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Journal Pre-proof
Antiviral potential of anthraquinones from Polygonaceae, Rubiaceae
and Asphodelaceae: potent candidates in the treatment of
SARS-COVID-19, A comprehensive review
Augustin Ntemafack , Rahul Vikram Singh , Sabeena Ali ,
Jules-Roger Kuiate , Qazi Parvaiz Hassan
PII: S0254-6299(22)00521-X
DOI: https://doi.org/10.1016/j.sajb.2022.09.043
Reference: SAJB 4032
To appear in: South African Journal of Botany
Received date: 27 May 2022
Revised date: 3 September 2022
Accepted date: 26 September 2022
Please cite this article as: Augustin Ntemafack , Rahul Vikram Singh , Sabeena Ali ,
Jules-Roger Kuiate , Qazi Parvaiz Hassan , Antiviral potential of anthraquinones from Polygonaceae,
Rubiaceae and Asphodelaceae: potent candidates in the treatment of SARS-COVID-19, A compre-
hensive review, South African Journal of Botany (2022), doi: https://doi.org/10.1016/j.sajb.2022.09.043
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1
Highlights
Emodin, rhein and aloe-emodin have been demonstrated for their significant antiviral
activity against SARS-CoV-2
Anthraquinones have been reported as potent antiviral agents against different viral
infections including those infecting human respiratory tract
Polygonaceae, Rubiaceae and Asphodelaceae have been found to be potential
reservoir of naturally occurring anthraquinones
Plants of Polygonaceae family have been found as the major source of antiviral
anthraquinones
2
Antiviral potential of anthraquinones from Polygonaceae, Rubiaceae and
Asphodelaceae: potent candidates in the treatment of SARS-COVID-19, A
comprehensive review
Augustin Ntemafacka,b*, Rahul Vikram Singhc, Sabeena Alid, Jules-Roger Kuiatea, Qazi
Parvaiz Hassand*
a Department of Biochemistry, University of Dschang, Dschang, Cameroon
bDepartment of Biochemistry and Molecular Biology, Indiana University-Purdue University
Indianapolis, Indiana, USA
cDepartment of Dietetic and Nutrition Technology, CSIR-Institute of Himalayan Bioresource
Technology, Palampur, India
d Molecular Biology and Plant Biotechnology Division, CSIR - Indian Institute of Integrative
Medicine, Sanat Nagar, Srinagar, India
*Corresponding authors
AN: ntemafackbc4@yahoo.fr ; QPH: qphassan@iiim.res.in
Abstract
Medicinal plants are being used as an alternative source of health management to cure various
human ailments. The healing role is attributed to the hidden dynamic groups of various
phytoconstituents, most of which have been recorded from plants and their derivatives.
Nowadays, medicinal plants have gained more attention due to their pharmacological and
industrial potential. Aromatic compounds are one of the dynamic groups of secondary
metabolites (SM) naturally present in plants; and anthraquinones of this group are found to be
attractive due to their high bioactivity and low toxicity. They have been reported to exhibit
anticancer, antimicrobial, immune-suppressive, antioxidant, antipyretic, diuretic and anti-
inflammatory activities. Anthraquinones have been also shown to exhibit potent antiviral
effects against different species of viruses. Though, it has been reported that a medicinal plant
with antiviral activity against one viral infection may be used to combat other types of viral
infections. Therefore, in this review, we explored and highlighted the antiviral properties of
anthraquinones of Polygonaceae, Rubiaceae and Asphodelaceae families. Anthraquinones
from these plant families have been reported for their effects on human respiratory syncytial
virus and influenza virus. They are hence presumed to have antiviral potential against SARS-
3
CoV as well. Thus, anthraquinones are potential candidates that need to be screened
thoroughly and developed as drugs to combat COVID-19. The information documented in
this review could therefore serve as a starting point in developing novel drugs that may help
to curb the SARS-COVID-19 pandemic.
Keywords: anthraquinones, Polygonaceae, Asphodelaceae, Rubiaceae, antiviral potential,
SARS-COVID-19
1. Introduction
A plethora of diseases and health conditions are being managed using plant-derived medicines
as a promising alternative. Throughout human history, plants and their derivatives have been
used to treat different human ailments (Kiani et al., 2016). Medicinal plants have a long
historical background of usage in the healthcare systems, probably some 4000 years back (Rai
et al., 2014). They have been used in traditional medicine for primary healthcare in many
developing and developed countries, including Ethiopia (90%), Benin (80%), India (70%),
Tanzania (60%), and China (40%) (WHO, 2002; Kassa et al., 2020). In Africa, about 80% of
the population uses medicinal plants to manage their diseases (Kassa et al., 2020). Nowadays,
approximately 40% of drugs used in the modern systems of medicine and more than 49% of
the new medicines recorded by the United States Food and Drug Administration (USFDA) are
known to owe their origin to natural resources, including plants (Patil et al., 2016). Interest in
plant-derived drugs has increased due to their negligible harmful and deleterious effects.
Herbal medicines have been reported as a promising treatment due to their rich secondary
metabolite profiles (Kiani et al., 2016).
Aromatic compounds are one of the major groups of secondary metabolites naturally present
in plants. They include anthraquinones which contain in their basic structure three benzene
rings (9,10-anthracenedione) belonging to the quinone family of naturally occurring
secondary metabolites (Duval et al., 2016). Anthraquinones are the largest group of this
family and have been found to be interesting due to their high bioactivity and low toxicity
(Chien et al., 2015; Malik et al., 2016). They are produced by different species, including
plants, lichen and fungi. Approximately 200 anthraquinones have been reported from
flowering plants (Diaz-Munoz et al., 2018). They are ubiquitous in plants and can be found in
different amounts in various plant tissues, including flowers, roots, stems, rhizomes, bark,
fruits and leaves. They are stored in their glycosylated form in plant tissues like rhizomes and
can be converted into aglycone anthraquinone by oxidation or β-glycosidase (Pandith et al.,
4
2014; Duval et al., 2016). About 700 anthraquinones have been described as dyes, making
them the most important group of naturally occurring pigments (Duval et al., 2016). They
have attracted more attention these days due to their pharmacological and industrial potential.
Apart from their use as dye pigments in cosmetics, pharmaceutical and food industries
(Dufossé et al., 2014; Duval et al., 2016), anthraquinones have been used as pulping catalysts
due to their ability to increase the delignification rate in pulping processes (Diaz-Munoz et al.,
2018). Due to their cathartic and laxative properties, anthraquinones of plant origin have been
found to be used since ancient times (Thomson, 1986). In addition, their pharmacological
potential includes anticancer, antimicrobial, immunosuppressive, antioxidant, antipyretic,
diuretic, anti-inflammatory and antiviral effects (Bisset, 1994; Chien et al., 2015; Zhao et al.,
2015, Singh et al., 2021).
Antiviral agents are any substance that can produce a therapeutic or protective effect in a
virus-infected host. The term excludes substances like a virus-containing vaccine or specific
antibodies against the virus (Swallow, 1977). High morbidity and mortality of human beings
worldwide are attributed to viral infections (Al-Ali and El-Badry, 2010). Currently, the whole
world is facing one of the devastating viral outbreaks, COVID-19, a disease caused by severe
acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (Tillu et al., 2020). In 2020, the
pandemic affected more than 45,667,780 individuals causing over 1,189,499 deaths globally
(ECDPC, 2020). In early 2021, approximately 100 million subjects in the world were reported
with confirmed SARS-CoV-2 infection and more than 2 million deaths have been attributed to
COVID-19 (Wang et al., 2021). To date, an estimated 4.7 million individuals worldwide have
died after being exposed to the disease (WHO, 2021). With the declaration of the pandemic,
significant efforts have been made in designing, manufacturing and testing a variety of
vaccines against COVID-19 worldwide (Spencer et al., 2021). Statistical data have been
released to display the impact of immunization on treatment and records of the death toll of
the disease (Hall et al., 2021; Vasileiou et al., 2021). Although different mutations have
occurred within the viral genome, leading to more virulent variants like delta and omicron
(Moona et al., 2021, Torjesen et al., 2021). To date, no other approved antiviral drug is
available to treat novel coronavirus infection except remdesivir (Henss et al., 2021). Thus, a
critical necessity has emerged to search for antiviral agents that could help to fight this
uncontrollable virus.
Viruses have shown more resistance to prophylaxis or therapy as compared to other pathogens
and only a few antiviral drugs are available today (Abd-Alla et al., 2012). To fight against
severe viral infections in living organisms, efforts have been devoted to exploring new
5
antiviral agents from natural resources (Mbanga et al., 2010). However, the occurrence of
antiviral agents in plants makes them potential candidates for the treatment of viral diseases
(Abd-Alla et al., 2012). The search for antiviral agents of plant origin has intensified since
2020 due to the COVID-19 outbreak. Plants and their derivatives have been known to show
promising antiviral effects and different phytochemicals have been screened against various
pathogenic viruses. Among them, anthraquinones have attracted more attention and have been
reported from different plant species including Rubia, Cassia, Galium, Morinda, Rheum and
Caprosma (Duval et al., 2016). The majority of anthraquinones with antiviral effects have
been reported from plants of Asphodelaceae and Polygonaceae families. It is known that the
antiviral effects of a medicinal plant against one viral infection may be demonstrated in other
types of viral diseases (Tegen et al., 2021). Hence, in this review, we have gathered vital
information on the antiviral potential of anthraquinones isolated from the plants of
Asphodelaceae, Rubiaceae and Polygonaceae families. Our goal is to draw the attention of
researchers toward the major resources of these naturally occurring anthraquinones which
could serve as the reservoirs for the isolation and development of antiviral drugs used in the
treatment of various viral infections, including COVID-19.
2. Extraction of anthraquinones from Polygonaceae, Asphodelaceae and Rubiaceae
Different methods such as maceration, soxhlet extraction, microwave assisted extraction,
ultrasound-assisted extraction, pressurized liquid extraction and super/subcritical fluid
extraction are commonly used for the extraction of naturally occurring anthraquinones (Duval
et al., 2016). In this review, we have focused on the methods used for the extraction of
anthraquinones from different plant parts of the Polygonaceae, Rubiaceae and Asphodelaceae
families.
Flower-peduncles and flowers of Aloe hijazensis (Asphodelaceae) have been used in the
preparation of plant extracts. The dried sample of each part has been powdered and extracted
by macerating in 80% aqueous methanol. The extract obtained after evaporation of the solvent
has been further defatted, resuspended in water and fractionated using solvents of increasing
polarity viz. ether, ethyl acetate and n-butanol. The fractions obtained have been used for the
isolation of phytochemicals of the plant (Abd-Alla et al., 2012). A similar protocol has been
used by Kim and Colleagues (2017) to extract 5 kg of the powder of Aloe vera
(Asphodelaceae). The extract has been partitioned successively thrice with n-hexane,
chloroform ethyl acetate and butanol. Chloroform and ethyl acetate fractions have been
further used for the isolation of the plant secondary metabolites. Successive partition in ethyl
6
acetate and n-butanol has been also used to fractionate aqueous suspension of 80% aqueous
ethanol extract prepared by macerating 8.5 kg of the bark powder of Morinda citrifolia L.
(Rubiaceae) (Wang et al., 2016). The root powder of Rheum tanguticum (Polygonaceae) has
been extracted under reflux in hydro-alcoholic solution (80% ethanol). The extract has been
further dissolved in water, mixed with 80% ethanol:acetone, ultrasonicated and used to isolate
anthraquinones (Xiong et al., 2011). Hydro-alcoholic extract (95% ethanol) has been prepared
by macerating 20 kg of pulverized dried roots of Knoxia valerianoides (Rubiaceae) in 10 L of
solvent. The extract has been dissolved in water and partitioned with ethyl acetate (Zhao et
al., 2015). The authors have further used the ethyl acetate fraction to isolate the plant
secondary metabolites. Ethanol extract of Dianella longifolia (Asphodelaceae) has been
prepared by macerating the powdered roots in the solvent at room temperature (Semple et al.,
2001). The powder of the tubers of Rumex dentatus and Rheum palmatum (Polygonaceae) has
been macerated separately in water and anthraquinones have been quantified from the
aqueous extract using HPLC analysis (Liu et al., 1997).
3. Antiviral anthraquinones of Polygonaceae, Rubiaceae and Asphodelaceae
Different plant species of the Asphodelaceae, Polygonaceae and Rubiaceae family have been
collected to isolate anthraquinones and screened for antiviral activities. Plants of the
Polygonaceae family have been shown with high frequency in the isolation of anthraquinones
(Fig.1). Rubiaceae was found as a potent source of anthraquinones with most of the
compounds isolated from Morinda elliptica followed by Heterophylleae pustulata (Fig.2).
3.1 Anthraquinones of Polygonaceae
Polygonaceae, commonly known as knotwood or smartweed is a family of flowering plants
which contains about 1200 species distributed among 50 different genera (Mishra et al., 2018;
Ammar et al., 2020). Anthraquinones have been reported from different genera of the
Polygonaceae family including Rheum, Polygonum and Rumex. Among these genera, plants
of Rheum and Polygonum species have demonstrated their ability to produce anthraquinones
with vital antiviral effects. Emodin (1), a potential antiviral anthraquinone, has been isolated
from Rheum palmatum, Rheum tanguticum, Rheum o
ffi
cinale Baill., Polygonum cuspidatum
and Polygonum multiflorum (Li et al., 2005; Ho et al., 2007; Xiong et al., 2011, Liu et al.;
2013). In addition, other anthraquinones such as rhein (2), physcion (3), chrysophanol (4),
aloe-emodin (5), chrysophanol 8-O-β- D-glucoside (6) have also been reported from Rheum
palmatum and Rheum o
ffi
cinale Baill (Li et al., 2007, Esposito et al., 2016). Sennoside A (7)
7
and Sennoside B (8) have been reported in Rheum palmatum and Rheum o
ffi
cinale Baill.
(Esposito et al., 2016). Rhein has been also reported as one of the major phytochemicals from
Polygonum multiflorum (Ho et al., 2007).
3.2 Antraquinones of Asphodelaceae
Plants of Asphodelaceae family are flowering plants classified in the order Asparagales (APG,
2016). The family contains approximately 40 genera and 900 species (Christenhusz and Byng,
2016), which are known to produce majorly anthraquinones. This class of secondary
metabolites has been isolated from Aloe hijazensis, Aloe vera and Dianella longifolia (Semple
et al., 2001; Abd-Alla et al., 2012; Kim et al., 2017; Borges-Argáez et al.,2019).
Anthraquinones named chrysophanol, aloe-emodin, ziganein (9), ziganein-5-methyl ether (10)
and aloesaponarin I (11) have been isolated along with other compounds such as p-coumaric
acid, aloenin, feralolide, alkaloids and barbaloin from the flowers and flower-peduncles of
Aloe hijazensis, (Abd-Alla et al., 2012). Aloe vera has demonstrated its capability to
biosynthesize anthraquinones, including aloesaponarin I and aloesaponarin II (12), along with
their derivatives such as 3,8-dimethoxy-aloesaponarin I (13), 3,8-diacetoxy-aloesaponarin I
(14), 3-(2´,3´,4´,6´-Tetra-O-acetyl-β-D-glucopyranosyl-aloesaponarin I (15), 3-glucosyl
aloesaponarin I (16) and 3-(2´,3´,4´,6´-Tetra-O-acetyl-β-D-glucopyranosyl-aloesaponarin II
(17) (Borges-Argáez et al., 2019). In addition, the plant has been reported to produce aloe-
emodin and elgonica dimer A (18) (Kim et al., 2017; Mpiana et al., 2020). Dianella longifolia
has been reported to produce chrysophanol (chrysophanic acid) (Semple et al., 2001).
3.3 Anthraquinone of Rubiaceae
Rubiaceae family contains majorly terrestrial plants comprising more than 13000 species
distributed in at least 600 genera (Simpson, 2019). Plants of this family are mostly distributed
in temperate, tropical and subtropical regions. Some species are of important medicinal value
and are widely used to treat diarrhoea, headache, cholera, fever, wounds, eye problem, cancer,
typhoid and enlarged spleen (Ali et al., 2000; Jeruto et al., 2011).
Only a few species of the Rubiaceae family have been reported to produce anthraquinones
with antiviral activity. Morinda elliptica, Heterophyllaea pustulata and Morinda royoc have
been shown to produce a variety of anthraquinones, including 1-Hydroxy-2-
methylanthraquinone (19), 2-formyl-1-hydroxyanthraquinone (20), nordamnacanthal (21),
damnacanthal (22), lucidin-ω-methyl ether (23), rubiadin (24), soranjidiol (25), morindone
8
(26), rubiadin-1-methyl ether (27), morindone-5-methyl ether (28) and alizarin-1-methyl ether
(29) (Ali et al., 2000; Borroto et al., 2008, Konigheim et al., 2012).
9
4. Antiviral activity of anthraquinones of Polygonaceae, Rubiaceae and Asphodelaceae
To fight against infectious viruses in humans and other living organisms, significant efforts
have been made for the discovery of new natural products with antiviral potential. A variety
of medicinal plants have been demonstrated for their potential in the treatment of various viral
infections and many of them have shown a broad-spectrum antiviral activity (Dao et al., 2011;
Perera and Efferth, 2012). Anthraquinones and anthraquinone-like compounds have been
reported earlier to represent a novel class of potential antiviral secondary metabolites and
hypericin has proven its effectiveness against infectious bronchitis virus (Tang et al., 1990;
Anderson et al., 1991; Hudson et al., 1991; Chen et al., 2019). Anthraquinones from different
species of Polygonaceae, Asphodelaceae and Rubiaceae have demonstrated their antiviral
activity against a variety of viruses including SARS-CoV-2, human immunodeficiency virus
(HIV), poliovirus, herpes simplex virus, hepatitis virus, respiratory syncytial virus (RSV) and
coxsackievirus (Ho et al., 2007, Li et al., 2007; Xiong et al., 2011; Liu et al., 2015; Esposito et
al., 2016; Parvez et al., 2019). Among them, chrysophanol has been reported to exhibit
potential antiviral effects against poliovirus type-2 and type-3, and SARS-coronavirus has
been shown to be inhibited by aloe-emodin and emodin (Table 1).
4.1 Herpes simplex virus type-1(HSV-1) and type-2 (HSV-2)
10
HSV-1 and HSV-2 are enveloped viruses belonging to the herpes virus family consisting of
more than 100 double-stranded DNA viruses (Shukla and Spear, 2001). They are divided into
α, β and γ subgroups, and HSV-1 and HSV-2 are of α subfamily with high prevalent
infections among humans (Whitley and Roizman, 2001). It is estimated that about 60 to 95%
of human adults are infected by type-1 or type-2 herpes virus worldwide. HSV-2 is
responsible for genital herpes in humans, in addition to other complications like cold sore,
meningitis, eye infections and encephalitis (Zandi et al., 2007, Burcea et al., 2015; Sauerbrei,
2016). The virus can also cause life-threatening malady in immune-compromised persons
such as newborns, HIV patients, or victims undergoing immunosuppressive remedies (Shukla
and Spear, 2001; Whitley and Roizman, 2001; Gottlieb et al., 2019; Obisesan et al., 2021).
Extract of Aloe vera has been reported for its inhibitory effects on pre- and post-attachment of
HSV-2 to the cell, with IC50 values of 428 µg/mL and 536 µg/mL (Zandi et al., 2007). It has
been reported as a potential candidate for the isolation of natural antiviral products that can be
used in the development of drugs against HSV infection. 0.5% of the extract and gel of the
plant in hydrophilic cream have been demonstrated for their efficacy in the management of
genital herpes in males (Syed et al., 1996). Aloe-emodin, an anthraquinone from the plant has
been shown to exhibit inhibitory effects on HSV-1 and HSV-2 by blocking nucleic acid
biosynthesis leading to immature termination of the viral proteosynthesis (Mpiana et al.,
2020). At the concentration of 50 µg/mL, emodin isolated from Rheum tanguticum has been
reported to inhibit the replication of both viruses (HSV-1 and type-2 HSV-2) in infected cells
with an antiviral index of 2.07 and 3.53, respectively. The compound has been found to
increase the survival rate of HSV-infected mice and to prolong significantly the efficacy of
HSV elimination from the organs such as the liver, brain, heart and ganglion (Xiong et al.,
2011). Nanoparticles containing emodin, aloe-emodin, chrysophanol, rhein and physcion from
the plant have shown their ability to inhibit the whole phase of HSV-1 replication. The
compounds have been reported to exhibit the inhibition of mRNA expression and
proteosynthesis of the viral proteins ICP4 and ICP8. In addition, the nanoparticles have been
demonstrated for their ability to decrease the viral load and alleviate pathological changes in
the brain tissues of HSV-1-induced mice (Shen et al., 2019).
4.2 Human immunodeficiency virus (HIV)
HIV is a retrovirus that can induce Acquired Immuno-Deficiency Syndrome (AIDS) in
humans. Individuals affected by the syndrome are characterized by immune deterioration
resulting finally in the failure of the immune system. The virus is the leading cause of
11
morbidity and mortality, mostly in African countries, including those in Sub-Saharan Africa
(GDB, 2017). The disease has been reported to be the cause of death of more than 25 million
people since its first recognition in 1981. The prevalence of HIV was estimated to 0.6% of the
global population in 2006 (Naithani et al., 2008). In 2017, the virus was reported to cause
75% of deaths and 65% of new cases have been further reported, and 71% of people have
been declared living with HIV in Sub-Saharan Africa (GDB, 2017, Dwyer-Lindgren et al.,
2019).
The focus on the discovery and usage of phytoconstituents as antivirals against HIV has been
extensively increased. Extracts of Rheum palmatum L. and Rheum o
ffi
cinale Baill. have
shown their ability to inhibit the activity of HIV-1 reverse transcriptase (RT)-associated
RNase H with IC50 values of 0.9 and 0.25 µg/mL, respectively (Esposito et al., 2016).
Sennosides A and B identified as novel dual functions RT inhibitors have been reported to
display potent inhibitory effects on both (RT)-associated DNA Polymerase (RDDP) and
RNase H RT-associated functions with IC50 values ranging from 1.9 to 5.3 µM. Chrysophanol
and aloe-emodin isolated from the plants have shown moderate inhibitory effects on both
enzymes (RT and RDDP) with IC50 values of 21–26 μM (Esposito et al., 2016).
4.3 Hepatitis B virus
Hepatitis B virus (HBV) is an enveloped DNA virus responsible for a major public health
problem. The virus has been reported to infect about two billion individuals and 350 million
people have been estimated to be chronic carriers of the pathogen worldwide (Ayoola et al.,
1988; WHO, 1998). Its infection leads to hepatocellular carcinoma, acute and chronic liver
ailments in humans such as liver cirrhosis and hepatitis, leading to the death of more than one
million people annually (Ayoola et al., 1988; WHO, 1998; Ott et al., 2012).
Extract of Aloe vera has shown its inhibitory effects against HBV by down-regulating the
synthesis of viral antigens by 38.1% at the concentration of 50 µg/mL. The virus has been
also found to be inhibited by the ethanolic extract of Rheum palmatum which encumbered the
viral DNA production and antigen (HBsAg) expression, with an IC50 value of 212.36 µg/mL
(Li et al., 2007; Parvez et al., 2019). The inhibitory effects have been observed with
aloe‐emodin, chrysophanol and aloin B isolated from the A. vera at the concentration of 10
µg/mL, displaying the inhibition percentage of 81.7%, 65.5% and 62%, respectively (Parvez
et al., 2019). Chrysophanol 8-O-β-D-glucoside from R. palmatum has been reported to
significantly inhibit antigen expression and DNA replication in HBV with an IC50 value of
36.98 µg/mL, and has been reported as a promising candidate in the development of antiviral
12
drugs against HBV infections (Li et al., 2007). In a docking study, aloe‐emodin, chrysophanol
and aloin B have been shown to bind to the active site of HBV polymerase with high binding
energy of –8.2 kcal/mol, –7.6 kcal/mol and –7.4 kcal/mol, respectively, thus forming a stable
complex with the enzyme suggesting its possible inhibition by the compounds (Parvez et al.,
2019).
4.4 Poliovirus
Poliovirus is an enterovirus and a causative agent of poliomyelitis (or polio) in humans. The
virus contains a single-stranded RNA in a non-enveloped capsid. It is of viral serotypes
responsible for the damage to the nervous system and induces paralytic disease in patients
(Racaniello, 2006). The disease is more prevalent in children of developing countries, mainly
in Asia and Africa, where polio immunization is less accessible (Naithani et al., 2008).
In vitro study has displayed the inhibitory effects of chrysophanol (chrysophanic acid)
isolated from Dianella longifolia against the replication of poliovirus types-2 and type-3 with
an EC50 value of 0.21 and 0.02 µg/mL, respectively (Semple et al., 2001). In vitro antiviral
effects have been also investigated and the compound has shown the ability to inhibit the
cytopathogenic effect of poliovirus types-2 and type-3 in buffalo and green monkey kidneys
with EC50 equal to 210 and 20 µg/mL, respectively. The compound has been also found to
attenuate the replication of the virus at its early stage (Yusuf et al., 2019)
4.5 Human respiratory syncytial virus
Human respiratory syncytial virus (RSV) is a negative-sense single-stranded RNA virus (Lin
et al., 2021) which is the most frequent cause of infection of the lower part of the respiratory
tract. The infection is most common in children under the age group of 5 years, causing
mainly bronchiolitis and pneumonia (Shi et al., 2017; Aranda and Polack, 2019). The virus is
responsible for infection in about 33 million cases annually worldwide and infants younger
than one year are more exposed to the disease (Shi et al., 2017). The virus is also reported to
infect the older age group and patients with chronic cardiopulmonary disease and
immunocompromised individuals, causing severe illness (Varga and Braciale, 2013).
Emodin, an active ingredient isolated from hydroalcoholic extract of Rheum palmatum has
demonstrated its inhibitory effects against RSV. The compound has been shown to inhibit the
virus significantly with an effective concentration (EC50) of 13.06 µmol/L. In addition,
emodin has been demonstrated to decrease mRNA expression of cytokine IFN-α (Lin et al.,
2021), suggesting that the compound could be developed as an antiviral candidate against
13
human respiratory viral infection. Rhein isolated from the same plant has shown its capability
to alleviate infection and injury in lungs caused by the virus in RSV-induced mice. The
compound has been reported to inhibit the immune inflammatory response of the infected
animals. Hence, rhein has been suggested to be a promising treatment for RSV infection and
to further prevent lung tissue damage (Shen et al., 2020).
4.6 Coxsackievirus B4 and B5
Coxsackievirus is a non-enveloped, single-stranded RNA virus belonging to the family of
Picornaviridae (Muckelbauer et al., 1995, Liu et al., 2013). Coxsackievirus B4 (CVB4) is an
Enterovirus responsible for a wide range of diseases, including pancreatitis, myocarditis,
aseptic, hepatitis, meningitis, pneumonia and necrotizing enterocolitis, and is fatal to
newborns (Crowell et al., 1997). Coxsackievirus B5 (CVB5) is highly prevalent in some
countries and is commonly associated with diseases such as myocarditis and encephalitis in
immunocompromised children. It has been also reported to induce central nervous system
illness in elderly people (Zhong et al., 2009; Trallero et al., 2010).
Emodin, an anthraquinone isolated from Polygonum cuspidatum has been shown to block the
penetration and replication of CVB4 in Hep-2 cells in a dose and time-dependent manner with
an EC50 value of 12.06 μM. In addition, the compound has been also shown to increase the
survival rate and prolong the mean time of death in CVB4-induced mice (Liu Z et al., 2013).
Emodin isolated from Rheum palmatum has shown inhibitory activity on CVB5 in Hep-2 cells
with an EC50 value of 12.11 µmol/L (Liu et al., 2015).
4.7 Influenza virus
Influenza is an enveloped negative-strand RNA virus (Palese et al., 2007) responsible for the
most common respiratory infections in humans with high morbidity and mortality (Wright et
al., 2007). The virus was recorded as the worst pandemic in 1918 and has led to the death of
about 50 million people worldwide (Taubenberger and Morens, 2008, Hutchinson, 2018).
Influenza A virus (IAV) and influenza B virus (IBV) are typically virulent, causing the death
of about 290 000 – 650 000 individuals a year globally (Hutchinson, 2018).
Rhein has been reported to inhibit the entry and replication of IAV in cells, in addition to its
ability to decrease IAV-induced oxidative stress and to activate NF-κB, Akt, TLR4, p38 and
JNK MAPK pathways (Wang et al., 2018). Rheum o
ffi
cinale Baillon, Aloe vera and
Polygonum cuspidatum have been demonstrated to display high inhibitory effects against IAV
and their activity has been assigned to their phytoconstituents, including anthraquinones.
14
Naturally occurring anthraquinones like emodin, aloe-emodin-8-O-β-D-glucopyranoside,
chrysophanol-8-O-glucoside and emodin-1-O-β-D-glucopyranoside have been shown to
significantly suppress IAV replication even at the lowest concentration of 3.125 μg/mL (Bei
et al., 2021). Aloe vera extract and its constituents, including aloe-emodin have been also
reported to inhibit IAV. The compound has shown a high affinity with the IAV M2 proton
channel protein in the docking study, with a binding energy of 5.47 kcal/mol (Choi et al.,
2019).
4.8 Japanese encephalitis virus
Japanese encephalitis virus (JEV) is a positive single-strand RNA virus belonging to the
Flaviviridae family. The virus is more prevalent in many countries of the western Pacific and
Asian continents. About 67,900 people are infected by the virus annually and approximately
75% of them are children age group 0-14 (Zheng et al., 2012). The virus is of high morbidity
and mortality, causing severe central nervous system ailments like encephalitis and aseptic
meningitis (Unni et al. 2011).
Extracts of R. palmatum and its anthraquinones viz. aloe-emodin and chrysophanol have been
demonstrated with a potent inhibitory effect on the virus with IC50 values ranging from 0.46
µg/mL to 51.41 µg/mL. Aloe-emodin has been reported as the most potent virucidal
compound with an IC50 value of 0.46 µg/mL (Chang et al.,2014). The compound and
methanol extract of the plant have shown a high therapeutic index and thus could be
developed as potential antiviral candidates against JEV.
4.9 SARS coronavirus
Severe acute respiratory syndrome coronavirus (SARS-CoV) is an enveloped single-stranded
positive-sense RNA virus that has been reported to be responsible for progressive respiratory
failure and death in up to 10% of infected patients in 2003 (Ksiazek et al., 2003; Peiris et al.,
2003). Currently, the world is facing the COVID-19 pandemic, a disease caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Tillu et al., 2020). In early 2021,
more than 100 million subjects globally have been reported with confirmed SARS-CoV-2
infection and more than 2 million deaths have been attributed to COVID-19 (Wang et al.,
2021). To date, no antiviral drug is available to treat novel coronavirus infection except
remdesivir.
15
Many reviews have already mentioned the potent inhibitory effects of emodin on the
interaction of S protein with angiotensin-converting enzyme-2 (ACE-2) reported by Ho and
colleagues (Nazir et al., 2013; Zhang et al., 2020). In addition, the authors showed that rhein
from Polygonaceae exhibited slight inhibition of the enzyme interaction with S protein (Ho et
al., 2007). In a study by Zannella and colleagues (2021), rhein has shown its capability to
inhibit the infection and replication of different human coronaviruses (HCoV-229E, HCoV-
OC43 and SARS-CoV-2). The compound has exhibited higher inhibitory effects against
HCoV-OC43 and SARS-CoV-2 by blocking the viral life cycles completely at a higher
concentration of 200 µg/mL. At the same concentration (200 µg/mL), 90% of inhibition has
been observed with the compound against HCoV-229E. Aloe-emodin has been demonstrated
with its anti-SARS coronavirus effects by inhibiting the cleavage activity of 3C-like protease
dose-dependently, with an IC50 value of 366 µM (Lin et al., 2005). Docking study showed the
ability of a variety of anthraquinones and their derivatives, including chrysophanol 8-O-β-D-
glucoside and emodin 8-glucoside to bind to SARS-CoV-2 proteins such as 3C-like protease,
spike protein and papain-like protease, with torososide B and 1,3,6-trihydroxy-2-methyl-9,10-
anthraquinone-3-O-(6′-O-acetyl)-β-d-xylopyranosyl-(1→2)-β-D-glucopyranoside, showing
the highest binding affinity with papain-like protease and 3C-like protease respectively
(Khanal et al., 2020). In silico study has been reported showing a high-affinity binding of
anthraquinones of R. emodi including aloe-emodin, anthrarufin, alizarine, dantron and emodin
to COVID-19 at the active sites of RNA binding domain of nucleocapsid phosphoprotein. The
compounds have been found to bind to all three active sites with the binding energy varying
from –25.45 Kcal/mol to – 45.48 Kcal/mol (Rolta et al., 2021), and hence could be screened
thoroughly and released as potential drug candidates to treat COVID-19.
5. Conclusion
This paper is an investigation of plants of three different families known to produce natural
anthraquinones which are well known for their antiviral potential. The review revealed that
plants of Polygonaceae, Asphodaceae and Rubiaceae are a potential source of anthraquinones
which have demonstrated their antiviral potential against a variety of infectious viruses. Still,
only a few numbers of this group of secondary metabolites have been screened for their
effects against coronavirus. Many anthraquinones from the plants of these families have
shown their effects against viruses that infect the respiratory tract, including human
respiratory syncytial virus and influenza virus which infect the respiratory tract like
coronavirus and can be potential candidates in the screening and development of drugs against
16
COVID-19. Further, many anthraquinones have demonstrated their capacity to inhibit
coronavirus in vitro as well as in silico and constitute potently targeted naturally occurring
phytochemicals that could be developed as anti-COVID-19 drugs. Hence, this review is a
repertoire of natural antiviral anthraquinones reported from Polygonaceae, Asphodaceae and
Rubiaceae that could serve as potential leads for antiviral drugs discovery, especially in
combating coronavirus and in the development of other new antiviral agents.
Authors’ contributions
AN contributed to conceiving and designing the investigation, and wrote the initial draft; RVS
contributed to data collection and writing of the manuscript; SA managed data collection and
reviewed the manuscript, JRK and QPH participated in guiding the progression of the
investigation and proofread the manuscript and figures/tables. All the authors read and
approved the final manuscript.
Funding
No specific grant was provided for this investigation
Ethics approval
Not applicable.
Consent to participate (include appropriate statements)
Not applicable.
Availability of data and material
Not applicable.
Code availability
Not applicable.
Declaration of competing interest
The authors declare that they have no conflict of interests
17
Declaration of competing interest
The authors declared that they have no conflict of interest
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