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Citaon: Raman K, Rajagopal K, Swaminathan G, et al. A Crical Review on the Potency of Phytoconstuents in the Management
of COVID-19. J Pure Appl Microbiol. 2023;17(3):1320-1340. doi: 10.22207/JPAM.17.3.38
© The Author(s) 2023. Open Access. This arcle is distributed under the terms of the Creave Commons Aribuon 4.0 Internaonal License which
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Raman et al | Arcle 8591
J Pure Appl Microbiol. 2023;17(3):1320-1340. doi: 10.22207/JPAM.17.3.38
Received: 29 March 2023 | Accepted: 10 July 2023
Published Online: 02 September 2023
REVIEW ARTICLE OPEN ACCESS
www.microbiologyjournal.org1320Journal of Pure and Applied Microbiology
P-ISSN: 0973-7510; E-ISSN: 2581-690X
*Correspondence: rkalirajan@jssuni.edu.in; talhabmb@bgctub.ac.bd
A Crical Review on the Potency of Phytoconstuents
in the Management of COVID-19
Kannan Raman1, Kalirajan Rajagopal1*, Gomathi Swaminathan1, Srikanth
Jupudi1, Kuldeep Dhama2, Rashu Barua3, Talha Bin Emran4,5*, Hamid
Osman6 and Mayeen Uddin Khandaker7
1Department of Pharmaceucal Chemistry, JSS College of Pharmacy, (JSS Academy of Higher Educaon &
Research), Ooty, The Nilgiris, Tamil Nadu, India.
2Division of Pathology, ICAR-Indian Veterinary Research Instute, Izatnagar, Bareilly, Uar Pradesh, India.
3Foundaons of Medicine, Diabetes and Obesity Research Center, New York University Grossman
Long Island School of Medicine, 101 Mineola Blvd, Mineola, New York 11501, USA.
4Department of Pharmacy, BGC Trust University Bangladesh, Chiagong 4381, Bangladesh.
5Department of Pharmacy, Faculty of Allied Health Sciences, Daodil Internaonal University, Dhaka 1207,
Bangladesh.
6Department of Radiological Sciences, College of Applied Medical Sciences, Taif University, 21944 Taif, Saudi
Arabia.
7Centre for Applied Physics and Radiaon Technologies, School of Engineering and Technology, Sunway
University, Bandar Sunway 47500, Malaysia.
Abstract
Natural products and their derivaves have tradionally been used as a source of therapeuc agents.
Their benecial properes are due to large variees in their chemical structures and biochemical acons.
The discovery of natural products such as phytoconstuents have crucial role in the development of less
toxic and more eecve drugs. Phytoconstuents have shown to be benecial in treang viral diseases
such as the previous chikungunya virus, hepas C virus, SARS, and MERS viral diseases. Flavonoids,
alkaloids, terpenoids, and other group of compounds combat against COVID-19 in several ways like
by protease inhibion, spike protein inhibion, Nrf2 inhibion. The accumulaon of NRF2 inhibits the
development of the SARS-CoV-2 virus and smulates an-inammatory acon. The present review
highlights the therapeuc importance of compounds isolated from medicinal plants and/or herbs, such
as crude extracts of Curcumin I-III, Leptodactylone, Ginsenoside-Rb1, Lycorine, Reserpine, Saikosaponin
B2, Cepharanthine, Withanoside V, Gingerol, Piperanine, chromans, avonoids, Amentoavone etc.
against SARS-CoV-2. Natural products are typically safe, stable, and dependable source for nding drugs
to control the current pandemic. Anviral secondary metabolites many medicinal plants have given
ingredients that were isolated. The selected plants based phytoconstuents may potenally be used
against viruses’ development on an-SARS-CoV-2 to oer a reference point in this eld.
Keywords: COVID-19, SARS-CoV-2, Natural Products, Alkaloids, Flavonoids, Target Proteins, Pharmacological Acvity
www.microbiologyjournal.org1321Journal of Pure and Applied Microbiology
Raman et al | J Pure Appl Microbiol. 2023;17(3):1320-1340. hps://doi.org/10.22207/JPAM.17.3.38
INTRODUCTION
The novel coronavirus (SARS-CoV-2 virus)
is the main issue of 2nd decade of 21st century in due
to its rapid spread across the globe and aacking
features. The disease COVID-19 dispatched by
contact with infecous, inhalaon and incubaon
duraon vary from 2 to 14 days.1-3 SARS-CoV-2
virus is like previous SARS-CoV and MERS (not
pandemic) virus with genome modicaon and
WHO declared the COVID-19 as a pandemic on 11
March 2020.4,5 It is noted that viral diseases such
as Hepas B virus, hepas C virus, Zika virus,
Ebola virus, malaria, HIV, SARS, and MERS virus
have oen survived and addressed serious public
health challenges in previous days. Although,
SARS-CoV-2 virus damages the respiratory system6
but increased rate is with pediatric and adult with
cardiovascular diseases7 and diabetes.8 The novel
virus represents a global warming and poses a
new provocaon where vaccine is required for
primary treatment and synthec compound to
treat infected patients.9,10 Vaccine (biological
preparaon) and immunotherapy which boost
the body immune system against pathogens
and treat various diseases. It has been the most
efficient medical method in immunology to
minimize death and morbidity of the previous
century.11 According to the researchers, synthec
angens are suscepble to evoke an-protein
immune feedback.12 Macromolecules may contain
a massive and variety of angenic sites but just
a specific number of possible antigenic sites
are signicant.13 The coronavirus family contain
huge number of spike proteins which are used as
mediator to entry into the epithelial cell in host
whereas, the ACE2 enzyme in the human body is
the recognion site for spike protein; authorized
for entry by this virus into the circulaon system
of the human being. On the other hand, RNA
virus (coronavirus is an RNA virus) manifest RNA
polymerase in epithelial cell of human body and
approaches new genome sequences or daughter
genome sequence using viral RNA template.14
The current study shows phytoconstuents are
capable to treat viral diseases 15 such as previous
chikungunya virus, hepas C virus, SARS and
MERS viral diseases and showed eecve posive
result.16-19 and various guidelines were issued
to treat and prevent COVID-19 using herbal
medicine in dierent stages.20 There are around
4000 phytochemicals where more than 150
phytochemicals are studied in detail. From these
phytochemicals avonoids, alkaloids, terpenoids,
and miscellaneous compounds are found in most
of the plants/herbs which prevent the microbial,
fungal and viral infection.21-28 Flavonoids have
been depicted to plummet various coronavirus
diseases by blocking funcon of protease and
helicase enzyme or interacng with spike protein
and suppressing the function of ACE2.29,30 In
addion, NRF2 is a transcripon factors which
conjugate with anoxidant response elements
to facilitate factor of transcription in target
gene to repair the macromolecular damage
and maintain redox homeostasis31,32 as well as
decrease the inflammation33 which present in
the cytoplasm. Accumulaon of NRF2 can inhibit
the SARS-CoV-2 virus replicaon and smulate
the anti-inflammatory activity.34-36 There are
available synthec drugs have been using such
as chloroquine, favipiravir, arbidol, remdesivir,37
interferon-alpha 1b, monoclonal antibodies,
novaferon and azithromycin as combine therapy
although these are not introduced into the
internaonal community by FDA.38
The aim of the study is to overview the
current strategy and role of phytoconstuents to
treat and manage COVID-19 dealing with in silico,
in vitro and in vivo experiments.
Eect of phytoconstuents against SARS-CoV-2
(in silico approaches)
Phytocompounds have long been thought
to be a source of medicinal substances. With a vast
range of opons in their chemical composions
and biochemical specicity they have proven to be
benecial properes. The development of natural
product drugs is crucial in the pharmaceucal
development of less toxic and more eecve drugs
and having potenal. These natural resources have
scienc evidence (Table 1).39,40
In principle, COVID-19, pedunculagin,
tercatain, and punicalin were used to avoid
outbreaks. The structural relaonship funconing
of the plant of hydrolysable tannins as potenal
antiviral agents & top 3 hit records inhibit
COVID-19’s initial protease and hence viral
replicaon.41 Polyphenols, including two an-HIV
medicines (darunavir and lopinavir) which are
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exposed to subatomic drugs, (brousochalcone
A (C2), papyriavonol A (C4), 30-(3-methylbut-
2-enyl)-30, 40,7-trihydroxyavane (C5), kazineol
A (C6), broussoflavane A (C8), kazinol F (C9)
and kazineol J (C10). AutoDock Vina’s energy
estimates for both these polyphenols were
higher than darunavir. Six of them were related
to large accumulaons of Mpro-reactants (C2,
C4, C5, C8, C9 and C10) (His41 The RMSD and
RMSF proles clearly indicate that the buildings of
these six Mpro polyphenols are highly stable and
conformable. Research from SASA found that all
Mpro-polyphenol buildings are slightly smaller and
probably larger. The existence of intermolecular
hydrogen connecons with B in households. The
polyphenols of papyrifera (C2, C4, C5, C8, C9 and
C10) indicate the security of these polyphenols in
the pocket connecons of Mpro more strikingly
than in the complex of Mpro-darunavir/lopinavir.
Both the structures of Mpro-polyphenol were
much more stable than the complexes of Mpro-
darunavir and Mprolopinavir. The more potent
inhibitors of Mpro than previously indicated were
T-brousochalcone A 30-(3-methylbut-2, enyl) -30,
40, 7-treihydroxyavane, and kazinol J. (darunavir
and lopinavir).42
In addion, following reputable protein
structures, three-dimensional compliance was
balanced by the phytocompounds amentoavone
unambiguously connected to the objective
proteins. In silico drug likeness and ADMET
profiling of the combinations also indicated
potenal therapeuc acvity. In SARS-CoV-2 3CL
M-master, compared to COVID-19 remdesivir,
oleanolic corrosive has a higher liming potenal.
They should be used in conjunction with the
ocial ACE2 to CASP-3 agging pathway, which
needs further research and is meant to offer
logical direcon, to have an impact on apoptosis.
COVID-19 is treated via a variety of organic cycles
and routes have been the fundamental goal
proteins CASP-3, CASP-9, and XIAP that aid in the
management of COVID-19 have been combined
into the synthec blends.43
The dierent Cryptolepis sanguinolenta
alkaloids have shown highly restricve parality
and thus anticipated inhibitory action against
two of the major SARS-CoV-2 prions, the primary
protease, and the RNA dependent polymerase.
The dierent Cryptolepis sanguinolenta alkaloids
have shown extremely restricve parality and
thus anticipated inhibitory action against two
of the major SARS-CoV-2 prisons, the primary
protease, and the polymerase-dependent RNA.44
Eucalyptol has high lt limits and minimum power
constraints. Therefore, it has been recommended
that Eucalyptol may be linked to possible treatment
opons and may be present in therapeuc plants,
as predicted by COVID-19 Mpro inhibitors.45
It was predicted that the operaon of
SARS-CoV-2 (Mpro) was Restorave plants, likely
acting as a constraint, and SARS-CoV-2, with
high affinity (Mpro), the deterring additional
understanding of the viral protein that helps to
harm the vital host organs. Certain phytochemicals
against COVID-19 may be repurposed. An
innocuous ADMET prole has the most eecve
docked mixtures having drug-like characteriscs
that can be used to develop more sophiscated,
efficient COVID-19 inhibitors. The directions
invesgang the contemplated buildings showed
clear protecon during MD runs.46
Glycyrrhizin, tryptanthrin,
bicylogermecrene, beta-sitosterol, indirubin,
indican, indigo, hesperen, crysophanic corrosives,
rhein, berberin and beta-caryophyllene, which can
be considered to be a possible natural competor
hostile to SARS-CoV-2 viral activity. Promising
mooring outcomes were carried out that validated
the useful essence of these preferred alternaves
to combat COVID-19 disease for potential
medicine advancement.47
Ginger phytoconstituents such as 10
Gingerol, 8-Gingerol and Piperanine, Piperdardiine
is substantially dynamic against COVID-19
with a signicant Glide score compared to the
second-hand medication Hydroxychloroquine
at present (-5.47). Docking results in a similar
mode of interacon between its compounds to
COVID-19. HIE41, GLN189, SER46, ARG189,
MET165, ASP187, THR24, LEU27, THR25, GLY143
and ASN142 Critical function residues attach
to ligands. Pepper phytoconstituents such as
Piperazine, Piperdardiine and Ginger, such as
10-Gingerol, 8-Gingerol, are signicantly opposed
to COVID-19.48
The phytoconstituents of turmeric
like Cyclocurcumin, Curcumin and similar to
andrographolide from Andrographis paniculata,
When compared to currently approved COVID-19
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medications such hydroxychloroquine (-5.47)
nelfinavir, dihydroxy dimethoxy flavone are
substanally bound to the acve site of the primary
SARS-CoV-2 protease (-5.93). Cyclocurcumin
from turmeric is signicantly more acve when
compared to common Remdesivir (-6.38).
According to the docking results, the drugs
interacted with SARS in a similar manner. SARS is
brought on by the CoV-2 virus. Important ligand
binding residues include THR24, THR25, THR26,
LEU27, SER46, MET49, HIE41, GLN189, ARG188,
ASP187, MET165, HIE164, PHE181, and THR54.48
From an in silico study, Glu288, Asp289,
Glu290, Lys5 are found as the key sites. In addion,
Ala285 and Leu286 are found as regulatory sites
of interacon. C23 indole-chalcone interacted at
Glu288, Asp289 residues with the docking score
-10.4 kcal/mol. Quercetin has been found to
block the interacon sites of viral spike as well
as the main protease’s Glu290 with -9.2 kcal/
mol docking score.49 Glycosylated flavonoids:
quercen 3-rhamnoside (-9.7 kcal/mol), myricen
3-runoside (-9.3 kcal/mol) and run (-9.2kcal/
mol) exhibit higher docking score than the other
avonoids in silico. Compounds result from the
substuon at C-3 posion of avonoids with
sugar moieties especially have more affinities
with main protease acve site.50 Kaempferol acts
as an inhibitor of 3CLpro and PLpro.51 Based on
a study ,52 other avonoids including luteolin-7-
O-glucoside, naringenin, desmethoxycurcumin,
curcumin, apigenin-7-O-glucoside, oleuropein,
catechin and epicatechin-gallate could potenally
inhibit SARS-CoV-2 3CLpro. Taifolin, the other
avonoid has strong inhibitory potenals against
SARS-CoV-2 according to a molecular docking
study.53 While anproteases’ key purpose is to
inhibit or deacvate proteases, newer research
is revealing that they also play a role in regulang
excessive inammaon and microbial infecon.54
Finding mulfunconal plant protease inhibitors
may thus provide multistep defense against
coronavirus infection. Among all the tropane
alkaloids from Schizanthus porrigens schizanthine
Z, schizanthine Y expressed binding affinity
values -7.5 kcal/mol & 7.1 kcal/mol, respecvely.
Molecular dynamic simulaon, ADME analysis
study confirmed that schizanthine Z could be
the best drug candidate that blocks papain like
protease.55
Phytoconstituents against COVID-19 (in vitro
and in vivo)
Natural phytoconstituents have been
shown to be benecial in treang viral diseases
such as the previous chikungunya virus, hepas C
virus, SARS, and MERS viral diseases. Among them,
avonoids and alkaloids have been invesgated in
vitro and in vivo to combat COVID-19 in many ways
like protease inhibion, spike protein inhibion,
Nrf2 inhibion. Role of phytoconstuents in the
treatment of COVID-19 are given in Table 2.
Alkaloids
The Nrf2 signaling system regulates
an-inammatory gene expression and prevents
inammaon from progressing.63 Upregulaon
of Nrf2 signaling, in particular, prevents the
overproduction of IL-6, pro-inflammatory
cytokines, and chemokines while also liming
NFB acvaon. Endothelial dysfuncon results
from a failure to guard against oxidave stress-
induced neuronal disruption in cardiovascular
disorders and other metabolic syndrome-related
pathologies. In cellular redox homeostasis,
many anoxidant pathways are involved, with
the Nrf2 signaling pathway being one of the
most important.64 Against oxidave pulmonary
disease, pathological inammatory and immune
reacons, and apoptosis, Nrf2 acvates cellular
rescue pathways (Figure). The Nrf2 pathway
has been shown to defend against acute lung
damage and acute respiratory distress syndrome.65
Basically, COVID-19 paents with crical situaons
present the signs of oxidave stress & systemic
inammaon, the main cause of lethality.66,67 Nrf2
controls the anoxidant response parcipang
genes, redox homeostasis genes expressions.
It also activates these genes leading to the
protecon of cells from inammaon 63. In an
in vivo test depicted that Nrf2 knockout mice
suered from uncontrolled inammatory reacon
contribute to tissue damage.68 Nrf2 activation
also causes the suppression of inflammation
through its transcriponal repressor acvity- in
macrophages it inhibits the expressions of cytokine
(IL-1ג, IL-6, TNFב) producon, the most pernent
cause of crical illness due to COVID-19.69 The
protecve role of Nrf2 was shown in numerous
animal inammatory models that Nrf2 inducers
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decreased the pro-inammatory cytokines in the
bloodstream.70-72 Oen, obesity is a signicant
factor in COVID-19 severity.73 Obesity, diet, and
COVID-19 can interact, and this could be aributed
to Nrf2.74
Alkaloids are one of the most diverse
groups of natural goods, with members of the
Ranunculaceae, Solanaceae, Papaveraceae,
Rubiaceae, Fabaceae, and Amaryllidaceae
families being the most abundant. The inclusion
of the nitrogen atom in their arrangement is the
group’s most disnguishing characterisc.75 These
are natural compounds with diversied acons
against various diseases including COVID-19.
Homoharringtonine and emene with notable an-
herpes acvity were reported inhibing replicaon
of SARS-CoV-2.76 Sinomenine is an isoquinoline
alkaloid isolated from Sinomenium acutum
(Thunb.) Rehder & E.H.Wilson’s stem and rhizome
(Menispermaceae). It decreases lung damage
caused by lipopolysaccharides (LPS) and E. coli by
regulang the inammatory signaling cascade,
which included downregulaon of IL-1, IL-6, NF-B,
TNF-a, iNOS, and COX-2, as well as upregulaon
of the an-inammatory adenosine A2A receptor.
Sinomenine also blocked oxidave stress indicators,
such as superoxide dismutase (SOD) producon
and malondialdehyde (MDA) production.77,78
Furthermore, 1 hour aer causing lung damage
in mice with LPS (8 mg/kg), sinomenine [100 mg/
kg, i.p.] upregulated the expression of Nrf2 and
autophagy-related molecules (Atg5, LC-3II, and
Beclin1), as essenal mediators in increasing cell
tolerance to inammaon and oxidave stress.
Furthermore, sinomenine reduced the pulmonary
edema, protein leakage, and lung wet/dry (W/D)
rao into bronchoalveolar lavage uid (BALF),
both of which are pathological indicators of lung
damage.79 In addion, total alkaloid extracon and
six isosteroid alkaloids (vercinone, imperialine,
imperialine-3—D-glucoside, vercine, peimisine,
and delavine) isolated from bulbs of Frillaria
cirrhosa D.Don (Liliaceae) showed protective
eects on lung injury induced by LPS and cigaree
smoke, increased the expression of Nrf2 and heme
oxygenase (HO-1), and reduced.80,81 Thalimonine
and sophaline D showed to be potential drug
candidate targeting Mpro of SARS-CoV-2 after
performing molecular dynamic simulaon and
other in silico approaches.82 Toll-like receptor
4 (TLR4) is an inflammatory signalling system
whose expression is elevated in patients with
acute lung injury.83 Sophocarpine (50 and 25 mg/
kg, i.p.), a quinolizidine alkaloid isolated from the
seeds of Sophora alopecuroides L. (Fabaceae),
inhibited TLR4 expression and thus decreased LPS-
induced lung damage in mice.84 In vitro (mouse
bone marrow-derived macrophages, 10 M) and
in vivo (20 mg/kg, i.p.) and studies found that
tabersonine, a monoterpenoid indole alkaloid
extracted from the root of Catharanthus roseus
(L.) G.Don (Apocynaceae), protected against lung
damage caused by LPS. Tabersonine inhibited the
acvies of p38MAPK-acvated protein kinase
2 (MAPK/MK2) and NF-kB by decreasing the
expression of TNF receptor-associated factor 6
(TRAF6). The improvement of the above signaling
pathways/mediators results in the suppression
of proinammatory mediators and a decrease
of pathological indices of lung damage, such as
total protein concentraons in BALF.85 Berberine,
an isoquinoline alkaloid extracted from Berberis
vulgaris L. (Berberidaceae) and Cops chinensis
Franch. (Ranunculaceae), has been shown to shield
C57BL/6 mice from LPS-induced lung damage at 10
mg/kg (i.p., 24 and 2 h before injecon of LPS, 2.5
mg/kg), as well as in vitro on the hu Berberine was
also benecial to mice suering from pulmonary
edema and protein deficiency in their BALF.86
Matrine (tetracycloquinolizindine),87 andesmone
(tetrahydroquinoline),88 epharanthine
(bisbenzylisoquinoline),89 epigoitrin (pyrrolidine),90
isotetrandrine (bisbenzyltetrahydroisoquinoline),91
neferine (bisbenzylisoquinline),92 and
oxysophoridine (quinolizidine)93 are other alkaloids
that have been found to have an-lung damage
impact in in vitro and in vivo studies. As a result,
they regulated pro-inflammatory mediators
and oxidave markers which show the chemical
compositions of certain alkaloids and other
phytochemicals that have defensive properes
against lung damage, as well as a graphical
diagram of their potenal modes of operaon.
In general, alkaloids, especially quinolines and
quinazolines, have shown therapeuc eects on
lung injury by inhibing the MAPK pathway and its
interconnected mediators, such as TLR4, as well
as inammatory cytokines including IL-1, TNF-a,
and IL-6. These compounds have also been shown
to improve anoxidave stress indicators such as
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Table 1. Phytoconstuents against the SARS-CoV-2 (in silico approaches)
Plant Name Compounds Structures Virus acng Reported Mechanisms Ref.
Boenningh- Leptodactylone SARS-CoV potent anviral acon 56
ausenia and protecon against
sessilicarpa virus-infected cells
Panax ginseng Ginsenoside- SARS-CoV Inhibits glycoprotein 43
Rb1 acvity
Lycoris radiate Lycorine SARS-CoV --- 57
Aesculus Aescin SARS-CoV ----- 57
hippocastanum
Rauwola Reserpine SARS-CoV --- 58
serpenna
Stephaniae Tetrandrine HCoV-OC43 Inhibits p38 MAPK 58
Radix pathway, suppress
Tetrandrae HCoV-OC replicaon,
Bupleuri Radix, Saikosaponin HCoV Invasion of cells by 59
B2 viruses and interference
with the rst stage of
viral replicaon
Salviae Dihydrotanshin MERS- CoV viral passage inhibitory 58
Milorrhizae one eects in MERS-CoV
Radix
Stephania Cepharanthine SARS-CoV-2 ACE inhibitor 60
japonica
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Camellia Epigallocatechin HCoV, SARS, viral passage inhibitory 41
sinensis (EGC) MERS eects in MERS-CoV
Camellia Gallocatechin HCoV, SARS, viral passage inhibitory 41
sinensis (GC) MERS eects in MERS-CoV
Camellia Catechin (C) HCoV, SARS, viral passage inhibitory 41
sinensis MERS eects in MERS-CoV
Camellia Epicatechin HCoV, SARS, viral passage inhibitory 41
sinensis (EC) MERS eects in MERS-CoV
Camellia Catechin HCoV, SARS, viral passage inhibitory 41
sinensis gallate (CG) MERS eects in MERS-CoV
Camellia Epigallocatechin HCoV, SARS, viral passage inhibitory 41
sinensis gallate (EGCG) MERS eects in MERS-CoV
Camellia Epicatechin HCoV, SARS, viral passage inhibitory 41
sinensis gallate MERS eects in MERS-CoV
Camellia Gallocatechin-3- HCoV, SARS, viral passage inhibitory 41
sinensis gallate (GCG) MERS eects in MERS-CoV
Clerodendrum Taraxerol HCoV, SARS, spike (S) glycoprotein 61
spp MERS
Curcuma Curcumin I-III SARS-CoV-2 spike protein 48
longa
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Cupressus Amentoavone SARS-CoV-2 ACE2 to CASP-3 agging 43
sempervirens L pathway
Cryptolepis Cryptospirolepine SARS-CoV-2 the primary protease 44
sanguinolenta and the RNA dependent
polymerase
Cryptolepis Cryptoquindoline SARS-CoV-2 the primary protease and 44
sanguinolenta the RNA dependent
polymerase
Cryptolepis Biscryptolepine SARS-CoV-2 the primary protease and 44
sanguinolenta the RNA dependent
polymerase
Withania Withanoside V SARS-CoV-2 Mpro 46
somnifera
Withania Somniferine SARS-CoV-2 Mpro 46
somnifera
Zingiber (10) Gingerol SARS CoV-2 Mpro 62
ocinale
Piper nigrum Piperanine SARS CoV-2 Mpro 62
Piper nigrum Piperadine SARS CoV-2 Mpro 62
Curcuma longa Cyclocurcumin SARS CoV-2 Mpro 48
Curcuma longa Curcumin SARS CoV-2 Mpro 48
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Andrographis Andrographolide SARS CoV-2 Mpro 48
paniculata
Andrographis Dihydroxy- SARS CoV-2 Mpro 48
paniculata dimethoxy
avone
the glutathione, Nrf2/HO-1 pathway, and SOD. As
a result of this impressive funcon in lung injury,
as well as the alkaloids’ other benecial funcons,
especially their anviral eects, these compounds
are now being considered as multarget agents
for the treatment of coronavirus infecon and
its complicaons. Lycorine, tylophorine, ouabain,
hypericin, myricetin, emodin, mycophenolate
mofel, silvestrol, scutellarein etc. demonstrated
strong inhibitory effects against SARS-CoV-2
and other human coronaviruses.94 Indigoca is
somemes used to cure a variety of infecous
diseases in the laboratory. Immunomodulatory
and anviral eects were observed in isolated
compounds from I. indigotica (indican, isatin,
indirubin, and indigotin). Chang et al. found
that indigo and indirubin, two alkaloids found
in I. indigotica extracts, prevented Japanese
encephalis virus replicaon in vitro.95 Various
clinical trials of using colchicine have been
announced are: (i) GRECCO-199 (ClinicalTrials.gov
Idener: NCT04326790) will recruit 180 COVID-19
diagnosed paents with the administraon of
colchicine for 21 days, (ii) Eects of colchicine in
COVID-19 Pneumonia (ClinicalTrials.gov Idener:
NCT04322565) where n = 100, (iii) COLCORONA
(ClinicalTrials.gov Idener: NCT04322682) aims
to recruit 6000 high-risk outpaents, (iv) Colchicine
co-administraon (or not) with lopinavir/ritonavir,
‘The ECLA PHRI COLCOVID’ Trial (ClinicalTrials.
gov Idener: NCT04328480) will recruit 2500
COVID-19 hospitalized paents.96
Flavonoids
Flavonoids are the common compounds
in medicinal plants which containing various
anti-viral and anti-bacterial activity132
in pattern of particular chemical structure
including hydroxylation, methoxylation and
glycosylaon.133,134 The avonoids, a promising
group of compounds, have potenals to treat
COVID-19. Chalcones, avonols, avones, and
isoavones are examples of this essenal family
of natural compounds.135 Flavonoids have a avan
heart and a 15-carbon skeleton. A heterocyclic
pyran ring (B ring) connects the two benzene
rings (A and C rings). In hydroxylaon, aachment
of more hydroxyl group in particular ring of
avonoids decreases the acvity such as luteolin
has less inhibitory acvity compared to apigenin
due to presence of more –OH group in B ring
whereas dinatin revealed unchanged activity
like apigenin. Quercen and myricen depicted
lower reducon eect comparison to kaempferol
due to more –OH group in B ring. These results
indicated that, more hydroxyl group in B ring
decrease the acvity of avonoids (Figure).136 In
the case of methoxylaon, addion of methoxy
group in avonoids ring plummated the anviral
activity such as 5,6,7,4′-tetramethoxyflavone
and tangeritin exhibited minimum antibiotic
acvity compared to kaempferol and luteolin but
tangerin showed beer anviral acvity than
5,6,7,4′-tetramethoxyavone because of methoxy
group in C-8 posion. Although, aachment of
methoxy group in avonoids ring decrease the
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antiviral activity but in C-8 position.137 As for
glycosylaon, puerarin revealed greater anviral
acvity compared to quercen and ampelopsin.138
It is esmated that avonoids group shows grater
anviral eects in contrast to isoavonoids. The
resorcinol molecule, which has two hydroxyl
groups in its aromac ring conguraon, and they
are posioned at meta-posions with respect to
another hydroxyl group, is the most important
functional group of flavonoids that could be
responsible for ACE2 inhibion. The benzene ring's
behavior is largely determined by the posion of
Figure. Exploring the potenal role of alkaloids and avonoids against SARS-CoV-2. A. The coronavirus replicaon
loop and main steps for anviral goals are depicted in this diagram. Anvirals that funcon extracellularly or
intracellularly are shown by white text boxes. Membrane fusion, receptor binding, sub-genomic RNA transcripon,
viral RNA replicaon, and translaon are all examples of phases in the coronavirus replicaon cycle. B. Flavonoids
acvate 3CL-like protease inhibitors which eventually inhibit SARS Cov-2. C. Flowchart of RNA synthesis by RNA-
dependent RNA polymerase (RdRP) of posive-sense and negave-sense ssRNA viruses which inhibit SARS Cov-2.
D. Natural alkaloids enter in the infected host cell and express Nrf2 and heme oxygenase which combat against
SARS Cov-2 and inhibit it
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these two hydroxyl groups.139 Ring A's resorcinol
moiety may be involved in ACE2 inhibion.140
In vitro studies have shown that
avonoids extracted from Angelica keiskei have a
potent inhibitory eect on both 3CLpro and PLpro.
Alkylated chalcones were able to inhibit PLpro in a
manner that was not compeve. The compounds
xanthoangelol E (IC50: 1.2 µM) and xanthoangelol
F (IC50: 5.6 µM) proved to be the most eecve
in this regard. In accordance with the ndings of
the SAR analysis, the perhydroxyl component of a
chalcone is an alkylated chalcone that has a more
potent inhibitory acon.141 There are a variety
of plants that contain the slbenoid known as
resveratrol, including Vaccinium macrocarpon, Vis
vinifera, and Polygonum cuspidatum. Resveratrol’s
pharmacological and therapeuc eects include,
but are not limited to, hepatoprotective,
cardioprotecve, and neuroprotecve abilies
as well as an-inammatory and anbacterial
acvies. Resveratrol has been shown to greatly
suppress the growth of MERS-CoV in vitro, as
well as diminish MERS-CoV infecon. As a direct
result of this, resveratrol is an essenal an-MERS
medicine and has the potenal to be an eecve
SARS-CoV-2 antiviral.142,143 The SAR analysis
conducted on quercetin-3-galactoside and its
analogues has revealed several key ndings. Firstly,
the presence of 4 OH groups on the quercen
moiety is crucial for elicing biological acvity.
Secondly, removal of the 7-OH group results in a
decrease in inhibitory eect on 3CLpro. Thirdly,
the sugar moiety plays a signicant role in the
compound’s acvity. Lastly, alteraons to the sugar
moiety do not appear to have any impact on the
ecacy of the inhibitor.144 Nigella sava is a source
of myricen and scutellarein, which have been
the subject of numerous invesgaons. Myricen
and scutellarein exhibit inhibitory effects on
SARS-CoV 3CLpro at concentrations ranging
from 0.01 to 10 µM. Broussochalcone B,
broussochalcone A, 4-hydroxyisolonchocarpin,
papyriavonol A, 4,7-trihydroxyavane, kazinol
A, kazinol B, broussoflavan A, kazinol F, and
kazinol J are bioacve compounds derived from
Broussonea papyrifera. These compounds have
been found to exhibit inhibitory eects against
SARS-CoV, as reported in literature sources.145,146
A total of twelve geranylated avonoids
were discovered from Paulownia tomentosa
(Thunb.) Steud., a tradional Chinese medicinal
(TCM) plant. Among these compounds, ve were
newly idened as tomenn A-E (8) (2.39-2.43).
These avonoids were found to exhibit mixed-
type inhibion against SARS Papain-Like Protease
(PLpro), with IC50 values ranging from 5.0 to 14.4
µM. The study found that among the group of
inhibitors tested, Tomenn A, B, and E exhibited
the highest level of effectiveness in inhibiting
PLpro, with IC50 values of 6.2, 6.1, and 5.0 µM,
respecvely. It was observed that each of the
newly synthesised compounds containing dihydro-
2H-pyran moiety exhibited superior inhibitory
acvity compared to their respecve precursor
compounds.147 The seeds of Cullen corylifolium
(L.) Medik. have been found to contain six
avonoids, namely bavachinin, neobavaisoavone,
isobavachalcone, 40-O-methylbavachalcone,
psoralidin, and corylifol A. These avonoids have
been observed to exhibit mixed-type inhibion
against SARS-CoV PLpro, with IC50 values ranging
from 4.2 to 38.4 µM.148 Amentoflavone, a
bioflavonoid obtained from Torreya nucifera,
has demonstrated noncompeve inhibion of
3CLpro with IC50 values in the low micromolar
range. Amentoavone (2.6) was idened as the
most potent inhibitor (IC50 = 8.3 µM), surpassing
the parent compound apigenin (IC50 = 280.8 µM)
in terms of inhibitory acvity. Luteolin (2.23) and
quercen (2.29), which are avones containing
apigenin, were found to inhibit 3CLpro to a
greater extent than the parent compound. The
presence of the apigenin moiety at posion C-30
of avones was determined to be essenal for
their eecveness. The IC50 values for luteolin
and quercetin were 20.2 µM and 23.8 µM,
respecvely. The primary avonoid present in
honeysuckle, namely luteolin, has been idened
as a constuent of Lianhua qingwen, a tradional
Chinese medicine ulized for the treatment of
COVID-19.149
The compound Quercetin has
demonstrated noteworthy inhibition activity
against SARS-CoV Mpro, which was expressed in
Pichia pastoris, with an IC50 value of 73µM150 The
administraon of Quercen in conjuncon with
vitamin C has demonstrated an-SARS-CoV-2 and
immunomodulatory properes. The combined use
of both agents exhibits a synergisc eect and may
be ulized for prophylacc purposes in populaons
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Table 2. In vitro and in vivo evidence regarding the use of phytochemicals (alkaloids and avonoids) in SARS-CoV-2
Phytochemicals Class Dose/conc. Acvity Ref.
Baicalin avonoid 0.04 to 400 µM ↓ X4 and R5 HIV-1 Env-mediated fusion, CAT 97
acvity
Baicalin avonoid 20 µg/mL ↑ survival rate, IFN-α and IFN-β 98
Baicalin avonoid 20 µM ↓ viral replicaon 99
Baicalin avonoid 20–80 µg/mL ↓ virus replicaon, ↑ cell viability in MDCK cells 100
Baicalin avonoid 0.5–320 µM ↓ NP transcripon, RIG-1, PKR, NS1 101
expression, viral replicaon
Baicalin avonoid 12.5–50 µg/mL ↑ mTOR phosphorylaon, ↓autophagy 102
Baicalein avonoid 40–100 µM ↓ viral replicaon, IL6, CXCL10, and TNF-α 103
Baicalein avonoid 200 mg/kg ↑ respiratory funcon 104
Taxifolin avonoid IC50 = 145.7 µM Anmicrobial acvies 105
Camellianin A avonoid 500 µg/mL 30.2% suppression at EC 106,107
Camellianin B avonoid 500 µg/mL 40.7% suppression at EC 106,107
Apigenin avonoid 500 µg/mL 30.3% suppression at EC 106,107
EGCG avonoid 50 µM 2-fold increase at EC by elevang intracellular 108
Zn2+ level
Catechin avonoid 50 µM 2-fold increase at EC by elevang intracellular 108
Zn2+ level
Puried avonoid 3–30 µg/mL ↓ IL-6 and MCP-1, ↓ NA acvity 109
avonoids
Puried avonoid ↓ HIV-1 protease 110
avones
Puried avonoid IC50 = 20–43 µM ↓ HIV-1 RDDP acvity 111
avonol
glycosides
EGCG avonoid 1–100 µM ↓ RT acvity, protease acvity,p24, viral entry, 112
and viral producon
EGCG avonoid 25–100 µM ↓ CD4 expression 113
EGCG avonoid 6–100 µM ↓ HIV-1 p24 angen, ↓ HIV-1 infecvity 114
EGCG avonoid 1–50 µM ↓ virus replicaon 115
EGCG avonoid 0.2–20 µM ↓ HIV-1 gp 120 binding to the CD4+ T cells 116
Tetrandrine Alkaloid 10 µM Increased endolysosomal pH concentraon 117
dependently
Dauricine Alkaloid 10 µM Increased endolysosomal pH, impaired 118
V-type ATPase acvity
Daurisoline Alkaloid 10 µM Increased endolysosomal pH, impaired 119
V-type ATPase acvity
Tylophorine Alkaloid 20 nM 3CLpro inhibitor, block the S and N proteins 120
Quinine Alkaloid 10.7 μM Mpro and S proteins inhibitor 121
Neferine Alkaloid 10 μM Decreased the levels of viral RNA 122
Lycorine Alkaloid 0.47 μM Mpro inhibitor 123
Hernandezine Alkaloid 10 μM Blocking the calcium transion 122
Fangchinoline Alkaloid 1.01 μM Blocked the expression of S and N proteins 58
Conessine Alkaloid 10.75 μM Mpro inhibitor 124
Tetrandrine Alkaloid 2.05 μM Mpro inhibitor, block the expression of S and 58
N proteins
Oxysophoridine Alkaloid 0.31 μM Nucleode biosynthesis inhibitor 125
Homohar- Alkaloid 0.46 μM Blocked S proteins 126
ringtonine
Harmine Alkaloid 13.46 μM Mpro inhibitor 124
Emene Alkaloid 2.55 μM Mpro inhibitor 127
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at high risk.151 Herbacetin, pectolinarin, and
rhoifolin, avonoids have been found to eecvely
inhibit the enzymatic function of SARS-CoV
Mpro.152 The methanolic extract of Paulownia
tomentosa fruits was found to exhibit an-papain
protease activity through fractionation. This
activity was attributed to various geranylated
flavonoid derivatives, which were identified
as potent inhibitors of the SARS-CoV papain
protease.153
The evidence menoned above suggests
that certain avonoids exhibit potenal inhibitory
acvity against SARS-CoV-2 by potenally targeng
crucial proteins involved in the virus’s life cycle. Yet
only a small number of avonoids have undergone
in vitro tesng. Thus, it is necessary to verify the
computational investigation by conducting a
suitable biological assay.154
Terpenoids
The primary pharmacologically active
triterpenoids, commonly in the form of glucosides,
are saikosaponins. These are typically derived
from tradional Chinese medicine (TCM) sources
such as Bupleurum spp., Heteromorpha spp., and
Scrophularia scorodonia, and possess anviral and
immunomodulatory properes.155 The anviral
acvity of four saikosaponins (saikosaponin A, B2,
C, and D) against human coronavirus-229E (CoV-
229E) (alphacoronavirus) was invesgated. The
EC50 values of these saikosaponins were found
to be 8.6, 1.7, 19.9, and 13.2 µM, respecvely,
at concentrations ranging from 5-25 M/L.
Addionally, saikosaponin B2 was observed to
inhibit viral adherence and penetraon stages.59
In 2012, an in vitro study was conducted to
evaluate the an-Human Coronavirus ecacy of
Triterpenoids and 3-friedelanol extracted from the
leaves of Euphorbia neriifolia. The screening of a
triterpenoid in combinaon with 3-Friedelanol
revealed a heightened potenal for anmicrobial
acvity and increased cellular viability following
incubaon with HCoV. Addionally, 3b-fridelanol
exhibited potent inhibitory activity against
3CLpro.156 The acve constuents of Glycyrrhiza
glabra, namely glycyrrhizin, exhibit antiviral
properties against a range of viruses such as
hepas A, B, and C, varicella-zoster, HIV, and
herpes simplex type-1.157 Salvia miltiorrhiza
synthesizes tanshinones that possess an abietane
diterpene framework. Tanshinones exhibit diverse
biological acvies such as an-inammatory,
cardiovascular, and an-neoplasc eects. The
aforementioned compounds exhibit selective
inhibion towards the SARS-CoV 3CLpro and PLpro
enzymes, with their ecacy being predominantly
inuenced by the subtype of the enzyme. Several
tanshinones have been found to exhibit greater
potency in inhibiting PLpro, with IC50 values
ranging from 0.8 to 30.0 µM.158
Miscellaneous
Marine microalgae belonging to the phyla
Rhodophyta and Phaeophyta were discovered
to contain phycocyanin, polysaccharides, lutein,
vitamins, and other phenolics, which exhibit
significant pharmacological effects such as
anbacterial, ancancer, and an-inammatory
properties.118 The study conducted by Hirata
et al. examined the anviral and anoxidave
characteristics of phycocyanobilins, which are
a class of tetrapyrrole chromophores present
in select marine cyanobacteria.159 The potenal
applicaon of Grithsin, a lecn derived from
Table 2. Cont...
Phytochemicals Class Dose/conc. Acvity Ref.
Leelamine Terpenoids 3 µM Decreased cellular endocytosis 128
Pulsalla Terpenoids 1.25 µM Downregulated cathepsins 129
saponin D
Myrtenal Terpenoids 100 µM Suppressed the acon of V-type ATPase 130
Saikosaponins Terpenoids 0.25–25 µmol/L Inhibitory eect on viral aachment and 59
penetraon
Ferruginol, Terpenoids 0–80 µM Reduced SARS-CoV replicaon substanally 131
betulonic acid
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red algae, has been studied and its antiviral
properes against HIV-1 and hepas C have been
demonstrated through tesng.160,161 According to
a recent in vitro invesgaon conducted by Millet
et al., grithsin exhibited inhibitory eects against
MERS-CoV.162 Axinella cf. corrugate, a marine
sponge, has been found to contain esculetin
ethyl ester, which has exhibited a significant
affinity towards the SARS-CoV-2 protease.
This compound has the potenal to serve as a
viable therapeutic agent for the treatment of
COVID-19.163 Carrageenans, a class of sulfated
polysaccharides derived from marine sources,
have been idened as potenal anviral agents.
The mechanism of acon involves the inhibion
of viral attachment and internalization. Nagle
and colleagues postulated that these compounds
possess the potenal to serve as coang agents
on sanitary products for the purpose of impeding
COVID-19 infection. The utilization of in silico
analyses has recently played a signicant role in
idenfying promising lead compounds for the
development of treatments against the COVID-19
pandemic.164
CONCLUSION AND FUTURE PERSPECTIVES
Several herbal extracts and natural
products can be useful in treang the symptoms
of SARS-CoV-2 infection. Antiviral secondary
metabolites have been isolated from a number
of medicinal plants and global studies have
been conducted to produce anviral drugs that
are effective against SARS-CoV-2. Searching
the compounds that modify or disrupt every
stage of the virus replicaon cycle may be the
most effective way of preventing COVID-19
infections. Natural products with the ability
to inhibit or change the structure of structural
proteins (spike glycoprotein), non-structural
proteins (3-chymotrypsin-like protease, papain-
like protease, helicase, and RdRP), and accessory
proteins encoded by the SARS-CoV-2 genome
must be invesgated. Phytochemicals, which have
low toxicity and are used in the pharmaceucal
industry for their bioacvity, including anviral
acvity, could oer a soluon to this problem.
SARS-CoV-1 and COVID-19 have a lot in common,
which may lead to the discovery of new medicines
or even a vaccine. The potenal an-SARS-CoV-2
action of flavonols, flavanones, and flavones,
as well as the fact that these metabolites are
abundant in angiosperm plants, have given
rise to a lot of opmism. Since the majority of
current research is theorecal or lacks empirical
validaon, there is sll a long way to go in terms
of biological science and opmized extracon and
development. Flavonoids and alkaloids combat
COVID-19 in several ways like protease inhibion,
spike protein inhibion, Nrf2 inhibion. This study
initiative would be bolstered by the rigorous
review outlined here. As pandemic situaon is
lasng for a long period, it is crucial to search
for best drug candidates that have potenalies
against SARS-CoV-2. Therefore, avonoids and
alkaloids may have such kind of potenalies to
treat COVID-19. Flavonoids and alkaloids provide
capabilies to ght against novel coronaviruses,
and researchers can connue to invesgate the
mechanisms of acon in order to develop eecve
prevenons so that the planet will get rid of this
deadly viral infecon.
ACKNOWLEDGMENTS
The authors would like to thank JSS
College of Pharmacy, JSS Academy of Higher
Education & Research, Rocklands, Ooty, The
Nilgiris, Tamilnadu, India, for their generous
research infrastructure and support.
CONFLICT OF INTEREST
The authors declare that there is no
conict of interest.
AUTHORS' CONTRIBUTION
KRAM and KRAJ conceptualized and
designed the study, and performed statistical
analysis. KRAM, GS and SJ performed acquision of
data. KD, MUK, TBE and HO performed analysis and
interpretaon of data. KRAM and TBE contributed
in administrave, technical, and material support.
KRAM, RB and KRAJ drafted the manuscript.
KRAM, GS, MUK and HO revised the manuscript.
All authors read and approved the nal manuscript
for publicaon.
FUNDING
None.
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DATA AVAILABILITY
All datasets generated or analyzed during
this study are included in the manuscript.
ETHICS STATEMENT
Not applicable.
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