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Accepted Manuscript

Flavones: An Important Scaffold for Medicinal Chemistry


Manjinder Singh, Maninder Kaur, Om Silakari
PII: S0223-5234(14)00619-9
DOI: 10.1016/j.ejmech.2014.07.013
Reference: EJMECH 7133
To appear in: European Journal of Medicinal Chemistry
Received Date: 20 May 2014
Revised Date: 3 July 2014
Accepted Date: 5 July 2014
Please cite this article as: M. Singh, M. Kaur, O. Silakari, Flavones: An Important Scaffold for Medicinal
Chemistry, European Journal of Medicinal Chemistry (2014), doi: 10.1016/j.ejmech.2014.07.013.
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Graphical abstract


Flavones: An Important Scaffold for Medicinal Chemistry
Manjinder Singh
a
, Maninder Kaur
a
, Om Silakari
a,*
a
Molecular Modeling Lab (MML), Department of
Pharmaceutical Sciences and Drug Research Punjabi
University, Patiala, Punjab, India, 147002.

Abstract: 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. Due to the wide range of biological activities of avones
have generated interest among medicinal chemists. This
review 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.


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TITLE PAGE
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, India, 147002.
*E-mail: omsilakari@gmail.com, Telephone: +919814412412
Abstract: 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 signicant that recent studies have shown the positive effect of avones on diseases
related to oxidative stress. Due to the wide range of biological activities of avones, their
structureactivity 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.
Keywords: Flavones; Flavonoids; Antioxidant; Poly-functional; Multi-factorial diseases.
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1. 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.
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-inammatory, anti-oestrogenic, antimicrobial [3], anti-allergic,
antioxidant [4], antitumor and cytotoxic activities [5]. The majority of metabolic diseases are
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speculated to originate from oxidative stress, and it is therefore signicant that recent studies have
shown the positive effect of avones on diseases related to oxidative stress, such as
atherosclerosis, diabetes, cancer, Alzheimers 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 diverse roles of flavones, investigating various methods for their synthesis and
structural modication 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.
2. Chemistry
Flavone is a class of flavonoids based on the backbone of 2-phenylchromen-4-one (2-phenyl-
1-benzopyran-4-one). The molecular formula of flavone molecule is C
15
H
10
O
2
. It has a three-ring
skeletons, C6-C3-C6, and the rings are referred to as A-, C-, and B-rings, 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 0.8-2.45 [6]. Flavones have a
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planar structure with its C-O-C bond angle 120.9
o
. Its bond length between C-O is 1.376 and
dihedral angle is around 179.2
o
.
Synonyms of flavone are 2-phenyl-4H-chromen-4-one; 2-phenyl-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 [13-15],
condensation[16], reaction with organometallic reagents [17].
Several synthetic methods have been developed and modied to get products of high
yield, purity and of the desired quality. Flavones can be synthesized by various synthetic schemes
like Claisen-Schmidt condensation [18], Baker-Venkatraman-rearrangement [19,20], Ionic Liquid
Promoted synthesis [21], Allan-Robinson [22], Vilsmeier-Haack reaction [23], Wittig reaction,
Fries rearrangement and modified Schotten-Baumann reaction. Now a day, most of the avones
are synthesized based on the Baker - Venkataraman method. It involves the conversion of o-
hydroxyacetophenone into phenolic ester, which undergoes an intramolecular Claisen
condensation in the presence of a base to form -diketone, which is cyclized to avones by an
acid-catalyzed cyclodehydration (Scheme 1 & 2).
Traditionally, flavones were synthesized with Baker-Venkatraman-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 2-hydroxychalcones resulting from condensation
between acetophenones and salicylaldehyde, undergo oxidative cyclization on heating in
the presence of catalytic iodine and generating diversified flavones under solvent-free
environmental friendly conditions [24]. (Scheme 3)
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3. Biosynthetic pathway for flavones
Flavonoid biosynthesis starts with the condensation of 1 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 phenyl-
propanoid pathway, Malonyl-CoA is synthesised by carboxylation of acetyl-CoA, a central
intermediate in the Krebs tricarboxylic acid cycle. The chalcone is consequently isomerised 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)
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 avones, their structureactivity
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,
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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 signicantly 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)
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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 6,7,3`-trihydroxyavone (4), showed scavenging effect up to 87.8% [32]. It was also
found that substitution of 3,4-dihydroxybenzoyl at position C-3 (5) increases scavenging activity
against free radicals [33].
Various conjugated flavones, C
60
-Flavone (6) were evaluated for antioxidant activity in
which the flavones phenolic moiety react with peroxyl radicals, while the C
60
part of the molecule
acts synergically by trapping alkyl radicals under reduced O
2
partial pressure. Thus, this molecule
act as promising lead for broad-spectrum radical scavengers. Fullerene derivatives are used as
protective drugs against diseases related with oxidative stress and Poly-hydroxylated fullerenes
[C
60
(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 avone, baicalein (8) is capable of attenuating oxidative stress in various in vitro
models, thus possess signicant 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].
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A natural avone, Chrysoeriol, (10) extracted from the tropical plant Coronopus didymus
were tested for their ability to inhibit lipid peroxidation induced by -radiation, Fe (III) and Fe
(II) and showed better protecting eect with DPPH radicals at millimolar concentrations [39].
5,7,3`,4`-tetrahydoxy-3-methoxyavone (THMF), 11 was investigated for antioxidant
effects on the N-formyl-methionyl-leucyl-phenylalanine-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 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 2`,3`,4`-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 (3, 4-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 3- and 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 electron-donating groups on the ring B reduce the OH
bond dissociation energy, thus these important groups or features impart radical scavenging
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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 avone 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 tumour conditions.
Various anticancer agents (also referred as antitumor, anti-proliferative 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 1967-1991, a large group study was organized to explore the protective role of
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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].
Various kinases such as cyclin-dependent kinases (CDKs), glycogen synthase kinase-3
(GSK3), dual specificity tyrosine-phosphorylation-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, P27600 (18)
entered into clinical studies as a small-molecule CDK inhibitor [54, 55].
Selective dual inhibitors of Raf1 and JNK1 kinases, 1-(3-chloro-4-(4-oxo-4H-chromen-2-
yl) phenyl)-3-phenylurea derivatives, have been developed for antitumor treatment. The Raf
protein involved in Ras-Raf-ERK 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 Ras-Raf-ERK signaling. Dysregulation of both Raf-MAPKs and JNK
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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 M 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, 2'-chloro-4'-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 rst-line
therapy in the treatment of breast cancer in postmenopausal women, But due to variety of side
effects, naturally occurring avonoid aromatase inhibitors are attracting more and more attention
recently for their future clinical uses [59]. Natural avone 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, -uoro, and -nitro) and evaluated by MTT assay for their anti-proliferative activity in
breast cancer cell line MDA-MB-231(ER-) and MCF-7(ER+). Compounds (20), (21) and (22), in
which an imidazole ring is fused with ring-A of the avone showed exhibit modest activity
against the target protein eukaryotic elongation factor 2A (eEF1A1) responsible for breast cancer
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cells. The subsequent SAR study suggested that the Nitro group at 6th position of 23 is necessary
for anticancer activity [61].
Angiogenesis is crucial for the growth of tumor cells because it sustains malignant cells
with nutrients and oxygen. In angiogenesis, tumor cells exude various growth factors VEGFR-2
or VEGFR-3 and phosphorylation of VEGF receptors elicits endothelial cells to form new
capillaries and further promote tumor size and metastasis.
Kimura et al. examined that Wogonin, (24) at a dose of 25 and 50 mg/kg, twice daily
showed anti-tumor and anti-metastatic actions in LM 8-bearing mice [62]. It acts by inhibition of
VEGF-C-induced lymphangiogenesis through a reduction in VEGF-C-induced VEGFR-3
phosphorylation in tumor-associated macrophages (TAMs). Some pyrroloazaavone derivatives
(25), able to exert anti-angiogenic activity and to neutralize pro-angiogenic effects of broblast
growth factor-2 (FGF-2). Therefore, the 2-phenyl derivatives of pyrroloazaavone at non-
cytotoxic concentrations are able to exert in-vitro anti-angiogenic activity [63, 64].
In 1998, Beutler et al. reported results of a comparative in vitro antitumor cytotoxicity
screening and subsequent tubulin polymerization studies with a series of 79 natural and synthetic
avones and found that compounds bearing an OH group at C-5 on the ring-A, 3-hydroxy-4-
methoxy groups on the ring-B and an OCH
3
at C-3 on the ring-C posses maximum interaction
with tubulin [65]. The compound 5,3-dihydroxy-3,6,7,8,4-pentamethoxy-avone (26), a natural
avone inhibit tublin polymerization and showed significant cytotoxicity [66, 67]. A semi-
synthetic method was then envisaged from a natural avone and several compounds were
synthesized, among all, aminoavone (27), displayed a strong anti-proliferative activity [68].
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Bensasson et al. reported about inhibition of human DNA topoisomerase-I by flavones
and suggested that the avones might interact with the DNAtopoisomerase-I complex after their
oxidation into quinones via auto-oxidation, enzymatic oxidation, or reactions with reactive
oxygen species [69].
Matrix metalloproteinase-9 (MMP-9) expression plays an important role in various
pathological states including cataract, rheumatoid arthritis, and tumor metastasis [70]. Oshitari et
al. reported Nobiletin (28) and its metabolite (29) for their inhibitory activity against matrix
MMP-9 production in human lens epithelial cell model. Nobiletin metabolite inhibits proMMP-9
expression much more potently than nobiletin itself, because of metabolic conversion of p-
methoxy on ring-B to hydroxyl group which may be responsible for its inhibitory activity against
the proMMP-9 production [71]. (Table 1)
Cai et al. studied the inhibitory effect of apigenin (3) on hepatoma cell growth through
alteration of gene expression patterns. Apigenin also exhibited strong cytotoxic activity in various
types of cancer including hepatocarcinogenesis, neuroblastoma, breast cancer, esophageal
squamous cell carcinoma, colon cancer, lung, prostate cancer cells, cell mitosis impairment and
cell apoptosis promotion. [72,73]. Liu et al. synthesized a series of novel avone derivatives
with the substitutions of chloride, isopropyl, methoxy, and nitro groups on avone skeleton to
develop effective anticancer agents possess notable activity against hepatocarcinoma cells
(HepG-2). The compound 30 (IC
50
=1.1 uM) with chloride at ring-A and dimethoxy modications
at ring-B, active against HepG-2, nasopharyngeal carcinoma cells (CNE-2 and CNE-1), breast
adeno-carcinoma cell (MCF-7), epithelial carcinoma cells (Hela), and mitochondrial-dependent
apoptosis via triggering the caspase cascade [74].
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Telomere and telomerase are closely related to the occurrence and development of gastric
cancer. 2-chloro-pyridine derivatives of avone moiety 31 (IC
50
=18.452.79 ug/mL) is a
potential telomerase inhibitor having marked effects against gastric cancer cells [75].
Glyoxalase-I (GLO-I) is a key enzyme in pathways leading to the detoxication of
methylglyoxal (MG), one of the side products of glycolysis and able to induce apoptosis [76].
Takasawa et al. reported numerous natural flavones having GLO-I inhibitor activity. Important
structural feature and stereochemical aspect necessary for GLO-I inhibition by flavones
derivatives, plane distance 2.8 A between cis C-4 ketone and C-5 hydroxyl group as observed in
Myricetin (32, IC
50
=0.56 uM), Luteolin (2, IC
50
=7.7 uM), Kaempferol (33, IC
50
=20.6 uM). It was
also suggested that the hydroxyl groups at the ring-B greatly contribute to the human GLO-I
inhibitory activity [77].
SAR depicts that substitution of p-hydroxyl, 3, 5`-dimethoxy, 5`-amino, 2`-chloro at ring-
B are important for anticancer activity by diverse mechanisms as described earlier. Substituted
aliphatic or aromatic amino moiety at C-6 or C-8 position, chloro at C-6, and hydroxyl at C-5 on
ring-A, nitrogen at 1st position and 3-methoxy on ring-C are important for anticancer activity.
Imidazole ring fused with flavone via C-6 and C-7 position and nitro at C-6 is active against the
target protein responsible for cytotoxicities in breast cancer cells. Overall SAR patterns of
flavone derivatives for anticancer activities via diverse mechanisms as described earlier is shown
in Fig. 7.
4.3 Anti-inflammation
Inammation has foremost role in several disease conditions like Asthma, atherosclerosis,
Alzheimers disease, rheumatoid arthritis, diabetes mellitus, carcinoma, Crohns disease, gout,
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multiple sclerosis, osteoarthritis, psoriasis, bacterial or viral infections etc [78,79]. Different
inammatory mediators involved in these conditions are plasma proteases, prostaglandins,
leukotrienes, histamine, serotonin, nitric oxide, interleukins (IL-1 to IL-16), iNOS production,
tumor necrosis factor- (TNF-), NF-B and chemokines [80-82]. These mediators are produced
through diverse signaling pathways involving cyclooxygenases, caspases and kinases like cyclin
dependent kinases (CDK1 and CDK5), mitogen activated protein kinase 38 (MAPK38), c-Jun N-
terminal kinase (JNK), serine threonine kinases (IKK1 and IKK2), interleukin receptor associated
kinase 4 (IRAK-4), Janus kinases (JAK1- JAK3) etc [83,84].
Although steroidal anti-inammatory drugs and NSAIDs are presently used to treat acute
inammation, these do not successfully cure chronic inammatory disorders and have number of
unexpected side effects. Thus, there is an urgent need to nd safer anti-inammatory compounds
for chronic inflammatory conditions [85]. Natural products and their semi-synthetic derivatives
may provide appropriate alternatives.
Traditionally, extracts of different plants have been used for the treatment of acute and
chronic inammation. Variety of natural, apigenin (3), luteolin (2) as well as synthetic flavones
has been reported to bind with various protein kinases directly and alter their phosphorylation
state that regulates multiple cell signaling pathways. Thus, flavones can have excellent
therapeutic value in the treatment of inflammatory and autoimmune diseases [86].
Kim et al. synthesized 5,6,7-trimethoxy- and 5,6,7-trihydroxyavones from cinnamic acid
derivatives. Among synthesized flavone derivatives, 4`-bromo-5,6,7-trimethoxyavone (34) was
the most potent compound that inhibited the production of Nitric Oxide (NO), a free radical and
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PGE2 in LPS-treated RAW 264.7 cells. It also reduced the LPS-induced expressions of iNOS and
COX-2 at the protein and mRNA levels and release of TNF-, IL-6, and IL-1 [87].
Shin et al. 2011, suggested that the avone moiety should acquire an electronegative
substituent at the C-5 position of the ring-A, a bulky substituent at the meta position of the ring-
B, and a hydrophobic substituent at the meta position of the ring-B for NF-B transcriptional
activities [88]. Oshitri et al. proposed various synthetic analogues of nobiletin and evaluated their
inhibitory activity for pro-MMP-9 (matrix-metalloproteinase) production in both phorbol 12-
myristate 13-acetate (PMA) and TNF--stimulated human lens epithelial cells. Along with
various synthesized analogues, 2`-hydroxylated analogue (35) of nobiletin exerted marked
inhibitory effects (IC
50
=0.4 M) [89].
Moon et al. synthesized various CC biavones by Suzuki CC cross-coupling reaction
and reported their inhibitory eect against phospholipase A2. Compound (36) was observed to be
the most potent CC biavonoid against phospholipase A2 (IC
50
=27.64.3M) [90]. Several
biavones such as amentoavone (37) and morelloavone (38), avone-avanone dimer, also
revealed good PLA2 inhibition. Chen et al. synthesized some other potent biflavones, among
which 39 (IC
50
=3.00.9 M) showed higher inhibitory activity than natural biavonoid,
ochnaavone (40, IC
50
=3.50.6 M) against phospholipase A2 (PLA2) [91]. (Table 1)
Additionally, Takano-ishikawa et al. showed that avones were the most effective anti-
inammatory agents among other subclasses of flavonoids such as flavonones, flavonols as the
C2=C3 double-bond and the 4-oxo functional group of the flavones are important contributing
factors for the anti-inflammatory activity [92]. Flavones also showed the strongest inhibitory
effect on the expression of COX-2 protein, a dominant source of Prostaglandins (PG) formation
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at the inammatory site. COX-2 activity has been related to the amplication of inammation,
through the preferred conversion of PGE2 to thromboxane B2, and PGD2 by concordant
induction of PGE2 synthase [93]. It has also been reported that absence of the C2=C3 double
bond results in loss of inhibitory activities on the cyclo-oxygenase pathway of PGE2 production
[94]. Also, the flavones without a hydroxyl residue on ring-B were more effective than flavones
analogues with two or more than two hydroxyl residues on the ring-B. Anuradha et al. isolated
two new furanoavonoids, (41) and (42) that showed analgesic and anti-inammation activity
and were synthesized incorporating a new methodology of benzyl deprotection [95].
Naturally occurring flavones such as luteolin, apigenin possess diverse biological
properties but their content in natural sources is very low so these are synthesized in required
quantity by various synthetic schemes. Nakatsuka et al. in 2004, found synthetic methods for the
synthesis of natural compounds and synthesized fused tricyclic avone (43) and its derivative
(44) by retro-synthetic analysis. Both showed stronger anti-inammatory eect than that of the
natural avonoid [96]. Similarly, Chrysin derivatives were prepared and evaluated against
prostaglandin production from lipopolysaccharide-treated RAW 264.7 cells. 3`,4`-dichloro
substituted chrysin flavones derivative (45) exhibited good inhibitory activity for prostaglandin
production [97].
The avones having hydroxyl group at C-2`,C-3`,C-4` of ring-B and methoxy group at C-5,
C-6, C-7 positions of ring-A have been reported to show good anti-inflammatory activity [98].
Methylation of the hydroxyl group of C-3, C-5 showed stronger activities than those having more
than two hydroxyl groups on ring-B. Methylation of the 3-hydroxyl group reduced the
cytotoxicity [99, 100].
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4.4 Neuroprotective Activity
Central nervous system (CNS) is balanced by enormous intracellular signaling pathways,
neurotransmitters, diverse type of enzymes like kinases, esterases etc. A minor modification in
these pathways or enzymes causes CNS disturbances which leads to various neurodegenerative
disorders like dementia, depression, anxiety, Alzheimer, parkinsons, convulsion etc. Dementia is
characterized by the loss of brain function and Alzheimers disease (AD) is the major cause of
dementia. AD is caused by protein misfolding and aggregation, oxidative stress, mitochondrial
abnormalities, and neuroinammatory processes. Acetylcholinesterases (AChE),
Butyrylcholinesterase (BuChE), secretase-1 (BACE-1) are the key enzymes that promotes the
acetylcholine hydrolysis and amyloid plaque formation.
Parkinson's disease is by numerous inflammatory mediators, neurotransmitters, oxidative
stress, glutamate neurotoxicity, alpha-synuclein protein-aggregation etc. Monoamine oxidase
(MAO) enzyme oxidizes various endogenous neurotransmitter monoamines. It exists in two
isoforms, MAO-A and MAO-B. MAO-A oxidizes 5-hydroxytryptamine (5-HT), norepinephrine
and epinephrine, whereas MAO-B preferentially deaminates dopamine, -phenyl ethylamine, and
benzylamine. Biotransformation of these neurotransmitters causes various CNS disturbances
including depression, Parkinsons disease etc.
Infinite neuroprotectives in the current market are used for different neurodisorders and
have marked effect but many of them have huge side effects. Therefore, research moves to find
some natural as well as their synthetic analogues for the treatment of neurodisorders, which have
marked effects with negligible adverse effects. Recently, flavonoids have been evaluated to treat
various neurodegenerative disorders and flavones is a class among all sub-classes of flavonoids,
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which can protect the brain by their ability to modulate intracellular signals to promote
cellular survival. Natural flavones Oroxylin A (46) and its analogues have marked effect on CNS
to improve memory, cognition due to their binding afnity with benzodiazepine or GABA
receptors [101].
Tropomyosin-receptor-kinase B (TrkB), a kinase is involved in depression like
neurodisorder, which upon phosphorylation by several agonists exhibits antidepressant action.
Various receptors like GABA, benzodiazepines, Adenosine A
3
receptors play important role in a
variety of intracellular signaling pathways and implicated in both neuroprotective and
neurodegenerative effects. Liu et al. reported that 7,8-dihydroxyflavones (47) are potential
agonist of tropomyosin-receptor-kinase B (TrkB) and possess significant antidepressant effects
[102]. Later, 4`-Dimethylamino-7,8-dihydroxyflavone (48) was synthesized that displayed higher
TrkB agonistic activity than the original hit (47) [103]. SAR analysis of these compounds
demonstrated that the 7,8-dihydroxy groups on the ring-A and the middle heteroatomic chromen-
4-one, ring-C are essential for the TrkB stimulatory effect. On the other hand, the electron-
withdrawing group, such as F, or an electron-donating OH at 4-position suppresses the activity
whereas dimethylamino or pyrrolidino group at 4-position yield the desired activity (49).
Replacement of 7, 8-dihydroxy groups with an imidazole ring also showed increase in activity.
Additionally, replacement of dimethylamino group with a pyrrolidino group in compound 50, not
only displayed higher agonistic activity than compound 49 but also attenuated the locomotor
enhancement and showed better antidepressant effect [104]. (Table 1)
In the treatment of AD, various flavones were used as adjuvant with some active moieties
like tacrine due to their antioxidant activity. In that context, a new family of tacrine-4-oxo-4H-
chromene hybrids has been designed, synthesized, and evaluated biologically for
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Alzheimers disease (AD), by Fernandez-Bachiller et al. The tacrine fragment with
cholinesterase inhibitory activity and the flavone scaffold with free radical scavenging and -
secretase (BACE-1) inhibitory activities, the hybrids were found to be more potent than the
parent inhibitor, tacrine as well as apigenin. Among all the hybrids, compound (Fig. 8) showed
potent combined inhibition of BACE-1 and ChEs, as well as good antioxidant and CNS-
permeable properties [105].
Moreover, flavones exhibited specic interactions within the ERK and PI3-kinase/Akt
signaling pathways and have been shown to increase the expression of neuroprotective and
neuromodulatory proteins and increase the number and strength of connections between neurons.
ERK activation results in a downstream cAMP response element binding protein (CREB)
activation, which may result in a number of benecial changes, such as long-lasting changes in
synaptic plasticity and memory [106]. Flavone backbone (2-phenyl-1,4-benzopyrone) has close
structural homology to specic pharmacological modulators of ERK signaling, such as PD98059
((51), 2-amino-3-methoxyavone).
It was found that baicalein, (8) has some effect on neuro-protection and displayed
symptomatic improvement in Parkinson's disease [107]. Also, nephrocizin, 52 (luteolin-7-O--D-
glucopyranoside), a avone glycoside have been reported to show protective effects on the
induced neurotoxicity in PC12 cells by 6-OHDA (6-hydroxydopamine, Neurotoxin used to
generate an experimental model of Parkinsons disease) and its oxidative products [108].
Flavones have also been reported to have the ability to delay the initiation or progression
of AD-like pathology and related neurodegenerative disorders by disrupting the -amyloid
aggregation through the inhibition of -secretase (BACE-1) and/or activation of -secretase
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(ADAM10) [109] (Fig. 9). Prenylated avones were reported to inhibit -secretase by Cho et. al.
Compound 53, bearing prenyl groups at C-3 and C-8, showed the strongest BACE-
1inhibitory activity (IC
50
=3.4 M) [110]. Whereas, compounds 54 (IC
50
=0.034 M) and 55
(IC
50
=0.055 M) showed the highest AChE inhibitory activity, IC
50
< 100 nM. It was suggested
that the presence of pyrrolidin-1-ylmethyl or piperidin-1-ylmethyl in C-4 and double bond at
C2=C3 may play an important role in the AChE inhibitory activity of flavones [111].
Further Sheng et al. synthesized flavones with different substitutions at para and meta
positions of ring-B and found that compound 56 (IC
50
=0.055 M) with aminomethyl group
substituted at the para-position of ring-B was more potent than meta substituted flavone 57
(IC
50
=0.704 M) [112].
Chimenti et al. synthesized and evaluated flavones as potential inhibitors of monoamine
oxidase isoforms (MAO-A and MAO-B). MAO inhibitory activity of several natural flavones
including jaceosidine (IC
50
=19.0 M), eupafolin (IC
50
=25.0 M), luteolin (MAO-A IC
50
=4.9
M; MAO-B IC
50
=59.7 M) 5, and apigenin (MAO-A IC
50
=1.7 M; MAO-B IC
50
=12.8 M) has
been reported in the literature. The flavones analogues with C2=C3 double bond, flouro group at
ring-A in 58 (IC
50
=1.340.02 M) and sulfur group at C-4 of ring-C in the thioavones 59
(IC
50
=0.480.024 M) are selective MAO-B inhibitors [113]. (Table 1)
Kang et al. examined neuroprotective eects of biavonoids obtained from natural source
on oxidative stress-induced and amyloid -peptide-induced cell death in neuronal cells and
suggested that amentoavone (37) and ginkgetin (60) exhibited strong neuroprotective effects in
ischemic stroke and AD [114].
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Most of the synthetic derivatives having electronegative groups (halogens, Nitro, etc.) at
C-6 and/or C-3' of the flavones, posses a high affinity for central benzodiazepine receptors.
Representative compounds such as 6,3-dinitroflavone (61) and 6-bromo-3'-nitroflavone (62)
exhibited a high affinity for the BDZ-Rs (Ki=1.5 to 30 nM) and posses anxiolytic effects [115].
Familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA) are associated
with transthyretin amyloid brils. It was reported that apigenin (3) completely inhibited
transthyretin amyloid fibril at a concentration of 36 M [116].
Several flavone derivatives have been evaluated as selective adenosine A3 antagonists
that can serve as a cerebroprotective anti-asthmatic and anti-inflammatory agent. Compound, (63)
is found to be potent and highly selective (200-fold) for human A3 receptors (Ki, 0.56 M).
Hydroxyl at C-3, chloro at C-6 and sterically bulky groups like Styryl, at position C-2` may prove
fruitful for adenosine A
3
antagonism. The C2=C3 double bond required for selectivity towards
A3 receptors along with a 2-phenyl substituent and a 3-hydroxyl group is present. The flavones
with aminomethyl radical at C-8 also showed CNS stimulant activity [117, 118].
4.5 Anti-diabetes
The apathetic lifestyle and energy-rich diet in present aggressively contribute to a stunning
increase in obesity resulting in insulin resistance which leads to type-2-diabetes along with
retinopathy and nephropathy like complications. Various enzymes like -glucosidase, aldose
reductase (AR), protein tyrosine phosphatases (PTP), protein kinse C (PKC), PPAR-
(peroxisome proliferator activated receptor-), Advanced glycation end products (AGES), etc are
linked directly or indirectly with diabetes mellitus.
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-Glucosidase enzyme is an intracellular glycoside hydrolase enzyme involved in
breaking down complex carbohydrates, helps in the absorption of ingested carbohydrates,
increases post-prandial glycemia and insulin peaks. Aldose reductase (AR) is a key enzyme in the
polyol pathway in which glucose break into sorbitol and its accumulation linked to diabetic
complications. It also involve in the formation of advanced glycation products (AGEs). PPAR-
regulates fatty acid storage and glucose metabolism. PPAR- has a direct action of on glucose
metabolism through various genes involved in insulin-stimulated glucose disposal. Diabetic
complications like retinopathy, nephropathy, neuropathy are caused by an increase of polyol
pathway ux, advanced glycation end-products (AGEs) formation, activation of protein kinase C
isomers, increase in hexosamine pathway ux [119]. Among them, AGEs are well known to be a
cause of aging as well as diabetic complications.
The disease state is being controlled by various anti-diabetic drugs acting by various
mechanisms, such as by increase in insulin secretion from pancreatic -cells by sulphonylureas
(e.g., glibenclamide) [120], an enhancement of insulin action by PPAR- (peroxisome proliferator
activated receptor-) 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
causitive factors of diabetes mellitus.
Verma et al. synthesized and evaluated various flavone-based hybrids of 6- and 7-hydroxy
avones 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 avone and smaller substituents at the nitrogen atom. The hybrids with
tert-butyl and isopropylamine functionality at N atom are superior in activity [123].
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Baicalein, (8) (5,6,7-trihydroxyavone, IC
50
=52 M ) and Luteolin (2) inhibited the -
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 8-aminomethylated derivatives of oroxylin A (46) as -glucosidase
inhibitor via Mannich reaction. Among synthesized derivatives, compound 66, (IC
50
=35.43 M)
was found to be the most active [125]. The 6-amino-5,7-dihydroxyavone 67, (IC
50
= 2.4 uM) is
a unique avone having a 6-amino group along with ordinary 5,7-dihydroxyl substituents, which
found to be active against rat intestinal -glucosidase. The initial SAR studies suggested that the
6-amino and 7-hydroxyl groups were essential for the activity. 5-hydroxyl 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 efficay 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 (-logIC
50
=11.064), yielded the most potent analog [128].
Dundar et al. synthesized new avonyl-2,4-thiazolidinediones, hybrids of avone 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 (IC
50
<1M) were obtained as aldose reductase inhibitors [129].
Zou et al. synthesized nitric oxide-releasing chrysin derivative (71), which also have
aldose reductase inhibitory activity (IC
50
=0.130.03 mol/L). The hyperactivity of AR has been
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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- ligand-binding activity. Various isolated flavones exhibited signicant PPAR-
ligand-binding activity, but prenylavone derivative, licoavanone A (72), showed the most
potent ligand-binding activity at 2 ug/ml [131].
Matin et al. designed and synthesized novel pharmacophore having 7-hydroxy-
benzopyran-4-one moiety as potential dual PPAR- and agonists. Among all compounds, (73)
5, 4-dihydroxyflavone and diosmetin (74) were identified as novel and potent dual PPAR- and
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
isoflavones having dual PPAR- and - agonist properties. The planar structure and hydroxyl
group at C-7 of the avone and isoavones 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 = 29.1 uM) [134]. Additionally, Cushman et al. reported the inhibitory eects of
hydroxyavones and aminoavones on protein-tyrosine kinases. The amino group has advantage
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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 5,7,3'-trihydroxy-3,6,4'-
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 mentionaed 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, IC
50
=93 M), luteolin (2, IC
50
=99 M) substantially exhibited AGEs
formation inhibitory activity with DPPH radical scavenging activity. Hydroxyl groups at the C-
3, C-4, C-3, C-5, and C-7 positions were found to be important for the activity whereas
methylation or glucosylation of the 4`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
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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 bioavailabilty. Current eorts are focused for novel compounds with good bioavailability and
lower toxicity [139, 140].
Several polyphenols, such as avones and isoavones, constitute one of the most important
classes used in the treatment of peptic ulcers. Rutin, a natural flavone has been evaluated for
ulcer-protecting 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-3', 4,5-trimethoxy flavone) 78, is a synthetic flavone that suppresses the H.
pylori-induced inflammatory bowel disease (IBD) in animal models by targeting NF-B 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/ethanol at doses of 8 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-4`, 7,4`-dimethoxyavone (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-
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methoxy-4'-fluoroflavone (85, ED
50
=5.5 (4.0-7.0) 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
2`-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 S. 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 semi-synthetic 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 [151]. This class of natural products is becoming the subject
of anti-infective research and many groups have isolated and identied different flavones
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possessing antifungal, antiviral and antibacterial activity. Nitrogen containing avones 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 [152]. Numerous
flavones like 6,7,4`-trihydroxy-3`,5`-dimethoxyavone (89), 5,5`-dihydroxy-8,2`,4`-
trimethoxyavone (90) and 5,7,4`-trihydroxy-3`,5`-dimethoxyavone (91), 6-methoxy-2-
(piperazin-1-yl)-4H-chromen-4-one (92) derivatives have been reported to exhibit activity
against Aspergillus avus, 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
Aspergillus avus [153].
Various synthetic biavones showed anti-bacterial, anti-fungal and anti-viral activity.
Considering the antifungal properties, amentoavone (37), isocryptomerin, ginkgetin, bilobetin
were shown to have good antifungal action [154-156]. Dimerization of avones resulted in
increased fungi toxicity. Compound (93) 3`-3```biflavone was found to be active against
Aspergillus niger at Minimum Inhibitory Concentration of 0.4mol/mL [157]. The compound 94,
2-(2-chloroquinolin-3-yl)-6-methoxy-4H-chromen-4-one also showed excellent antifungal
activity against Aspergillus niger [158]. 4`-Bromo derivative (95, IC
50
=28.2 g/ml) have
displayed significant antifungal activity against Aspergillus niger and Fusarium oxysporium
[159].
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On the other hand, flavone glycoside (96) were found to have signicant antifungal
activity against Trichophyton mentagrophytes and Cryptococcus neoformans at MIC 6.25 g/ml
[160]. (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) [161].
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 Staphylococcus aureus. Compound (97, MIC=0.08 g/ml) was found to be
the most active flavonolignan derivative [162]. Stermitz et al. reported that a avonolignan,
namely (G)-5`-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 lipophillic 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 [163].
Flavones also exhibit bactericidal activity by interference with iDNA synthesis. A series
of flavones was studied for their DNA-gyrase inhibitory activities [164]. Luteolin (2), apigenin
(3), were identified to have antibacterial activity. Wang and colleagues synthesized 5-hydroxy-
7,4`-dimethoxyavone with a number of transition metals complexes and found that, hydroxyl
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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 [165].
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 [166]. SAR depicted that 5-hydroxyavones with additional hydroxyl groups at
the 7 and 4` positions did not exhibit anti-bacterial activity [167]. Methoxy groups substituted on
ring-B drastically decrease the antibacterial activity of avones. Interestingly, antibacterial
activity of avones increased by replacing oxygen atom with sulfur and nitrogen atoms at 4-
position of flavones. 4-thioavones (101) and 4-iminoavones (102) having flouro group at
position 4` 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, OCH
3
and NO
2
at 4`-
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 avone derivatives [168].
Babu et al. synthesized novel C-7 modied chrysin analogues and evaluated against a
panel of susceptible and resistant Gram-positive and Gram-negative organisms. It was observed
that most of the derivatives displayed signicant activity as compared to parent chrysin. Flavone
was linked to the alkyl amines by dierent 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 [169].
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Yin et al. discussed the prenylflavone derivatives as anti-bacterial agents. Among all,
(104) showed signicant antibacterial activity against the tested microbes at the level of MICs
0.009-0.073 mM. Prenyl group at ring-A and 7-methoxy group is required for activity [170].
Halogen substituted flavones were evaluated for anti-tuberculosis activity and it was observed
that 8-bromoflavone (105) derivative is more active than any other halide derivative like fluoro,
chloro or iodo [171].
Several natural and synthetic biavonoids were also evaluated for inhibitory activity
against Mycobacterium tuberculosis. The presence of OCH
3
and NO
2
substituents in
biavonoids may contribute to the observed inhibitory activity. Compound (106) (6`
6``biapigenin hexamethylether) exhibited highest inhibitory activity (96%) at a concentration of
12.5 mg/mL [172]. 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 [159].
Flavones with cyclohexyl groups substituted at their 2-positions, compound (109) and
(110) inhibited the growth of methicillin-resistant S. aureus [160]. The compounds having
monoamidinobenzimidazoles at the C-6 position of the flavones, (111) showed potent
antibacterial activities, particularly against Gram-positive bacteria. Compounds 111 and 112
exhibited the best inhibitory activity with MIC values of 1.56g/mL and 6.25g/mL respectively
against S. aureus [173]. (Table 1)
4.7.3 Antiviral Activity
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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, Epstein-Barr virus, human immunodeciency virus (HIV), and hepatitis B (HBV).
Inuenza 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 inuenza. Various scientists explored the structure requisites of flavone derivatives
for inuenza 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 substituents at 8th position of ring-A, possess the NA inhibitory activity [174]. 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 [175].
Ryu et al. reported that the parent avone, 115 (IC
50
= 1.1 uM) was more effective at
neuraminidase inhibition than alkylated avones, 116 (IC
50
=10.143.0M) [176]. The
biavonoids like amentoavone (37) were reported to show the inhibitory activity against
respiratory syncytial, herpes and measles viruses. New ginkgetin-sialic acid conjugates (117,
IC
50
=5.50g/ml) remarkably have potent anti-inuenza virus activity against A/PR/8/34 (H1N1)
than F36 (118, IC
50
=9.78 g/ml) [177, 178].
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It was also reported that flavones have an important role in inhibiting the poliovirus by
interfering with RNA synthesis of poliovirus [179]. The synergistic effect of flavone-flavonol
combinations was observed against herpes simplex virus type 2 (HSV), thus explaining that
combinations are more active than the individual compounds [180, 181]. 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 [182].
The EpsteinBarr virus (EBV) is one of the most common viruses in human which are
associated with various types of cancers, such as Hodgkin's lymphoma, Burketts lymphoma,
nasopharyngeal carcinoma, autoimmune diseases like dermatomyositis, systemic lupus
erythematosus, rheumatoid arthritis etc. Flavone, 3, 5, 6, 7, 8, 3`, 4`-heptamethoxyflavone (HPT)
(120) exhibited significant inhibitory effects on the EBV- early antigen activation induced by the
tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA) [183-185]. Robustaflavone, 121
(EC50=0.25 M) 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 [186].
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 5 years and responsible
for a child death in every 30s [187]. Various drugs have been developed to treat malaria, but due
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to associated adverse effects and development of multidrug resistance against different strains of
Plasmodium falciparum, further development of new anti-malarial is required [188].
In this context, various natural, semi-synthetic and synthetic flavones have been
discovered and evaluated for activity against various parasites like Plasmodium 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
infected-erythrocyte cyto-adherence property and decrease their sequestration in small vessels
[189, 190]. Casano et al. reported that aminomethoxyavone (122, IC
50
=7.7M) is the most
active derivative and exhibited the highest specicity and selectivity on P. falciparum. It was
investigated that subsequent substitutions on ring-B, uoro in position C-2` promoted a specic
anti-plasmodial activity of methoxyavone 123, (IC
50
=15M) and aminomethoxyavone 124,
(IC
50
=23M) [191].
Various biavonoids were isolated and flavone units linked with a avanone moiety
showed antiplasmodial activity [192]. Isochamaejasmin (125) was the most active compound,
with a moderate anti-plasmodial activity (IC
50
=7.33.8M) and relatively low cytotoxicity
(CC
50
=29.010.9 M) when compared with chloroquine [193]. Auret et al. synthesized and
tested different flavonoid derivatives having a piperazinyl chain for their anti-plasmodial activity.
The compounds having a 2,3,4-trimethoxybenzylpiperazinyl chain attached to the avone at the
7-hydroxyl group of ring-A, showed in vitro activity against P. falciparum strains in the
micromolar to submicromolar range. Among all the synthesized compound, 126 and 127,
(IC
50
=1, 0.6 M respectively) were found to be the most active [194].
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Various natural anti-protozoal flavones were isolated from different sources. Flavone 128,
isolated from Lonchocarpus spp. was found to be the most active against Leishmania parasites
[195]. Lanaroavone (129, IC
50
= 0.48 M), a biapigenin with a C-4OC-8 interavonoid
linkage exhibited antiplasmodial, leishmanicidal and antitrypanosomal activities without any
cytotoxicity [196]. (Table 1)
4.9 Anti-HIV
Over the past 25 years, since the rst case of HIV/AIDS was identied, 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 HIV-inhibitors 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 [197]. 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 (3,3`,4`,5,6,7-Hexahydroxy avone), Morin
(2`,3,4`,5,7-Pentahydroxy avone) 130 and 131, have been isolated from the leaves of N. nucifera
[198].
Flavones act by reacting chemically or by forming complex with essential groups of the
enzyme [199]. More negative charge on carbonyl oxygen atom lead to an increase of the anti-
HIV-1 integrase activity [200]. Thalassiolins, a natural flavone having HIV-integrase inhibitory
property has been isolated from the Caribbean sea grass Thalassia testudinum. It contains -D-
glucopyranosyl-2``-sulfate at hydroxyl group of C-7 of flavone, that increased potency against
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HIV-integrase by interacting with catalytic core domain of HIV-1 integrase. Thalassiolin A (132,
luteolin 7--D-glucopyranosyl-2``-sulfate) was the most active, inhibiting the integrase terminal
cleavage and strand transfer activities with IC
50
values of 2.1 and 0.4 mM, respectively [201].
Casano et al. synthesized and evaluated various flavones and chalcones for inhibition of
HIV multiplication. Amongst all, 3-methoxyavone (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 specic inhibitors of the HIV-2 multiplication
[202]. (Table 1)
SAR studies have revealed that A ring bearing an amino group at position 6, C ring with
H, OH, and OCH
3
at position 3 and mono substituents (H, OCH
3
, F, CF
3
) 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, 3 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 anti-
inflammatory effects [203]. 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.
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A natural flavone luteolin-7-O--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 [Ca
2+
]. SAR revealed that the
C2=C3 double bond on ring-C and 3`,4`-dihydroxyl on ring-B are necessary for cardioprotective
effects. 4-keto group is a requisite for vasodilation [204, 205]. The effects of avone on
myocardial post-ischemic-reperfusion recovery were studied by Ning et al. and found that avone
treatment caused better recovery of left ventricular developed pressure [206].
Budriesi et al. have synthesized a series of 1,4-dihydropyridines bearing a 3-
methoxyavone 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 eects could be potentially deleterious [207]. Various flavone
derivatives have been evaluated for lipid peroxidation inhibitory activity on isolated rat hearts.
Compound (138) reduced ischemia/reperfusion-induced cardiac dysfunction [208].
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
substituents of the secondary amine was found to be necessary for drug-receptor interactions.
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Substitution of the para position of the ring-B with a variety of substituents, i.e., NO
2
, NH
2
,
OCH
3
and CH
3
causes a loss of activity [209].
In cardiac disorders, abnormal rhythm of the heart increases the risk of death, congestive
heart failure, and heart strokes. Atrial brillation is the most common form of cardiac
dysarrhthmia. Several anti-arrhythmic agents like amiodarone, sotalol are effective in treating
atrial brillation but have major limitations, such as inducing severe ventricular arrhythmia [210].
Acacetin, (5,7-dihydroxy-4`-methoxyavone, 140), a natural flavone, selectively inhibits human
atrial repolarization potassium currents and prevents atrial fibrillation. Acacetin is an orally
effective atrium-selective agent [211].
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 [212]. Different avone and isoavone derivatives have been found to exhibit
anti-platelet and vasorelaxing properties [213, 214]. 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 [215]. Correia-da-Silva et al. incorporated
oligo-O-sulfated 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=66M).
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
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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 of a dual
anticoagulant and anti-platelet activities of compounds could enhance their potential as
antithrombotic agents [216]. Wang et al. reported that oxime- and methyloxime-containing
isoavone-7-yl derivatives having good anti-platelet activity with respect to flavones [217].
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 [218]. Macrophage initiates release of several pro-inamatory 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 [219, 220]. 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-B 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 [221]. Luteolin (2) has been reported to interfere with
lipopolysaccharide-triggered Akt (PKB) phosphorylation and NF-B activation [222, 223].
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Activated endothelium cells and macrophages produces nitric oxide through the activity
of nitric oxide synthase (NOS), that is important in maintaining the dilation of blood vessels
[224]. 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 avones [225]. 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 [226].
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 pro-inammatory enzymes like inducible nitric oxide synthase
(iNOS) and COX-2. Moreover, Flavones with 3`,4`-dichloro substituents 142 on the B ring
exhibit strong COX-2 inhibitory activities irrespective of the substitution pattern on ring A [227,
228].
4.13 Phosphodiesterase Inhibitors
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
benets like cardiotonics, vasodilators, smooth muscle relaxants, antidepressants, anti-
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thrombotics, and anti-asthmatics. This enzyme has also been involved in erectile dysfunction
[229]. Various approved phosphodiesterase (PDE5A1) inhibitors such as sildenal and
vardenal, used to enhance blood ow and improve erectile response by increasing the cGMP
level, but exhibit unwanted side effects including visual disturbance and cutaneous ushing
[230]. 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 [231-233].
The SAR study revealed that position of hydroxyl group determines the selectivity towards
several PDE isoforms e.g. hydroxyl group at the C-4` position is important for PDE
3
inhibition,
same substituents at the C-5 position for PDE
1
, PDE
2
, PDE
4
, and PDE
5
inhibition and
hydroxylation at C-7 is important for inhibition of PDE
1
, PDE
3
, and PDE
4
[234-236]. Flavone
glycoside isolated from Ginkgo biloba have also been demonstrated PDE inhibitory activity, by
inhibition of cAMP PDE [237].
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 [238, 239]. (Fig. 10)
Xanthine oxidase (XO) is concerned in the pathogenesis of viral infections, inammation,
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 [240].
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The planar structure and C-5 and C-7 hydroxyl group of avones are important for the
inhibition of XO enzyme at low concentrations. The C-5 and C-7 hydroxyl groups of avones
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 [241]. Apigenin (3, K
i
=0.52 M) and luteolin
(2, K
i
=2.9 M) exhibited strong inhibitory effect on the XO as compared to a synthetic XO
inhibitor allopurinol (K
i
of 7.3 M) [242]. Baicalein, 8 (5,6,7-trihydroxy flavones) also inhibit the
XO in competitive manner [243].
Flavones act in the dissociated (anionic) form that originates from the dissociation of the
C7-hydroxyl group. The anionic oxygen of the avone 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 avones is involved in hydrophobic interactions with the enzyme in the
same region as the purine analog inhibitors [244]. The hydroxyl group at C-7 is also crucial for
inhibitory activity, as it enables the avones to create hydrophobic interactions in the optimal
region of the enzyme [245]. 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 avones
[246].
4.15 Lipid-lowering agent
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
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diseases [247]. The lipids are catabolized through the activation of nuclear receptors like
peroxisome proliferator-activated receptors (PPARs) in adipocytes. It has been reported that
polymethoxyavones signicantly increase or activate PPAR- and PPAR-, that further reduced
triglyceride (TG) content in the liver and heart. It also regulates adipocytokines by signicantly
suppressing TNF-a (tumor necrosis factor-a), INF-g (interferon-g), IL-1b (interleukin-1b) and IL-
6 (interleukin-6) expression [248]. The avone 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 [249]. The hybrid congeners 6- and 7-hydroxy avones with aminopropanol have been
synthesized and evaluated for anti-dyslipidemic activities. The compound 144 and 145 lowered
cholesterol and TG proles 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
avones, the oxygen atoms at the 3,5-positions in the B ring seem necessary for
antidyslipidemic activities [250].
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 avones and among them, 146 showed competitive muscarinic receptor binding
activity with K
i
=76.5M. The potency of the methoxyavones to inhibit muscarinic receptor
binding is inuenced by the position and number of methoxy group substitutions. All the avones
that bind to the muscarinic receptor possessed C-3, C-5 methoxy groups and C2=C3 double bond
in conjugation with 4-oxo group [251].
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Flavoxate, 147 possess anti-cholinergic activity along with anti-muscarinic effects. Thus,
it can be used to treat urinary bladder spasms, while avoxate 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 [252].
4.17 Vasorelaxant
Hypertension, one of the most common cardiovascular diseases, is dened 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. [253]. Series of
flavones like 3-hydroxyavone (148), 6-hydroxyavone (149), 7-hydroxyavone (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 PGI
2
in a
concentration-dependent manner [254]. (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 eld
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 substituents
at ortho- and meta- positions on ring-B (151) of avone derivatives decrease the potency of
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vasorelaxant activities. 5, 7-dihydroxy-3`-bromo-avone (152) exhibited the highest vasodilator
activity [255, 256].
It was reported that prenyl groups could increase the lipophilicity and confer to the
molecule a strong afnity to biological membranes, and result in the signicant enhancement of
bioactivities. Hydrophobic substituents in ring-B of avone exhibit medium activities 153 and
154 (Br, trimethoxyl), while the 3-hydroxyl substituent (155) attenuated the relaxation activity
[257, 258].
The most eective 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 [259].
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. 1- and 2-adrenoceptors cause the contraction of the human prostate. So, -blockers (1-
adrenergic receptor antagonists) including doxazosin, terazosin are used for initial therapy of
Prostate hyperplasia [260-262]. -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
1-adrenoreceptor agonists or hypogastric nerve stimulation with decreased side effects [263,
264].
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Arylpiperazine substituted flavones derivatives have high anity and selectivity for 1-
and 2-adrenoceptors. SAR explained that the arylpiperazine moiety was crucial for anity with
the o-isopropoxy substituted derivative better than the corresponding o-methoxyl substituted
compound. Affinity is decreased by replacement of arylpiperazine with pyridazinone-piperazine
system. Additionally, the alkyl bridge connecting the arylpiperazine to flavone fragment was
found to be important for anity, as variation in its length caused slight decrease in anity.
Whereas, substitutions on flavone ring do not have any inuence on anity toward 1- and 2-
adrenoceptors [265].
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,
IC
50
=5-50 M) decrease the secretion of prostate specic antigen (PSA), a glycoprotein that
causes BPH [266].
4.19 Antileishmanial Agents
Leishmaniasis is one of the major parasitic diseases. Currently, there is no eective
vaccine for leishmaniasis. Therefore, there is an urgent need to speed up the development of a
new generation of eective and safe antileishmanials. Various natural and synthetic avones
have been reported to have potent leishmanicidal activity [267]. 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 (IC
50
=0.13 to 0.21 M) 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
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linker, as shortening the linker length resulted in lost of activity. (2) Changing the attachment
position of the two avones to the amino PEG linker, attachment at C-3 position ring-B showed
significant activity as compared to compound having linker attached at C-4 position. However,
attachment at C-2 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 avones with dierent groups like methoxy at C-3
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
eect 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 [268].
Several compounds were investigated in-vivo for their anti-leishmanial and anti-
trypanosomal activity in mouse models. The best in-vitro trypanocidal activity was exerted by 7,
8-dihydroxyavone (158, IC
50
=68 ng/ml). For leishmanicidal activity 3-hydroxyavone (159,
IC
50
=0.7 g/ml), luteolin (2, IC
50
=0.8 g/ml) were most potent compounds. The insertion of
hydroxyl groups at C-7, C-8, and signicantly enhanced the leishmanicidal potential. Further,
methylation of the hydroxyl groups was impoverished and reduced the leishmanicidal activity
signicantly 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 avone skeleton, caused a slight
to appreciable reduction in anti-leishmanial potency [269].
4.20 Anti-oesteoporotic agents
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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 dihydroavonol derivative K 058 (160) from Ulmus
wallichiana, and found that it increased mRNA levels of various oesteoblast-specic genes. It
was not oesteogenic in the rat uterus, but promotes oesteoprogenitor cells in immature rats [270].
4.21 Cell membrane protective activity
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 avones at the membrane interface [271].
Additionally, the partitioning of avones 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 [272].
4.22 Cosmetic agents
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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 [273, 274].
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
non-competitive inhibitor. Luteolin 7-O-glucoside, also showed tyrosinase inhibitory activity
[275].
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 [276]. Other flavones involve in tyrosinase inhibition activity are 6-
hydroxyapigenin, 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 [277].
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
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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 [278].
4.23 Immuno-modulator activity
The immune system is bodys defense system against various types of diseases, pathogens
like viruses, parasites, etc. Sometimes immune cells fail to recognize bodys own constituents and
become hyperactive and attack normal tissues, such anomalous immune response is called an
autoimmune disease. Common autoimmune diseases include rheumatoid arthritis, diabetes
mellitus type-I, psoriasis etc.
Various plant-derived and synthetic avones inhibited the autoimmune diseases by
interfering with intracellular processes, particularly phosphorylation pathways [279]. 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 -B-crystallin, an auto-antigen
in multiple sclerosis. Major contributor antigen-specic IFN- production was reduced effectively
by avones thus, manage the T-cell mediated multiple sclerosis [280, 281].
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 immune-suppressive agents in the treatment of
autoimmune disorders. Another novel flavone PMF 165 (5,3-dihydroxy-3,6,7,8,4-
pentamethoxyflavone) induced immune response against tumor by suppressing Signal
Transducers and Activators of Transcription (STAT3) [282].
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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 2mg/ml, but also showed signicant cytotoxic eect on T-cells survival
[283].
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 [284].
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 [285]. Radio-protective effects of quercetin (3-hydroxy-flavone),
chrysin (1), luteolin (2), vicenin (166) and orientin (167) avones are well reported in the
literature [286-289].
4.25 Anti-asthmatic activity
FcRI receptors, present on the surface of mast cells and basophills, are critically involved in
various chronic inflammatory conditions like atopic dermatitis, allergic rhinitis and asthma.
Interaction of allergen bound IgE with FcRI receptors triggers the mast cell signaling resulting
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in the release of allergic mediators, histamine, proteases, chemotactic factors, leukotrienes and
arachidonic acid metabolites [290]. Anti-asthmatic therapy can be targeted at blocking the first
step, i.e. FcRI receptor expression or antagonizing the effects of the mediators released in the
later steps. Flavones have been reported to have an inhibitory effect on FcRI receptor
expression, anti-histaminic activity and leukotriene antagonism.
Tricetinidin (168) possesses similar inhibitory activity as compared to epicatechin gallate
(ECG) (169), a potent FcRI expression inhibitor. Both these compounds possess pyrogallol
moiety in common, thus, this partial structure can be proposed to signicantly associated with
inhibition of FcRI expression [291].
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 [292]. Numerous carboxyavones like (170), signicantly
modulate the action of leukotrienes.
SAR depicted that 4-substituted flavones showed 10-20 times less leukotriene
antagonism as compared to 3-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) [293]. Additionally, the racemic
aryloxypropanolamine derivatives 173 and 174 antagonized the effect of leukotrienes and 5-
lipoxygenase [294]. Moreover, Yamamura et al. has reported anti-histaminic activity of flavones
[295]. (Table 1)
4.26 GABA antagonistic activity
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-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 have some additional binding
sites for compounds like benzodiazepines (BZDs), -carboline, barbiturates etc that allosterically
modifies chloride channel gating [296, 297]. Among these, BZDs form most important GABAA
receptor modulating drugs with anxiolytic, anticonvulsant, muscle relaxant, and sedative hypnotic
effects [298]. It has been found that some naturally occurring and synthetic flavones binds to
BZD binding site with high affinity and exhibits anxiolytic effect selectively [299, 300].
It has been reported by Dekermendjian et al. in 1999 that flavones with substitution at 6th
position (methyl) and 3 position (nitro group), (175) have high affinity for benzodiazepines
[301]. But later in 2002, Kahnberg et al. identified 5-bromo-2-hydroxy-6-methylavone (176)
as potent binder of BZD with Ki value of 0.9 nM [302]. Azaflavones were also considered to
have binding affinity for BZDs (177) but were found to be less potent as compared to flavones
[303].
GABA is metabolized by two enzymes, i.e. GABA-transaminase (GABA-T) and succinic
semialdehyde dehydrogenase (SSADH) [304]. The decreased levels of GABA in neurological
conditions, including epilepsy, Parkinsons disease, Huntingtons chorea, and Alzheimers
disease can be increased by inhibiting GABA-T and SSADH. Flavonoid components of E.
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 GABA-T with an IC
50
value of 12.81.2 mM, and scutellarein (161) exhibited
the best inhibitory effect on SSADH with an IC
50
value of 7.200.9 Mm [305].
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4.27 Anti-diarrheal
Secretory diarrhea is a massive health problem in the developing countries. Escherichia coli
and Vibrio cholerae are the two major pathogenic bacterias causing secretory diarrhea.
Enterotoxins released by these organisms results in increased cellular levels of cAMP and cGMP
that further activates the cystic brosis transmembrane conductance regulator (CFTR) Cl channel
present in the apical membrane of epithelia [306, 307]. 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 avones 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 9mol/L and inhibits forskolin-
stimulated CFTR with a Ki of 81mol/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
[308, 309].
Recently, Schuier et al. identified that central aromatic -pyrone ring of flavones that
determines the binding site affinity (probably by - 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 -pyrone ring. Thus, flavones can target CFTR as blockers to
treat secretory diarrhea [310].
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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 avone (180) with an EC50 of 3.1g/mL was revealed as most potent anthelmintics, but no
clear pattern of structure activity relationship was observed [311]. (Table 1)
5. Conclusion
The avones are important members of the avonoid 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, specically 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, avones are yet to achieve the status of promising drug
candidates, and only a few avones 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. This information may provide an opportunity to scientists of
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medicinal chemistry discipline to design selective, optimize as well as poly-functional flavone
derivatives for the treatment of multi-factorial diseases.
Acknowledgement
I am grateful to my many colleagues and assistants who over the years have contributed much
of the data shown here This publication was made possible by University grant commission, New
Delhi, for provide me financial support with UGC-BSR (Basic Scientific Research) fellowship
(No. 7-265). Finally, thanks are due to Dr. Om Silakari for helpful discussions during the
preparation
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Abbreviations
FDA: Food drug adminstration
NSAIDs: Non-steroidal anti-inflammatory drugs
COX: Cyclooxygenase
CNS: Central nervous system
RNA: Ribonucleic acid
AIDS: Acquired imunnodeficiency virus
DPPH: di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium
HIV: Human immunodeficiency virus
cDNA: Complementary Deoxyribonucleic Acid
LDH: Lactate dehydrogenase
IFN: Interferon gamma
FcRI: Fc epsilon receptor inhibitors
SSADH: Succinic semialdehyde dehydrogenase
PAL: Phenylalanine ammonia-lyase
C4H: Cinnamate-4-hydroxylase
4CL: 4-coumaroyl-coenzyme A ligase
CHS: Chalcone synthase
CHI: Chalcone flavanone isomerase
ROS: Reactive Oxygen Species




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Figure Captions
Fig. 1. Basic scaffold of flavone
Fig. 2. Therapeutic Activity Profile of Flavones
Fig. 3. Structure features required for Antioxidant Activity
Fig. 4. Flavone chelates with oxidizing metal ions
Fig. 5. Fenton Reaction
Fig. 6. Scavenging of ROS (Ro) by 3`,4`-Dihydroxylflavone
Fig. 7. Structure Activity Relationship for Anti-cancer activity of flavones
Fig. 8. Tacrine-4-oxo-4H-chromene hybrids showed potent combined inhibition of BACE-1
and ChEs
Fig. 9. The modulation of amyloid (A) pathology by flavones.
Fig. 10. Oxidation of hypoxanthine and xanthine to uric acid
Table 1. The structures of Flavone derivatives.
Scheme 1. Synthesis of flavones via beta diketon intermediate.
Scheme 2. Baker Venkataraman rearrangement reaction.
Scheme 3. Claisen-Schmidt condensation reaction
Scheme 4. Biosynthetic pathway of flavones.

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Structure C.
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O OH
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3

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6

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O
O
N
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O
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114

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O
O
O
O
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127

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128

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132

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O
O
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O
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CH
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50

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O
O
OSO
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OSO
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OSO
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O
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SO
O
O
O
O
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SO
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3
OSO
3
O
OSO
3
OSO
3
OSO
3 H
3
C

52

142

53

143

54

144

55

145

56

146

57

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O
O
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66

156

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157

68

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69

159

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O HO
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O
O
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80

170
O
O
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81

171

82

172

83

173

84

174

85
O
O
OCH
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F

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Highlights

The numerous biological activities of flavones has been discussed.
Synthesis and Chemistry of flavone scaffold has been discussed.
The various examples of flavones derivatives with different activities has been
discussed.
Structure activity relationship (SAR) of flavone scaffold for different activities
has been discussed in this review.