytokines. The cytokines can activate chemotaxis and phagocytosis of neutrophils and macrophages producing cytokine-induced reactions that causes tissue inflammation.153 Disodium cromoglycate (DSCG, Figure 8) is a chromone-based drug

Figure 8. Disodium cromoglycate (DSCG).

Figure 9. Passive cutaneous anaphylaxis (PCA) inhibitors based on chromone scaffold.

that is used as a mast cell stabilizer in allergic rhinitis, asthma, and allergic conjunctivitis. The precise mechanism of action is not yet clarified, although there is evidence that it may inhibit the degranulation and mediator release from mast cells in the nasal mucosa. However, it has two major disadvantages: first, only 30−70% of asthmatics respond to cromoglycate therapy and, second, as it is not orally absorbed it must be given by inhalation. Consequently, an intense research has been performed to modify its structure to achieve more effective compounds.154 4.1.3.1. Slow-Reacting Substance of Anaphylaxis Antagonists. Anaphylaxis is a severe immediate-type hypersensitivity reaction affecting multiple organ systems that is characterized by bronchospasm, upper airway angioedema, or hypotension. It is a serious rapid-onset allergic reaction that may cause death. Food, insect venoms, or medication can trigger most cases of anaphylaxis.155 The slow-reacting substance of anaphylaxis (SRS-A) is a potent constrictor of smooth muscle and has a major bronchoconstrictor role in asthma. It contains products from the lipoxygenase pathway of the arachadonic acid cascade, the leukotrienes (Figure 4). Mast cells secrete SRS-A during the anaphylactic reaction, inducing inflammation. In accordance, the search of potent SRS-A antagonists has been the focus of substantial research. From these studies one can mention the discovery of FPL 55712 (Figure 7A) a relatively selective SRS-A receptor antagonist. As the chromone compound presents poor bioavailability and short half-life, additional studies must be performed to improve its potency or absorption, distribution, metabolism, and excretion (ADME) properties.156 4.1.3.2. Passive Cutaneous Anaphylaxis Inhibitors. Passive cutaneous anaphylaxis (PCA) is an immediate dermal response to an allergen−IgE interaction and is characterized by increased permeability of vessels. A diverse type of chromones has been described to be potential PCA inhibitors153a,b,157 and therefore some selected studies will be here emphasized. In this context, a new series of chromone carboxylic acids was obtained based on 3-chromone3-acrylic acid (6) (Figure 9). The parent compound and analogues were highly active in an antiallergic bioassay and active when administered intravenously and orally.157a Follow-

ing the observation that introduction of a carbonyl group at the 3 position enhance the antiallergic activity of chromones several chromone-3-carboxylic acids derivatives were synthesized. However, they were found to be inactive in inhibiting PCA in rats, a fact that was related to its weak acidity because of the formation of an intramolecular hydrogen bond.153b Chromone-2-carboxylic acids (7) and 2-(5-tetrazolyl)chromones (8) (Figure 9) have been screened about their capacity to inhibit passive cutaneous anaphylaxis and the release of histamine from rat mast cells. The activity of the compounds was compared with DSCG (Figure 7). The most potent inhibitor of anaphylaxis was 7-methoxy-N-(5-tetrazolyl)chromone-2-carboxamide (9), which contain structural features from both 7 and 8, showing the importance of N-(5tetrazolyl)carboxamido group as a novel pharmacophoric fragment (Figure 9).157b 3-(1H-Tetrazol-5-yl)chromones have also been shown to inhibit homologous PCA reactions induced by reaginic antibody in the rat, when administered intravenously or orally. After examining the pharmacological and toxicological properties of a variety of chromone derivatives 6ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) was selected as one of the most promising chromones.153a The synthesis of arylsulfonylchromones as PCA inhibitors was also reported in the literature and some derivatives based on structure 10 (Figure 9) reveal to be active against PCA in rats.157c 4.1.4. Interleukin-5 Inhibitors. Interleukins are a group of cytokines (secreted proteins/signaling molecules) that regulate the growth, differentiation, and activation of eosinophils. When activated, eosinophils release an array of pro-inflammatory and cytotoxic products, such as basic granule proteins, proteases, sensory neuropeptides, leukotrienes, oxygen radicals, and cytokines, and act as prominent effector cells in the process of allergic inflammation.158 Accumulating evidence suggest that eosinophil-activating cytokines, such as interleukin-5 (IL-5), and granulocyte macrophage GSF (GM-GSF) are the key molecules implicated in the pathway of inflammatory process associated with eosinophils. Depriving eosinophils of IL-5 may therefore represent a viable approach to treat allergic disorders.159 In 4976

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fact, IL-5 is a proven target for finding new drugs for eosinophilia-associated allergic inflammation. Pranlukast (Figure 7), a leukotriene receptor antagonist, inhibits not only airway smooth muscle contraction, but also allergic inflammation. It inhibits IL-5 production via a mechanism distinct from leukotriene receptor antagonism. Recently, N-substituted hydroxyethylaminomethylchromones were also synthesized and evaluated for their IL-5 inhibitory activity. The SAR study allows settling some structural requirements, such as the importance of the cyclohexylmethoxyl group at 5-position of the chromone ring and the presence of a chain length spacer of two carbon located between the amino and the hydroxyl groups.149b,160 The most active analogue was 5-cyclohexylmethoxychromone (11) (Figure 10).161 Figure 11. Local of actuation of antiplatelet agents. Thromboxane and platelet activation factor inhibitors and ADP-receptor antagonists interact with mechanisms of platelet activation stopping the platelet aggregation process and subsequent thrombus formation.163

compound was 2-(diethylamino)-7-ethoxychromone (13) (Figure 12).69c,164

Figure 10. Interleukin-5 and intercellular adhesion molecule inhibitors based on chromone scaffold.

4.1.5. Intercellular Adhesion Molecule Inhibitors. The collective interaction between cells is, in part, mediated by different families of adhesion molecules. Intercellular adhesion molecules (ICAMs) are structurally related members of the immunoglobulin supergene family and are ligands for the beta2 integrin molecules present on leukocytes. ICAM-1 participates in trafficking of inflammatory cells and is expressed by the vascular endothelium, macrophages, and lymphocytes and can be induced by interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFα) (Figure 4).162 A series of chromone derivatives have been screened for their ICAM-1 inhibitory activity on human endothelial cells, as well as their effect on NADPH-catalyzed rat microsomal lipid peroxidation. The results showed that the compound (12) (Figure 10) was the most potent. In addition, it was shown that the chromone derivative also significantly inhibit the TNF-α induced expression of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin, which also play key an important role in various inflammatory diseases.104

Figure 12. Antiplatelet drugs based on chromone scaffold.

The synthesis and biological evaluation of a series of 2morpholinylchromones as antiplatelet inhibitors has been described.163a The SAR study performed so far led to the discovery of a series of 7-[(aminoethyl)oxy]-8-methylchromone derivatives as potent inhibitors of ADP-induced platelet aggregation.163a Several members of the series proved to be active in preventing platelet-dependent thrombus formation in the dog, namely 8-methyl-7-[2-(4-methyl-l-piperazinyl)ethoxyl]-2-(4-morpholinyl)chromone (14) (Figure 12). This compound has was devoided of hemodynamic effects at the effective antithrombotic dose.163a Substituted piperazinylchromone derivatives have been also evaluated as potential inhibitors of human platelet aggregation induced in plateletrich plasma by ADP, collagen and the Ca2+ ionophore A23187. However, they reveal to be not so active as their coumarin counterparts.165

4.2. Antiplatelet Drugs

The processes of activation and subsequent aggregation of blood platelets play a significant role in thrombolytic disorders. In turn, the search for pharmacological drugs has been focused on several approaches including the discovery of receptor antagonists, inhibitors of enzymes or mediators of platelet aggregation, such as thromboxane A2 and platelet activating factors (Figure 11).163 From the discovery process based on chromone scaffold the following works are emphasized: with different types of substituents 2-(diethylamino)- or (ethylamino)chromones were synthesized and tested in vitro for their inhibitory activities against human platelet aggregation induced by collagen, adenosine diphosphate (ADP), and arachidonic acid. It was concluded that the presence of electron releasing substituents (OH, OMe, Me) at C-7 led to an increase in activity.69a Afterward, several 2-(diethylamino)-7-ethoxychromone derivatives were obtained and tested to check their effect on human blood platelet aggregation. The most active

4.3. Anticancer Drugs

Cancer is a disease characterized by out-of-control of cell growth. There are over 100 different types of cancer and each is classified by the type of cell that is initially affected. Cancer can occur in almost any organ or tissue, such as the lung, colon, breast, skin, bones, or nerve tissue and can be treated by surgery, chemotherapy, radiation therapy, immunotherapy, monoclonal antibody therapy, or other methods.166 Targeted cancer therapy involves drugs or other substances that block the growth and spread of cancer by interfering with specific molecules/pathways involved in tumor growth and progression (Figure 13). Targeted therapy, which first became available in the late 1990s, has had a significant impact in the treatment of specific types of cancer, and is currently a very active research area. The 4977

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three. To note that there are also protein kinases that phosphorylates other amino acids, e.g. histidine kinases. From the diversity of works realized in the area some studies related with the discovery of chromone-based inhibitors toward DNA-dependent protein kinase, phosphatidylinositol-3-kinase (PI3K) and cyclin-dependent kinase (CDK) will be particularly debated. From the others, one can mention the discovery of selective inhibitors of p561ck tyrosine kinase, expressed predominantly in lymphocytes, performed with 2-benzoylchromone derivatives,176 and a medicinal chemistry program intended to develop p38 mitogen activated protein (MAP) kinase inhibitors based on the 3-(4-fluorophenyl)-2-(4-pyridyl)chromone derivatives.52 In addition, a series of 1-(3-chloro-4(chromon-2-yl)phenyl)-3-phenylurea derivatives were designed, synthesized and explored as potential dual inhibitors of Raf1 (a protein that is a key component of the Ras-Raf-ERK mitogen-activated protein kinases) and c-Jun-N-terminal kinase (JNK) for antitumor treatment.177 4.3.1.1. Phosphatidylinositol-3-kinase Inhibitors. Phosphatidylinositol-3-kinase (PI3K), which catalyzes the production of phosphatidylinositol-3,4,5-trisphosphate, is one of the most important regulatory proteins that are involved in different signaling cell survival pathways and in the control of key functions of the cell.178 The PI3K pathway is implicated in several human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapeutic intervention.179 PI3K inhibitors, alone or in combination with other cytotoxic drugs, can potentially be used to treat cancer. In this context, LY294002 (2-morpholin-4-yl-8-phenylchromone) was proposed as a selective and reversible PI3K inhibitor (Figure 14). Several new analogues depicted in Figure 14 have also been reported, such as TGX-102 and TGX-286, with improved selectivity and potency.179,180

Figure 13. Cancer: Interplay among risk factors, targets, and damage. Because of a diversity of stimulus, such as growth factors, environmental stressors, and inflammatory cytokines, the cell can growth out-of-control with appearance of carcinogenic processes. The appearance of this type of events is often linked with the damage of biomolecules, cell cycle abnormalities, gene mutations and change of gene expression, among others. In this context a diversity of cytoplasmic and nuclear viable targets, expressed in this figure, has been anticipated as useful for drug discovery and development programs.166 Abbreviations: Protein kinases (PKs), phosphatidylinositol-3-kinase (PI3K), DNA-dependent protein kinases (DNA-PKs), cyclin-dependent kinase (CDK), protein tyrosine phosphatases (PTPs), topoisomerase (TOPO) enzymes, reactive oxygen species (ROS), and reactive nitrogen species (RNS).

advances achieved in understanding the genetic and molecular basis of cancer over the last few decades have actually enable the rational design and development of new types of cancer therapies. Efforts have been performed to use chromones as privileged scaffolds in medicinal chemistry programs that involve different type of cancer targets. Although some of them will be emphasized in this section there are others that must be mentioned, such as the chromone-based compounds that act as inhibitors of TNF-α-signaling,104,167 NF-κB mediated chemokine transcription168 and kinesin spindle protein (KSP),169 of signal transducers and activators of transcription (SATs) factors,170 as cancer microtubule-stabilizing agents,171 as antagonists of the vanilloid VR1,172 and neurokinin 1 receptors.173 In addition, it is important to mention several interesting metal-chromone complexes containing Ln(III), Cu(II), Ni, Sm, and Zn have been studied in DNA binding studies.121,174 4.3.1. Kinase Inhibitors. Protein kinases (PK) are key regulators of cell function (Figure 13). By adding phosphate groups to substrate proteins, the activity, localization, and overall function of many proteins can be directed and orchestrated in almost all cellular processes. Kinases are particularly prominent in signal transduction and co-ordination of cell cycle complex functions. They are considered as auspicious target for drug discovery and development as phosphorylation is a required step in some cancers and inflammatory diseases.175 Protein kinase inhibitors can be characterized by the type of amino acids whose phosphorylation is inhibited: most kinases act on both serine and threonine, the tyrosine kinases act on tyrosine, and a number (dual-specificity kinases) act on all

Figure 14. Phosphatidylinositol-3-kinase inhibitors based on chromone scaffold.

A novel prostate cancer-targeted water-soluble and latent prodrug181 PI3K inhibitor based on LY294002 (Figure 14) was synthesized. It can specifically inhibit PI3K in PSA-secreting prostate cancer cells and induce apoptosis with potency comparable to that of the original LY294002 compound. The prodrug activation was dependent on prostate-specific antigen (PSA) cleavage (Figure 15).182 4978

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kinase (DNA-PK), which is an enzyme that in humans is encoded by the PRKDC gene. DNA-PK has an important role in DNA double-strand break repair. It has been speculated that tumor cells were more sensitive to a specific DNA damaging agent if the cellular pathway responsible for the repair of that lesion could be inhibited.185 DNA-PK represents a new target for cancer drug development. A number of small molecule inhibitors of DNA-PK catalytic subunit have been developed, which sensitize cells to DNA-damaging agents, but are relatively nontoxic in the absence of DNA breaks. The benzochromone NU7026 is described to be a novel specific DNA-PK inhibitor that has been shown to sensitize mouse embryonic fibroblasts and Chinese hamster ovary cells to radiation in vitro186 Structure− activity relationships have been established allowing to identify 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromone (NU7441) as a highly potent and selective DNA-PK inhibitor with ATPcompetitive inhibition kinetics (Figure 17A).187

Figure 15. Prostate cancer-targeted phosphatidylinositol-3-kinase prodrug based on LY294002 and its proposed activation process.

4.3.1.2. Cyclin-Dependent Kinase Inhibitors. Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases whose activity depends on binding and activation by cyclin partners. These heterodimeric complexes can phosphorylate various substrates involved in the control of transcription processes. The pursuit for drugs that inhibit CDKs has been an intense area of research with more than 15 years. The firstgeneration inhibitors such as flavopiridol (Figure 16A), are in

Figure 17. DNA-dependent protein kinase inhibitors based on chromone scaffold.

6-Aryl-2-morpholin-4-yl-4H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones were synthesized and evaluated as potential inhibitors of the DNA repair enzyme DNAPK.188 In each series several compounds exhibited superior activity than chromone LY294002 (Figure 14), and comparable potency to the NU7026.188 8-Biaryl based chromone libraries were screened towards DNA-PK and structure−activity relationship studies allowed to propose 8-(3-(thiophen-2yl)phenyl)chromone and 8-(3-(thiophen-3-yl)phenyl)chromone as potent inhibitors (Figure 17B).189 From other studies, another type of chromone (Figure 17C) was proposed as a potent and selective DNA-PK inhibitor.190 4.3.2. Protein Tyrosine Phosphatases Inhibitors. Protein tyrosine phosphatases (PTPs) are a group of enzymes, present in eukaryotic signal transduction that remove phosphate groups from phosphorylated tyrosine residues on proteins. Together with protein tyrosine kinases (PTKs) PTPs regulate various cellular activities essential for the initiation and maintenance of malignant phenotypes. Protein tyrosine phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular localization, affect protein

Figure 16. Cyclin-dependent kinase (CDK) inhibitors based on chromone scaffold: flavopiridol (first-generation inhibitors) (A) and thio- and oxoflavopiridols analogues (B).

late-stage clinical trials, but so far they have demonstrated only modest activity.183 In this framework, several thio- and oxoflavopiridols analogues, which contain sulfur or oxygen atoma as a linker between a chromone ring and the hydrophobic side chain, have been described to be as selective cyclin-dependent kinase 1 (CDK1) inhibitors. The thio and oxoflavopiridols shown in Figure 16B were selective within the CDK family and can also discriminate unrelated serine/ threonine and tyrosine protein kinases. CDK1 selective thioand oxoflavopiridol analogues inhibit the colony-forming ability of multiple human tumor cell lines and possess a unique antiproliferative profile in comparison to flavopiridol (Figure 16A).184 4.3.1.3. DNA-Dependent Protein Kinase Inhibitors. There is currently much interest in the discovery and development of novel small molecule inhibitors of the enzymes involved in DNA repair. One of such enzymes is DNA-dependent protein 4979

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stability, and regulate enzyme activity. PTPs are increasingly viewed as integral components of signal transduction cascades and consequently the maintenance of an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Although PTK inhibitors are used routinely for the treatment of cancer, the PTP inhibitor development field is still in the discovery phase. To date few PTP inhibitors have been identified. Several flavonoids have been screened toward PTPs and on the basis of the reported activity a series of simple chromones have been proposed as low molecular weight protein tyrosine phosphatases (LMW-PTPs) inhibitors (Figure 18A).37a In addition, the synthesis of formylchromone

Figure 19. Apoptotic inhibitors based on chromone scaffold.

(ADP-ribosyl)transferase inhibitors based on chromone were also developed.195 In addition, one can mention the in vitro antitumor screening, performed on a panel of seven cell lines, of a series of chromone derivatives bearing diverse dithiocarbamate moieties. The compounds revealed to be able to arrest the cell cycle of SW-480 and MDA-MB-435s with dose-dependent effect in G2/M phase. In that way they might display apoptosisinducing effect on the tumor cell lines. The two most promising chromones are chloro derivatives whose general structure is depicted in Figure 19B.135 4.3.5. Topoisomerases Inhibitors. The topoisomerase (TOPO) enzymes (topoisomerase I and II) have been proposed as targets for the development of new cancer treatments. These enzymes control the changes in DNA structure, by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands, during the normal cell cycle and as consequence when they are inhibited the cell die. The two enzymes work in dissimilar ways: topoisomerase I cuts a single strand of the DNA double helix while topoisomerase II cuts both DNA strands, using ATP for fuel. The rest of the process by which the two enzymes work is very similar.196 Topoisomerase inhibitors are agents that have the ability to kill all cells undergoing DNA replication. Since cancer cells divide much more rapidly than normal cells, the cancer cells will be killed by the topoisomerase inhibitors, although some normal cells with topoisomerase activity will also be destroyed. Recently, 7-chloro/fluorochromones presenting heterocylic substitutions have been designed as potential topoisomerase inhibitors. They exhibit high in vitro anticancer activity against Ehrlich ascites cancer cells (EAC) as well as in EAC implanted mice.197 4.3.6. Drug Transporter Inhibitors. Cancer cells display a strong ability to acquire resistance to anticancer drugs, termed multidrug resistance (MDR) phenotype, which constitutes a critical hurdle to cancer therapy.198 While several mechanisms can mediate cellular resistance to chemotherapeutic agents, the energy-dependent drug efflux mediated by ATP-binding cassette (ABC) transporters is well recognized.199 ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, white). ABCG2 ATP-binding cassette, subfamily G (White)

Figure 18. Development of protein tyrosine phosphatases inhibitors (A and B) and thymidine phosphorylase inhibitors (C) based on chromone scaffold.

derivatives as inactivators of protein tyrosine phosphatase has been also performed. The more encouraging chromone emerged from the studies is shown in Figure 18B.191 4.3.3. Thymidine Phosphorylase Inhibitors. Thymidine phosphorylase (TP), also known as ‘‘platelet-derived endothelial cell growth factor’’ (PD-ECGF), is an enzyme that is upregulated in a wide variety of solid tumors including breast and colorectal cancers. Elevated levels of TP have been associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors must be developed in an attempt to prevent tumor angiogenesis and metastasis.192 3-Formylchromone derivatives and its Schiff bases have been synthesized and their TP inhibitory activity evaluated. The Schiff bases with aromatic functionalized substituents (Figure 18C) were shown to exhibit an excellent thymidine phosphorylase inhibitory activity. Nevertheless, the parent 3formylchromone was found to be inactive.193 4.3.4. Apoptotic Inhibitors. A series of 2-styrylchromone analogs (Figure 19A) were synthesized and examined for their antiproliferative effects on a panel of carcinoma cells. Flow cytometric analysis using 4′,6-diamidino-2-phenylindole (DAPI) staining revealed that HeLa cells exposed to compound (15) induced cell death through sub-G1 arrest and DNA fragmentation. It was demonstrated that chromone derivatives have a recognized inference on the molecular mechanisms of apoptosis.112 Other studies performed with compound (16) proven that it has the capacity to promote cell death can probably result of the induction of procaspase-9 and other procaspases and by a strong decrease of the available ATP.194 Moreover, poly(ADP-ribose)synthetase and mono4980

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postmenopausal women. Estrogen plays a crucial role in the development of breast cancer and the inhibition of estrogen synthesis has been found to be an important target for the prevention and treatment.202 Aromatase inhibitors work by blocking aromatase, which convert the hormone androgen into small amounts of estrogen in the body.203 The design of the new aromatase inhibitors is still a hot topic of research. Beyond the natural-based ones, chromone nuclei have been used as a scaffold and preliminary SAR studies have been performed. Several chemical features supposed to be critical for binding to the aromatase active site have been proposed, such as an heterocyclic ring (imidazole or 1,3,4-triazole) linked by a methylene unit and an H-bond accepting group (CN, NO2, Br) located on the aromatic ring of the chromone core at a suitable distance from the heterocyclic nitrogen carrying the lone pair.204 Moreover, it was found that styrylchromones exhibit selectivity for estrogen receptor beta binding and antiproliferative activity in human breast cancer cell lines.205 4.3.8. Screening toward a Panel of Cancer Lines. In the past decade a number of chromone derivatives were screened toward a panel of cancer cell lines.35c,112,125,128,174h,206 Some of results are herein highlighted: (a) Substituted-3-(5phenyl-3H-[1,2,4]dithiazol-3-yl)chromones possessing both dithiazole and chromone moieties, and a substituted chromone with a N-phenylthioamide in position-3 (Figure 21A) have displayed significant cytotoxic activity against a number of human cancer cell lines.207 (b) A set of chromone derivatives (Figure 21B) were tested against the TA3 mouse carcinoma cell line and its multidrug-resistant variant TA3-MTX-R. These

transporter was recently discovered, and it has been demonstrated to confer resistance to a wide variety of anticancer agents. In this context, from the diverse drug discovery programs, one can highlight the studies performed with the chromones (17 and 18) presented in Figure 20 that

Figure 20. Development of drug transporter inhibitors based on chromone scaffold.

displayed a high-affinity inhibition and low cytotoxicity and a high therapeutic index. The chromone derivatives specifically inhibit specifically ABCG2 versus other multidrug ABC transporters. They constitute promising candidates for chemosensitization of ABCG2-expressing tumors.199,200 Additionally, is important to mention some piperazine and phenalkylaminochromones as they have been reported as potent inhibitors of the breast cancer resistance protein (BCRP), a member of the ABC.201 4.3.7. Aromatase Inhibitors and Estrogen-Receptor Modulators. Aromatase is a target of pharmacological interest for the treatment of breast cancer and ovarian cancer in

Figure 21. Chromone scaffolds emerged from the biological screening on cancer lines. 4981

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Figure 22. Antibacterial and antifungal drug prototypes based on chromone scaffold.

or 7-mercapto-chromone analogs were synthesized and evaluated in vitro against four human tumor cell lines [KB (nasoph aryngeal), KB-vin (vincristine-resistant subline), A549 (lung) and DU145 (prostate)] with paclitaxel as the positive control.35c

compounds show moderate activity against both cell lines and exhibit very similar activities. In addition, when the formyl group in position 3 is replaced by a hydroxymethyl group, the activity is abolished.208 (c) From a series of heterocyclicsubstituted chromones screened toward a diverse panel of cell lines, 6-chloro-2-(2-quinolyl)chromone (Figure 21C) emerged as an interesting compound as it display a significant activity toward Sarcoma 180.209 (d) Schiff base derivatives of 3formylchromone, and their copper(II) complexes, have been reported to have interesting antiproliferative activities. Conjugation of these derivatives with copper ions yields compounds with enhanced antiproliferative activities against hormoneindependent (BT20 and PC-3) cells, as well as COLO 357 (Kras mutant) and BxPC-3(K-ras wild type) pancreatic cancer cells.210 (e) Several chromone phosphorus hydrazides derivatives (Figure 21D) have been described as having antineoplastic activity against P388 and L1210 leukemia either in monotherapy or combined with methotrexate.128,193,211 (f) A chromone that can be considered an analogue of geiparvarin (Figure 21E) was found to be more potent than geiparvarin127 in F10 metastatic murine melanoma cells117,212 (g) 7-Hydroxy-

4.4. Antimicrobial Drugs

Microbes, collectively, include bacteria, viruses, fungi, and parasites. For the past 70 years, antimicrobial drugs, such as antibiotics, have been successfully used to treat patients with infectious diseases. However over time many infectious organisms have adapted to the drugs designed to kill them, making them less effective. The need for new antimicrobial agents is greater than ever because of the appearance of multidrug resistance in common pathogens and the rapid emergence of new infections. The continuum development of antimicrobial drugs is needed to create solutions to overcome these barriers. In accordance, the efforts done toward the discovery antibacterial, antifungal and antiviral agents based on chromone structure will be herein emphasized.213 4.4.1. Antibacterial and Antifungal Drugs. Chromones of both synthetic and natural origin have been recognized to 4982

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display valuable antibacterial and antifungal activity.17,99,214 In fact, indolyl, chloroquinolinyl and phenylglicine chromonebased derivatives have been proposed to be relevant scaffolds215 In addition, copper(II) complexes with chromone-derived compounds have also shown to be effective antimicrobial agents.216 2-Vinylchroman-4-ones, analogues of the natural products aposphaerin A and B, were identified as potent antibiotics against multiresistant strains of S. aureus, such as MRSA (methicillin-resistant Staphylococcus aureus).217 The ligand [(chromon-3-yl)methylene]benzohydrazide, and its complexes [Cu(II), Ni(II), Co(II), Mn(II), and Zn(II)], were screened on four bacteria and two fungi, and it was concluded that the metal chelates are more active than the free Schiff base ligands.218 As an example of the artwork performed in this area some successful approaches are herein described: (a) A series of antibacterial and antifungal sulfonamide (sulfanilamide, sulfaguanidine, sulfamethaxozole, 4-aminoethylbenzenesulfonamide and 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide) chromone derivatives (Figure 22A), previously reported as inhibitors of carbonic anhydrase, have been screened in vitro for antibacterial and antifungal activity. The derivatives shown in the Figure 22A have been considered the most promising ones.219 (b) Pyrazolylidene, imidazolydene and pyrimidinyliden chromone-based compounds were also tested for their antibacterial activity. Some compounds have shown a significant activity against Staphylococcus aureus and Escherichia coli (Figure 22B).220 (c) The conversion of 2-anilino-3formylchromones to N-phenylamides and 3-formylchromones to the corresponding thioaldehydes give rise to compounds that display very high antifungal and antibacterial activities against a number of strains. The dithiazole shown in Figure 22C reveal to have a better antifungal activity against Geotrichum candidum than fluconazole and also possesses a noteworthy antibacterial activity against Shigella f lexneri.221 (d) The glucosides and aglycones of 7-hydroxy-3-(3-aryl-1H-pyrazol-5-yl)chromones (Figure 22D) revealed to be promising antimicrobial agents.222 (e) Three series of novel fused nitrogen heterocyclic systems, such as 1,2,4-triazolo[1,5-a]pyridines, pyrido[1,2-b][1,2,4]triazine and pyrido[1,2-b][1,2,4]triazepines, linked to a chromone moiety were synthesized and screened in vitro for their antimicrobial activity, being compounds (19) (without a double bound in the nitrogen heterocycle) and (20) (Figure 22E) the most potent compounds.223 (f) Chitosan-chromone derivatives have been developed and tested against E. coli. They have a positive antimicrobial effect and do not present cellular toxicity on mouse embryonic fibroblasts (MEF).224 4.4.2. Antiviral Drugs. Human rhinoviruses (HRVs) (from the Greek “rhin’’, which means “nose”), members of the Picornaviridae family, are small single-stranded RNA viruses. There are over 100 serotypes of HRVs and they are the most frequent cause of the common cold and probably the most usual etiological agents of acute illness.225 Although these infections are often mild and self-limiting in healthy adults HRVs can exacerbate several chronic conditions, such as asthma, sinusitis, and emphysema, and cause serious sequelae in children.226 The widespread nature of the HRVs diseases their economic and medical importance and the difficulty of vaccine development, due to of the existence of multiple serotypes, has stimulated the hunt for effective chemotherapeutic agents. Several chromones have been screened for their antirhinoviral activity. 2-Styrylchromones with 3-hydroxyl and 3-

methoxyl substituents were screened in HeLa cell cultures infected with rhinoviruses 1B and 1A, selected as representative serotypes of human rhinoviruses (HRVs), respectively. The compounds exhibit significant activity against both serotypes.227 The data indicate the positive influence of a fluorine atom on the activity allowing to propose the 6-fluoro-2-styrylchromones (Figure 23A) as an interesting scaffold.228

Figure 23. Antiviral drug prototypes based on chromone scaffold.

Human noroviruses are the leading cause of food- or waterborne gastroenteritis illnesses.229 Despite the significant economic impact and considerable morbidity of norovirus disease, no drug or vaccine is currently available to treat or prevent this disease. Therefore it remains an unmet area for drug discovery. 2-Styrylchromones, namely (E)-5-hydroxy-2styrylchromone and (E)-4′-methoxy-2-styrylchromone, reveal to have a noteworthy antiviral activity. Therefore, (E)-2styrylchromone scaffold was proposed as a lead that can after optimization conduct to a new antiviral drug.230 Chronic hepatitis C virus (HCV) infection, which affects more than 180 million patients worldwide, is one of the leading causes of cirrhosis and liver failure. Following a drug discovery program 5-hydroxychromones (Figure 23B) were proposed as an interesting scaffold for the development of anti-HCV drugs.231 Another study showed that a chromone derivative (Figure 23C) exhibit a high activity against hepatitis B virus (HBV) infection and HBV-related liver cancer.232 Human immunodeficiency virus (HIV) is the causative agent of acquired immune deficiency syndrome (AIDS). Several biological processes in the life cycle of this virus have been targeted for anti-HIV therapy and a number of drugs have been approved acting in HIV reverse transcriptase and HIV protease targets. However, the capacity of HIV-protease to develop resistance to therapeutic drugs has been mandatory to the relevance of multidrug therapy, and this approach represents a challenge to medicinal chemists to develop new inhibitors. In this context, several inhibitors of HIV-1 reverse transcriptase 4983

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(RT), protease and integrase based on chromone skeleton have been developed: (a) a chromone moiety was covalently linked to the 5′ end of various oligonucleotides (ODN) allowing its application as a primer and as a RT inhibitor233 (Figure 23D), (b) an analogue of the HIVprotease inhibitor Ritonavir containing a hydroxyethylene dipeptide isostere234and a chromone moiety (Figure 23E),235 and (c) a chromone derivative that inhibit HIV-1 integrase-mediated strand transfer (Figure 23F).236 4.5. Drugs for Neurodegenerative Diseases

Neurodegenerative diseases, defined as hereditary and sporadic conditions, are characterized by progressive nervous system dysfunction. These disorders, often associated with atrophy of the affected central or peripheral structures of the nervous system, include Alzheimer’s (AD), Parkinson’s (PD), among others. 4.5.1. Acetylcholinesterase Inhibitors. The loss of basal forebrain cholinergic cells results in an important reduction in acetylcholine (ACh) a problem that is believed to play an important role in the cognitive impairment associated with AD (Figure 24).237 Accordingly, the increase of the levels of ACh

Figure 25. Development of acetylcholinesterase (A and B) and monoamine oxidase-B (C) inhibitors based on chromone scaffold.

the deamination of β-phenylethylamine, an endogenous amine that stimulates the release of DA and inhibits its neuronal reuptake. The loss of dopaminergic neurons in the substantia nigra and the role of MAO-B in DA metabolism are the best known aspects of the PD. Expression levels of MAO-B in neuronal tissue enhance 4-fold with aging, resulting in an increased level of dopamine metabolism and in the production of higher levels of hydrogen peroxide, which are thought to play a major role in the etiology of neurodegenerative diseases. Therefore, selective MAO-B inhibitors, alone or combined with dopa, are being examined in the treatment of PD.240 In recent years an intensive search for the discovery of novel MAO-B inhibitors was carry out and in line chromones have been recognized as an important scaffold for the development of novel MAO inhibitors. Preliminary studies performed with chromones 21 and 22 (Figure 25C) allow disclosing the importance of the location of a carboxylic moiety in the γpyrone nucleus. In fact, when the −COOH substituent is in position 3 of the heterocyclic scaffold it bind irreversibly to the hMAO-B exerting a selective inhibition with respect to A isoform. In an attempt to develop novel reversible and selective MAO-B inhibitors the synthesis of 2- and 3-carboxamide chromone derivatives, capable of establishing hydrogen interactions with the enzyme, was performed. Functionalized chromones designed to establish structure−activity relationships were obtained by expedite synthetic strategies and screened toward human MAOs isoforms (hMAOs). The SAR study performed allow to conclude that chromone derivatives showing substituents in position-3 of γ-pyrone nucleus (compound 23, Figure 25C) act preferably as MAO-B inhibitors, with IC50 values in the nanomolar to micromolar range.131,132,241 The molecular modeling studies used to model or mimic the behavior of these compounds, by the employment of theoretical methods and computational techniques, revealed

Figure 24. Acetylcholine and dopamine metabolic processing at cholinergic and adrenergic neurons.

has been regarded as one of the most promising approaches for the symptomatic treatment of AD. In a recent investigation centered on coumarin and chromone derivatives, it was discovered that some compounds display inhibitory activity toward AChE. In fact, chromones of the type presented in Figure 25A were found to be mixed AChE inhibitors.238 By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer’s disease (AD) a new family of tacrine-4-oxochromone hybrids has been synthesized and evaluated toward different type of AD targets. The tacrine fragment was selected for its inhibition of cholinesterases, and the chromone scaffold was chosen for its radical capture and β-secretase 1 (BACE-1) inhibitory activities. The chromone represented in Figure 25B has been found to present a dual target mechanism toward human BACE-1 and AChE as well as antioxidant and CNS-permeable properties.239 4.5.2. Monoamine Oxidase-B Inhibitors. Neurodegenerative diseases remain a huge unmet pharmaceutical need as for some diseases, like PD, there are only palliative therapies. In mammals monoamine oxidases (MAOs), a family of enzymes that catalyze the oxidation of monoamines like dopamine (Figure 24), present two isoforms: MAO-A and MAO-B. MAO-B is the predominant subtype in the human brain, where it acts in the breakdown of the dopamine (DA), as well as in 4984

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activity is linked to gene repression, metabolic control, apoptosis, and cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. As sirtuins modulation can have beneficial effects on human diseases there is a growing interest in the discovery of small molecules that modify their activity. Sirtuin 1 (SIRT1) inhibition has been proposed in the treatment, for instance, of cancer and immunodeficiency virus infections, whereas SIRT2 inhibitors are thought to be useful for the treatment of cancer and neurodegenerative diseases.246 In this context, a series of chromones substituted at positions 2, 6, and 8, have been synthesized and evaluated as SIRT2 inhibitors, with inhibitory concentrations in the low μM range. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchromone (Figure 26B). The synthesized compounds show high selectivity toward SIRT2 and represent an important starting point for the development of novel SIRT2 inhibitors.247 4.5.5. Imaging Probes. Alzheimer’s disease is a progressive neurologic disease of the brain leading to the irreversible loss of neurons and of intellectual abilities, including memory and reasoning properties that become severe enough to hamper social or occupational functioning. The brains of Alzheimer patients have high accumulations of β-amyloid, which appear in the form of plaques. Several promising radioiodinated styrylchromone derivatives (Figure 26C) have been successfully developed as imaging probes of β-amyloid plaques in AD showing a high binding affinity to the aggregates. However, additional modifications have been found to be necessary to improve brain uptake and rapid clearance of the nonspecifically bound radiotracer.248

to be a valuable tool allowing to accelerate the drug discovery and development process. Benzyloxy substituted chromones (Figure 25A) were also found to have a significant binding affinities for human monoamine oxidase B. After the preliminary studies the series was expanded with homologues containing polar functional groups on C3 position of the chromone ring. The data obtained so far demonstrate that 6-[(3′-bromobenzyl)oxy]chromones containing acidic and aldehyde functional groups on C3 act as potent and reversible MAO-B inhibitors.242 In addition, 7benzyloxychromones have also been found to be potent reversible MAO-B inhibitors.243 4.5.3. Dopamine D2 Receptor Agonists. The dopaminergic hypothesis, which postulates that dopaminergic activity is increased in the mesolimbic system of the brain, has been the dominant theory for the biological basis of schizophrenia.244 Accordingly, neuroleptics are drugs that modify psychotic symptoms being believed to elicit their therapeutic effect by blockade of dopamine D2 receptors. Interestingly it was found that dopamine receptor agonists also constitute a class of drugs useful to treat Parkinson’s disease symptoms as they can mimic the action of dopamine. This type of drugs acts directly on the dopamine receptors without the need of metabolic conversion, transport, storage and release, as is the case for Dopa. The concept of continuous dopaminergic stimulation is well thought-out to be a guiding principle in the treatment to look for therapeutic strategies and so the discovery of novel dopamine D2 agonists is still a hot topic of research. In this context, a series of (aminoalkoxy)chromones has been prepared and the binding activity to dopamine D2 receptor, and other multiple pharmacological targets, was evaluated. In this kind of compounds, the nature of the substitution at C2 is found to be an important feature to improve the desire activity or selectivity (Figure 26A).245 4.5.4. Sirtuin Inhibitors. Sirtuins (SIRT) are deacetylase enzymes that are dependent on NAD+ for activity. Sirtuins

4.6. Antiobesity Drugs

Obesity and overweight have become a global problem in the past decade. The scale of the obesity problem has a number of serious consequences for individuals and government health systems. Although obesity has long been associated with serious health issues, it has recently been regarded as a disease in the sense of being a specific target for therapy. Consequently, the development of new drugs that target novel pathways is a growing focus for medicinal chemistry programs.249 The melanin-concentrating hormone-1 receptor (MCH1R) is a G-protein-coupled receptor expressed in the brain and peripheral tissues that regulates energy storage and body weight. Therefore, MCH receptors may be important potential targets for the treatment of obesity. The studies performed so far in the discovery of antagonists of MCH1R type based on chromone-2-carboxamide scaffold led to the finding of a promising compound, the 7-fluorochromone-2-carboxamide (Figure 26D).250 4.7. Novel Applications: Development of Adenosine Receptors Antagonists

Adenosine is an endogenous extracellular purine nucleoside that modulates multiple vital physiological and pathophysiological processes, mainly through the interaction with four subtypes of cell-surface G-protein coupled adenosine receptors (ARs), named A1, A2A, A2B, and A3 receptors. Their subdivision was performed on the base of their respective coupling to second messengers, tissue distribution and pharmacological profiles.251 In fact, a variety of physiological actions can be ascribed to adenosine including effects on heart rate and atrial contractility, vascular smooth muscle tone, release of neurotransmitters, lipolysis, renal, platelet and white blood cell functions.252 Hence, selective AR modulators may hold

Figure 26. Dopamine D2 receptor agonists (A), sirtuin inhibitors (B), imaging probes (C) and melanin-concentrating hormone-1 receptor antagonists (D) based on chromone scaffold. 4985

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Biographies

therapeutic value in cardiovascular, neoplastic, chronic inflammatory and neurodegenerative diseases. In this context, the importance of the rational design of selective AR antagonists is boosted by the recent findings of adenosine involvement in cancer and various CNS dysfunctions. Despite the proven success of G protein-coupled receptor (GPCR) targets and the intense research performed the greater part of the antagonists developed so far failed in the clinical trials and so new discovery and development programs are needed to improve the pipeline. Finding new leads, namely, those based in privileged structures, is a priority research area. So, the development of chromone-based AR ligands is an appealing subject and in this framework some preliminary results have already been described in the literature.132b,253 These studies can correspond to an interesting step for the discovery of new chemical entities useful for tackling adenosine receptors.254

Alexandra Gaspar received her MSc in Pharmaceutical Sciences from the Faculty of Pharmacy, University of Porto, Portugal, and PhD in Chemistry in the Faculty of Sciences, University of Porto. Her research interest is focused on the Medicinal chemistry area, particularly in the early stages of the drug discovery process that involves the design synthesis and biological screening of new chemical entities.

5. CONCLUDING REMARKS Over the past years the privileged structure concept has emerged as a fruitful approach in drug discovery and development. Privileged structures have been described to be molecular scaffolds, which can exhibit good drug-like properties, with versatile binding properties. Along this review simple chromones, a group of heterocyclic compounds, have been shown to be a fruitful approach in medicinal chemistry and consequently, with value as a privileged scaffold. For this reason, the isolation and the structural characterization of novel derivatives, the development of new synthetic methods and the evaluation of biological properties are topics of growing interest for a great number of research groups. Yet, many of the synthetic procedures used in the preparation of chromone core have been already known for a considerable time and are still in use because of their efficiency and simplicity. In the coming years, it is expected that the research performed with type of compounds will uncover further interesting aspects in the fields covered in this review as well as in other areas. Efforts were made to review the state of the art in the area of simple chromones, mainly as regards to what has been done during the last years. Not surprisingly, many questions arise from the literature that remains to be answered. The survey was made to encompass the literature published during the intended period, although there were several difficulties in finding some references or to place the subject owing to the lack of clarity of some topics. Apologies are due to the authors who were not, for one reason or another, mentioned in this work.

Maria João Matos has a PhD from the University of Santiago de Compostela and is a researcher of CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto. She received her MSc in Pharmaceutical Sciences from the Faculty of Pharmacy, University of Porto, Portugal. Her professional interests include drug discovery and development of novel heterocyclic compounds based on coumarin and chromone scaffolds.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Phone: +351 220 402 560. Fax: +351 220 402 009.

Jorge Garrido is Assistant Professor at the Department of Chemical Engineering of School of Engineering (ISEP), Polytechnic of Porto, Portugal. He graduated in Chemistry from the University of Porto and obtained his PhD in Biochemistry at the University of Coimbra.

Notes

The authors declare no competing financial interest. 4986

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Current research interests are medicinal chemistry, namely, SAR, SPAR and mechanistic studies, nanotechnology, and electroanalytical chemistry.

Eugenio Uriarte is Professor of Organic and Medicinal Chemistry at the Organic Chemistry Department, Faculty of Pharmacy, University of Santiago de Compostela, Spain. He heads an active research group in the organic and medicinal chemistry field. He spent research periods and was visiting professor at several well-known research centers and universities and has many national and international regular collaborations. He authored more than 240 publications in international journals, presenting over 200 communications to congresses and was director of more than 20 doctoral students.

Fernanda Borges is Associate Professor of the Department of Chemistry and Biochemistry of Faculty of Sciences of University of Porto and senior researcher of CIQUP. She received her MSc and PhD (Pharmaceutical Chemistry) in Pharmacy 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/therapy of neurodegenerative diseases She authored more than 170 publications in peer review journals, 8 international book chapters, and 3 patents.

ACKNOWLEDGMENTS This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/ 113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/ BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants. REFERENCES (1) (a) Ellis, G. P. In Chromenes, Chromanones, and Chromones: The Chemistry of Heterocyclic Compounds; Ellis, G. P., Ed.; John Wiley & 4987

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