REVIEW ARTICLE
Flavonoids: an overview
A. N. Panche
1,2
, A. D. Diwan
2
* and S. R. Chandra
1
1
Department of Bio-Engineering, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India
2
MGM’s Institute of Biosci ences and Technology, Mahatma Gandhi Mission, N-6, CIDCO, Aurangabad-431003, India
(Received 18 July 2016 – Final revision received 4 October 2016 – Accepted 5 October 2016)
Journal of Nutritional Science (2016), vol. 5, e47, page 1 of 15 doi:10.1017/jns.2016.41
Abstract
Flavonoids, a group of natural substances with variable phenolic structures, are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine.
These natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients so called flavonoids.
Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This
is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular
enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also prevention of
CHD. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that deri-
vatives of plant origin possess a broad spectrum of biological activity. Current trends of research and development activities on flavonoids relate to iso-
lation, identification, characterisation and functions of flavonoids and finally their applications on health benefits. Molecular docking and knowledge of
bioinformatics are also being used to predict potential applications and manufacturing by industry. In the present review, attempts have been made to
discuss the current trends of research and development on flavonoids, working mechanisms of flavonoids, flavonoid functions and applications, prediction
of flavonoids as potential drugs in preventing chronic diseases and future research directions.
Key words: Flavonoids: Structure and composition: Biological activity: Research trends: Future research directions
Flavonoids are an important class of natural products; particu-
larly, they belong to a class of plant secondary metabolites hav-
ing a polyphenolic structure, widely found in fruits, vegetables
and certain beverages. They have miscellaneous favourable
biochemical and antioxidant effects associated with various
diseases such as cancer, Alzheimer’s disease (AD), atheroscler-
osis, etc.
(1–3)
. Flavonoids are associated with a broad spectrum
of health-promoting effects and are an indispensable compo-
nent in a variety of nutraceutical, pharmaceutical, medicinal
and cosmetic applications. This is because of their antioxida-
tive, anti-inflammatory, anti-mutagenic and anti-carcinogenic
properties coupled with their capacity to modulate key cellular
enzyme functions. They are also known to be potent inhibitors
for several enzymes, such as xanthine oxidase (XO),
cyclo-oxygenase (COX), lipoxygenase and phosphoinositide
3-kinase
(4–6)
.
In nature, flavonoid compounds are products extracted
from plants and they are found in several parts of the plant.
Flavonoids are used by vegetables for their growth and
defence against plaques
(7)
. They belong to a class of
low-molecular-weight phenolic compounds that are widely dis-
tributed in the plant kingdom. They constitute one of the most
characteristic classes of compounds in higher plants. Many fla-
vonoids are easily recognised as flower pigments in most
angiosperm families. However, their occurrence is not
restricted to flowers but are found in all parts of plants
(8)
.
Flavonoids are also abundantly found in foods and beverages
of plant origin, such as fruits, vegetables, tea, cocoa and wine;
Abbreviations: Aβ, amyloid protein; AChE, acetylcholinesterase; AD, Alzheimer’s disease; BACE-1, β active site cleavage enzyme-1; BChE, butyrylcholinsterase; COX, cyclo-
oxygenase; NDM-1, New Delhi metallo-β-lactamase-1; XO, xanthine oxidase.
* Corresponding author: Dr A. D. Diwan, email arvinddiwan@yahoo.com
© The Author(s) 2016. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creative-
commons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is
properly cited.
JNS
JOURNAL OF NUTRITIONAL SCIENCE
1
https://doi.org/10.1017/jns.2016.41 Published online by Cambridge University Press
hence they are termed as dietary flavonoids. Flavonoids have
several subgroups, which include chalcones, flavones, flavo-
nols and isoflavones. These subgroups have unique major
sources. For example, onions and tea are major dietary sources
of flavonols and flavones.
Flavonoids play a variety of biological activities in plants,
animals and bacteria. In plants, flavonoids have long been
known to be synthesised in particular sites and are responsible
for the colour and aroma of flowers, and in fruits to attract
pollinators and consequently fruit dispersion to help in seed
and spore germination, and the growth and development of
seedlings
(9)
. Flavonoids protect plants from different biotic
and abiotic stresses and act as unique UV filters
(10)
, function
as signal molecules, allopathic compounds, phytoalexins,
detoxifying agents and antimicrobial defensive compounds.
Flavonoids have roles against frost hardiness, drought resist-
ance and may play a functional role in plant heat acclimatisa-
tion and freezing tolerance
(11)
. Jorgensen
(12)
has mentioned
that the early advances in floral genetics were primarily due
to mutation techniques making an impact on flavonoid-
derived flower colours, and demonstrated that functional
gene silencing in plants was associated with flavonoid biosyn-
thesis. Flavonoids have been ascribed positive effects on
human and animal health and the current interest is for disease
therapy and chemoprevention. Currently there are about 6000
flavonoids that contribute to the colourful pigm ents of fruits,
herbs, vegetables and medicinal plants. Dixon & Pasinetti
(13)
reviewed plant flavonoids and isoflavonoids in detail and dis-
cussed their applications to agriculture and neurosciences in
human beings. Kumar & Pandey
(14)
reviewed the protective
roles of flavonoids against human diseases as well as their
functions in plants. Recently Panche et al.
(15)
, while reviewing
AD and current therapeutic methods, discussed in detail
uses of flavonoids as plant secondary metabolites for the treat-
ment of AD and the mechanisms involved. In the present
review, attempts have been made to discuss the current trends
of research and development on flavonoids, their applications
as dietary and health benefits along with broad classification
and future research directions.
Classification
Flavonoids can be subdivided into different subgroups
depending on the carbon of the C ring on which the B ring
is attached and the degree of unsaturation and oxidation of
the C ring (Fig. 1). Flavonoids in which the B ring is linked
in position 3 of the C ring are called isoflavones. Those in
which the B ring is linked in position 4 are called neoflavo-
noids, while those in which the B ring is linked in position 2
can be further subdivided into several subgroups on the
basis of the structural features of the C ring. These subgroups
are: flavones, flavonols, flavanones, flavanonols, flavanols or
catechins, anthocyanins and chalcones (Fig. 1).
Flavones
Flavones are one of the important subgroups of flavonoids.
Flavones are widely present in leaves, flowers and fruits as
glucosides. Celery, parsley, red peppers, chamomile, mint
and ginkgo biloba are among the major sources of flavones.
Luteolin, apigenin and tangeritin belong to this subclass of fla-
vonoids (Fig. 2). The peels of citrus fruits are rich in the poly-
methoxylated flavones, tageretin, nobiletin and sinensetin
(16)
.
They have a double bond between positions 2 and 3 and a
ketone in position 4 of the C ring. Most flavones of vegetables
and fruits have a hydroxyl group in position 5 of the A ring,
while hydroxylation in other positions, for the most part in
position 7 of the A ring or 3
′
and 4
′
of the B ring, may
vary according to the taxonomic classi fi cation of the particular
vegetable or fruit.
Flavonols
Flavonols are flavonoids with a ketone group. They are build-
ing blocks of proanthocyanins. Flavonols occur abundantly in
a variety of fruits and vegetables. The most studied flavonols
are kaempferol, quercetin, myricetin and fisetin (Fig. 2).
Onions, kale, lettuce, tomatoes, apples, grapes and berries
are rich sources of flavonols. Apart from fruits and vegetables,
tea and red wine are also sources of flavonols. Intake of flavo-
nols is found to be associated with a wide range of health ben-
efits which includes antioxidant potential and reduced risk of
vascular disease.
Compared with flavones, flavonols have a hydroxyl group in
position 3 of the C ring, which may also be glycosylated. Like
flavones, flavonols are very diverse in methylation and hydrox-
ylation patterns as well and, considering the different glycosy-
lation patterns, they are perhaps the most common and largest
subgroup of flavonoids in fruits and vegetables. For example,
quercetin is present in many plant foods
(17)
.
Flavanones
Flavanones are another important class which is generally pre-
sent in all citrus fruits such as oranges, lemons and grapes.
Hesperitin, naringenin and eriodictyol are examples of this
class of flavonoids (Fig. 2). Flavonones are associated with
a number of health benefits because of their free radical-
scavenging properties. These compounds are responsible for
the bitter taste of the juice and peel of citrus fruits. Citrus
flavonoids exert interesting pharmacological effects as antioxi-
dant, anti-inflammatory, blood lipid-lowering and cholesterol-
lowering agents. Flavanones, also called dihydroflavones, have
the C ring saturated; therefore, unlike flavones, the double
bond between positions 2 and 3 is saturated and this is the
only structural difference between the two subgroups of flavo-
noids. Over the past 15 years, the number of flavanones has
significantly increased
(17)
.
Isoflavonoids
Isoflavonoids are a large and very distinctive subgroup of fl a-
vonoids. Isoflavonoids enjoy only a limited distribution in the
plant kingdom and are predominantly found in soyabeans and
other leguminous plants. Some isoflavonoids have also been
reported to be present in microbes
(18)
. They are also found
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to play an important role as precursors for the development
of phytoalexins during plant microbe interactions
(19,20)
.
Isoflavonoids exhibit tremendous potential to fight a number
of diseases. Isoflavones such as genistein and daidzein are
commonly regarded to be phyto-oestrogens because of their
oestrogenic activity in certain animal models (Fig. 2).
Szkudelska & Nogowski reviewed the effect of genistein indu-
cing hormonal and metabolic changes, by virtue of which they
can influence various disease pathways
(21)
.
Neoflavonoids
Neoflavonoids are a class of polyphenolic compounds. While
flavonoids have a 2-phenylchromen-4-one backbone, neofla-
vonoids have a 4-phenylchromen backbone with no hydroxyl
group substitution at position 2. The first neoflavone isolated
from natural sources in 1951 was calophyllolide from
Calophyllum inophyllum seeds. It is also found in the bark and
timber of the Sri Lankan endemic plant Mesua thwaitesii
(22–24)
.
Flavanols, flavan-3-ols or catechins
Flavanonols, also called dihydroflavon ols or catechins, are the
3-hydroxy derivatives of flavanones. They are a highly diversified
and multisubstituted subgroup. Flavanols are also referred to
fla van-3-ols as the hydroxyl group is always bound to position
3 of the C ring. Unlike many flavonoid s, there is no double
bond between positions 2 and 3. Flavanols are found abundantly
in bananas, apples, blueberries, peaches and pears (Fig. 2).
Anthocyanins
Anthocyanins are pigments responsible for colours in plants,
flowers and fruits. Cyanidin, delphinidin, malvidin, pelargoni-
din and peonidin are the most commonly studied anthocyanins
(Fig. 2). They occur predominantly in the outer cell layers of
various fruits such as cranberries, black currants, red grapes,
merlot grapes, raspberries, strawberries, blueb erries, bilberries
and blackberries. Stability coupled with health benefits of these
compounds facilitate them to be used in the food industry in a
variety of applic ations
(25)
. The colour of the anthocyanin
depends on the pH and also by methylation or acylation at
the hydroxyl groups on the A and B rings
(17)
.
Chalcones
Chalcones are a subclass of flavonoids. They are characterised
by the absence of ‘ ring C’ of the basic flavonoid skeleton struc-
ture shown in Fig. 1. Hence, they can also be referred to as
open-chain flavonoids. Major examples of chalcones include
Fig. 1. Basic skeleton structure of flavonoids and their classes.
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phloridzin, arbutin, phloretin and chalconaringenin. Chalcones
occur in significant amounts in tomatoes, pears, strawberries,
bearberries and certain wheat products. Chalcon es and their
derivatives have garnered considerable attention because of
numerous nutritional and biological benefits. Table 1 describes
the food sources of all dietary flavonoids discussed throughout
the article for their bioactivity and research trends
(26–63)
. The
intake of flavonoids through food sources could be the sim-
plest and safest way to combat diseases as well as modulate
activities.
Current research and trends on flavonoids
Anti-cholinesterase activity
Acetylcholinesterase (AChE) is a key enzyme in the central
nervous system and inhibition of it leads to increases of neural
acetylcholine levels which is one of the therapies for symptom-
atic relief of mild to moderate AD
(64)
. Hence the inhibition of
cholinesterases is one of the central focus for drug develop-
ment to combat AD. A number of flavonoids have been
reported for their anti-cholinesterase activity. The in vitro
inhibitory studies done on various flavonoids like quercetin,
rutin, kaempferol 3-O-β-
D-galactoside and macluraxanthone
showed that quercetin and macluraxanthone possess a
concentration-dependent inhibition ability against AChE and
butyrylcholinsterase (BChE)
(34)
. Macluraxanthone was found
to be the most potent and speci fi c inhibitor of both the
enzymes with 50 % inhibitory concentration (IC
50
) values of
8·47 and 29·8µ
M, respectively. The enzyme kinetic studies
revealed that quercetin inhibited both the enzymes in a
competitive manner whereas macluraxanthone was non-
competitive against AChE and competitive against BChE.
To get insight of the intermolecular interactions, molecular
docking studies of these two compounds were performed at
active sites of both the enzymes. The docking studies showed
that macluraxanthone binds much more tightly with both the
enzymes than that of quercetin. Sheng et al.
(65)
, while design-
ing, synthesising and performing the evaluation of flavonoid
derivatives as potent AChE inhibitors, observed that most
of the flavonoid derivatives have properties of inhibitory activ-
ities to AChE. The most potent inhibitor, isoflavone derivative
10d, inhibits AChE with an IC
50
of 4 nM, showing a high
BChE:AChE inhibition ratio (4575-fold), superior to donepe-
zil (IC
50
=12nM, 389-fold). Molecular docking studies were
also performed to explore the detailed interaction with AChE.
Anti-inflammatory activity
COX is an endogenous enzyme which catalyses the conversion
of arachidonic acid into prostaglandins and thromboxanes
(66)
.
Fig. 2. Flavonoid classes, subclasses and natural sources.
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The enzyme exists in two isoforms, COX-1 and COX-2.
COX-1 is a constitutive enzyme and is responsible for the sup-
ply of prostaglandins which maintain the integrity of the gastric
mucosa and provide adequate vascular homeostasis whereas
COX-2 is an inducible enzyme and is expressed only after
an inflammatory stimulus
(67)
. The function of COX-2 is to
synthesise prostaglandins for the induction of infl ammation
and pain
(68)
. The studies done by using in silico methods on
the binding modes of flavonoids with COX-2 explored that
some flavonols and flavones containing a 2, 3-double bond
may act as preferential inhibitors of COX-2
(69)
. These observa-
tions were found for the flavonol, fl avone, and flavanone or
isoflavone classes. This discovery led to the development of
selective COX-2 inhibitors which are a class of compounds
with good anti-inflammatory activity and reduced gastrointes-
tinal side effects. The commercially available flavonoids like
silbinin, galangin, scopoletin, hesperitin, genistein, daidzein,
esculatin, taxifolin, naringenin and celecoxib were also evalu-
ated for COX-inhibitory activity
(70)
. The selected flavonoids
showed higher binding energy ranging between −8·77
to −6·24 kcal/mol (–36·69 to –26·11 kJ/mol) when com-
pared with that of the standard (−8·30 kcal/mol; –34·73
kJ/mol) which led to the development of potent COX inhibi-
tors for the treatment of inflammation. Madeswaran et al.
(70)
evaluated the COX-inhibitory activity of flavonoids using in
silico docking studies. In this perspective, they used flavonoids
like farobin-A, gericudranin-B, glaziovianin-A, rutin and
xanthotoxin. Their docking results showed that all the selected
flavonoids contributed better aldose reductase inhibitory activ-
ity because of their structural parameters. Hence, further dee-
per studies could develop potent aldose reductase inhibitors
for the treatment of diabetes. Madeswaran et al.
(71)
also
reported in silico docking studies of lipoxygenase-inhibitory
activity of commercially available flavonoids. In this perspec-
tive, they selected flavonoids like aromadedrin, eriodictyol,
fisetin, homoeriodictyol, pachypodol, rhamnetin, robinetin,
tangeritin, theaflavin and azelastine for investigation. It was
observed that all the selected flavonoids contributed to
lipoxygenase-inhibitory activity because of their structural
parameters and the whole analysis could lead to the further
Table 1. Flavonoids, their classes and rich dietary sources
Serial
no. Flavonoid Class Dietary sources References
1 Quercetin Flavonols Vegetables, fruits and beverages, spices, soups, fruit
juices
Hertog et al.
(26)
; Justesen &
Knuthsen
(27)
; Stewart et al.
(28)
; Zheng &
Wang
(29)
2 Rutin Flavonols Green tea, grape seeds, red pepper, apple, citrus
fruits, berries, peaches
Atanassova & Bagdassarian
(30)
;
Gudrais
(31)
; Chang et al.
(32)
; Malagutti
et al.
(33)
3 Macluraxanthone Xanthones Maclura tinctoria (Hedge apple), Dyer’s mulberry Khan et al.
(34)
4 Genistein Isoflavone Fats, oils, beef, red clover, soyabeans, psoralea,
lupin, fava beans, kudzu, psoralea
Thompson et al.
(35)
; Umpress et al.
(36)
;
Krenn et al.
(37)
; Coward et al.
(38)
;
Kaufman et al.
(39)
5 Scopoletin Coumarin Vinegar, dandelion coffee Gálvez et al.
(40)
6 Daidzein Isoflavone Soyabeans, tofu Zhang et al.
(41)
7 Taxifolin Flavanonol Vinegar Cerezoa et al.
(42)
8 Naringenin Flavanone Grapes Felgines et al.
(43)
9 Abyssinones Flavanone French bean seeds Rathmell & Bendall
(44)
; Cruickshank
et al.
(45)
10 Rutin Flavonol Citrus fruits, apple, berries, peaches Cruickshank et al.
(45)
; Chang et al.
(32)
11 Eriodictyol Flavanone Lemons, rosehips Hvattum
(46)
12 Fisetin Flavonol Strawberries, apples, persimmons, onions,
cucumbers
Sahu et al.
(47)
13 Theaflavin Catechins Tea leaves, black tea, oolong tea Leung et al.
(48)
14 Peonidin Anthocyanidin Cranberries, blueberries, plums, grapes, cherries,
sweet potatoes
Truong et al.
(49)
15 Diosmetin Flavone Vetch Andreeva et al.
(50)
16 Tricin Flavone Rice bran Cai et al.
(51)
17 Biochanin Isoflavone Red clover, soya, alfalfa sprouts, peanuts, chickpeas
(Cicer arietinum), other legumes
Medjakovic & Jungbauer
(52)
18 Hesperidin Flavanone Bitter orange, petit grain, orange, orange juice, lemon,
lime
National Agricultural Library
(53)
; Khan
et al.
(34)
19 Epicatechin Flavan-3-ols Milk, chocolate, commercial, reduced fat Arts et al.
(54)
20 Myricetin Flavonols Vegetables, fruits, nuts, berries, tea, red wine Ross & Kasum
(55)
; Basli et al.
(56)
21 Taxifolin Flavanonol Citrus fruits Grayer & Veitch
(57)
; Kawaii et al.
(58)
22 Kaempferol Flavonols Apples, grapes, tomatoes, green tea, potatoes,
onions, broccoli, Brussels sprouts, squash,
cucumbers, lettuce, green beans, peaches,
blackberries, raspberries, spinach
Calderon-Montaño et al.
(59)
; Liu
(60)
; Kim
& Choi
(61)
23 Luteolin Flavones Celery, broccoli, green pepper, parsley, thyme,
dandelion, perilla, chamomile tea, carrots, olive oil,
peppermint, rosemary, navel oranges, oregano
Kayoko et al.
(62)
; López-Lázaro
(63)
24 Apigenin Flavones Milk, chocolate, commercial, reduced fat Hertog et al.
(26)
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