Tong quan ve Flavonoid 2014
European Journal of Medicinal Chemistry 84 (2014) 206e239 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Invited review Flavones: An important scaffold for medicinal chemistry Manjinder Singh, Maninder Kaur, Om Silakari* Molecular Modeling Lab, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India a r t i c l e i n f o a b s t r a c t Article history: Received 20 May 2014 Received in revised form July 2014 Accepted July 2014 Available online July 2014 Flavones have antioxidant, anti-proliferative, anti-tumor, anti-microbial, estrogenic, acetyl cholinesterase, anti-inflammatory activities and are also used in cancer, cardiovascular disease, neurodegenerative disorders, etc Also, flavonoids are found to have an effect on several mammalian enzymes like protein kinases that regulate multiple cell signaling pathways and alterations in multiple cellular signaling pathways are frequently found in many diseases Flavones have been an indispensable anchor for the development of new therapeutic agents The majority of metabolic diseases are speculated to originate from oxidative stress, and it is therefore significant that recent studies have shown the positive effect of flavones on diseases related to oxidative stress Due to the wide range of biological activities of flavones, their structureeactivity relationships have generated interest among medicinal chemists The outstanding development of flavones derivatives in diverse diseases in very short span of time proves its magnitude for medicinal chemistry research The present review gives detail about the structural requirement of flavone derivatives for various pharmacological activities This information may provide an opportunity to scientists of medicinal chemistry discipline to design selective, optimize as well as poly-functional flavone derivatives for the treatment of multi-factorial diseases © 2014 Elsevier Masson SAS All rights reserved Keywords: Flavones Flavonoids Antioxidant Poly-functional Multi-factorial diseases Introduction Flavonoids are low molecular weight polyphenolic phytochemicals, derived from secondary metabolism of plants and play important role in various biological processes They exhibit diverse type of properties that are beneficial for human health via interacting with a number of cellular targets involved in critical cell signaling pathways in the body Research in the field of flavonoids has increased since the French paradox concept was formulated by French epidemiologists in the 1980s, i.e., lower cardiovascular mortality rate observed in Mediterranean populations in association with red wine consumption and a high saturated fat intake [1,2] Flavonoids are components of a wide variety of edible plants, fruit, vegetables and of beverages such as tea, coffee, beer, and wine So, in-vitro inhibition of LDL oxidation by flavonoids derived from red wine was demonstrated Several other beneficial properties of flavonoids have since been ascertained as information about the mechanisms of flavonoids was scarce, but with time the flavonoids were explored hastily * Corresponding author E-mail address: omsilakari@gmail.com (O Silakari) http://dx.doi.org/10.1016/j.ejmech.2014.07.013 0223-5234/© 2014 Elsevier Masson SAS All rights reserved Flavonoids can be classified into various classes i.e Flavonols (Quercetin, Kaempferol, Myricetin, Fisetin), Flavones (Luteolin, Apigenin), Flavanones (Hesperetin, Naringenin), Flavonoid Glycosides (Astragalin, Rutin), Flavonolignans (silibinin), Flavans (Catechin, Epicatechin), Isoflavones (Genistein, Daidzein), Anthocyanidins (Cyanidin, Delphinidin), Aurones (Leptosidin, Aureusidin), Leucoanthocyanidins (Teracacidin), Neoflavonoids (Coutareagenin, Dalbergin), Chalcones All classes of flavonoids exhibits variety of biological activities, but among them, the flavones have been considerably explored Various natural, semi-synthetic and synthetic derivatives of flavones have been synthesized and evaluated for several therapeutic activities like anti-inflammatory, antioestrogenic, antimicrobial [3], anti-allergic, antioxidant [4], antitumor and cytotoxic activities [5] The majority of metabolic diseases are speculated to originate from oxidative stress, and it is therefore significant that recent studies have shown the positive effect of flavones on diseases related to oxidative stress, such as atherosclerosis, diabetes, cancer, Alzheimer's disease, etc Some of the flavones of natural origin like Naringenin (Natural Female Support), Gingko Flavone glycosides (Gingko Smart), and synthetic origin like Flavopiridol are presently available in the market Flavones are present in fruits and vegetables which we consume inadvertently in our daily diet and they have a positive impact on our health without any major side effects In order to explore M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 diverse roles of flavones, investigating various methods for their synthesis and structural modification of flavone ring have now become important goals of several research groups Thus, naturally obtained flavone moiety having a variety of biological activities can be taken as lead compound for the synthesis of semi- and purely synthetic flavone derivatives with different functional groups at different positions of flavone skelton Chemistry Flavone is a class of flavonoids based on the backbone of 2phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) The molecular formula of flavone molecule is C15H10O2 It has a three-ring skeletons, C6eC3eC6, and the rings are referred to as A-, C-, and Brings, respectively (Fig 1) Flavones have three functional groups, including hydroxy, carbonyl, and conjugated double bond; consequently they give typical reactions of all three functional groups Flavones are colorless-to-yellow crystalline substances, soluble in water and ethanol They give yellow color solution when dissolve in alkali Flavones are moderate-to-strong oxygen bases, and are soluble in acids due to the formation of oxonium salts having pKa values ranging from 0.8 to 2.45 [6] Flavones have a planar structure with its CeOeC bond angle 120.9 Its bond length between CeO is 1.376 Å and dihedral angle is around 179.2 Synonyms of flavone are 2-phenyl-4H-chromen-4-one; 2phenyl-1-benzopyran -4-one Flavones can react in several ways, including reduction reactions [7], degradation in the presence of base [8], oxidation [9], rearrangement [10], substitution [11,12], addition [13e15], condensation [16], reaction with organometallic reagents [17] Several synthetic methods have been developed and modified to get products of high yield, purity and of the desired quality Flavones can be synthesized by various synthetic schemes like ClaiseneSchmidt condensation [18], BakereVenkataraman-rearrangement [19,20], Ionic Liquid Promoted synthesis [21], AllaneRobinson [22], VilsmeiereHaack reaction [23], Wittig reaction, Fries rearrangement and modified SchotteneBaumann reaction Now a day, most of the flavones are synthesized based on the BakereVenkataraman method It involves the conversion of ohydroxyacetophenone into phenolic ester, which undergoes an intramolecular Claisen condensation in the presence of a base to form b-diketone, which is cyclized to flavones by an acid-catalyzed cyclodehydration (Schemes and 2) Traditionally, flavones were synthesized with BakereVenkataraman-rearrangement but these reactions undergo the use of strong bases, acids, long reaction time and low yields consequently Sashidhara et al reported expedient, simplistic and alternate synthesis of medicinally important flavones in which 2hydroxychalcones resulting from condensation between acetophenones and salicylaldehyde, undergo oxidative cyclization on heating in the presence of catalytic iodine and generating Fig Basic scaffold of flavone 207 diversified flavones under solvent-free environmental friendly conditions [24] (Scheme 3) Biosynthetic pathway for flavones Flavonoid biosynthesis starts with the condensation of molecule of 4-coumaroyl-CoA and three molecules of malonyl-CoA yielding naringenin chalcone, carried out by the enzyme chalcone synthase (CHS) The two immediate precursors of the chalcone originate from two different pathways of primary metabolism Coumaroyl-CoA is synthesized from the amino acid phenylalanine by three enzymatic steps, collectively called the general phenylpropanoid pathway, Malonyl-CoA is synthesized by carboxylation of acetyl-CoA, a central intermediate in the Krebs tricarboxylic acid cycle The chalcone is consequently isomerized by the enzyme chalcone flavanone isomerase (CHI) to yield a flavanone From this central intermediate the pathway diverges into several different classes of flavonoids [25] (Scheme 4) Pharmacological activities of flavones Flavones scaffold can be termed ‘skeleton key’ as it is an important core in many compounds acting at different targets to elicit varied pharmacological properties with various substitution patterns (Fig 2) It is the diversity of this structure that gives flavones wide range of biological activity Due to the wide range of biological activities of flavones, their structureeactivity relationships have generated interest among medicinal chemists, and this has culminated in the discovery of several lead molecules in numerous disease conditions This review gives a comprehensive account of SAR or structural requirement of flavone derivatives, necessary for wide biological activity spectrum 4.1 Anti-oxidant The high levels of free radicals in living systems are able to oxidize bio-molecules, leading to tissue damage, cell death or various diseases such as cancer, cardiovascular diseases, arteriosclerosis, neural disorders, skin irritations and inflammations [26] Free radicals are highly reactive and therefore can attack membrane lipids, generating carbon radicals and produce peroxy radicals which cause lipid peroxidation Therefore, a single radical may damage many molecules by initiating lipid peroxidation chain reactions To oppose the vicious effect of free radicals, the body has a number of antioxidant defense mechanisms in the form of enzymes such as superoxide dismutase and catalase, copper and iron transport proteins, as well as water-soluble and lipid-soluble antioxidants [27] It was studied that imbalance between free radicals and the antioxidant defense mechanism is associated with several human diseases Antioxidants may act with two mechanisms: prevention of initiation of oxidation, or as chain breaking antioxidants Prevention of initiation of oxidation occurs by inhibiting superoxide anion production, degrading hydrogen peroxide and chelating or reducing metal ions, while chain breaking antioxidants act by scavenging radicals, mostly hydroxyl radicals, thereby inhibiting the chain of oxidative events that leads to damage of lipid membranes, proteins and DNA [28] Oxidative species and free radical involve in the pathophysiology of numerous diseases like in neurodegenerated disorders, cardiovascular, cerebrovascular, autoimmune disorders like diabetes, rheumatoid arthritis, psoriasis etc Therefore, various natural as well as synthetic antioxidants are used to scavenging free radicals It was reported that flavones have well known antioxidant activity; and can act by several pathways Therefore, flavones are 208 M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 Scheme Synthesis of flavones via beta diketone intermediate Scheme BakereVenkataraman rearrangement reaction significantly used in pharmaceutical and food industries [29] Flavones like chrysin (1), luteolin (2) and apigenin (3) which contain two or three free hydroxyl groups in rings A/B, show antioxidant properties at low concentrations [30,31] (Table 1) Hyun et al generate a QSAR model for different flavones having a number of hydroxyl groups to evaluate structure requirement for antioxidant activity and concluded that as the number of hydroxyl groups increases, the scavenging effects also increases In addition, two hydroxyl groups neighboring to each other, show better effects too They found that among all flavone analogues 6,7,30 -trihydroxyflavone (4), showed scavenging effect up to 87.8% [32] It was also found that substitution of 3,4-dihydroxybenzoyl at position C3 (5) increases scavenging activity against free radicals [33] Various conjugated flavones, C60-Flavone (6) were evaluated for antioxidant activity in which the flavones phenolic moiety react with peroxyl radicals, while the C60 part of the molecule acts synergically by trapping alkyl radicals under reduced O2 partial pressure Thus, this molecule acts as promising lead for broadspectrum radical scavengers Fullerene derivatives are used as protective drugs against diseases related with oxidative stress and Poly-hydroxylated fullerenes [C60(OH)n] are also excellent antioxidants able to reduce the free radical damage of neuronal tissues [34,35] Gazak et al evaluated antioxidant activity of several flavones derivatives using three different assays (DPPH scavenging, inhibition of lipid peroxidation, and inhibition of superoxide) and found that 2,3-dehydrosilybin (7) governed radical-scavenging activity [36] A 5,6,7-trioxygenated flavone, baicalein (8) is capable of attenuating oxidative stress in various in vitro models, thus possess significant antioxidant activity [37] Eupafolin, (9) caused a reduction of enzymatic activities between complexes I and III of the respiratory chain It also protects cultured neurons against glutamate-induced oxidative stress and inhibits xanthine oxidase activity [38] A natural flavone, Chrysoeriol, (10) extracted from the tropical plant Coronopus didymus were tested for their ability to inhibit lipid peroxidation induced by g-radiation, Fe (III) and Fe (II) and showed better protecting effect with DPPH radicals at millimolar concentrations [39] 5,7,30 ,40 -tetrahydoxy-3-methoxyflavone (THMF), 11 was investigated for antioxidant effects on the N-formyl-methionyl-leucylphenylalanine-induced (fMLP) superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils and found that THMF was more effective than luteolin and quercetin due to Scheme ClaiseneSchmidt condensation reaction M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 209 Scheme Biosynthetic pathway of flavones methoxy group at position-3 [40] Various di-tert-butylhydroxyphenyl (DBHP) substituted flavones derivatives were synthesized and evaluated for radical scavenging activity, these acts synergistically with butylated hydroxytoluene (BHT), a well-known lipid peroxidation inhibitor [41] Two butylated flavones (12) and (13), were powerful scavengers of stable free radical DPPH They exhibit high antioxidant protective activity against peroxidations induced by metal ions or peroxyl radical [42] Cotelle et al reported that 20 ,30 ,40 -trihydroxyflavone (14) exhibit interesting antioxidant properties expressed either by the capacity to scavenge free radicals or to competitively inhibit xanthine oxidase [43] Reported SAR studies of antioxidant activities of flavone derivatives indicate that three structural features are essential for antioxidant activity (marked in bold) are: the catechol group (30 , 40 OH) in the B-ring, the C2]C3 double bond in the C-ring, that enables the conjugation of the B-ring to the 4-oxo group, and the 3and 5-OH groups together with the 4-oxo group (Fig 3) A 2,3-double bond in conjugation with 4-keto functional group provides electron delocalization from the ring B and the electrondonating groups on the ring B reduce the OeH bond dissociation energy, thus these important groups or features impart radical scavenging properties to flavones Hydroxyl group on the ring A appears to be of lower importance Flavones also have the capability to form chelates with oxidizing metal ions and prevent various redox reactions, thus imparting antioxidant effects (Fig 4) The 5-hydroxyl group in association with the 4-keto and catecholic hydroxyl groups chelates catalytically active metal ions involved in redox reactions, which may prevent the formation of oxidizing species [44] The most detrimental of the reactive oxygen species is the hydroxyl radical, that may induce lipid peroxidation generated in the Fenton reaction (Fig 5) [45,46] Hydroxyl groups on the B-ring donate hydrogen and an electron to hydroxyl, peroxyl, and peroxynitrite radicals, stabilizing them and giving rise to a relatively stable flavone radical [47] (Fig 6) 4.2 Anti-cancer activity Cancer is one of the most death-defying health hazard which is distressing a greater part of the world population that constrains the progressive transformation of normal cells towards malignancy It involves the cell proliferation, differentiation, angiogenesis, and apoptosis of the normal cell which leads to tumor conditions Various anticancer agents (also referred as antitumor, antiproliferative and anti-neoplastics) reported for treatment of varied kinds of cancers act through different mechanisms However, the major side effect associated with these agents is cytotoxicity towards normal cells due to lack of selectivity for the abnormal cells Thus, a search for anticancer agent has been in continuum since many years In 1960, Zutphen studied that the mortality or risk for alimentary or respiratory tract cancers is reduced with different flavonoids like myricetin, quercetin, kaempferol, luteolin and apigenin [48] In 1967e1991, a large group study was organized to explore the protective role of flavonoids against lung cancer and other malignant neoplasms and the risk of ovarian cancer [49,50] The study confirmed that apigenin, a naturally occurring flavone can reduce the recurrence rate and risk of certain cancers, predominantly the breast, digestive tract, skin, prostate and certain hematological malignancies [51] 210 M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 Fig Therapeutic activity profile of flavones Various kinases such as cyclin-dependent kinases (CDKs), glycogen synthase kinase-3 (GSK3), dual specificity tyrosinephosphorylation-regulated kinase 1A (DYRK-1A) critically participate in cancer [52] Nowadays, around 250 small molecule kinase inhibitors are undergoing clinical trials for the treatment of cancer, showing that kinases constitute important therapeutic targets for its treatment Nguyen et al developed 8-substituted regioisomer, among all compound (15) was more active than its 6-substituted analogue Capitavine (16) as well as chrysin against various kinases [53] The amino moiety and the free hydroxyl group at C-5 of flavones nucleus were essential for interaction with several kinases involved in cancer The structures of these molecules are reminiscent of flavopiridol (17), the first synthetic cCDK inhibitor entered in clinical trials as an anticancer drug Similar to flavopiridol, another new synthetic flavonoidal alkaloid, P276-00 (18) entered into clinical studies as a small-molecule CDK inhibitor [54,55] Selective dual inhibitors of Raf1 and JNK1 kinases, 1-(3-chloro4-(4-oxo-4H-chromen-2-yl) phenyl)-3-phenylurea derivatives, have been developed for antitumor treatment The Raf protein involved in RaseRafeERK mitogen-activated protein kinases (MAPKs) pathway, regulates cellular processes like cell proliferation, migration and apoptosis c-Jun-N-terminal Kinase (JNK), another MAPK member, is activated in some cancers by Ras to cooperatively promote cancer together with the RaseRafeERK signaling Dysregulation of both RafeMAPKs and JNK pathways had been well elucidated in various human cancers Some compounds targeting either Raf or JNK had been approved or in preclinical trials for anti-cancer treatment, but none of multi-targeted drugs had entered clinical trials till date Compound (19) at 50 mM has selectivity against p38-alpha kinase, good anti-proliferative activity against HepG2 cell-line and relatively low toxicity against normal liver cell-lines QSG7701 and HL7702 Due to low toxicity, 20 -chloro40 -aminoflavones scaffold may be potentially explored for deriving multi-target Raf1 and JNK1 inhibitors [56,57] In breast cancer, tumor cell proliferation is stimulated via anomalous estrogen receptors signaling pathways when estrogen binds Aromatase (CYP19) catalyzes the aromatization reaction of androgen substrates to estrogens, the last and rate-limiting step in estrogen biosynthesis Therefore, aromatase take major role to develop hormone-dependent breast cancer Inhibition of aromatase is a new and promising approach to treat breast cancer [58] Various aromatase inhibitors like letrozole, anastrozole etc approved by FDA and are used as first-line therapy in the treatment of breast cancer in postmenopausal women, but due to variety of side effects, naturally occurring flavonoid aromatase inhibitors are attracting more and more attention recently for their future clinical uses [59] Natural flavone chrysin (1) and their analogs synthesized by introducing various functional groups like halides, nitro and amino have been reported to show inhibitory effects against aromatase enzyme [60] Yao et al developed number of flavones scaffolds having various functional groups (carboxy, -fluoro, and -nitro) and evaluated by MTT assay for their anti-proliferative activity in breast cancer cell M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 211 Table The structures of flavone derivatives C No Structure C No 91 92 93 94 95 96 97 98 99 Structure (continued on next page) 212 M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 Table (continued ) C No Structure C No 10 100 11 101 12 102 13 103 14 104 15 105 16 106 17 107 18 108 19 109 Structure M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 213 Table (continued ) C No Structure C No 20 110 21 111 22 112 23 113 24 114 25 115 26 116 27 117 28 118 Structure (continued on next page) 214 M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 Table (continued ) C No Structure C No 29 119 30 120 31 121 32 122 33 123 34 124 35 125 36 126 37 127 Structure M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 215 Table (continued ) C No Structure C No 38 128 39 129 40 130 41 131 42 132 43 133 44 134 45 135 46 136 Structure (continued on next page) M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 The disease state is being controlled by various anti-diabetic drugs acting by various mechanisms, such as by increase in insulin secretion from pancreatic b-cells by sulphonylureas (e.g., glibenclamide) [120], an enhancement of insulin action by PPAR-g (peroxisome proliferator activated receptor-g) agonists (e.g., rosiglitazone) [121], or by reduction of hepatic glucose production (metformin) [122] Numerous scientists reported diverse flavone derivatives from natural as well as synthetic origin for the treatment of diabetes and its complications by targetting causative factors of diabetes mellitus Verma et al synthesized and evaluated various flavone-based hybrids of 6- and 7-hydroxy flavones with aminopropanol as novel anti-diabetic agents Among all synthesized hybrids 64 and 65 were found to be the most potent These active compounds possess bulky lipophilic substitution on ring-B of flavone and smaller substituents at the nitrogen atom The hybrids with tertbutyl and isopropylamine functionality at N atom are superior in activity [123] Baicalein, (8) (5,6,7-trihydroxyflavone, IC50 ¼ 52 mM) and Luteolin (2) inhibited the a-glucosidase enzyme up to 36% at a concentration of 0.5 mg/ml and exhibit to have potential to suppress postprandial hyperglycemia in non-insulin dependent diabetes mellitus [124] Further, in 2008, Babu et al prepared 8aminomethylated derivatives of oroxylin A (46) as a-glucosidase inhibitor via Mannich reaction Among synthesized derivatives, compound 66, (IC50 ¼ 35.43 mM) was found to be the most active [125] The 6-amino-5,7-dihydroxyflavone 67, (IC50 ¼ 2.4 mM) is a unique flavone having a 6-amino group along with ordinary 5,7dihydroxyl substituents, which found to be active against rat intestinal a-glucosidase The initial SAR studies suggested that the 6amino and 7-hydroxyl groups were essential for the activity 5hydroxyl substitution was favorable, whereas 8-amino group was unfavorable for the activity [126] Various AR inhibitors have been tested in clinical trials like tolrestat, zopolrestat, zenarestat, and ponalrestat but their efficacy is not satisfactory [127] Flavone scaffold was also explored for designing Aldose reductase (AR) inhibitors for the treatment of diabetic complications In 2008, Mercader et al designed various flavones derivatives and estimated AR inhibitory activity with QSAR model and suggested that naphthyl group at C-2 position of flavone, 68 (Àlog IC50 ¼ 11.064), yielded the most potent analog [128] Dundar et al synthesized new flavonyl-2,4-thiazolidinediones, hybrids of flavone and acetic acid/acetic acid ethyl ester groups on N-3 position of the 2,4-thiazolidinediones ring system and their insulin releasing and AR inhibitory effects were evaluated Compounds 69 and 70 (IC50 < mM) were obtained as aldose reductase inhibitors [129] Zou et al synthesized nitric oxide-releasing chrysin derivative (71), which also have aldose reductase inhibitory activity (IC50 ¼ 0.13 ± 0.03 mmol/L) The hyperactivity of AR has been linked to the development of cardiovascular and neurological complications as well as peripheral neuropathy, retinopathy, and cataracts in diabetic patients [130] Kuroda et al isolated various flavonoids from Glycyrrhiza glabra roots and evaluated their PPAR-g ligand-binding activity Various isolated flavones exhibited significant PPAR-g ligand-binding activity, but prenylflavone derivative, licoflavanone A (72), showed the most potent ligand-binding activity at mg/ml [131] Matin et al designed and synthesized novel pharmacophore having 7-hydroxy-benzopyran-4-one moiety as potential dual PPAR-a and g agonists Among all compounds, (73) 5, 40 -dihydroxyflavone and diosmetin (74) were identified as novel and potent dual PPAR-a and g agonists It has been proposed that dual agonists may exhibit enhanced effectiveness in treatment of type II diabetes and metabolic syndrome [132] Some natural flavones and 225 isoflavones having dual PPAR-a and -g agonist properties The planar structure and hydroxyl group at C-7 of the flavone and isoflavones are essential or primary requirements for PPAR activation [133] Low molecular weight protein tyrosine phosphatases (PTP-1B), have been known to be negative regulator of insulin-mediated mitotic and metabolic signaling Its inhibition can be considered as an attractive approach for the design of new therapeutic agents for the therapy of type II diabetes Several compounds were prepared and their inhibitory activity against the LMW-PTP was assessed Among all compound (75) showed to be somewhat selective against PTP-1B (Ki ¼ 29.1 mM) [134] Additionally, Cushman et al reported the inhibitory effects of hydroxyflavones and aminoflavones on protein-tyrosine kinases The amino group has advantage over hydroxyl substituents while, both have been used as hydrogen donors as well a hydrogen bond acceptors [135] It was also reported that various flavonoids like 5,7,30 -trihydroxy-3,6,40 -trimethoxyflavone, (76) isolated from Brikkellia veronicaefolia increase insulin release from isolated islets of Langerhans in a dose dependent manner thus, showed hypoglycemic effect Chrysin alkyl derivative (77), with methyl at para position of the benzene ring also exhibited significant hypoglycemic effect [136,137] As we mentioned earlier that AGEs are also well known cause of diabetic complications Several flavonoids have been reported to inhibit AGEs because of their radical scavenging activities Baicalein (8, IC50 ¼ 93 mM), luteolin (2, IC50 ¼ 99 mM) substantially exhibited AGEs formation inhibitory activity with DPPH radical scavenging activity Hydroxyl groups at the C-30 , C-40 , C-3, C-5, and C-7 positions were found to be important for the activity whereas methylation or glucosylation of the 40 and 7-hydroxyl reduced the activity [138] 4.6 Anti-ulcer activity Peptic ulcer is a common disorder of the gastrointestinal tract and proximal duodenum Stomach and small intestine are protected from various irritating acids produced in the stomach like hydrochloric acid, pepsin, biles etc by protective lining The destruction of protective lining results in inflammation (gastritis) or an ulcer Most of the time protective lining is damaged due to infection by bacteria called Helicobacter pylori (H pylori) Regular use of various non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etc or other drugs which stimulate gastric acid secretions, alcohol consumption, smoking, chewing tobacco, stress, heredity and lower socio-economic status, increases the risk of peptic ulcers A combination of medications is used to kill the H pylori bacteria and reduce acid levels in the stomach like antacids, sucralfate, histamine-2-receptor antagonists, prostaglandins inhibitors, proton pump inhibitors, Bismuth etc However, all these agents exhibited various side effects and low bioavailability Current efforts are focused for novel compounds with good bioavailability and lower toxicity [139,140] Several polyphenols, such as flavones and isoflavones, constitute one of the most important classes used in the treatment of peptic ulcers Rutin, a natural flavone has been evaluated for ulcerprotecting effects against gastric lesions induced by 50% ethanol and also for gastritis and peptic ulcer provoked by oxidative stress and inflammation [141,142] DA-6034 (7-carboxymethyloxy-30 , 40 ,5-trimethoxy flavone) 78, is a synthetic flavone that suppresses the H pylori-induced inflammatory bowel disease (IBD) in animal models by targeting NF-kB and extracellular signal-regulated kinase (ERK), a representative MAPK [143,144] Nobiletin (28), another natural flavone protects the gastric mucosa of rats from gastric injuries induced by ethanol and HCl/ 226 M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 ethanol at doses of and 25 mg/kg respectively [145] The different flavonoids obtained from Oroxylum indicum has been used for centuries for the treatment of various gastric disorders [146] Several substituted flavones were also found to show good gastroprotective activity Flavone glycosides (79) along with the other compounds 7-O-methylchrysin (80), 5-hydroxy-40 , 7,40 -dimethoxyflavone (81), oroxylin A (46), chrysin (1) and baicalein (8) (constituents from O indicum) showed gastroprotective properties in rats under various ulcer inducing conditions [147] Replacement of the aromatic ring-B with a small alkyl group or heterocyclic rings of similar size (i.e., thiophene, 82 and pyridine, 83) or even of much larger size (i.e., indole, 84) retain gastroprotective properties Compound 5-methoxy-40 -fluoroflavone (85, ED50 ¼ 5.5 (4.0e7.0) was found to be the most potent compound to protect against indomethacin-induced gastric damage [148] (Table 1) SAR depicts that the presence of hydroxyl groups at C-5 and C-7 in chrysin cannot be ruled out, as its absence in compounds 79 and 80 drastically decreased gastroprotective activities However, methoxy group at C-7 position appears to improve gastroprotection Glycosidation at 20 -position on the ring-B in compound 79 was observed to enhance the activity as compared to 81 A C2] C3 double bond and an intact C-ring appear necessary for optimum activity [149] It was reported that substitution with methoxy at different positions of the flavone nucleus like at 5-position (86), at C-7 (87) or methyl substitution at the 7-position (88), retained the potency as gastroprotective activity Whereas, Substitution with methoxy or hydroxy groups at the C-3, C-6, or C-8 positions, led to reduction in gastroprotective activity 4.7 Anti-microbial Resistance to antimicrobial agents has become progressively more important and vital global problem e.g., a major cause for concern in the UK is methicillin-resistant Staphylococcus aureus (MRSA) [150] In this context major pharmaceutical industries have concentrated their efforts to improve antimicrobial agents Natural products have particularly been a rich source of anti-infective agents, so by lead optimization of natural scaffolds various semisynthetic or synthetic compounds have been designed and synthesized Flavones have been reported for protective role against microbial invasion In plants, flavones accumulate as phytoalexins in response to microbial attack Due to this protective role flavones have been used for many years in traditional medicine to treat infectious diseases [3] This class of natural products is becoming the subject of anti-infective research and many groups have isolated and identified different flavones possessing antifungal, antiviral and antibacterial activity Nitrogen containing flavones have been reported to have considerable antimicrobial activity The compounds, bearing amino alkyl, cyano or alkenylalkyl group on piperazine are found to be the potent antibacterial and antifungal agents 4.7.1 Antifungal activity Certain types of flavones are known to have spore germination inhibitory activity against plant pathogens, so their uses have been explored against fungal pathogens of human [151] Numerous flavones like 6,7,40 -trihydroxy-30 ,50 -dimethoxyflavone (89), 5,50 dihydroxy-8,20 ,40 -trimethoxyflavone (90) and 5,7,40 -trihydroxy30 ,50 -dimethoxyflavone (91), 6-methoxy-2-(piperazin-1-yl)-4Hchromen-4-one (92) derivatives have been reported to exhibit activity against Aspergillus flavus, a species of fungi that causes invasive disease in immunosuppressed patients Among all, 92 was found to possess the most potent anti-fungal activity against A flavus [152] Various synthetic biflavones showed anti-bacterial, anti-fungal and anti-viral activity Considering the antifungal properties, amentoflavone (37), isocryptomerin, ginkgetin, bilobetin were shown to have good antifungal action [153e155] Dimerization of flavones resulted in increased fungi toxicity Compound (93) 30 -3000 biflavone was found to be active against Aspergillus niger at Minimum Inhibitory Concentration of 0.4 mmol/ml [156] The compound 94, 2-(2-chloroquinolin-3-yl)-6-methoxy-4H-chromen-4-one also showed excellent antifungal activity against A niger [157] 40 Bromo derivative (95, IC50 ¼ 28.2 mg/ml) have displayed significant antifungal activity against A niger and Fusarium oxysporium [158] On the other hand, flavone glycoside (96) were found to have significant antifungal activity against Trichophyton mentagrophytes and Cryptococcus neoformans at MIC 6.25 mg/ml [159] (Table 1) 4.7.2 Anti-bacterial Efflux pumps are transport proteins involved in the extrusion of toxic substrates like antibiotics, from cells into the external environment and over-expression of this pump will result in resistance to antibiotics of more than one class as well as some dyes, detergents and disinfectants The resistance mechanism can be avoided by Inhibition of such pumps It is reported that flavones have been used as Efflux pump inhibitors (EPIs) [160] Alkylated flavones were reported to be quite active MDR pump inhibitors Several flavones and flavonolignans derivatives were synthesized and evaluated for inhibitory activity against MDR efflux pump NorA of S aureus Compound (97, MIC ¼ 0.08 mg/ml) was found to be the most active flavonolignan derivative [161] Stermitz et al reported that a flavonolignan, namely (G)-50 -methoxyhydnocarpin-D (98), act as a potent NorA MDR pump inhibitor Compounds free from the hydroxyl group at ring-A were active and substitution with hydroxyl group gradually decreased activity In flavones the lipophilic alkyl chain was found to be important for activity as in most potent flavones (99) but further increase in lipophilicity, resulted in loss of activity [162] Flavones also exhibit bactericidal activity by interference with iDNA synthesis A series of flavones was studied for their DNAgyrase inhibitory activities [163] Luteolin (2), apigenin (3), were identified to have antibacterial activity Wang and colleagues synthesized 5-hydroxy-7,40 -dimethoxyflavone with a number of transition metals complexes and found that, hydroxyl group at position C-5 is important for anti-bacterial activity Additionally, 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one (100) was found to be the most active anti-bacterial agent against Escherichia coli [164] It was proposed that the ring-B of flavones is involved in intercalation or hydrogen bonding with the stacking of nucleic acid bases, thus imparting inhibitory action on DNA and RNA synthesis [165] SAR depicted that 5-hydroxyflavones with additional hydroxyl groups at the and 40 positions did not exhibit anti-bacterial activity [166] Methoxy groups substituted on ring-B drastically decrease the antibacterial activity of flavones Interestingly, antibacterial activity of flavones increased by replacing oxygen atom with sulfur and nitrogen atoms at 4-position of flavones 4thioflavones (101) and 4-iminoflavones (102) having flouro group at position 40 in ring-B have been evaluated for anti-bacterial activity and found to be active against different strains of bacteria The compounds having substituents like F, OCH3 and NO2 at 40 -position in the ring-B exhibited enhanced activity The antibacterial activity increased as the electronegativity of the halogen atom on ring-A increases and incorporation of sulfur and nitrogen atoms enhance the antibacterial activity of flavone derivatives [167] Babu et al synthesized novel C-7 modified chrysin analogues and evaluated against a panel of susceptible and resistant Grampositive and Gram-negative organisms It was observed that most M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 of the derivatives displayed significant activity as compared to parent chrysin Flavone was linked to the alkyl amines by different spacers at C-7 position with a view to enhance their lipophilicity The 4-carbon spacer in between chrysin and heterocyclic ring, (103) is optimum for good anti-bacterial activity [168] Yin et al discussed the prenylflavone derivatives as antibacterial agents Among all, (104) showed significant antibacterial activity against the tested microbes at the level of MICs 0.009e0.073 mM Prenyl group at ring-A and 7-methoxy group is required for activity [169] Halogen substituted flavones were evaluated for anti-tuberculosis activity and it was observed that 8bromoflavone (105) derivative is more active than any other halide derivative like fluoro, chloro or iodo [170] Several natural and synthetic biflavonoids were also evaluated for inhibitory activity against Mycobacterium tuberculosis The presence of eOCH3 and eNO2 substituents in biflavonoids may contribute to the observed inhibitory activity Compound (106) (60 e600 biapigenin hexamethylether) exhibited highest inhibitory activity (96%) at a concentration of 12.5 mg/ml [171] Venkatesan et al synthesized C-2 substituted flavones derivatives and observed that indolyl derivative of flavones (107) and (108) showed appreciable antibacterial activity against all the test bacteria [158] Flavones with cyclohexyl groups substituted at their 2positions, compound (109) and (110) inhibited the growth of methicillin-resistant S aureus [159] The compounds having monoamidinobenzimidazoles at the C-6 position of the flavones, (111) showed potent antibacterial activities, particularly against Grampositive bacteria Compounds 111 and 112 exhibited the best inhibitory activity with MIC values of 1.56 mg/ml and 6.25 mg/ml respectively against S aureus [172] (Table 1) 4.7.3 Antiviral activity Antiviral properties of various flavone derivatives have been evaluated using different virus strains, such as Influenza virus, human herpes simplex virus (HSV-2), measles virus, poliovirus, rotavirus, EpsteineBarr virus, human immunodeficiency virus (HIV), and hepatitis B (HBV) Influenza virus is an RNA virus that infects avian and mammalian cells with the assistance of two glycoprotein, hemagglutinin and neuraminidase (NA) The NA plays critical roles in the life cycle of the virus Therefore, NA has been recognized as a good target for the treatment of influenza Various scientists explored the structure requisites of flavone derivatives for influenza H1N1 neuraminidase (NA) inhibition by various computational approaches like, 3D-QSAR and molecular docking Natural flavones like, scutellarin (113), dinatin (114), the hydroxyl group substituted at different positions of ring-B and ring-A, C]O at C-4, C2]C3 and different substituent's at 8th position of ring-A, possess the NA inhibitory activity [173] It was suggested that hydrogen bonds, hydrophobic and electrostatic interactions were closely related to the NA inhibitory activity 5-OH and 7-OH might be essential for NA inhibitory activity; electron withdrawing group at 8th position decreased the activity, while hydrophobic groups increased the activity Among all the compounds, (115) is the most active compound that displayed six hydrogen bonding interactions (including Glu225, Glu116, Arg115, Arg146, and Asp148) with key residues of the NA active site [174] Ryu et al reported that the parent flavone, 115 (IC50 ¼ 1.1 mM) was more effective at neuraminidase inhibition than alkylated flavones, 116 (IC50 ¼ 10.14 ± 3.0 mM) [175] The biflavonoids like amentoflavone (37) were reported to show the inhibitory activity against respiratory syncytial, herpes and measles viruses New ginkgetinesialic acid conjugates (117, IC50 ¼ 5.50 mg/ml) remarkably have potent anti-influenza virus activity against A/PR/8/34 (H1N1) than F36 (118, IC50 ¼ 9.78 mg/ml) [176,177] 227 It was also reported that flavones have an important role in inhibiting the poliovirus by interfering with RNA synthesis of poliovirus [178] The synergistic effect of flavoneeflavonol combinations was observed against herpes simplex virus type (HSV), thus explaining that combinations are more active than the individual compounds [179,180] Kwon et al showed that polyphenolic flavones isolated from the roots of Glycyrrhiza uralensis relief acute gastroenteritis with fever, vomiting, abdominal pain, diarrhea, dehydration, and rhinitis by inactivating rotaviruses via interfering viral absorption and replication and found that, compound (119) was found to be the most potent inhibitor of bovine rotavirus [181] The EpsteineBarr virus (EBV) is one of the most common viruses in human which are associated with various types of cancers, such as Hodgkin's lymphoma, Burkett's lymphoma, nasopharyngeal carcinoma, autoimmune diseases like dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis etc Flavone, 3, 5, 6, 7, 8, 30 , 40 -heptamethoxyflavone (HPT) (120) exhibited significant inhibitory effects on the EBV- early antigen activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA) [182e184] Robustaflavone, 121 (EC50 ¼ 0.25 mM) a naturally occurring biflavone isolated from the seed kernel extract of Rhus succedanea, was found to be a potent inhibitor of hepatitis B virus acting via DNA polymerase inhibition [185] 4.8 Anti-protozoal activity Protozoal diseases particularly malaria, leishmaniasis, Chagas disease and trypanosomiasis, represent a major cause of mortality in various tropical and subtropical regions Malaria is one of the most common infectious disease mainly affecting the children under years and responsible for a child death in every 30s [186] Various drugs have been developed to treat malaria, but due to associated adverse effects and development of multidrug resistance against different strains of Plasmodium falciparum, further development of new anti-malarial is required [187] In this context, various natural, semi-synthetic and synthetic flavones have been discovered and evaluated for activity against various parasites like P falciparum, Plasmodium vivax, Plasmodium berghei etc Different flavones like luteolin (2), apigenin (3) can inhibit parasite growth by targeting various metabolic pathways occurring in the apicoplast, a plastid-like organelle encountered in apicomplexan parasites Flavonoids could disturb the infectederythrocyte cyto-adherence property and decrease their sequestration in small vessels [188,189] Casano et al reported that aminomethoxyflavone (122, IC50 ¼ 7.7 mM) is the most active derivative and exhibited the highest specificity and selectivity on P falciparum It was investigated that subsequent substitutions on ring-B, fluoro in position C-20 promoted a specific anti-plasmodial activity of methoxyflavone 123, (IC50 ¼ 15 mM) and aminomethoxyflavone 124, (IC50 ¼ 23 mM) [190] Various biflavonoids were isolated and flavone units linked with a flavanone moiety showed antiplasmodial activity [191] Isochamaejasmin (125) was the most active compound, with a moderate anti-plasmodial activity (IC50 ¼ 7.3 ± 3.8 mM) and relatively low cytotoxicity (CC50 ¼ 29.0 ± 10.9 mM) when compared with chloroquine [192] Auffret et al synthesized and tested different flavonoid derivatives having a piperazinyl chain for their antiplasmodial activity The compounds having a 2,3,4trimethoxybenzylpiperazinyl chain attached to the flavone at the 7-hydroxyl group of ring-A, showed in vitro activity against P falciparum strains in the micro molar to submicromolar range Among all the synthesized compound, 126 and 127, (IC50 ¼ 1, 0.6 mM respectively) were found to be the most active [193] Various natural anti-protozoal flavones were isolated from different sources Flavone 128, isolated from Lonchocarpus spp was 228 M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 found to be the most active against Leishmania parasites [194] Lanaroflavone (129, IC50 ¼ 0.48 mM), a biapigenin with a C4000 eOeC-8 interflavonoid linkage exhibited antiplasmodial, leishmanicidal and antitrypanosomal activities without any cytotoxicity [195] (Table 1) 4.9 Anti-HIV Over the past 25 years, since the first case of HIV/AIDS was identified, AIDS has become the largest and most devastating public health pandemic of our time, that has infected nearly 70 million people and left 25 million dead Around the world, the number of people living with HIV is now 40.3 million For HIV infection, drugs are currently designed and synthesized to target HIV reverse transcriptase and protease But drug resistance and several side effects necessitate the continued search for new HIVinhibitors targeted towards other viral proteins like HIV-1 integrase (IN) which catalyzes the integration of viral cDNA into the host genomic DNA causes HIV-1 replication [196] Various potent HIV-1 integrase inhibitors are presently in clinical trials Several polyhydroxylated aromatics have been reported to inhibit HIV-1 integrase Numerous flavones having anti-HIV activity like Quercetagetin (3,30 ,40 ,5,6,7-Hexahydroxy flavone), Morin (20 ,3,40 ,5,7Pentahydroxy flavone) 130 and 131, have been isolated from the leaves of N nucifera [197] Flavones act by reacting chemically or by forming complex with essential groups of the enzyme [198] More negative charge on carbonyl oxygen atom lead to an increase of the anti-HIV-1 integrase activity [199] Thalassiolins, a natural flavone having HIVintegrase inhibitory property has been isolated from the Caribbean sea grass Thalassia testudinum It contains b-D-glucopyranosyl-200 -sulfate at hydroxyl group of C-7 of flavone, that increased potency against HIV-integrase by interacting with catalytic core domain of HIV-1 integrase Thalassiolin A (132, luteolin 7-b-Dglucopyranosyl-200 -sulfate) was the most active, inhibiting the integrase terminal cleavage and strand transfer activities with IC50 values of 2.1 and 0.4 mM, respectively [200] Casano et al synthesized and evaluated various flavones and chalcones for inhibition of HIV multiplication Amongst all, 3methoxyflavone (133) was found to be active against HIV-1 & HIV-2 The para substitution on the ring-B (134) seemed to increase HIV-2 potency Compounds 134, 135 and 136 were found to be specific inhibitors of the HIV-2 multiplication [190] (Table 1) SAR studies have revealed that A ring bearing an amino group at position 6, C ring with H, OH, and OCH3 at position and mono substituents (H, OCH3, F, CF3) in various positions of B ring is needed to increase HIV-2 potency Inhibitory activity is reduced or eliminated by methoxy or glycosidic substitutions or by saturation of the 2, double bond 4.10 Cardiovascular activity Since ancient times, numerous flavonoids, including flavones (Apigenin, 3) have been reported to reduce occurrence of various heart diseases like coronary diseases, arrhythmias, atherosclerosis, hypertension, ischemic stroke, peripheral arteriopathy, congestive heart failure etc Flavones attributed to an increase HDL-cholesterol levels, antioxidant capacity, lipid regulation, inhibition of platelet aggregation, improving endothelial function, and the antiinflammatory effects [201] Apart from all these properties, flavones are involved in the direct inhibition of some radical-forming enzymes (xanthine oxidase, NADPH oxidase and lipoxygenases) for the management of several cardiovascular disorders A natural flavone luteolin-7-O-b-D-glucopyranoside exhibited cardioprotective effects against doxorubicin-induced toxicity in H9c2 cells, reduced LDH and CK (Creatine kinase) level, and decreased the elevated intracellular concentration of ROS and [Ca2ỵ] SAR revealed that the C2]C3 double bond on ring-C and 30 ,40 -dihydroxyl on ring-B are necessary for cardioprotective effects 4-keto group is a requisite for vasodilation [202,203] The effects of flavone on myocardial post-ischemic-reperfusion recovery were studied by Ning et al and found that flavone treatment caused better recovery of left ventricular developed pressure [204] Budriesi et al have synthesized a series of 1,4-dihydropyridines bearing a 3-methoxyflavone ring at 4-position, and evaluated them for cardiovascular activity in isolated right atria of the guinea pig Among all synthesized compounds, 137 was found to be a potent calcium channel modulator, thus it could be useful in the treatment of myocardial ischemia, where negative inotropic and hypotensive effects could be potentially deleterious [205] Various flavone derivatives have been evaluated for lipid peroxidation inhibitory activity on isolated rat hearts Compound (138) reduced ischemia/ reperfusion-induced cardiac dysfunction [206] Oxypropanolamine substituted flavones were shown to exhibit antihypertensive activity in spontaneously hypertensive rats The position of the oxypropanolamine side chain, hydroxy group of the side chain, steric bulkiness and length of N-substituents, and degree of the N-substitution and substitution on ring-B, of the flavones scaffold play significant role in imparting antihypertensive effects Among all tested analogues, the most effective one was flavodilol (139) Compounds with the functionality at the C-7, displayed better activity than the corresponding congeners at the 5-, 6-, and 8-position The optimal chain length of three carbon atoms in substituent's of the secondary amine was found to be necessary for drugereceptor interactions Substitution of the para position of the ring-B with a variety of substituents, i.e., NO2, NH2, OCH3 and CH3 causes a loss of activity [207] In cardiac disorders, abnormal rhythm of the heart increases the risk of death, congestive heart failure, and heart strokes Atrial fibrillation is the most common form of cardiac dysrhythmia Several anti-arrhythmic agents like amiodarone, sotalol are effective in treating atrial fibrillation but have major limitations, such as inducing severe ventricular arrhythmia [208] Acacetin, (5,7dihydroxy-40 -methoxyflavone, 140), a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation Acacetin is an orally effective atriumselective agent [209] 4.11 Anti-platelets/antithrombotic activity Platelet aggregation is an important pathogenic factor in the development of atherosclerosis and associated thrombosis in humans Thromboxane B2 formation is a major factor for platelets aggregation [210] Different flavone and isoflavone derivatives have been found to exhibit anti-platelet and vasorelaxing properties [211,212] Various anticoagulant agents like heparin exert a therapeutic effect by binding the enzyme inhibitor antithrombin III (ATIII) which results in the inactivation of factor Xa (FXa) and thrombin [213] Correia-da-Silva et al incorporated oligo-Osulfated moiety into a flavone scaffold in order to improve the anticoagulant potency by increasing both molecular size and number of sulfate groups The flavonoside 141 was the most potent in prolonging Activated Partial Thromboplastin Time (APTT) (APTT2 ¼ 66 mM) Compound 141 act by interfering with coagulation cascade factors or platelet function Their influence on platelets, thrombin, FXa, and ATIII was studied The anticoagulant effects are increased with the increasing the number of sulfates groups in the compound Decasulfated compound 141 was more potent than all other compounds which increase clotting time, clot formation time, and decrease deceleration progress of the clot The possibility M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 of a dual anticoagulant and anti-platelet activities of compounds could enhance their potential as antithrombotic agents [214] Wang et al reported that oxime- and methyloxime-containing isoflavone7-yl derivatives having good anti-platelet activity with respect to flavones [215] 4.12 Anti-atherogenic agents Deposition of fat, cholesterol, low-density lipoprotein (LDL) and other forms of fatty materials in the walls of arteries form hard structures called plaques and the hardening of the arteries is known as atherosclerosis These plaques can block the arteries and cause problems throughout the body [216] Macrophage initiates release of several pro-inflamatory mediators by uptake of oxidized low-density lipoprotein (LDL), which induces expression of various adhesion molecules by endothelial cells These adhesion molecules, including cell adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and endothelial-leukocyte adhesion molecule-1 (E-selectin), contribute to form atherosclerotic lesions or plaques in coronary arteries [217,218] Flavones inhibit monocyte adhesion to a stimulated endothelium by blocking the induction of cell adhesion molecules on endothelial cells Flavones have also been found to block TNF-alpha through action on NF-kB transcriptional activation, which induce cell adhesion molecule proteins in human endothelial cells Apigenin (3) exhibited a reversible effect on cell adhesion molecule expression, and inhibited its upregulation at the transcriptional level [219] Luteolin (2) has been reported to interfere with lipopolysaccharide-triggered Akt (PKB) phosphorylation and NF-kB activation [220,221] Activated endothelium cells and macrophages produce nitric oxide through the activity of nitric oxide synthase (NOS), that is important in maintaining the dilation of blood vessels [222] Higher concentrations of nitric oxide react with free radicals, producing highly damaging peroxynitrite, which oxidizes low-density lipoproteins, resulting in irreversible oxidative damage of cell membranes Flavones are well known antioxidants and free radical scavengers Thus, the flavones scavenge free radicals and making them less available for reacting with nitric oxide, resulting in reduced damage Nitric oxide itself can be scavenged by flavones [223] The flavones like Kaempferol (33) and apigenin (3) act as the most potent inhibitors of NOS-2 induction via inhibiting NOS-2 gene transcription at micro molar concentrations [224] Inflammation plays a central role in the development of atherosclerotic disease Cyclo-oxygenase-2 enzyme (COX-2) is involved in the formation of inflammatory lesions by catalyzing the conversion of arachidonic acid to prostaglandins Chrysin (1) and wogonin (24) down-regulates the expression of key proinflammatory enzymes like inducible nitric oxide synthase (iNOS) and COX-2 Moreover, Flavones with 30 ,40 -dichloro substituent's 142 on the B ring exhibit strong COX-2 inhibitory activities irrespective of the substitution pattern on ring A [97,225] 229 used to enhance blood flow and improve erectile response by increasing the cGMP level, but exhibit unwanted side effects including visual disturbance and cutaneous flushing [227] In addition to various approved phosphodiesterase (PDE5A1) inhibitors, several flavone and its derivatives like luteolin, diosmetin, apigenin, chrysin, and luteolin-7-O-glucoside exhibited phosphodiesterase inhibitory activity [228e230] The SAR study revealed that position of hydroxyl group determines the selectivity towards several PDE isoforms e.g., hydroxyl group at the C-40 position is important for PDE3 inhibition, same substituent's at the C-5 position for PDE1, PDE2, PDE4, and PDE5 inhibition and hydroxylation at C-7 is important for inhibition of PDE1, PDE3, and PDE4 [231e233] Flavone glycoside isolated from Ginkgo biloba have also been demonstrated PDE inhibitory activity, by inhibition of cAMP PDE [234] 4.14 Xanthine oxidase inhibitors Xanthine oxidase (XO) generates reactive oxygen species like superoxide anion and hydrogen peroxide XO plays a vital role in purine metabolism via catalyzing the oxidation of hypoxanthine and xanthine to uric acid which leads to hyperuricemia or Gout due to impaired renal (kidney) excretion [235,236] (Fig 10) Xanthine oxidase (XO) is concerned in the pathogenesis of viral infections, inflammation, brain tumors and post-ischemic reperfusion injury Thus, its inhibition is important to decrease the production of excessive uric acid and to prevent the formation of superoxide radicals, and provides protection against post-ischemic reperfusion injuries [237] The planar structure and C-5 and C-7 hydroxyl group of flavones are important for the inhibition of XO enzyme at low concentrations The C-5 and C-7 hydroxyl groups of flavones may contribute to the inhibition by mimicking C-2 and C-6 binding interaction sites of xanthine that forms hydrogen bonds in the active site of XO [238] Apigenin (3, Ki ¼ 0.52 mM) and luteolin (2, Ki ¼ 2.9 mM) exhibited strong inhibitory effect on the XO as compared to a synthetic XO inhibitor allopurinol (Ki of 7.3 mM) [239] Baicalein, (5,6,7-trihydroxyflavones) also inhibit the XO in competitive manner [240] Flavones act in the dissociated (anionic) form that originates from the dissociation of the C7-hydroxyl group The anionic oxygen of the flavone possesses a very strong carbonyl character due to the extended delocalization of the negative charge over the entire benzopyrone ring The carbonyl group of flavones is essential for interaction with XO The favorable positioning of the 2-phenyl substituent of flavones is involved in hydrophobic interactions with the enzyme in the same region as the purine analog inhibitors [241] The hydroxyl group at C-7 is also crucial for inhibitory activity, as it enables the flavones to create hydrophobic interactions in the optimal region of the enzyme [242] It has been concluded that 5- and 7-hydroxyl groups, a catechol, along with a planar molecule, are necessary features for xanthine oxidase inhibition by flavones [243] 4.13 Phosphodiesterase inhibitors 4.15 Lipid-lowering agent Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that affect cellular signaling in the body The cAMP and cGMP are involved in a number of biological processes, such as cell division, smooth muscle contractility and platelet aggregation Thus, inhibitors of PDEs would show therapeutic benefits like cardiotonics, vasodilators, smooth muscle relaxants, antidepressants, anti-thrombotics, and anti-asthmatics This enzyme has also been involved in erectile dysfunction [226] Various approved phosphodiesterase (PDE5A1) inhibitors such as sildenafil and vardenafil, Lipids including cholesterol, cholesteryl esters, phospholipids and triglycerides, lead to the pathophysiology of many metabolic diseases like diabetes, dyslipidemia, CVS related disorders, cancer, etc Hypercholesterolemia is a major risk factor for coronary heart disease So, the regulation of lipid levels is important in the treatment of cardiovascular and cerebrovascular diseases [244] The lipids are catabolized through the activation of nuclear receptors like peroxisome proliferator-activated receptors (PPARs) in adipocytes It has been reported that polymethoxyflavones significantly 230 M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 Fig 10 Oxidation of hypoxanthine and xanthine to uric acid increase or activate PPAR-a and PPAR-g, that further reduced triglyceride (TG) content in the liver and heart It also regulates adipocytokines by significantly suppressing TNF-a (tumor necrosis factor-a), INF-g (interferon-g), IL-1b (interleukin-1b) and IL-6 (interleukin-6) expression [245] The flavone derivative CM108 (143) has also been reported for lipid regulation It was observed that this compound increases the high-density lipoprotein (HDL) level and reduced triglyceride, cholesterol, low-density lipoproteins (LDL) in serum and liver [246] The hybrid congeners 6- and 7hydroxy flavones with aminopropanol have been synthesized and evaluated for anti-dyslipidemic activities The compound 144 and 145 lowered cholesterol and TG profiles and improved high-density lipoprotein cholesterol in db/db mice From the SAR point of view bulky lipophilic substitution like tert-butyl- on ring-B of flavones, the oxygen atoms at the 30 ,50 positions in the B ring seem necessary for antidyslipidemic activities [247] 4.16 Spasmolytic agents Several flavones have been reported to possess muscle-relaxant properties Flavones relax smooth muscles via blockade of muscarinic receptors Chung et al isolated various polyoxygenated flavones and among them, 146 showed competitive muscarinic receptor binding activity with Ki ¼ 76.5 mM The potency of the methoxyflavones to inhibit muscarinic receptor binding is influenced by the position and number of methoxy group substitutions All the flavones that bind to the muscarinic receptor possessed C-3, C-5 methoxy groups and C2]C3 double bond in conjugation with 4-oxo group [248] Flavoxate, 147 possess anti-cholinergic activity along with antimuscarinic effects Thus, it can be used to treat urinary bladder spasms, while flavoxate hydrochloride is prescribed for symptomatic relief of interstitial cystitis, dysuria, nocturia, suprapubic pain and incontinence, which may occur in various other disorders like cystitis, prostatitis, urethritis and urethrocystitis/urethrotrigonitis [249] 4.17 Vasorelaxant Hypertension, one of the most common cardiovascular diseases, is defined as repeatedly elevated systolic and/or diastolic blood pressure above 140/90 mm Hg Vasodilators and vasorelaxants are used to manage the hypertension by the production of some secondary messengers like nitric oxide (NO), cGMP, cAMP, Calmodulin protein etc [250] Series of flavones like 3-hydroxyflavone (148), 6hydroxyflavone (149), 7-hydroxyflavone (150), chrysin (1) have been evaluated for ex-vivo and in-vitro vasorelaxant effect, therefore, can be the drugs of interest as novel antihypertensive agents All the flavone derivatives possess endothelium-dependent vasorelaxant effect, with an increased production of NO and prostacyclin PGI2 in a concentration-dependent manner [251] (Table 1) Dong et al designed and synthesized several flavones derivatives for vasorelaxant activity SAR was developed with 3D- QSAR analysis, carried out by comparative molecular field analysis (CoMFA) method Hydroxyl group at C-5 and C-7 positions in the ring-A, C-4 carbonyl group, C2]C3 double bond and hydroxyl groups at different positions in ring-B are important features for the vasorelaxant activity, while the presence of C-glycosyl group at C-8, hydroxyl group at the C-3 position, greatly reduce relaxation effect On the other hand, bulky substituent's at ortho- and meta- positions on ring-B (151) of flavone derivatives decrease the potency of vasorelaxant activities 5, 7-dihydroxy-30 -bromo-flavone (152) exhibited the highest vasodilator activity [252,253] It was reported that prenyl groups could increase the lipophilicity and confer to the molecule a strong affinity to biological membranes, and result in the significant enhancement of bioactivities Hydrophobic substituent's in ring-B of flavone exhibit medium activities 153 and 154 (Br, trimethoxyl), while the 3-hydroxyl substituent (155) attenuated the relaxation activity [254,255] The most effective vasorelaxing agents, luteolin (2), apigenin (3) exhibit lower energy, and small molecular volume size so have diverse interactions like steric and electronic between the compounds and receptors [256] 4.18 Prostate hyperplasia therapeutics Prostate hyperplasia (PH) involves hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large and discrete nodules in the periurethral region of the prostate causing partial or complete obstruction of the urethra, which interferes with the normal flow of urine a1- and a2-adrenoceptors cause the contraction of the human prostate So, a-blockers (a1-adrenergic receptor antagonists) including doxazosin, terazosin are used for initial therapy of Prostate hyperplasia [257e259] a-blockers relax smooth muscle in the prostate and the bladder with some common side effects including orthostatic hypotension, ejaculation changes, nasal congestion and weakness Thus, there is still a need for Prostate hyperplasia therapy with lesser side effects Flavone (156) has been reported to block urethral contraction induced by exogenous a1-adrenoreceptor agonists or hypogastric nerve stimulation with decreased side effects [260,261] Arylpiperazine substituted flavones derivatives have high affinity and selectivity for a1- and a2-adrenoceptors SAR explained that the arylpiperazine moiety was crucial for affinity with the oisopropoxy substituted derivative better than the corresponding omethoxyl substituted compound Affinity is decreased by replacement of arylpiperazine with pyridazinoneepiperazine system Additionally, the alkyl bridge connecting the arylpiperazine to flavone fragment was found to be important for affinity, as variation in its length caused slight decrease in affinity Whereas, substitutions on flavone ring not have any influence on affinity toward a1- and a2-adrenoceptors [262] Han et al isolated and evaluated various kinds of flavonoids for the treatment of benign prostatic hyperplasia (BPH) from the pollen of Brassica napus They reported that luteolin (2, IC50 ¼ 5e50 mM) decrease the secretion of prostate specific antigen (PSA), a glycoprotein that causes BPH [263] M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 231 4.19 Antileishmanial agents 4.21 Cell membrane protective activity Leishmaniasis is one of the major parasitic diseases Currently, there is no effective vaccine for leishmaniasis Therefore, there is an urgent need to speed up the development of a new generation of effective and safe antileishmanials Various natural and synthetic flavones have been reported to have potent leishmanicidal activity [151] Wong et al reported synthetic flavone dimers with either polyethylene glycol linker or amino ethylene-glycol linker, having marked leishmanicidal activity Among all compounds, 157 (IC50 ¼ 0.13e0.21 mM) showed very reliable and promising leishmanicidal activity with a high therapeutic index without toxicity SAR revealed that pyridine ring with nitrogen at position-4 is important for selective anti-leishmanials activity Activity depends upon various structural features like (1) length of the linker, as shortening the linker length resulted in lost of activity (2) Changing the attachment position of the two flavones to the amino PEG linker, attachment at C-30 position ring-B showed significant activity as compared to compound having linker attached at C-40 position However, attachment at C-20 position of the ring-B or C-3 position of ring-C resulted in at least 10-fold decrease in activity (3) Substituting the two flavones with different groups like methoxy at C-30 of ring-B caused remarkable cytotoxicity toward both promastigotes and host peritoneal elicited macrophage (PEM) cells, whereas methoxy at C-3 or fluorine at C-6 did not cause any toxic effect toward the PEM cells and retained the activity (4) Position of attachment of pyridine ring at the amino PEG linker The activity profile rank order is obtained like substitution through para position > meta position [ ortho positions Also, substitution with bromo and cyano group at meta-position or ortho-position of the pyridine ring reduced the activity Replacement of the pyridine ring by pyrimidine ring further lowered activity 2-fold [264] Several compounds were investigated in-vivo for their antileishmanial and anti-trypanosomal activity in mouse models The best in-vitro trypanocidal activity was exerted by 7,8-dihydroxyflavone (158, IC50 ¼ 68 ng/ml) For leishmanicidal activity 3hydroxyflavone (159, IC50 ¼ 0.7 mg/ml), luteolin (2, IC50 ¼ 0.8 mg/ ml) were most potent compounds The insertion of hydroxyl groups at C-7, C-8, and significantly enhanced the leishmanicidal potential Further, methylation of the hydroxyl groups was impoverished and reduced the leishmanicidal activity significantly and additions of hydroxyl at ring-B completely diminished the activity Attachment of one or more sugar units at the C-5 or the C-7 position of the flavone skeleton, caused a slight to appreciable reduction in antileishmanial potency [265] The inductive forces cause changes in physical properties of membranes resulting in oxidation of membrane lipids and proteins It has been reported that flavones contain lipophilic (non-polar) and hydrophilic (polar) fragments, so flavones can easily interact with membrane bilayers by partitioning of the non-polar fragment between the hydrophobic interior of the lipid bilayers, which leads to the formation of hydrogen bonds between the polar head groups of the lipids and the hydrophilic fragments of flavones at the membrane interface [267] Additionally, the partitioning of flavones in the hydrophobic core can also result in a chain-breaking antioxidant activity and the interactions of polyphenols at the bilayer surface through hydrogen bonds can reduce the access of deleterious molecules, thus protects the structure and functions of membranes [268] 4.20 Anti-oesteoporotic agents Osteoporosis, a silent epidemic, is characterized by decreased bone mineral density (BMD), increased risk of fractures and is associated with micro architectural deterioration of bone tissue that results in low bone mass Osteoporosis is especially common in women after menopause as a result of reduced estrogen level Flavonoids, have been intensively reported on regarding their estrogen-like activities and particularly their ability to affect bone metabolism Flavones like Baicalin, were screened for their osteogenic properties by measuring alkaline phosphatase activity in cultured rat osteoblasts Maurya et al have isolated dihydroflavonol derivative K 058 (160) from Ulmus wallichiana, and found that it increased mRNA levels of various oesteoblast-specific genes It was not oesteogenic in the rat uterus, but promotes oesteoprogenitor cells in immature rats [266] 4.22 Cosmetic agents Tyrosinase is a copper-containing enzyme that catalyzes different reactions in melanin synthesis; firstly, the hydroxylation of a monophenol and secondly, the conversion of an o-diphenol to the corresponding o-quinone Undergoes several reactions, it's oxidized L-tyrosine to melanin Melanin synthesis is of considerable importance because its alteration causes many skin diseases A mutation in the tyrosinase gene resulting in impaired tyrosinase production leads to type I oculocutaneous albinism, a hereditary disorder The mutated tyrosinase, results in increased melanin synthesis So, tyrosinase inhibitors have gradually become more important in medicinal and cosmetic products Tyrosinase inhibitors have been reported for the treatment of melanin hyper-pigmentation and used in cosmetic materials for whitening of the skin after sunburn [269,270] It was reported that luteolin (2), showed tyrosinase inhibitory activity by acting via disruption of the tertiary structure of the enzyme through intermolecular hydrogen bonding as a noncompetitive inhibitor Luteolin 7-O-glucoside, also showed tyrosinase inhibitory activity [271] Baicalein (8) has also been used as a de-pigmentation agent in cosmetics, having several numbers and relative positions of the hydroxyl groups which enhance its tyrosinase inhibitory activity [272] Other flavones involve in tyrosinase inhibition activity are 6hydroxyapigenin, scutellarein (161), 6-hydroxygalangin (162) and 6-hydroxykaempferol (163) It was predicted that 6-hydroxy group is required for tyrosinase inhibitory activity as its absence leads to loss of potency [273] Venous insufficiency is a closely related condition to varicose veins, affecting larger veins deep within the leg and is characterized by pain, aching, swelling and feelings of heaviness and fatigue The varicose veins condition is considered as a cosmetic problem with stuffed, blue or purple lines visible on the skin of the lower legs Troxerutin, 164 has been tested for the management of varicose veins and venous insufficiency that showed substantial relief from swelling, aching, leg pains, and other uncomfortable symptoms [274] 4.23 Immuno-modulator activity The immune system is body's defense system against various types of diseases, pathogens like viruses, parasites, etc Sometimes immune cells fail to recognize body's own constituents and become hyperactive and attack normal tissues, such anomalous immune response is called an autoimmune disease Common autoimmune 232 M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 diseases include rheumatoid arthritis, diabetes mellitus type-I, psoriasis etc Various plant-derived and synthetic flavones inhibited the autoimmune diseases by interfering with intracellular processes, particularly phosphorylation pathways [275] Verbeek et al reported that luteolin (2) and apigenin (3) were found to be strong inhibitors of both murine and human T-cell responses and inhibited the human auto-antigen a-B-crystallin, an auto-antigen in multiple sclerosis Major contributor antigen-specific IFN-g production was reduced effectively by flavones thus, manage the T-cell mediated multiple sclerosis [276,277] SAR revealed that the presence of C2]C3 double bond in ring-C and absence of a hydroxyl group at C-3 are required for immunesuppressive agents in the treatment of autoimmune disorders Another novel flavone PMF 165 (5,30 -dihydroxy-3,6,7,8,40 -pentamethoxyflavone) induced immune response against tumor by suppressing Signal Transducers and Activators of Transcription (STAT3) [278] Oroxylin (46) and wogonin (24), natural flavones isolated from Bupleurum scorzonerifolium, act as immunosuppressive agents and exhibited potent inhibitory activities on CD28-costimulated T-cells at dose less than mg/ml, but also showed significant cytotoxic effect on T-cells survival [279] 4.24 Photo-protective activity Ionizing radiation by interaction with living cells through generation of toxic free radicals causes single strand breaks, double strand breaks, oxidative damage, chromosomal abnormality and mutation leading to the cell death and an increased risk for numerous genetic diseases [280] To protect the normal cells from radiations, efforts have been increased to search photo-protective agents Unfortunately, most of chemical radio-protectors have severe toxic effects, which limit their use in medical practice Therefore, research turned towards non-toxic, natural compounds for photo-protective activity Recently, various polyphenols like flavones have been evaluated for photo-protective activity Flavones having the UV-absorbing and radical-quenching capability exerted photo-protective properties Flavones are able to trap peroxyl and related radicals with slight modifications in their structure [281] Radio-protective effects of quercetin (3hydroxy-flavone), chrysin (1), luteolin (2), vicenin (166) and orientin (167) flavones are well reported in the literature [282e285] 4.25 Anti-asthmatic activity FcεRI receptors, present on the surface of mast cells and basophils, are critically involved in various chronic inflammatory conditions like atopic dermatitis, allergic rhinitis and asthma Interaction of allergen bound IgE with FcεRI receptors triggers the mast cell signaling resulting in the release of allergic mediators, histamine, proteases, chemotactic factors, leukotrienes and arachidonic acid metabolites [286] Anti-asthmatic therapy can be targeted at blocking the first step, i.e., FcεRI receptor expression or antagonizing the effects of the mediators released in the later steps Flavones have been reported to have an inhibitory effect on FcεRI receptor expression, anti-histaminic activity and leukotriene antagonism Tricetinidin (168) possesses similar inhibitory activity as compared to epicatechin gallate (ECG) (169), a potent FcεRI expression inhibitor Both these compounds possess pyrogallol moiety in common, thus, this partial structure can be proposed to significantly associated with inhibition of FcεRI expression [287] Flavones also exhibited leukotriene antagonism The leukotrienes cause constriction of the pulmonary airways and small blood vessels, so involved in asthma, psoriasis, myocardial infarction and vasospasmic diseases [288] Numerous carboxyflavones like (170), significantly modulate the action of leukotrienes SAR depicted that 40 -substituted flavones showed 10e20 times less leukotriene antagonism as compared to 30 -substituted analogues (171 vs 170) Also, substitution of carboxylic acid at C-8 position is favorable for the antagonism Moreover, the presence of nitrogen atom in the substituent group is essential for leukotriene antagonistic activity as the activity decreased by replacing quinoline moiety with other aromatic groups (172) [289] Additionally, the racemic aryloxypropanolamine derivatives 173 and 174 antagonized the effect of leukotrienes and 5-lipoxygenase [290] Moreover, Yamamura et al has reported anti-histaminic activity of flavones [291] (Table 1) 4.26 GABA antagonistic activity g-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and plays a crucial role in the managing neuronal excitability in various CNS related disorders by binding to GABAA receptors GABAA receptor also has some additional binding sites for compounds like benzodiazepines (BZDs), b-carboline, barbiturates etc that allosterically modifies chloride channel gating [292,293] Among these, BZDs form most important GABAA receptor modulating drugs with anxiolytic, anticonvulsant, muscle relaxant, and sedative hypnotic effects [294] It has been found that some naturally occurring and synthetic flavones binds to BZD binding site with high affinity and exhibits anxiolytic effect selectively [295,296] It has been reported by Dekermendjian et al in 1999 that flavones with substitution at 6th position (methyl) and 30 position (nitro group), (175) have high affinity for benzodiazepines [297] But later in 2002, Kahnberg et al identified 50 -bromo-20 -hydroxy-6methylflavone (176) as potent binder of BZD with Ki value of 0.9 nM [298] Azaflavones were also considered to have binding affinity for BZDs (177) but were found to be less potent as compared to flavones [299] GABA is metabolized by two enzymes, i.e., GABA-transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH) [300] The decreased levels of GABA in neurological conditions, including epilepsy, Parkinson's disease, Huntington's chorea, and Alzheimer's disease can be increased by inhibiting GABA-T and SSADH Flavonoid components of Erigeron breviscapus have been reported to have potent and noncompetitive inhibitory activity on both enzymes Among different flavanoids components of E Breviscapus, baicalein (8) was the most potent inhibitor for GABAT with an IC50 value of 12.8 ± 1.2 mM, and scutellarein (161) exhibited the best inhibitory effect on SSADH with an IC50 value of 7.20 ± 0.9 Mm [301] 4.27 Anti-diarrheal Secretory diarrhea is a massive health problem in the developing countries E coli and Vibrio cholerae are the two major pathogenic bacteria's causing secretory diarrhea Enterotoxins released by these organisms results in increased cellular levels of cAMP and cGMP that further activates the cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel present in the apical membrane of epithelia [302,303] CFTR is significantly upregulated in diarrhea resulting in excessive salt and water secretion Thus, pharmacological blocking of CFTR can be expected to inhibit salt and water loss during diarrhea Previously, a number of flavones exhibited concentration dependent stimulatory (at low concentrations) and inhibitory (at high concentration) effects on the regulation of CFTR Apigenin (3) stimulates CFTR at a half-maximal concentration of mmol/L and M Singh et al / European Journal of Medicinal Chemistry 84 (2014) 206e239 inhibits forskolin-stimulated CFTR with a Ki of 81 mmol/L This bivalent effect of flavones restricted its use in secretory diarrhea Limited use of flavones specifically in secretory diarrhea provoked to optimize the activity by separating stimulatory component from inhibitory component of drug [304,305] Recently, Schuier et al identified that central aromatic g-pyrone ring of flavones that determines the binding site affinity (probably by pep stacking) while the 4-hydroxyl group determines the efficiency of flavone-based CFTR blocker On the other hand, Flavanols (catechin and epicatechin) have 4-hydroxyl and non-aromatic central C-ring having low binding affinities as compared to quercetin (flavanol) and luteolin (flavone) that were strong inhibitors of CTFR containing 4-hydroxyl and a central g-pyrone ring Thus, flavones can target CFTR as blockers to treat secretory diarrhea [306] 4.28 Anthelmintics Various parasitic diseases caused by helminthes pose major threat to public health worldwide Anthelmintics currently in use encounter resistance, thus there is a need for a new anthelmintics with a specific mode of action In 2008, Ayers et al reported the isolation of three flavones from the whole plant extract of Struthiola argentea, having anthemintic activity (178, 179, and 180) A new flavone (180) with an EC50 of 3.1 mg/ml was revealed as most potent anthelmintics, but no clear pattern of structure activity relationship was observed [307] (Table 1) Conclusion The flavones are important members of the flavonoid family present in fruits and vegetables, which have received wide interest for their antioxidant potential and their ability to modulate several enzyme systems involved in a number of diseases Flavones are lipophilic as well as hydrophilic, having polar functionalities in different positions, and the skeleton itself is amenable for the generation of functionalities for selective modulation of different enzymes Recent studies in various disease areas have shown that many diseases, specifically those that are metabolic, multi-factorial and are best treated with combinations of drugs acting either with different mechanisms or with a drug exhibiting multiple pharmacological actions In spite of exhibiting a wide range of biological activities, flavones are yet to achieve the status of promising drug candidates, and only a few flavones have undergone clinical studies The reason for this could be the lack of optimization of biological activities The present review gives detail about the structural requirement of flavone derivatives for various pharmacological activities 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Selective dual inhibitors of Raf1 and JNK1 kinases, 1-(3-chloro4-(4-oxo-4H-chromen-2-yl) phenyl)-3-phenylurea derivatives, have been developed for antitumor treatment The Raf protein involved in