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Fundamentals of Flavonoids
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Figure 4.2: Flavonoid classes, subclasses, and natural sources.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465813/.
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The cover of citrus fruits is rich in tageretin, nobiletin, sinensetin, and
polymethoxylated avones (Manach et al., 2004). They had a double bond
amongst positions 2 and 3 and a ketone in position 4 of the C ring. Most
avones of fruits and vegetables had a hydroxyl group in position 5 of the A
ring, however hydroxylation in other sites, for the most portion in position 7
of the A ring or 3′ and 4′ of the B ring, might differ according to the taxonomic
classication of the specic fruit or vegetable.
4.2.2. Flavonols
Flavonols are flavonoids having a ketone group. They are constructing
blocks of proanthocyanins. Flavonols are found abundantly in a variety
of vegetables and fruits. The most considered flavonols are quercetin,
myricetin, fisetin, and kaempferol (Figure 4.2). Lettuce, tomatoes, grapes,
apples, berries, onions, and kale are rich sources of flavonols. Apart from
vegetables and fruits, red wine and tea are also sources of flavonols. Intake
of flavonols is noticed to be related to an extensive range of health benefits
which comprises antioxidant potential and decreases the risk of vascular
disease (Iwashina, 2013).
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of the C ring, which might also be glycosylated. Like avones, avonols are
very varied in hydroxylation and methylation patterns as well, and, taking the
different glycosylation patterns, they are possibly the largest and common
subgroup of avonoids in vegetables and fruits. For instance, quercetin is
present in numerous plant foods (Matthies et al., 2008).
Natural Compounds: An Introduction
Comparative with avones, avonols had a hydroxyl group in position 3
4.2.3. Flavanones
Flavanones are another significant class which is usually existing in all
citrus fruits like oranges, grapes, and lemons. Naringenin, eriodictyol, and
hesperetin are instances of this class of flavonoids (Figure 4.2). Flavanones
are related to several health benefits due to their free radical scavenging
properties. These compounds are liable for the peel and bitter taste of the
juice of citrus fruits. Citrus flavonoids apply interesting pharmacological
impacts as anti-inflammatory, blood lipid-lowering, antioxidant, and
cholesterol dropping agents. Flavanones, also termed dihydroflavones,
have the C ring saturated; thus, unlike flavones, the double bond amongst
positions 2 and 3 is saturated, and this is the only structural variance amongst
the two subgroups of flavonoids. Over the earlier 15 years, the number of
flavanones had significantly enhanced (Aoki et al., 2000).
4.2.4.Isoavonoids
Isoflavonoids are a huge and very distinct subgroup of flavonoids.
Isoflavonoids enjoy only a restricted distribution in the plant kingdom
and are mainly found in soybeans and further leguminous plants. Certain
isoflavonoids had also been reported to exist in microbes. They are also
noticed to play a significant role as originators for the progress of phytoalexins
throughout plant-microbe interactions. Isoflavonoids show incredible
potential to contest several diseases. Isoflavones like daidzein and genistein
are usually considered to be Phyto-estrogens due to their estrogenic activity
in some animal models (Figure 4.2). Nogowski and Szkudelska reviewed
the impact of genistein inducing metabolic and hormonal changes, through
virtue of which they could influence numerous disease pathways (Dixon and
Ferreira, 2002).
4.2.5.Neoavonoids
Neoflavonoids are a type of polyphenolic compound. Although neoflavonoids
had a 4-phenylchromen backbone with no hydroxyl group replacement at
Fundamentals of Flavonoids
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position 2, flavonoids have a 2-phenylchromen-4-one backbone. The first
neoflavone quarantined from natural sources in 1951 was calophyllolide
from Calophyllum inophyllum seeds. It also occurs in the bark and timber of
the Sri Lankan endemic plant Mesua thwaitesii (Szkudelska and Nogowski,
2007).
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4.2.6. Flavanols, Flavan-3-Ols or Catechins
Flavanonols, also termed catechins or dihydroflavonols, are the 3-hydroxy
products of flavanones. They are multi substituted and an extremely
diversified subgroup. Flavanols are also stated to flavan-3-ols as the hydroxyl
group is permanently bound to position 3 of the C-ring. Unlike numerous
flavonoids, there is no double bond amongst positions 2 and 3. Flavanols are
found richly in blueberries, peaches, apples, bananas, and pears (Figure 4.2).
4.2.7. Anthocyanins
Anthocyanins are pigments liable for colors in flowers, fruits, and plants.
Pelargonidin, malvidin, peonidin, delphinidin, and cyanidin are the most
generally studied anthocyanins (Figure 4.2). They are found predominantly
in the outer cell layers of numerous fruits like red grapes, raspberries,
strawberries, bilberries, merlot grapes, black currants, cranberries,
blueberries, and blackberries. Stability joined with the health benefits of
these compounds assists them to be utilized in the food industry in a diversity
of applications. The color of the anthocyanin relies on the pH and also by
acylation or methylation at the hydroxyl groups on the A and B rings (Figure
4.3) (Linuma et al., 1987).
Figure 4.3: The structural formula of anthocyanins.
Source: https://byjus.com/chemistry/anthocyanins/.
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Natural Compounds: An Introduction
4.2.8. Chalcones
Chalcones are a subclass of flavonoids. They are characterized through the
absence of ‘ring C’ of the simple flavonoid skeleton structure presented in
Figure 4.1. Therefore, they could also be mentioned as open-chain flavonoids.
Major instances of chalcones comprise arbutin, chalconaringenin, phloretin
phloridzin chalcones are found in substantial amounts in strawberries,
pears, tomatoes, bearberries, and some wheat products. Chalcones and
their derivatives had garnered significant attention due to numerous
biological and nutritional benefits. Table 4.1 explains the food sources of all
dietary flavonoids debated all over the article for their research trends and
bioactivity. The consumption of flavonoids by food sources could be the
safest and simplest method to fight diseases as well as modulate activities
(Figure 4.4) (Nishimura et al., 2000).
Figure 4.4: The organic structure of chalcones.
Source: https://en.wikipedia.org/wiki/Chalcone.
4.3. CURRENT RESEARCH AND TRENDS ON
FLAVONOIDS
4.3.1. Anti-Cholinesterase Activity
AChE (Acetylcholinesterase) is the main enzyme in the central nervous
system (CNS) and inhibition of it takes to the enhancement of neural
acetylcholine levels, which is one of the rehabilitations for indicative relief
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113
of minor to moderate AD. Therefore, the inhibition of cholinesterases
is one of the main focuses for drug development to fight AD. Several
flavonoids had been stated for their anti-cholinesterase activity. The in vitro
inhibitory studies completed on numerous flavonoids like rutin, kaempferol
3-O-β-D-galactoside, macluraxanthone, and quercetin, revealed that
macluraxanthone and quercetin hold a concentration-dependent inhibition
capability against BChE(butyrylcholinesterase) and AChE (Garazd et al.,
2003). Macluraxanthone was noticed to be the most effective and precise
inhibitor of both the enzymes with 50% IC
(inhibitory concentration)
50
values of 29·8 and 8·47 µM, respectively. The enzyme kinetic studies show
that quercetin repressed both the enzymes in a competitive manner, however,
macluraxanthone was competitive against BChE and noncompetitive against
AChE. To get an understanding of the intermolecular interactions, studies
on molecular docking of these two compounds were done at dynamic sites
of both the enzymes. The docking studies revealed that macluraxanthone
binds much more firmly with both the enzymes than that of quercetin. Sheng
et al. (2009), through designing, synthesizing, and executing the evaluation
of flavonoid derivatives as effective AChE inhibitors, noticed that most of
the flavonoid derivatives had properties of inhibitory actions to AChE. The
most effective inhibitor, isoflavone derivative 10d, prevents AChE with an
IC
of 4 nM, presenting a high BChE: AChE inhibition ratio (4575-fold),
50
greater to donepezil (IC
= 12 nM, 389-fold). Molecular docking studies
50
were also done to explore the comprehensive interaction with AChE (Giusti
and Wrolstad, 2003).
4.3.2.Anti-InammatoryActivity
COX is an endogenous enzyme, which catalyzes the transformation of
arachidonic acid into thromboxanes and prostaglandins. The enzyme occurs
in two isoforms, COX-1, and COX-2. COX-1 is a constitutive enzyme and is
liable for the supply of prostaglandins which keep the reliability of the gastric
mucosa and provides sufficient vascular homeostasis; however, COX-2 is
an inducible enzyme and is stated only after an inflammatory stimulus. The
role of COX-2 is to synthesize prostaglandins for the induction of pain and
inflammation. The studies done through utilizing in silico techniques on the
binding ways of flavonoids with COX-2 revealed that some flavonols and
flavones comprising a 2,3-double bond might work as superior inhibitors
of COX-2. These observations were found for the flavone, flavanone,
flavonol, or isoflavone classes. This detection led to the development of
discriminating COX-2 inhibitors, which are a type of compound with better
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Natural Compounds: An Introduction
anti-inflammatory activity and decrease gastrointestinal side effects (Hertog
et al., 1993).
Table 4.1: Flavonoids, Their Classes, and Rich Dietary Sources
SL.
Flavonoid Class Dietary Sources References
No.
1. Myricetin Flavonols Nuts, berries, tea, vegetables, fruits, red wine
2. Rutin Flavonols Red pepper, green tea, berries, peaches, grape seeds,
apple, citrus fruits
3. Quercetin Flavonols Fruits and beverages, vegetables, soups, spices, fruit
juices
4. Kaempferol Flavonols Tomatoes, cucumbers,
peaches, green beans,
apples, spinach, grapes, potatoes, raspberries, leuce,
green tea, onions, broccoli,
Brussels sprouts, squash,
blackberries, raspberries,
5. Fisetin Flavonol Apples, cucumbers, persimmons, strawberries, onions,
6. Rutin Flavonol Peaches, berries, citrus
fruits, apple,
7. Maclurax-
anthone
8. Genistein Isoavone Soybeans, Psoralea, kudzu,
9. Daidzein Isoavone Tofu, soyabeans Zhang et al. (1999)
10. Biochanin Isoavone Alfalfa sprouts, peanuts, red
11. Scopoletin Coumarin Dandelion coee, vinegar Gálvez et al. (1994)
12. Taxifolin Flavanonol Vinegar Cerezoa et al.
13. Taxifolin Flavanonol Citrus fruits Umpress et al.
Xanthones Dyer’s mulberry, Maclura
tinctoria (Hedge apple)
fats, oils, lupin beef, red
clover, fava beans,
clover, chickpeas (Cicer arietinum), soya, other legumes
Chang et al. (2000)
Atanassova and
Bagdassarian
(2009); Gudrais
(2012)
Hertog et al.
(1993); Zheng and
Wang (2001)
Kim et al. (2016)
Sahu et al. (2014)
Cruickshank et al.
(1974); Chang et
al. (2000)
Khan et al. (2009)
Thompson et al.
(2006)
Medjakovic and
Jungbauer (2008)
(2010)
(2005)
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115
14. Abyssino-
nes
15. Hesperidin Flavanone Petitgrain, orange, lemon,
16. Eriodictyol Flavanone Rosehips, lemons Hvaum (2002)
17. Naringenin Flavanone Grapes Felgines et al.
18. Theaavin Catechins Black tea, tea leaves, oolong
19. Peonidin Anthocy-
20. Diosmetin Flavone Vetch Andreeva et al.
21. Tricin Flavone Rice bran Cai et al. (2005)
22. Luteolin Flavones Green pepper, chamo-
23. Apigenin Flavones Chocolate, reduced fat, milk,
24. Epicatechin Flavan-
Flavanone French bean seeds Rathmell and
Bendall (1971);
Cruickshank et al.
(1974)
National Agri-
anidin
3-ols
lime bier orange, orange
juice,
tea
Plums, grapes, cherries,
sweet potatoes, Cranberries,
blueberries,
mile tea, perilla, olive oil,
rosemary, celery, carrots,
oregano, broccoli parsley,
thyme, dandelion, peppermint, navel oranges,
commercial
Chocolate, reduced fat, milk,
commercial
cultural Library
(2014); Khan et al.
(2009
(2000)
Leung et al. (2001)
Truong et al.
(2010)
(1998)
Garazd et al.
(2003)
Hertog et al.
(1993)
Hwang and Yen
(2008)
The commercially accessible avonoids like galangin, scopoletin,
genistein, daidzein, hesperitin, silibinin, naringenin, celecoxib, esculatin,
and taxifolin, were also assessed for COX-inhibitory activity. The nominated
avonoids displayed higher binding energy extending between –36.69 and
–26.11 kJ/mol (−8.77 to −6.24 kcal/mol) when compared with that of the
standard −8.30 kcal/mol; –34.73 kJ/mol which directed to the progress
of potent COX inhibitors for the inammation treatment. Madeswaran et
al. (2012) assessed the COX-inhibitory activity of avonoids utilizing in
studies of silico docking. In this viewpoint, they utilized avonoids like
farobin-A, glaziovianin-A, xanthotoxin, rutin, and gericudranin-B. Their
docking outcomes displayed that all the nominated avonoids contributed
enhanced aldose reductase inhibitory activity due to their structural
parameters. Therefore, further enhanced studies could develop effective
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aldose reductase inhibitors for diabetes treatment. Madeswaran et al. (2011)
also described in silico docking studies the lipoxygenase-inhibitory activity
of commercially accessible avonoids. In this viewpoint, the selected
avonoids like aromadedrin, homoeriodictyol, rhamnetin, robinetin,
pachypodol, azelastine, eriodictyol, setin, tangeritin, and, theaavin for
investigation. It was noticed that all the nominated avonoids contributed
to lipoxygenase-inhibitory activity due to their structural parameters, and
the entire analysis could lead to the further progress of potent drugs for the
inammation treatment. Wu et al. (2007) worked on antiplatelet impacts and
selective binding of COX with lignans and avonoids through utilizing the
molecular docking technique. The avonoids deliberated were ginkgetin,
Taiwan-homo-avone A, Taiwan-homo-avone B, and Taiwan-homoavone C, ginkgetin, and 8 recognized lignans justicidin B, justicidin C,
justicidin D, procumphthalide A, procumbenoside A, chinensinaphthol
methyl ether, and ciliatosides A and B from medicinal herbal plants, Justicia
species, and Cephalotaxus wilsoniana respectively. Out of these avonoids
justicidin B and justicidin D, Taiwan-homo-avone C, and ginkgetin were
noticed to be effective for the antiplatelet effects.
Natural Compounds: An Introduction
4.3.3. Steroid-Genesis Modulators
Abyssinones and associated flavonoids could be utilized as potential steroid-
genesis modulators against 3 enzymes 17β-HSD, aromatase, and 3βHSD
(hydroxysteroid dehydrogenase) (HSD), of the steroid-genesis pathway.
The virtual screening trials showed a higher affinity for flavanones than
their particular chalcones. The flavanones hold a constant binding affinity
to all the 3 enzymes utilized and are good steroidogenesis modulators in
hormone-dependent cancer (Justesen and Knuthsen, 2001).
4.3.4. Xanthine Oxidase (XO) Modulators
Xanthine oxidase (XO) catalyzes the transformation of hypoxanthine
to xanthine and afterward xanthine to uric acid. The rise of the uric acid
level in blood serum, which is termed hyperuricemia, could lead to major
complications like kidney stones and gout. Alnajjar (2008) worked on natural
flavonoids for the detection of a potential XO inhibitor. Licoisoflavone-A
taken from the roots of Glycyrrhiza glabra (liquorice) revealed the most
effective activity in the inhibition of XO. Umamaheswari et al. (2011)
assessed the XO-inhibitory activity of flavonoids utilizing in studies of
silico docking. The flavonoids diosmetin, fisetin, vitexycarpin, herbacetin,
Fundamentals of Flavonoids
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isorhamnetin, peonidin, okanin, tricin, butein, fisetin, triacetin, genistein,
biochanin, rhamnetin, and robinetin, were studied and it was noticed that all
flavonoids applied inhibition activity. The existence of a benzopyran ring
in their main nucleus would have added to its XO-inhibitory activity. This
molecular docking analysis might further lead to the progress of effective
XO inhibitors for the avoidance and treatment of gout and associated
inflammatory diseases. Novel drugs for the inhibition of the enzyme aldose
reductase are in growth and exertions are being made for their preclinical
and clinical assessment.
A new method emphasizing the importance of natural products as the
main solution to unanswered queries like the treatment of the ‘silent killer’
‘PKD’ (polycystic kidney disease) had been inspected. The main protein,
namely cystic brosis transmembrane conductance controller (which is
liable for PKD), and its altered three-dimensional structure were deliberated
to molecular docking and in silico toxicity studies with avonoids from the
vegetable bases. The result revealed the probable application of avonoids
from vegetable sources as natural and potential therapeutic agents to ght
PKD.
4.3.5. Countering Antibiotic Resistance
β-Ketoacyl acyl carrier KAS III (protein synthase III), which pledges
fatty acid synthesis in bacteria, is the main target enzyme to overwhelmed
the antibiotic resistance issue. Lee et al. (2011), while functioning on
the recognized flavonoid inhibitors of β-KASIII against the methicillin-
resistant bacteria Staphylococcus aureus, noticed that flavonoids
like as eriodictyol (5,7,3
′
(5,7,4
-trihydroxyflavanone) are powerful antimicrobial inhibitors of
Staphylococcus aureus KAS III. Ganugapati et al. (2011a) functioned on in
silico modeling and docking studies of a super germ enzyme, that is NDM1 (New Delhi Metallo-β-lactamase-1), it is found in Escherichia coli. It
had been described that this enzyme belongs to a B1 subclass of Metallo
β-lactamases and is recognized to persuade resistance to normal intravenous
antibiotics. Similar studies were taken out on inhibition of NDM-1 in the
superbugs through flavonoids utilizing the method of in silico molecular
docking. Currently, there are no efficient antibiotics against the NDM1-positive pathogen, and thus, this study provides hints to examine the
molecular basis of enhanced antibiotic resistance of NDM-1 and then hasten
the search for novel antibiotics against the NDM-1-positive strain in the
′,4′
-tetrahydroxyflavanone) and naringenin
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clinical studies. Quercetin and its equivalent Penta-O-ethylquercetin were
noticed to be potential inhibitors of NDM-1 (Stewart et al., 2000).
Natural Compounds: An Introduction
4.3.6. Disease-Combating Activity
Ganugapati et al. (2011b) considered green tea flavonoids as insulin
mimetics. Diabetes mellitus is a metabolism ailment where glucose, a major
source of energy, cannot enter the cells because of insulin deficiency. The
study proposed that epicatechin works as an insulin receptor activator and
decreases the harmful impacts of diabetes. Lu and Chong (2012) taken
out the computational work to forecast the binding methods of flavonoid
derivatives through the neuraminidase of the 2009 H1N1 (haemagglutinin 1
neuraminidase) influenza virus. They used molecular dynamics simulation
methods to optimize the 2009 H1N1 influenza neuraminidase X-ray crystal
structure. All the 20 flavonoid derivatives were found to be reasonable in
inhibiting and binding the activity of the virus. These outcomes might help
to produce a potential drug form of the flavonoid derivatives for the H1N1
influenza disease treatment. Cardenas et al. (2016) displayed through a study
on mice that apigenin, a nutritional flavonoid, applies immune-regulatory
activity. The study done on NF-κB luciferase transgenic mice displayed
efficient modulation of NF-κB with no impact on the rate of cell death, a
decrease in lipopolysaccharide-induced apoptosis in lungs, and penetration
of inflammation, leading to restoration of regular lung architecture. These
effects show the immune-regulatory functions of flavonoids. Kim et al.
(2017) described that a flavonoid-rich diet is related to a decreased risk of
CVD. The study is attentive to an individual as well as entire flavonoid diet
impacts. Higher flavonoid consumption was found to be associated with the
enhanced CVD risk factors. Mulvihill et al. (2016) focused on the capability
of citrus flavonoids to restrain lipid metabolism and other metabolic
limitations associated with metabolic syndrome. This is one of the latest
trends which have attentive to citrus flavonoids as prospective therapeutic
agents for the therapy of metabolic dysregulation. The observational studies
completed by Hügel et al. (2016) showed that dietary flavonoids are related
to a reduced risk of CVD and hypertension. A diet rich in all flavonoid
types through beverages and herbs enhances vascular health leading to less
risk of diseases. It had been noticed that the intake of them is related to
improvement in endothelial function through vascular endothelial nitric
oxide synthase and Akt (protein kinase B) activation. The impact of regular
quercitin consumption on blood pressure in obese and overweight patients
with pre-hypertension and stage I hypertension was observed in 70 patients.
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