IJRPC 2014, 4(4), 1046-1085 Ewies F Ewies et al. ISSN: 2231 −−−2781 INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY Re search Article Available online at www.ijrpc.com SYNTHESIS OF CHROMONES AND THEIR APPLICATIONS DURING THE LAST TEN YEARS Hanaa A. Tawfik 1, Ewies F. Ewies 2 and Wageeh S. El-Hamouly 1 1Department of Chemistry of Natural and Microbial Products, Pharmaceutical Industries Division, National Research Centre, Cairo, Egypt. 2Department of Organometallic and Organometalloid Chemistry, Chemical Industrial Division, National Research Centre, 12622, Dokki, Cairo, Egypt. ABSTRACT The present review represents a board description for the methods used in the synthesis of chromones and some of its derivatives. The rigid bicyclic chromone fragment has been classified as a privileged structure in drug discovery, due to its use in a wide variety of pharmacologically active compounds; few examples as therapeutic agents chromones are used as scaffolds for the development of bioactive compounds, the application in medicinal chemistry, such as preparation of fluorescence probes, due to photochemical properties of chromones have been also mentioned. This review is limited to the work done during the last ten years. Keywords: Chromone, Synthesis, Reactions, Biological Activity, Applications, Drugs. GENERAL INTRODUCTION Chromone chemistry has been widely explored and extensively reviewed over the past few years. The following review is intended to give a broad overview of the synthesis of chromones and is by no means exhaustive. Particular attention has been given to the synthesis of chromones, since their uses and applications in last ten years. O O C A O O O B Chromone Flavone Flavonoid O O O O Flavanone Isoflavone O O OH OH O O Flavonol Flavanonol Fig. 1: Examples of common chromones(flavonoids) and their derivatives 1046 IJRPC 2014, 4(4), 1046-1085 Ewies F Ewies et al. ISSN: 2231 −−−2781 1.1 Chromones The chromone ring system, 1-benzopyran-4-one (Figure 2), is the core fragment in several flavonoids, such as flavones, flavonols and isoflavones 1. The word chromones is derived from the Greek word chroma, meaning “color”, which indicates that many chromone derivatives exhibit a broad variation of colors. The rigid bicyclic chromone fragment has been classified as a privileged structure in drug discovery, due to its use in a wide variety of pharmacologically active compounds such as anticancer 2, anti-HIV, antibacterial and anti-inflammatory agents 3-12 . Several chromone derivatives have also been reported to act as kinase inhibitors, to bind to benzodiazepine receptors and as efficient agents in the treatment of cystic fibrosis 13-15 . O 5 4 6 3 7 O 2 8 1 Fig. 2: The general structure and numbering of chromones Although there are a large number of chromone derivatives known for their pharmacological properties there are only a few examples that have been or that are used as therapeutic agents today. Khellin (Figure 3)as an example extracted from the seeds of the plant Ammi visnaga , was the first chromone in clinical practice and it has been used for centuries in the Mediterranean area as a diuretic to relieve renal colic 16 . Around the 1950s, khellin was used as a smooth muscle relaxant in the treatment of angina pectoris and asthma 17 . However, present use of khellin as a therapeutic agent focuses on the treatment of vitiligo, a pigmentation disorder 18 . Other current medical treatments with chromone derivatives is exemplified by sodium cromoglycate (Lomudal®) used as a mast cell stabilizer in allergic rhinitis, asthma and allergic conjunctivitis; diosmin (Daflon®) for the treatment of venous diseases; flavoxate as smooth muscle relaxant to treat urge incontinence (Figure 5) 16,19-23. OH HO CH3 OCH3 O O HO O O OH O O CH3 HO OCH3 O Khellin HO O O OH OCH Diosmin 3 OH O COONa COONa O O O O O O O O N OH Sodium cromoglycate Flavoxate Fig. 3: Examples of chromone-based compounds that have been or that are used as pharmaceutical agents 1047 IJRPC 2014, 4(4), 1046-1085 Ewies F Ewies et al. ISSN: 2231 −−−2781 Beside their diversity as structural scaffolds possible to modify to achieve different pharmacological activities, several chromone derivatives exhibit a wide range of fluorescent properties. In particular, the 3-hydroxyflavones have been used as hydrogen bonding sensors, fluorescent probes for DNA- binding affinity studies and as fluorophores for protein labeling and apoptosis 24-27 . 1.2. Chromones as scaffolds for bioactive compounds Chromones are used as scaffolds for the development of bioactive compounds. These frameworks are naturally occurring derivatives containing anoxa-pyran ring 28,29 . General structures of chromone moieties are illustrated in Figure 1. The most frequently found chromone-based natural products are the 2-arylsubstituted chromones (flavonoids) carrying hydroxy and/or methoxy groups on the Aand/or B rings 30,31 . They are constituents of pigments in leaves and are present in a range of food sources such as olive oil, tea, fruits, and red wine 32 . Flavonoids are well represented inthe literature 33,34 . The substitution pattern of the chromone scaffolds determines their different biological effects. Known effects of these types of compounds are antioxidant35,36 , antiviral 37 , antibacterial 38, or kinase inhibition 39,40 . Hence, chromones can be considered privileged structures, defined as “ a single molecular framework ableto provide ligands for diverse receptors ”41-43. 2. Synthesis of chromones One of the first methods for the synthesis of chromones was introduced by Heywang and Kostanecki [44,45], which involved the decarboxylation of chromone-2-carboxylic acid. Since then, several other routes with higher yields and less drastic experimental conditions have been developed. Acid catalyst O O O Base catalyst R Microwave irradition O Solid support O R Other methods R N O OEt R1 P O Ar O R2 O O Y Y N R S R Fig. 4: Systematic diagram illustrate different synthetic methods of chromones derivatives Chromones could be synthesized under either acidic or basic conditions. The classical, 3- disubstituted benzopyranone 3 synthesis utilized acidic conditions (Scheme 1) and was by far the most common method 46. It proceeded through an intramolecular condensation of molecules such as 2, which were usually obtained through a Baker–Venkataraman 47 rearrangement of compound 1, or via a Claisen ester condensation 48 (Scheme 1). Most synthesis required harsh acidic conditions as the final step. On the other hand, synthesis utilizing basic conditions typically consisted of piperidine in 1048 IJRPC 2014, 4(4), 1046-1085 Ewies F Ewies et al. ISSN: 2231 −−−2781 refluxing pyridine for several hours to affect ring closure. This was far less common 48 . Recently, microwave heating has also been used to affect ring cyclization 49 . O R1 Backer-Venkataraman rearrangement O O O R2 O O R1 1 H+ R2 R1=R2= alkyl, aryl, OH R1 O R2 OH (3) 2 Scheme. 1: 2.1. Acid as catalyst in chromone ring closure . Acid comprised a major catalyst in chromone ring closure, and many acids can be used including hydriodic acid, polyphosphoric acid (PPA), acetic acid, methanesulfonylchloride, hydrochloric acid, para toluene sulfonic acid (PTS), triflic anhydride, phosphorus oxychloride, perchloric acid, and sulfuric acid. 2.1.1. Hydriodic acid as a catalyst It has been reported 50 that synthesis of a mixture of 2-methyl-8-hydroxy-6,7-benzochromone (7) and 2-methyl-8-methoxy-6,7-benzochromone ( 6) using hydriodic acid as a catalyst in the ring closure (Scheme 2). O O O O Na + CH3COCH3 O 5 O O 4 O O O R HI 6 R= CH3 O 7 R= H Scheme. 2: 2.1.2. Polyphosphoric acid as a catalyst . Polyphosphoric acidwas taken as a catalyst in the chromone ring closure for the formation of chromone-2-carboxylic acids from phenols, which was converted to the chromone 11 through Polyphosphoric acidas the catalyst in the last step. This method was more suitable in the phenolic hydroxyl side chain in a carboxylic acid of the cyclization 51 . 1049 IJRPC 2014, 4(4), 1046-1085 Ewies F Ewies et al. ISSN: 2231 −−−2781 O Ph(CH2)5 Ph 2 1. H2.Pd/C 2. Zn/Hg,HCl 3. Pyr, HCl OH OCH3 8 9 O Ph(CH ) Ph(CH2)5 2 5 HO2C PPA H3CO2C C C CO2CH3 NaOH O CO H O CO2H 2 11 10 Scheme. 3: 2.1.3. Acetic acid as a catalyst . A new synthesis of chromones 16 and flavones 52 was based on the ortho -directed metalation of methoxymethyl aryl ethers with alkyl lithium reagents (Scheme 4), using acetic acid as catalyst in the chromone ring closure. This synthetic approach appeared general in its applicability. It has been applied to the synthesis of a series of polycyclic chromone and flavone compounds containing the naphthalene and pyrene ring systems that hold promise as agents for the chemoprevention of cancer. R R H C 3 H3C O O O O H3C O O [O] RCH=CHCHO OH O BuLi, TMEDA 13 R 14 R O O HOAc O PHT O 15 16 R= H, CH3, Ph Scheme. 4: 2.1.4. Methane sulfonyl chloride as a catalyst In 2001, Ismail and Abd El Aziem 53 reported the synthesis of the new 3-substituted-7-methoxy-4H-1- benzopyran-4-ones ( 21 ) starting from 2-hydroxy-4-methoxyacetophenone (17 ) according to Scheme 5 the key step in this synthesis involved alkylation of2-(t-butyldimethylsilyloxy)-4-methoxyacetophenone (18 ) with alkyl halide using potassium tertiary butoxide was prepared from 17 by using t-butyldimethyl silylchloride. The o-silyl protected alkylacetophenone derivatives ( 19 ) were, therefore, treated with tetra-n-butylammonium fluoride to produce the corresponding 2’-alkyl-2-hydroxy-4- methoxyacetophenone ( 20 ) was synthesized in good yield.