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256 Flavonoids as Nutraceuticals
fruits, vegetables, nuts, honey, beverages, such as red wine and tea, etc., with
various pharmacological activities including antiviral potential (
Ahmad et al.,
2015; Yahia, 2019). The major classes of avonoids are illustrated in Figure
13.1. Flavonoids pose various potent biological activities like antioxidant,
anti-inammatory, and antiviral activities (Figure 13.2) (Krych & Gebicka,
2013; Ragab et al., 2014; Zhang et al., 2020). It was demonstrated that these
bioactive molecules have the potential to inhibit viral pathogenesis targeting
essential stages of the viral life cycle (Chikhale et al., 2020). Catechins Quer-
cetin, baicalein, and kaempferol are the key examples in the avonoid family
exhibiting antiviral properties (Ngwa et al., 2020; Ahmadian et al., 2020).
Therefore, the intent of this chapter was to provide focused, valuable, and
comprehensive insights on the role of avonoids and their antiviral prospec-
tive against COVID-19 or SARS-CoV-2-related viruses. Particularly, the
focus will be on the type of avonoids which are described to be able to
considerably mitigate entry of CoV or infection and hence may perhaps too
play a crucial role in fortication against the COVID-19.
FIGURE 13.1 Biological activities of flavonoids.
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257 Plant-Based Flavonoids as Promising Tools
FIGURE 13.2 The major types of flavonoids.
13.2 FLAVONOIDS-MEDIATED MITIGATION MECHANISMS OF
COVID-19: IN SILICO STUDY
Several in-silico studies revealed the role of various flavonoids depicting
interaction with SARS-CoV-2 proteins. The results are summarized in Table
13.2. It was studied that M
pro
and S proteins are key proteins involved in
replication of COVID-19 virus (Mahmoud et al., 2020). Earlier genome-wise
studies have shown that there is a high resemblance between the genome
of SARS-CoV and the SARS-CoV-2 virus. Hence these proteins can be
suitable therapeutic drug targets. A recent molecular docking-based study
indicated that flavonoid naringenin has capacity to bind to active site amino
residues of M
pro
protein of SARS-CoV-2 virus through H-bond interactions
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258 Flavonoids as Nutraceuticals
indicating mitigation capacity of flavonoid to SARS-CoV-2 (Khaerunnisa
et al., 2020). Hesperidin, another flavonoid, has shown a binding tendency
towards SARS-CoV-2 M
pro
, the peptidase domain of ACE-2 (PD-ACE-2)
and the receptor binding domain of S protein (RBD-S) (
Tallei et al., 2020;
Utomo et al., 2020). Molecular docking study on quercetin flavonoid also
depicted inhibitory action against SARS-CoV-2 (
Sekiou et al., 2020). It
depicted tremendous binding towards Mpro protein. In another in silico
study, it was revealed that food-based flavonoid bioactive compounds like
cyanidin and genistein exhibited similar binding affinity to RdRp and Mpro
compared with synthetic drugs like Lopinavir and Nelfinavir (
Pendyala &
Patras, 2020). Another computational analysis revealed the significance
of numerous flavonoids like luteolin-7-glucoside, quercetin, kaempferol,
naringenin, apigenin-7-glucoside, catechin, epigallocatechin to SARSCoV-2
Mpro (Khaerunnisa et al., 2020). In another study, Rutin was screened
and proposed a key compound that might be active against the COVID-19
Mpro/3CLpro. Chrysin exhibited exceptional binding towards Mpro of
MERS-CoV, SARS-CoV, and SARS-CoV-2 (Tables 13.1–13.4).
TABLE 13.1 Food Items Having Flavonoids
Types of flavonoids Food item References
Flavones Parsely Ayoub et al, (2016)
Anthocyanidins Blueberries Levaj et al., (2009)
Flavan-3-ols Black tea
Flavonoids include hesperidin (a glycoside of
the flavanone hesperetin), quercetin, rutin (two
glycosides of the flavonol quercetin), and the
flavone tangeritin
citrus Ayoub et al, (2016)
Flavonoids Wine Ayoub et al, (2016)
Flavonoids Dark chocolate Levaj et al., (2009)
Flavonoids Peanut (red)
Skin
Levaj et al., (2009)
Quercetin Capers
Buckwheat
Ghidoli et al., (2021)
Onions
Kaempferol Capers
Saffron
Ghidoli et al., (2021)
Brassicaceae
Naringenin
hesperetin
Citrus fruits
Tomatoes
Ghidoli et al., (2021)
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259 Plant-Based Flavonoids as Promising Tools
TABLE 13.2 Flavonoid Classes Identified In-Silico as Potential Inhibitors to SARS-CoV-2
Targets
Flavonoid Compound SARS-CoV-2 References
target
Apigenin, Catechin, Cyanidin Mpro Chikale et al (2020), Khaerunnisa et al., (2020),
Epigallocatechin, Genistein, Ngwa et al., (2020), Pendyala and Patras
Hesperidin, Luteolin, Myricetin (2020), Sekiou et al., (2020)
Icariin, Naringenin, Quercetin
Caflanone, Hesperidin, ACE-2 Chikale et al (2020), Khaerunnisa et al., (2020),
Kaempferol, Linebacker Ngwa et al., (2020), Sekiou et al., (2020)
Cyanidin, Genistein RdRp Pendyala and Pantras (2020)
Kaempferol, Luteolin S Chikale et al (2020), Khaerunnisa et al., (2020),
Sekiou et al., (2020)
Myrecetin, Icariin, Naringin TMPRSS2 Cheng et al., (2020), Chikale et al (2020),
Khaerunnisa et al., (2020), Sekiou et al., (2020)
TABLE 13.3 In Vitro Studies Reporting Antiviral Activity of Natural Flavonoids Against
Coronaviruses
Corona Flavonoid Type Model Effects References
Virus
SARS-CoV Baicalin fRhK4 cell line EC
50
= 12.5–25 Chen et al.
μg/ml (2004)
Cinnamomi – IC
50
= 7.8 μg/ml Zhuang et al.
(2009)
Luteolin Vero E6 cells EC
50
= 10.6 μM Yi et al. (2004)
Procyanidin A2 IC
50
= 30–40 Zhuang et al.
Procyanidin B1 μM (2009)
Cinnamtannin B1
Kaempferol derivatives Heterologously IC
50
= 2.3 µM Schwarz et al.
expression of 3a (2014)
protein of SARS-CoV
in Xenopus oocyte.
Purified chalcones SARS-CoV proteases IC
50
= 5.8–50.8 Park et al.
(3CLpro and PLpro) µM (2016)
Purified flavonoids
expressed in E. coli
BL21
IC
50
=
30.2–233.3 µM
Park et al.
(2016)
Quercetin-β-galactoside IC
50
= 128.8 µM Park et al.
(2017)
Theaflavins SARS-CoV proteases IC
50
= 3–9.5 µM Zu et al. (2012)
(3CLpro) expressed in
E. coli.
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260 Flavonoids as Nutraceuticals
TABLE 13.3 (Continued)
Corona
Virus
Flavonoid Type Model Effects References
Geranylated flavonoids
(tomentin AE)
fluorogenic peptide
Z-RLRGG-AMC
IC
50
= 5.0–14.4
μM
Kim et al.
(2014)
Bavachinin Corylifol
A Isobavachalcone
4′-O-methylbavachalcone
Neobavaisoflavone
fluorogenic peptide
Z-RLRGG-AMC
IC
50
= 4.2–38.4
μM
Cho et al.
(2013)
Herbacetin Pectolinarin
Rhoifolin
Recombinant protein;
FRET method
IC
50
= 33.17
IC
50
= 27.45
Jo et al. (2020)
IC
50
= 37.78 μM
Amentoflavone Recombinant protein;
FRET method.
IC
50
= 8.3 μM Ryu et al. (2010)
Epigallocatechin gallate
gallocatechin gallate
quercetin
Recombinant protein;
FRET method
IC
50
= 47–73
μM.
Nguyen et al.
(2012)
Quercetin Recombinant protein
FRET-based dsDNA
IC
50
= 8.1 μM Lee et al. (2009)
unwinding assay.
7-O-arylmethylquercetin
derivatives
Recombinant protein
FRET-based dsDNA
unwinding assay.
IC
50
= 2.7–5.2
μM
Park et al.
(2012)
Myricetin Recombinant protein
FRET-based dsDNA
IC
50
= 2.71 μM Yu et al. (2012)
unwinding assay.
HIV/SARS
pseudo-typed
virus
Cinnamomi cortex extract. Vero E6 cells IC
50
= 37.3 μg/
ml
Zhuang et al.
(2009)
SARS-CoV-2 Baicalein hACE2 transgenic
mice infected with
SARS-CoV-2.
200 mg/kg Zhan et al.
(2021)
Flavonoid compounds SARS-CoV proteases
(recombinant 3CLpro)
expressed in Pichia
pastoris GS115.
IC
50
= 47–381
µM
Nguyen et al.
(2014)
Isoliquiritigenin
Kaempferol
SARS-CoV proteases
(3CLpro and PLpro)
expressed in E. coli
BL21.
MERS-CoV proteases
(3CLpro and PLpro)
expressed in E. coli
BL21.
IC
50
= 61.9 µM
IC
50
= 33.9 µM
IC
50
= 116.3 µM
IC
50
= 206.6
µM,
Park et al.
(2017)
Park et al.
(2017)
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261 Plant-Based Flavonoids as Promising Tools
TABLE 13.3 (Continued)
Corona Flavonoid Type Model Effects References
Virus
Naringenin Vero E6 cells infected 62.5, 250 µM Clementi et al.
with HCoVOC43, (2020)
HCoV229E, and
SARS-CoV-2.
Quercetin ACE2h cells infected 50 µM Song et al.
with SARS-CoV-2. (2021)
Porcine Quercetin 7-rhamnoside Vero cells IC
50
= 0.014 μg/ Choi et al.
epidemic
(2009)
diarrhea virus
(PEDV)
Bovine Theaflavins HRT-18 cells EC
50
= 34.7 Clark et al.
coronavirus μg/ml (1998)
(BCV)
HIV/SARS Quercetin Hep-G2 cells EC
50
= 83.4 μM Yi et al. (2004)
pseudotyped
virus
TABLE 13.4 Immunomodulatory and Anti-Inflammatory Effects of Different Flavonoid
Classes
Flavonoid Class Immunomodulatory mechanism of References
action
Apigenin Inhibits CCL5, IL-6, VCAM1 and Zhang et al., (2014)
ICAM1
Caflanone Inhibition of 5-lipoxygenase and Erridge et al., (2020)
microsomal prostaglandin E synthase 1
Chrysin Inhibits COX-2 and MPO activity Shen et al., (2015)
Sassi et al., (2017)
Fisetin Impedes COX-2, PKCd activity and Peng et al., (2018); Lee et al.,
Prostaglandin E2 production (2018)
Hesperetin Inhibition of NF-jb and ERK pathway Ma et al., (2015); Ye et al.,
(2019)
Luteolin Increase the number of CD4, CD25 Kuo et al., (2011); Kim et al.,
regulatory T-cells (2018)
Naringenin Inhibition of ERK, decreases iNOS Fouad et al., (2016); Ali et al.,
(2017)
Quercetin Regulates Th1/Th2 balance Michalski et al., (2000)
Wan et al. (2020) recently observed that a well-dened therapeutic
strategy to combat infection of SARS-CoV-2 virus is targeting the ACE-2
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262 Flavonoids as Nutraceuticals
receptors on host cells. S-proteins of SARS-CoV viruses are the key protein
involved in this interaction. Several docking studies at the molecular
level were executed to study the necessary afnity of various avonoids
like myricetin, hesperetin, caanone, and linebacker, which revealed nice
afnity towards S protein, ACE-2 receptor, and helicase and thus could
block the virus entry (Ngwa et al., 2020). Naringenin avonoid exhibited a
strong afnity towards the ACE-2 receptor (
Cheng et al., 2020). An in-silico
study exposed that avonoid baicalin exhibited tremendous binding afnity
towards S protein comparable to synthetic drugs like abacavir and hydroxy-
chloroquine (Pandey et al., 2021).
Hoffmann et al. (2020) observed that Human TMPRSS2 is a very
important protease involved in virus activation via S protein cleavage.
Through docking studies, it was shown that various avonoids like quer-
citrin myricitrin naringin, neohesperidin, and icariin have an excellent
binding afnity to TMPRSS2 (Chikhale et al., 2020). It was also cited by
a comprehensive computational study that silybin is involved in binding to
TMPRSS2 required for viral entry. Chrysin also mitigated the contact of S
protein with ACE-2 in SARS-CoV-2 (
Jha et al., 2020). Docking analysis
on MERS-CoV 3CLpro protein revealed the interaction of helichrysetin
avonoid via forms of a hydrogen bond (Jo et al., 2019). Using compu-
tational methods, a recent study demonstrated that narcissoside, present
in several wild plants, is an effective inhibitor of SARS-CoV-2 3-CLpro
protease (Dubey et al., 2020). Docking simulation studies to nd the
binding afnity of avonoids, like luteolin apigenin, daidzein, epigallo
-
catechin, quercetin, and kaempferol, indicated potential binding towards
SARS-CoV 3-CLpro (Jo et al., 2019). A similar observation on molecular
interaction and inhibitory effect was observed by molecular docking study
on quercetin-3-β-galactoside against SARS-CoV 3-CLpro (Chen et al.,
2006). It was summarized that interaction was mediated by H-bond inter-
actions (Chen et al., 2006).
RdRP is an important viral RNA polymer involved in virus replication.
Zandi et al. (2021) revealed the in vitro antiviral effect of baicalein and
baicalin against infection of SARS-CoV-2 in the Vero CCL-81 cell line
through RdRp inhibition, with a higher potency by baicalein. Further in
silico evaluations showed these two compounds to have a higher afnity
to RdRp in comparison to remdesivir. The attachment site of baicalin and
baicalein also seems to be different from that of remdesivir; thus, these
avonoids can be used as an adjuvant treatment along with remdesivir.
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Plant-Based Flavonoids as Promising Tools 263
13.3 FLAVONOIDS-MEDIATED MITIGATION MECHANISMS OF
COVID-19: IN VIVO/VITRO STUDIES
Flavonoids like baicalin and baicalein have recently been cited as the unique,
natural product inhibitors of Mpro/3CL protease in vitro (
Jo et al., 2020;
Chen et al., 2005, 2006; Su et al., 2020; Park et al., 2016; Liu et al., 2020),
and could be potential anti-COVID-19 inhibitors. The same authors screened
about 64-flavonoid library against SARS-CoV 3CLpro, and It was concluded
that pectolinarin, rhoifolin, and herbacetin are the utmost potent inhibitors
with IC
50
values of 37.78, 27.45, and 33.17 μM, respectively.
Using enzymatic assays in a competitive mode, Chen et al. (2006)
described inhibition of 3CLpro inhibition activity by glycoside avonoids
quercetin-3-β-galactose with IC
50
value of 42.79 ± 4.97 μM. A similar
study examined the required interaction way of the compounds with virus
proteases. Puerarin displayed less inhibitor activity against 3CLpro, with an
IC
50
value of 381 μM (Nguyen et al., 2012). In an additional study, through
cell-free cleavage assay,
Lin et al. (2005) identied numerous compounds
containing the isoavone daidzein and avanone hesperetin showing IC
50
values against SARS-CoV 3CLpro, of 105 and 60 μM, respectively. Four
avonoids: sciadopytiscin, amentoavone, bilobetin, and ginkgetin, were
Fractionation from leaves extract of Torreya nucifera that revealed 3CLpro
inhibitory activity with IC
50
values are 38.4, 32.0, 72.3, and 8.3 μM, respec-
tively (Ryu et al., 2010).
In vitro analyses against proteases of SARS-CoV, comprising PLpro,
were observed with nine alkylated chalcones sequestered from Angelika
keiskei. IC
50
of 1.2, 5.6, 11.7, 19.3, 11.7, 21.1, 26.0, and 46.4 μM against
PLpro were observed for xanthoangelol E, xanthoangelol F, xanthoangelol,
xanthoangelol D, xanthoangelol B, xanthokeistal A, 4-Hydroxyderricin and
xanthoangelol G, respectively, with xanthoangelol E is the extreme active
(Park et al., 2016). The same authors described isobavachalcone with IC
50
of
13.0 μM against PLpro of SARS-CoV.
Bioactive extracts obtained from Paulownia tomentosa fruits directed to
the separation of avonoids and its evaluation against SARS-CoV PLpro, and
it was observed that entire compounds displayed inhibitory activity. Tomentin
E, tomentin D, tomentin C, tomentin B, tomentin A, 40-O-methoxydiplacol,
30-O-methyldiplacol, 40-O-methyldiplacone, 30-O-methyldiplacone,
6-geranyl-40,5,7-trihydroxy-30,50-dimethoxyavanone, diplacone, and
mimulone and showed IC
50
values of 5.0, 12.5, 11.6, 6.1, 6.2, 9.2, 9.5, 12.7,
13.2, 13.9, 10.4, and 14.4 μM, respectively (Cho et al., 2013).
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264 Flavonoids as Nutraceuticals
Nguyen et al. (2012) equated the activity of epigallocatechin gallate
(EGCG), ampelopsin, epigallocatechin, and gallocatechin gallate (GCG)
from Pichia pastoris. It was suggested that avonoid compounds EGCG and
ampelopsin possess stronger 3CLpro inhibitory activity with IC
50
values of
73 and 47 μM, respectively. An additional study on components of black tea
validated that theaavin-3,30-gallate and 3-theaavin-3-gallate were active
against SARS-CoV 3CLpro, with IC
50
values of 9.5 and 7.0 μM. It indicated
that black tea possibly will avert or diminish infection of CoV (Chen et al.,
2005).
Zhuang et al. (2009) used Cinnamomi cortex extracts and demonstrated
inhibition in wild-type SARS-CoV. Authors isolated dimer cinnamtannin B1,
procyanidin B2, and procyanidin A2, viewing complete inhibitory effects
having IC
50
values of 32.9, 161.1, and 120.7 μM, respectively (Zhuang et
al., 2009). IC
50
value of 2.5 μM was observed with the avonoids juglanin
against SARS-CoV (Schwarz et al., 2014).
In another study, authors revealed that quercetin abridged infection of
bovine and human coronaviruses, NCDCV, and OC43, respectively, by
50% at 60 μg/ml concentration. Kaempferol, at a concentration of 10 μg/ml,
abridged virus replication by 50% in OC43 and 65% in NCDCV (Debiaggi
et al., 1990). Using the HRT-18 cell line, it was proved that theaavins from
black tea (theaavin, theaavin-3-mono gallate, theaavin-3,3′ gallate,
theaavin-3′-mono gallate) were very effective against Bovine CoV, BCV,
with a mean value of EC50 of 34.7 μg/ml. The other two avonoids, quer-
cetin and luteolin, depicted the capability to occlude the SARS-CoV entry
within host cells (
Yi et al., 2004). Results using infection of SARS-CoV of
Vero E6 cells revealed that Luteolin inhibited in a dose-dependent manner,
with EC50 value of 10.6 μM (CC50 = 155 μM), whereas quercetin mitigate
HIV-luc/SARS pseudo-typed entry of virus with value of EC50 of 83.4 μM
(CC50 = 3.32 mM) (Yi et al., 2004). Traditional Chinese medicine (TMC)
from Scutellaria baicalensis Georgi (avone glycoside baicalin) is used for
the deterrence and management of SARS-CoV. This molecule was veried
on fRhK4 cell lines using SARS-CoV coronavirus from 10 diverse patients.
Flavone glycoside baicalin presented a value of EC50 of 12.5–25 μg/ml at
48 h, deprived of substantial cytotoxicity (Yi et al., 2004).
By using cell-based and cell-free methods by measuring SARS-CoV
3CLpro cleavage activity, aqueous avonoid having extract from Isatis
indigotica root depicted a dose-dependent capacity to mitigate the 3CLpro
proteolytic cleavage activity with a value of IC
50
of 191.6 and 53.8 μg/ml,
respectively (Soukhova et al., 2004). In the same assays, various herb-derived
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265 Plant-Based Flavonoids as Promising Tools
avonoids were tested (naringenin, quercetin, hesperetin). Results showed
that merely hesperetin depicted dose-dependently inhibited cleavage activity
of the 3CLpro in cell-based and cell-free assays with IC
50
8.3 and 60 μM,
respectively (Soukhova et al., 2004).
Another set of avonoids was veried in a diverse work (Nguyen et
al., 2012). It was observed that gallocatechin gallate (GCG) and quercetin
depicted utmost effective inhibitory activity of recombinant SARS-CoV
3CLpro with a value of IC
50
in the range 47 to 73 μM. Others, like puerarin,
daidzein, and ampelopsin, exposed to an IC
50
greater than 350 μM. In ways,
novel and infrequent geranylated avonoids like: tomentin E, D, C, B, and A
repressed SARS-CoV PLpro with IC
50
raging between 5.0 and 14.4 μM (Cho
et al., 2013). Papyriavonol A, a prenylated quercetin derivative, presented
a powerful, non-competitive inhibitory action on PLpro of COVID-19 virus
with a value of IC
50
of 3.7 μM (Park et al., 2017).
Against MERS-CoV 3CLpro, researchers established that amongst 40
avonoids veried at 20 μM concentration, only four of them, viz. quercetin,
isobavachalcone, herbacetin, and helichrysetin were the maximum active
with an IC
50
value of 35.85, 40.59, 67.04, and 37.03 μM, respectively (Jo
et al., 2019). Other identied avonoids were: rhoifolin, pectolinarin, and
herbacetin, and as the very projecting inhibitors with an IC
50
of 27.45, 37.78,
and 33.17 μM, respectively (Jo et al., 2020).
Another study on chalcones indicated their capability to hinder both
SARS-CoV PLpro protease activity and SARS-CoV 3CLpro using cell-
free assays against SARS-CoV PLpro with IC
50
value of 1.2–26.0 μM and
against 3CLpro with IC
50
of 11.4–39.4 μM. The very potent xanthoangelol
E displayed a value of IC
50
of 1.2 and 11.4 μM for SARS-CoV PLpro and
SARSCoV 3CLpro, respectively. In the case of cell-based cleavage, this
chalcone ensued to inhibit SARS-CoV 3CLpro with a CC50 of 65.6 μM and
a value of IC
50
of 7.1 μM (Park et al., 2020).
Ramalingam et al. (2018), through expression studies in E. coli on
Isoliquiritigenin, a chalcone, showed that it could be utilized as a therapeutic
or remedial agent on SARS-CoV and MERS-CoV 3CLpro and PLpro. Using
Vero CCL-81 cell, a topical examination by Zandi et al. (2021) discovered the
in vitro antiviral consequence of baicalein and baicalin against SARS-CoV-2
infections by inhibition of RdRp. Another in vitro study using quercetin
and isorhamnetin on SARS-CoV-2 revealed that these avonoids pose the
capability to bind ACE2 receptors and thus decline viral entry by inhibition
of spike protein attachment to ACE2 (Zhan et al., 2021). Another study using
Vero E6 cells and hACE2 transgenic mice evaluated the result of baicalein
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