key: cord-0064437-qfj7cu06
authors: Devi, A. Brindha; Sarala, R.
title: Substantial effect of phytochemical constituents against the pandemic disease influenza—a review
date: 2021-06-12
journal: Futur J Pharm Sci
DOI: 10.1186/s43094-021-00269-5
sha: ff3d3570fcab4e7c8130c3e36e0fd28c83cd684f
doc_id: 64437
cord_uid: qfj7cu06

BACKGROUND: Influenza is an acute respiratory tract infection caused by the influenza virus. Vaccination and antiviral drugs are the two methods opted to control the disease. Besides their efficiency, they also cause adverse side effects. Hence, scientists turned their attention to powerful herbal medicines. This review put focus on various proven, scientifically validated anti-influenza compounds produced by the plants suggested for the production of newer drugs for the better treatment of influenza and its related antiviral diseases too. MAIN BODY: In this review, fifty medicinal herb phytochemical constituents and their anti-influenza activities have been documented. Specifically, this review brings out the accurate and substantiates mechanisms of action of these constituents. This study categorizes the phytochemical constituents into primary and secondary metabolites which provide a source for synthesizing and developing new drugs. CONCLUSION: This article provides a summary of the actions of the herbal constituents. Since the mechanisms of action of the components are elucidated, the pandemic situation arising due to influenza and similar antiviral diseases can be handled promisingly with greater efficiency. However, clinical trials are in great demand. The formulation of usage may be a single drug compound or multi-herbal combination. These, in turn, open up a new arena for the pharmaceutical industries to develop innovative drugs.

Influenza virus infections remain a major formidable disease of man defying control. It is a widespread disease of man occurring in epidemics and pandemic forms [1]. Influenza severity varies from mild to extreme and is determined by the virus type and its host [2] .

Influenza viruses belong to the Orthomyxoviridae family which comprises seven genera Alpha influenza virus, Beta influenza virus, Delta influenza virus, Gamma influenza virus, Isa virus, Quaranja virus, and Thogotovirus [3, 4] . Influenza A, B, D, and C viruses belong to Alpha, Beta, Delta, and Gamma genera respectively. Influenza A virus (IAV) hosted a wide range of species including wild aquatic birds, humans, poultry, pigs, horses, and sea mammals [5] which cause epidemics and pandemic conditions [6] . Influenza B virus (IBV) infects humans and seals [5, 7] . Influenza C virus (ICV) infections have been documented in humans and swine [5, 7] . Influenza B and C viruses create epidemics but lack pandemic potential [8] . Influenza D virus (IDV) infection was observed in farmed cattle, goats, pigs, and buffalo [9] . Serological evidence detects the presence of the virus in humans [10] but the investigation of transmission remains unclear [7, 11] .

The World Health Organization (WHO) along with the National Influenza Centers (NIC) and Centers for Disease Control and Prevention (CDC) strengthen global influenza surveillance during every seasonal outbreak [12, 13] . These authorized centers monitor global influenza circulation, detecting the emergence of new strains followed by the recommendation of vaccine usage [12, 13] . Many ongoing research activities like vaccine preparation, clinical trial of new drugs, and Traditional and Complementary medicine (T&CM) using herbs are carried worldwide to anticipate their work. Traditional and Complementary medicine (T&CM) role is indispensable for the prevention and management of chronic diseases [14] and WHO estimates 65-80% of the world population rely on it [15] . Interestingly, 34 countries include herbal medicines in their national essential medicines list (NEML) [14] . Hence, herbal medicines are always in great demand for the ailment of severe diseases.

This review article enlists several anti-influenza potential herbs along with their phytochemical constituents showing multi-targeted action against influenza. This study significantly provides experimentally validated phytoconstituents showing the evidence of efficacy against influenza.

Influenza viruses are spherical (100 nm in diameter) or filamentous (300 nm in length) in shape [16] . They have a central core surrounded by an envelope. The central core region has RNA segments covered with a nucleocapsid protein (NP). The entire core is surrounded by a matrix protein (M1) consequently covered by a lipid bilayer from which two spiked surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) arise. The glycoprotein HA is a tetramer whereas NA is a trimeric molecule [16] .

IAV contains 8 RNA segments coding 7 structural proteins (PB1, PB2, PA, HA, NA, NP, and M1) and 3 nonstructural proteins (NS1, NS2, and M2) [17] . The structural proteins HA and NA are the antigenic determinants [18] and the main targets for antiviral drugs [17] . Based on these proteins, influenza A is classified into different subtypes hemagglutinin (H1-H18) and neuraminidase (N1-N11).

IBV contains 8 RNA genome segments where the nonstructural protein M2 is replaced by BM2. Influenza B has 2 lineages B/Yamagata and B/Victoria and they are not classified into subtypes [19] . ICV has 7 genome segments with a single trimeric glycoprotein called hemagglutinin esterase fusion [HEF] which equalize the function of HA and NA protein [20] along with a minor envelope protein CM2 [21] . Currently, the influenza C virus has 6 lineages [22] .

IDV is a newly emerging virus with 7 genome segments with a matrix protein DM1 and ion channel protein DM2 [23] in association with glycoprotein hemagglutinin esterase fusion (HEF) like influenza C virus. At present, it has 2 distinct co-circulating lineages [24] . Figure 1 displays the structural description of influenza viruses.

Influenza viruses profoundly alter their surface glycoprotein resulting in an antigenic variation [25, 26] which exhibits in two forms antigenic drift and antigenic shift [26] . Antigenic drift is a small, gradual change of the surface antigen due to genomic point mutations [27] forming new strains of the virus, cause epidemics [28] . Random occurrence of antigenic drift is observed in influenza A, B [24] , and C viruses [29] . In contrast, drastic antigenic change has not been recorded for the IDV [23] . Hence, its epidemic nature also remains undetermined. Antigenic shift occurs when a sudden extreme and profound change in genome reassortment results in the formation of a new subtype [28] . It is observed only in influenza A virus which leads to the pandemic condition [30] .

Vaccines are substances that provide immunity and protection against a particular infectious disease. Introducing vaccines into the body refers to vaccination and getting immunity through vaccination is immunization [31] . Every year, 3 million deaths are prevented by vaccines, and through vaccinations, the human life span has increased [32] . This shows the promising notice that vaccinations are the best way of preventing the serious effect of the dangerous disease.

Influenza is often called flu and flu vaccination is a principal tool for the prevention of influenza severity. Influenza A viruses cause pandemics whereas influenza A and B viruses cause seasonal epidemics. The World Health Organization [WHO] assisted with the National Influenza Centers [NIC] and Centers for Disease Control and Prevention (CDC) makes the recommendation for two different vaccine formulations every year, one for the Northern and one for the Southern Hemisphere [33] .

In general, influenza vaccines are prepared in two forms as inactivated influenza vaccines (IIV) and live attenuated influenza vaccines (LAIV) [34] . Intramuscular injection of the flu vaccine is referred to as a flu shot which may be in trivalent inactivated (TIV) or quadrivalent inactivated form (QIV). The TIV is comprised of two influenza A strains and one influenza B lineage while QIV includes two influenza A strains and two influenza B lineages [35] . Figure 2 displays influenza vaccine types and drug brand names recommended by the CDC.

TIV is a standard vaccine recorded as safe and creates immunogenicity among children of 6 through 35 months of age and elderly of 65 and above [36, 37] . QIV under the brand names of AFLURIA Quadrivalent, Devi Fluarix Quadrivalent, and FluLaval Quadrivalent consists of embryonated egg-grown medium vaccines, recommended for children of 6 months to 3 years, and older. People with egg allergy adapt egg-free quadrivalent vaccines like quadrivalent recombinant vaccine and quadrivalent cell-based vaccine. Quadrivalent recombinant vaccines are produced by recombinant technology where the vaccines obtained from mammalian cell culture produce quadrivalent cell-based vaccine [38] . Recently, the U.S. Food and Drug Administration (FDA) approved Flublok Quadrivalent recombinant vaccine and Flucelvax Quadrivalent cell-based vaccine for use in adults 18 years and older [39] . The High-Dose Quadrivalent vaccine with the brand name Fluzone contains four times the antigen intended to give protection for elderly people [40] . A recent study reveals that the high-dose vaccine increases the immune response [41] . AFLURIA Quadrivalent® is the only vaccine approved for use with a jet injector that comes in multi-dose vials recommend for 18-to 64-year-old people [42] .

Adjuvants are the compounds that enhance immunity. Currently, adjuvants like Alum, MF59 (oil-in-water emulsion), AS03 (oil-in-water adjuvant), AF03 (oil-inwater adjuvant containing squalene, montane 80, and eumulgin b1 ph), virosomes (phospholipids), and heatlabile enterotoxin (LT) [43] are used in TIV and QIV as FLUAD and FLUAD Quadrivalent.

The Nasal Spray Flu Vaccine under the brand name of FluMist Quadrivalent is a live attenuated influenza vaccine [LAIV] is recommended by FDA in 2012 for people ages 2 to 49. Even though the nasal vaccine stimulates the long-standing immune response, CDC not recommends it during the 2016-2017 and 2017-2018 flu seasons. This is due to its less effectiveness than IIV during the 2009 pandemic. After obtaining positive protection data of LAIV, CDC recommends it for the 2018-2019 season [44] .

Mutations make the influenza viruses change over time. Hence, the genetic materials also change and new subtypes are evolved [45] which often replace the older strain [46] . It is a fact that influenza vaccines save countless lives and prevent pandemics but annual reformulation in vaccine preparation for the new emerging strains remains a challenge for the scientist [47] .

Vaccine preparation takes a long time since it relies on the official declaration of the prevailing viral strain by WHO [48] . Marketing vaccine strains do not give enough protection against novel emerging strains [49] . At present, vaccines are prepared by three production technologies: egg-based, cell culture, and recombinant methods. The majority of the vaccine production is eggbased which is time-consuming and mismatching from the available and prevailing strains [48] . To overcome this, cell culture and recombinant methods of vaccine production are recently adapted, which are still in need of appropriate infrastructure to attain the goal.

Global demand for vaccines and shortage of production are growing exponentially. This is noted from the recent survey indicating that the requirement of seasonal vaccine is 1.504 billion doses but the production capacity is decreased to 1.467 billion doses [46, 50] . The selectivity of vaccines for elderly people is also biased since vaccine efficacy differs by age and chronic diseases [51] . Hence, these conditions make developing universal influenza vaccines a big task.

Conventional drugs for the disease Antiviral drugs are another alternative way to control and manage seasonal and post-exposure influenza [52] . They are classified into three broad categories as M2 inhibitors, neuraminidase inhibitors, and nucleoprotein inhibitors [53] . The antiviral drugs Amantadine and Rimantadine fall under M2 inhibitors, Rapivab (Peramivir), Relenza (Zanamivir), and Tamiflu (Oseltamivir Phosphate) are the neuraminidase inhibitor drugs whereas Xovluza (baloxavir marboxil) is a Nucleoprotein-inhibitor drug.

The M2 ion channel-inhibitor drugs (Amantadine and Rimantadine) are specifically used to treat influenza A infection. Currently, CDC has not recommended these drugs since they create resistance against many strains [52] .

In the present scenario, CDC recommends four FDA (Food and Drug Administration)-approved antiinfluenza drugs, namely Rapivab (Peramivir), Relenza (Zanamivir), Tamiflu (Oseltamivir Phosphate), and Xovluza (baloxavir marboxil) [54] . These drugs are effective against both influenza A and B viruses [55] [56] [57] .

The Neuraminidase-inhibitor drugs showed ineffectiveness against influenza C infection [l]. However, Baloxavir exhibits broad-spectrum antiviral activity, including influenza C and D viruses [58] .

Generally, antiviral drugs are targeting the viral components that are not able to combat the genetically altered emerging strains [59, 60] so drug-resistant strains emerge. Recent studies show neuraminidase inhibitor drug Oseltamivir also generates resistant viruses [17] like the M2-inhibitor drugs. Excessive dosages of the antiviral drugs [61] and selection pressure due to global Oseltamivir administration [62] unlikely contribute to the emergence of drug-resisting viruses.

The drawback in vaccine preparation and conventional therapies makes scientists turn their attention to powerful herbal medicines that are in great demand in the developing world [63] . A substantial increase in the consumption of herbal medicines for chronic diseases like influenza is growing exponentially [64, 65] . They are the promising alternatives reckoned for their safety, compatibility, efficacy, and minimum side effects [66] . Hence, in this review, we highlight the potent herb exhibits anti-influenza activities for the control and management of influenza.

An intense database search conduct by using the keywords like herbs used against influenza, traditional medicines for influenza, and ethno medicines for influenza. Through this, we get the relevant literature up to October 2020 from scientific databases like Google Scholar, Springer, Elsevier, Sage, Taylor & Francis, Hindawi, Wiley, Research Gate, PubMed, Scopus, Web of Science, and Shodhganga. The required data were obtained from both research and review articles published in national and international reputed journals.

Complementary and traditional medicines have been utilized for several years in various parts of the world to reduce human diseases [67] . For all these medicines, plants are the richest source. They have the active constituent phytochemical metabolites produced by the process called metabolism. This metabolism is categorized into two types as primary and secondary. Table 1 is a list of various herbs with phytochemical constituents with anti-influenza activity.

Primary metabolism is the group of all metabolic pathways synthesizing essential compounds for plant survival. Primary metabolites perform physiological functions, and these include nucleic acids, amino acids, proteins, carbohydrates, lipids, alcohol, and other natural products [152] like ester and shikimic acid.

i. Amino acid: The amino acid glutamine is essential for the synthesis of proteins and plays a critical role in the immune system. Theanine is one of the derivatives of glutamine that enhances gammadelta T cell function in influenza infection. Matsumoto et al. conducted a randomized, double-blind, placebo-controlled trial among 197 healthcare workers to evaluate the efficacy of Camellia sinensis Theanine and Catechin. The author divided the participants into two groups. The first group of 98 members receives catechin (378 mg) and theanine (210 mg) daily whereas the second group of 99 members act as the control group receives placebos. The main source of outcome is the incidence of clinically defined influenza infection, laboratoryconfirmed influenza with viral antigen, and the time patient is free from clinically defined infection.

From this study, the authors observed 4 participants in the first group and 13 from the control group report clinically defined influenza infection, whereas the laboratory-confirmed infection prevails in 1 member of the first group and 5 from the control group and they are statistically insignificant. From this, they concluded Theanine and Catechin might be an effective prophylaxis against influenza infection [81] . ii. Proteins: Lectins are the carbohydrate-binding protein noted in plants like Pandanus amaryllifolius [110, 117] , Narcissus tazetta, and Polygonatum odoratum which exerts antiviral activity against influenza viruses [110] .

Pandanin, a new antiviral lectin protein, shows its antiviral activity against the H1N1 virus at EC 50 of 15.63 μM with hemagglutinating activity [117] .

Ooi VEC et al. screened 10 purified herbal compounds from 30 herbal extracts and perform antiviral potential studies. From the 10 herbal compounds, three proteins PYM2 of Pandanus amaryllifolius, NTL of Narcissus tazetta, and POL of Polygonatum odoratum exhibit antiviral infectivity against H1N1, H3N2, H5N1, and influenza B viruses, observed through plaque reduction assay. AntiH5N1 efficacy of PYM2 (IC 50 26 .03μg/mL) and POL (IC 50 6.23μg/mL) are further investigated by introducing 5 mg/kg of the proteins in mouse macrophages where the upregulation of cytokines IL-1β, IL-12, IFN-γ, and TNF-α was observed [110] .

Narcissus tazetta lectin is a mannose- 50 values ranging from 0.02 μg/mL to 1.33 μg/mL) but with moderate inhibition on H5N1. The study also shows evidence of NTL inhibiting the H1N1's early phase of replication by interacting with surface glycoproteins, thereby avoid the virus for adherence and fusion [111] .

NTP is a fetuin-binding non-specific lipid transfer protein (nsLTPs) of Narcissus tazetta that blocks the neuraminidase of H1N1 (EC 50 of 4.47 mg/mL) thereby inhibiting the replication which is revealed from a MTT assay [112] .

iii. Carbohydrates: Carbohydrates are the major constituents of the plant which are produced by the photosynthetic process [153] . They are produced in larger amounts and are classified into four types as Monosaccharides, Disaccharides, Oligosaccharides, and Polysaccharides. [78] .

Houttuynia cordata polysaccharide [HCP] lessens the severity of organ injury due to influenza virus infection. Zhu et al. discovered its role by administered orally by gavages to H1N1 (A/FM/1/47)-infected mice and observed an increase in survival rate through inhibition of the release of pulmonary inflammatory cytokine and expression of TLR4-NF-κB. Restoring and improvement of damaged tissue also noted [103] .

Isatis indigotica root polysaccharide (IRPS) show a low cytotoxic effect and promote proliferation (1.25 mg/mL concentration) in MDCK cells infected with swine influenza virus (SIV) H3N2 of the strain (A/swine/Henan/ 2010). Through MTT assay, the preventive, inhibitory, and direct effect of IRPS against SIV was observed. IRPS (312.5-1250 μg/mL) increases the percentage of prevention from 12.64 to 74.00% which shows the MDCK cell protection with enhanced antiviral ability. In addition to that, the cell membrane was stabilized by IRPS, which provides the potential to inhibit adsorption, penetration, and infection of SIV. A dose-dependent increase of IRPS (156.25-1250 μg/mL) increased the percentage of inhibition from 31.92% to 84.95% suggested; IRPS may play a potent role in inhibiting viral RNA and protein synthesis. Surprisingly, IRPS direct effect was found to be weak in SIV-adapted MDCK cells. By in vivo study, the mice were orally administered with varying doses of IRPS chosen as 75 mg/kg/day, 50 mg/kg/day, and 25 mg/kg/ day before the infection. The mice at 3 dpi show significant clinical signs, while at high dosage applied, 5 dpi regained the weight. The IRPS reduced pathological changes, with improved lesions and normal alveolar structure. Host immunity signaling molecule NO (Nitric oxide) was increased at 2 and 5 dpi; similarly, the antibody IgG in blood serum is increased significantly at 9 dpi. IRPS induces cytokine production and reduces pulmonary inflammation, which was evident from the detection of cytokine in lung homogenate [105] . The GP-treated H1N1 infect mice exhibit a lower level of viral titer along with reduced inflammatory cytokine (IL-6). It is noted that a higher dosage does not increase the survival rate. GP provides protection effect even before the influenza infection, and regular consumption protects against heterosubtypic lethal challenges [114] .

In this study, Kallon et al. use Astragalus polysaccharide (APS) against H9N2-infected chick embryo fibroblasts (CEF) culture. APS of 321.25 μg/mL concentrations is determined as optimal for the stimulation of CEF Proliferation. Appropriate dosage of APS administered during pre-addition (321.25 μg/mL), postaddition, and simultaneous addition shows a significant reduction of viruses. APS upregulated IL-4, IL-10, LITA F, and IL-12 cytokine expression but IFN-γ, LITAF, IL-6, and IL-12 were downregulated. APS inoculation decreased MHC I and MHC II expression but increased after H9N2 infection. Peripheral blood lymphocytes expressing CD3+, CD4+, and CD8+ T cell surface markers were increased after APS immunization. Postimmunization of APS (5mg/kg) enhanced the antibody titer at 7 and 14 days [76] . iv. Ester: Ester has ideal characteristics with chemical stability. Its unique characters attract to create prodrug [156] . Several ester compounds show promising anti-influenza features.

Zhang et al. isolated 13 compounds from the dried fruit powders of Chaenomeles speciosa and identify 3, 4dihydroxybenzoic acid (Benzoic acid derivative), quercetin (flavonol), and methyl 3-hydroxybutanedioic ester (Ester) showed remarkable anti-influenza activity. The compounds 3, 4-dihydroxybenzoic acid (IC 50 1.02 μg/ mL), and quercetin (IC 50 3.82 μg/mL) displayed significant dose-dependent DPPH radical scavenging activity. 5μg/mL of 3, 4-dihydroxybenzoic acid, quercetin, and methyl 3-hydroxybutanedioic ester inhibit TNF-α by 22.73%, 33.14%, and 37.19% and NO production inhibition. High IL-6 production inhibition (39.79%) was observed in methyl 3-hydroxybutanedioic ester. The compounds 3, 4-dihydroxybenzoic acid (IC 50 1.27 μg/ mL) and methyl 3-hydroxybutanedioic ester (IC 50 1.90 μg/mL) featured H1N1 (A/PR/8/34) NA inhibition activity in a dose-dependent manner [88] .

The study of Ibrahim et al. informed that a new diglyceride ester along with asebotin (a dihydrochalcone) from Thallasodendron ciliatum exerted anti-AIV activity against A/chicken/Egypt/1055/2010 (H5N1) in MDCK cells. This compound inhibited the virus with a concentration of 1 ng mL −1 by a percentage of 67.26 and 53.81. Its efficacy was similar to zanamivir which showed a higher concentration of inhibition of 10 ng mL − 1 [146] .

Cai et al. validated Withaferin A of Withania somnifera as a potent source for H1N1 NA inhibition through docking studies. In the study, Withaferin A shows a high binding affinity towards NA [149] .

xxii. Shikimic acid: Shikimic acid is an important biochemical metabolite and its pathway is essential for the synthesis of plant amino acid [157] . Antiviral drug Tamiflu® is prepared by using shikimic acid as base material [158] . Several plants and their parts like fruits of Illicium religiosum and Illicium verum, barks of Illicium anisatum, Pinus thunbergii, and Pinus densiflora, stems and leaves of Saxifraga stolonifera, and Houttuynia cordata exhibits high shikimic acid content [159] .

Recently shikimic acid has been noted in Taxodium distichum extract and it is a carbocyclic sialic acid analog. Hence, the authors Hsieh et al. [145] suggest that it may also exert the function as a neuraminidase inhibitor.

Secondary metabolism comprises metabolic pathways which are not essential for the functioning or survival of the plant. Both primary and secondary metabolism, along with their regulatory pathways facilitates the plant to survive under stressful conditions [160] . Interestingly the secondary metabolites are derived from the primary metabolites and their various pathways [161] . Indeed, plants produce a wide array of secondary metabolites, but there is no precontrived and commonly agreed system of classification [162] . However, based on their chemical structure and biosynthetic origin, they are classified into three major classes as terpenes, alkaloids, and phenolics [163] . In addition to this, some special categories like terpenoids, glycosides, diaryl heptanoids, and isothiocyanates are included under secondary metabolites. Figure 3 categorizes the various classes of secondary metabolites.

Terpenes are a large class of secondary metabolites and they are classified based on the isoprene unit. monoterpenes, sesquiterpene, triterpene, and meroterpene are the various classes of terpenes [164, 165] . infected mice. This study noticed the improved survival rate of the infected mice. The humoral immune response is detected by using an enzyme-linked immunosorbent assay (ELISA) which detects the elevation of IgA, IgM, and IgG antibodies. The flow cytometric analysis is used to detect cell-mediated immune response which results in the increased CD3+ and CD4+ T cell levels. An increase in the production of antiinflammatory cytokines IL-10 and IFN-γ reveals the reduction of lung inflammation due to infection [122] . Wu et al. [123] investigate in vitro, in vivo, and in silico studies on Patchouli alcohol (PA) against influenza A virus (A/Leningrad/134/17/1957, H2N2). In vivo, MTT assay reveals PA at IC50 of 4.03 ± 0.23 μM inhibits the viral penetration. Through in vivo, PA at a dose of 5 mg/kg/day protects the infected mice, comparable with Oseltamivir. In silico docking and molecular dynamic simulations exhibit PA binding in the Asp151, Arg152, Glu119, Glu276, and Tyr406 active site regions of H2N2 NA with interaction energy of -40.38 kcal mol -1 .

The study of Hong et al. investigates triterpene compounds, Betulinic acid (BeA), of Zizyphus jujuba have antiviral activity against influenza A/PR/8-infected A549 cell line and C57BL/6 mice. In in vivo study, the SRB method assesses proliferation inhibition in a dosedependent manner (0.4-50 μM) in A549 cells without major cytotoxicity. Intraperitoneally administering BeA (10 mg/kg/dose) into the infected mice reveals the attenuation of increased necrosis, inflammatory cells, and pulmonary edema. ELISA study marks the decreased level of inflammatory cytokine IFN-γ level in BeAtreated infected mouse lung [150] .

Bakuchiol is a meroterpene compound derived from 

Terpenoids are a modified class of terpenes with various cyclizations and rearrangement of the carbon skeleton [165, 166] . Sesquiterpenoids, diterpenoids, and triterpenoids are the various types of terpenoids. Terpenoidderived drugs gained significant attention towards the treatment of human infectious diseases [167] .

Sesquiterpenoids are derived from sesquiterpenes showing diverse hydrocarbon backbone [168] . The Sesquiterpenoid Germacrone is one of the active components found in the rhizome of Curcuma longa. The neuraminidase assay in A549 cells and plaque reduction assay show reduced NA and plaque numbers. Through indirect immunofluorescence assay, reduction of viral protein expression, RNA synthesis, and the progeny viruses observed both in MDCK and A549 cells. In a time-of-addition study, the early stage of viral inhibitory activities was observed. Germacrone administered at 100 mg/kg provides effective protection. Moreover, the studies suggested Germacrone in combination with oseltamivir produces a significant effect [92] .

Diterpenoid compounds belong to the Terpenoid class [169] that is produced by diterpene synthases (diTPSs) and other enzymes resulting in a wide structural diversity [170] . Generally, these compounds are odorless with strong flavors.

Andrographolide is a Diterpenoid obtained from Andrographis paniculata. Recent studies show Andrographolide derivatives have potent activity opposing influenza infection. 14-a-lipoyl andrographolide (AL-1) is the synthesized Andrographolide derivative studied by Chen et al. against influenza A viruses (A/Chicken/ Guangdong/96 (H9N2), A/Duck/Guangdong/99 (H5N1), and A/PR/8/34 (H1N1)) in MDCK cells. The in vivo plaque reduction assay using EC 50 of 7.2 to 15.2 mM exhibited the most effective antiviral activities in MDCK cells. Hemagglutination assays show a minimum inhibitory concentration range of 5.3-16.8 mM indicate that AL-1 directly inhibits hemagglutinin and prevents virus adsorption. In vivo render positive information like prolonged survival, decreased lung consolidation of infected mice by oral gavages of AL-1 ranged from 100 to 200 mg/kg/days. The best result was obtained by administered twice daily for 7 days beginning 24 h before viral exposure [72] .

Another Andrographolide derivatives compound, 14deoxy-11,12-dehydroandrographolide (DAP), has potency against influenza A viruses [73] .

Triterpenoids are the oxygen derivatives of triterpenes [171] . Triterpenoids 3α-hydroxylup-20(29)-ene-23,28dioic acid and 3-epi-betulinic acid 3-O-sulfate isolated from Schefflera heptaphylla profoundly active against influenza A (H1N1) virus with IC 50 values of 25 and 31.3 μg/mL [131] .

Alkaloids are nitrogen-containing secondary metabolites. Most of the alkaloids are pharmacologically active compounds [172] . Some of the noted alkaloids like dendrobine of Dendrobium nobile, Indirubin of Isatis indigotica and Strobilanthes cusia, Lycorine and Hemanthamine of Lycoris radiate, Quinalizidine alkaloids of Sophora species, ormosinine appraise for their efficacy against influenza viruses.

The plant Dendrobium nobile stem is enriched with alkaloids namely Dendrobine. Li et al. expose dendrobine anti-influenza activity against H1N1 (A/FM-1/1/47, A/ Puerto Rico/8/34 H274Y) and H3N2 (A/Aichi/2/68) with IC 50 values of 3.39 ± 0.32, 2.16 ± 0.91, 5.32 ± 1.68 μg/mL, respectively. dendrobine inhibited the production of viral HA mRNA, HA, and NP proteins in both MDCK and A549 cells in a dose-dependent manner. It inhibited the early stage of viral replication by binding with the viral NP (Affinity constant K D value: 1.19 × 10 −2 μg/mL) thereby suppress its export resulting in the deactivation of the vRNP complex. In support of these findings, a docking study performed using AutoDock software revealed the binding of dendrobine in the highly conserved region of viral NP [95] .

Herbs like Isatis indigotica and Strobilanthes cusia are enriched with Indirubin pigment used to treat respiratory viral infection. Mak This showed the target of the viruses is the cytoskeleton in particular the monomer Actin. The compoundtreated infected cells displayed a decrease in the S phase of the cell cycle and protect against cytoskeleton disruption [109] .

Sophora species of Leguminosae family endowed with quinolizidine alkaloids exhibit anti-influenza activity. This is evident from the study of Dang et al. against H1N1 (A/Puerto Rico/8/34) virus and H3N2 Oseltamivir-sensitive virus (VR1679) which shows dihydroaloperine potent inhibitory activity with EC 50 of 11.2 μM targeting NP. Interestingly, chemical modifications on the N12 and C16 positions of the aloperine scaffold improve the efficacy approximately about 5-fold [140] .

On more quinolizidine alkaloids, Matrine of Sophora flavescens has been proposed to be a target for the development of anti-influenza drugs. Yang et al. made the first attempt to utilize the molecular imprinted polymer technique, a non-biological method to identify the active components against the influenza virus. In this study, chloroform extracts of chlorogenic acid, phillyrin, matrine, oxymatrine, sophoridine, oxysophoridine, and aspirin were used as test compounds. Synthesized Oseltamivir molecularly imprinted polymer (OSMIP) was applied to liquid chromatography (LC) which exposed the retention time of 140 min used as template (OSMIP-LC column) for the selection of test compounds. The compound polarity was detected by OSMIP-LC column online and by electrospray ionization (ESI) MS offline shows Matrine with m/z 249 shows similar correlation like Oseltamivir. Further, in vitro study revealed matrine efficacy against H9N2 (A/Goose/Dalian/3/2001) in reducing cytotoxic effect and HI inhibition similar to Oseltamivir. Stereostructural resemblance consent matrine with Oseltamivir [141] .

In silico studies of Gangopadhyay et al. [151] explain the alkaloid ormosinine might be a potential inhibitor of wild-type and mutant haemagglutinins of H5N1 virus.

Phenolic compounds are the major secondary metabolite classified into several types as Phenylpropanoid, Tannin, Catechol, and Anthraquinone [173] .

Phenylpropanoids comprise a wide diverse group of secondary metabolites which are synthesized from the primary metabolites, phenylalanine or tyrosine amino acids, either through the shikimate or the phenylpropanoid pathway. Phenylpropanoids can be categorized into five different groups as Flavonoids, Lignans, Phenolic acids, Stilbenes, and Coumarins [174] .

Flavonoids are the major group of Phenylpropanoids which comprise 8000 and more compounds [175] . The basic skeleton structure of flavonoids is C6-C3-C6 having a fused benzene ring designated as ring A and the pyran as ring c, along with a phenyl group as ring B [176] . Flavonoids classified into three different classes as Flavonoids have 2-phenylbenzopyrans, Isoflavonoids with 3-benzopyrans, and neoflavonoids with 4benzopyrans [177] . Besides these, Biflavonoid [178] and prenylflavonoid [179] are the other classes included under flavonoid.

Flavonoids are the natural compounds widely found in fruits, vegetables, flowers, seeds, nuts, spices, stems, chocolate, tea, and wine [180] . They have become an indispensable component in drug discovery research and have been ascribed promising resources for combating several viral diseases including influenza [181] . They are subdivided into different subgroups as flavones, flavanones, flavonols, flavanonol, flavan-3-ol, anthocyanin, and chalcones [182] . Intravenous baicalin injection proved an increased survival rate with improved lung parameters in influenza virus-infected mice [132] .

Neuraminidase enzyme also called sialidase cleaves the sialic acid link, between the virions and the host cell surface thereby maintaining the cycle of infection [183] . Nagai et al. checked the Sialidase inhibitory activity of flavonoids about 103 species using sodium pnitrophenyl-N-acetyl-z-D-neuraminate as substrate and found 5, 7, 4′-trihydroxy-8-methoxyflavone (F36) from the roots of Scutellaria baicalensis as potent inhibitor (IC 50 μM). Besides that, it blocked the infection and replication of the A/PR/8/34 influenza virus [133] .

The authors showed the sialidase inhibitory effect of isoscutellarein (5,7,8,4′-tetrahydroxyflavone) isolated from the leaf of Scutellaria baicalensis (Ki 41 μM) and observed replication inhibition in A/WSN/33 and A/PR/ 8/34 viral strains in MDBK cells (IC 50 20 pM) and allantoic sac of an embryonated egg. The authors observed Isoscutellarein produce a similar effect as F36 and administered both into the mouse-adapted A/PR/8/34. Intranasal administration disclosed F36 (0.5 mg/kg) complete prevention of virus proliferation, intraperitoneal administration showed F36 (4 mg/kg) reduced lung virus titers to 10 <2 , and oral administration explicit isoscutellarein (400 and 40 mg/kg) significantly reduced lung virus titers [134] .

The author continues further study by isolating 5, 7, 4′-trihydroxy-8-methoxyflavone (F36) from the roots of Scutellaria baicalensis and noted its effect in the reduction of H3N2 (A/Guizhou/54/89) and B (B/Ibaraki/2/85) viruses in MDCK after 4 hours of incubation. It reduces the virus yield by 50% at 20 μm and 90% at 40 μm in a dose-dependent manner. Fusion assay reported F36 was the inhibitor of virus fusion with the endosome/lysosome of the host cell. Intranasal 7 times (3.5 mg/kg) administration of F36 completely prevented the proliferation but did not inhibit proliferation of mouseadapted with virus inoculation from 18h before to 54 h after [135] . The investigators perform the same mode of research work by applying F36 (50μm) on mouseadapted influenza virus A/PR/8/34 (A/PR8) and obtain a similar result like progeny inhibition and endosome/ lysosome membrane fusion inhibition [136] . Seong 50 2.06 μg/mL) exhibited the highest activities against H3N2 [96] . Perilla frutescens seeds contain four main polyphenolic compounds namely, rosmarinic acid-3-O-glucoside, rosmarinic acid, luteolin, and apigenin which were tested for the antiviral potential against recombinant virus H1N1 neuraminidase (rvH1N1 NA E.C. 3. 2.1.18 ). Of these, the flavones luteolin (IC 50 8.4 μM) and the rosmarinic acid (Phenolic acid with IC 50 of 46.7 μM) showed potent NA activity and proved as noncompetitive inhibitors [118] .

Choi et al. investigated the antiviral effects of the flavone quercetin 3-rhamnoside (Q3R) from Houttuynia cordata against H1N1 strain A/WS/33 and observed the reduction of cytopathic effect in virus-infected MDCK cells. Pre-exposure of virus or Pre-inoculation of MDCK cells with Q3R did not alter its infectivity but Q3R role is appreciable only added at 1, 2, and 4 h after virus inoculation with the reduction in viral mRNA synthesis. This made the investigators conclude Q3R inhibits the initial stage of viral replication [104] .

In vitro studies of Roschek B Jr et al. reveals the inhibitory efficiency of Sambucus nigra extract (IC 50 252 ± 34 μg/mL) against H1N1(A/PR/8/34) and identified two flavonoid compounds 5,7,3′,4′-tetra-O-methylquercetin (1) and 5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl) chroman-3-yl-3,4,5trihydroxycyclohexanecarboxylate (2) through direct binding assay and DART TOF-MS analysis. The authors urged these compounds were primarily responsible for anti-influenza activity by synthesizing flavanonol compound 1 and a flavanonol compound dihydromyricetin (corresponding 3hydroxyflavonone of 2) and observed H1N1 inhibition with IC 50 value of 0.13μg/mL and 2.8μg/mL. These compounds directly bind to the virus particles and prevent host cell entry and/or recognition similar to the antiviral drugs Oseltamivir and Amantadine [130] .

Aronia melanocarpa fruits are rich in polyphenolic compounds which displayed wide antiviral activity against H1N1, H3N2, recombinant H1/PR8 expressing green fluorescent protein (rPR8-GFP), and influenza B virus. The Aronia mode of virucidal action is targeting the HA protein of H1N1 (A/Korea/01/2009) which is evident from the HI assay. Its flavone myricetin and the phenolic acid compound ellagic acid successfully inhibited the replication and did not show any cytotoxic effect against MDCK cells. The in vivo study exhibited myricetin and ellagic acid increase the survival rate by 50% and 37.5% of rPR8-GFP virus-infected mice [75] .

Flavonols exist as Hyperoside in Azadirachta indica, Gossypetin and Kaempferol in Rhodiola rosea, and quercetin of Chaenomeles speciosa endowed as a promising agent for suppressing viral activities.

Ahmad et al. perform in silico docking studies by selecting Azadirachta indica active compounds nimbaflavone, rutin, and hyperoside along with drugs OMS, CBX, LGH, naproxen, BMS-883559, and BMS-885838 as ligands and the nucleoprotein structure [PDB ID:3RO5] as a receptor. All these ligands displayed perfect binding by interacting in the conserved residue (ASP302, TYR52, SER50, GLY288, SER376, and ARG99) of the receptor. But the best interaction was obtained from hyperosides along with the drugs LGH, naproxen, BMS-885838, and BMS-883559 [77] .

Rhodiola rosea is a herbaceous plant used for food and medicine which contains constituents like flavonoids, phenylpropanoid and phenyl ethanol derivatives, and aliphatic glycosides. In this study, Jeong et al. isolated five flavonols (3, 5, and 9-11), and their structure-activity relationship (SAR) is compared with available flavonoids (1, 2, 4, 6-8, and [12] [13] [14] . All these compounds unveiled NI activity against Clostridium perfringens (IC 50 0.8 to56.9 μM) and rvH1N1 (IC 50 The kinetic studies exposed all isolated flavonols act as noncompetitive inhibitors [127] .

The flavonol quercetin of Chaenomeles speciosa exhibited significant dose-dependent DPPH radical scavenging activity with IC 50 3.82 μg/mL. Quercetin of 5μg/mL inhibits TNF-α by 33.14% and NO production [88] .

Flavanonol dihydromyricetin isolated from Sambucus nigra activated and induced the immune system to combat the influenza virus H1N1 (A/PR/8/34) through binding with virions and blocking entry and recognition of the host cell [130] .

Flavan-3-ol compounds catechin, epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), epigallocatechin-3-gallate (EGCG), (−) epigallocatechin gallate (EGCg), and theaflavin digallate (TF3) have been reported in Camellia sinensis, (+)-catechin of Ephedrae herba, catechin-3-O-gallate of Polygonum cuspidatum, and gallocatechin-7-gallate (J10688) of Pithecellobium clypearia contribute significantly against influenza viruses.

Tea is produced from the leaves of Camellia sinensis and classified into three types as non-fermented green tea, semi-fermented oolong tea, and fermented black and red tea [184] . The green tea is enriched with flavonol catechin. There are four main types of catechin predominantly found in green tea, namely epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG) [185] . Differing from that, the black tea contains the polymerized catechins, namely theaflavins and thearugins [184] . Worldwide Green tea consumption is increasing due to the awareness of its health benefits [186] . Park et al. conducted a population-based study of school children in Kikugawa City, Japan, using the anonymous questionnaire survey and concluded the work that consumption of 1-5 cups/ day of green tea might prevent influenza infection among schoolchildren in a tea plantation area [187] nM which were 7.1-to 44-fold lower than EGCG and CC 50 value was 82 μM which was 3.1-fold lower than EGCG. Hence, EGCG-16 proved as a potent inhibitor with an SI value 2.2-to 14-fold greater than EGCG [84] . Nakayama et al. purified (−) epigallocatechin gallate (EGCg) and theaflavin digallate (TF3) from green and black tea and performed an inhibitory activity in opposition to H1N1 (A/Yamagata/120/86) and B (B/USSR/ 100/83) virus-infected MDCK cells. Virus agglutination was observed when it was mixed with EGCg and TF3 even at a low concentration of 1.5 μM and prevents its adsorption to MDCK cells. EGCg and TF3 at the concentration of 1-16 μM bind to HA, thereby preventing haemagglutination and obstructing its infectivity. However, EGCg (> 200 μM) and TF3 (> 100 μM) were toxic to MDCK cells [85] . In support of the above findings, Sahoo et al. perform in silico docking studies and concluded theaflavin as a potent natural inhibitor bind with the lowest energy (-5.21 kcal/mol) to H1N1 neuraminidase [86] . 50 29.77 ± 6.12 μg/mL) and 2 (IC 50 36.91 ± 3.80 μg/mL) exhibited moderate activity against H1N1. All the compounds inhibited the expression of proinflammatory cytokines IL-6 or MCP-1 induced in H1N1 virus-adapted A549 cells. The structural verification of the compounds was performed using spectroscopic analysis [119] .

From the leaves and twigs of Pithecellobium clypearia, Li et al. isolated flavan-3-ol gallocatechin-7-gallate (J10688) which acts as a novel CLK1 inhibitor with potent anti-influenza activity. In vivo studies performed by using intravenous administration of J10688 (30 mg/kg/ day) in H1N1-infected ICR mice which showed inhibition of pro-inflammatory cytokines IFN-γ, IL-6, TNF-α, 50 3.2μg/mL and directly inactivated 99% of the virus by 10μg/mL with a pH 2.8. Post-exposure treatment of the extracts presented complete inhibition suppression in H1N1 (10-100μg/mL) which indicates the extract suppresses the late stage of virus growth. After 8-9 h of infection (both IVA and IVB) showing MDCK cells are treated with the extract of 100 μg/mL for 1 h, and the virus titers in culture fluids show complete inhibition indicates extract inhibits the virus release [128] .

The same authors and other investigators further investigated the crude extract and found anthocyanins as major constituents responsible for anti-influenza activity. Using TLC, the extract was fractionated into A to D and Anthocyanin D fraction was further fractionated into A′ to G′. The fractions D′ to G′ produced potent antiinfluenza activity against A and B viruses. E′ and F′ exposed additive antiviral effects and identified as 3-Oalpha-L-rhamnopyranosyl-beta-D-glucopyranosyl-cyanidin and 3-O-beta-D-glucopyranosyl-cyanidin, and 3-Oalpha-L-rhamnopyranosyl-beta-D-glucopyranosyl-delphinidin and 3-O-beta-D-glucopyranosyl-delphinidin using HPLC. F′ inhibits virus adsorption, release but not directly inactivate it [129] . Hayashi pelargonidin, pelargonidin 3-p-coumaroylglucose with 5-glucose, and pelargonidin 3-p-coumaroylglucose with 5malonylglucose were tested for anti-influenza activity against H1N1(A/PR/8/34) and B(B/Gifu/2/73). The result revealed that anthocyanin powder showed the best inhibitory activity against H1N1 (IC 50 48μg/mL) and B (IC 50 54 μg/mL) than other pigments. The authors suggested that the antiviral activity of the potato anthocyanin is due to its additive or synergistic effect on other constituents including anthocyanin [139] .

Chalcones bestowed with therapeutical properties have been noted for their anti-influenza activities. Recently chalcones isolated from Glycyrrhiza uralensis, Glycyrrhiza inflata, Thalassodendrin ciliatum, and Caesalpinia sappan showed strong anti-influenza activities.

Ryu et al. isolated 18 polyphenol compounds consisted of four chalcones, nine flavonoids, four coumarins and one phenylbenzofuran from the roots of Glycyrrhiza uralensis and evaluate their NA inhibitory activity. Of these the chalcone isoliquiritigenin (IC 50 9.0μM) and coumarin glycyrol (IC 50 3.1μM) showed strong inhibition on rvH1N1 NA (A/Ber-vig_Mission/1/18) and these are proved to be non competitive inhibitors [100] .

From the acetone extract of Glycyrrhiza inflata, 8 chalcones were isolated, and their NA (H1N1, H9N2, H1N1 (WT), and H1N1 (H274Y)) inhibitory activities were accessed. Of these, compounds 3 (echinantin) and 6 (isoliquiritigenin) without the prenyl group exhibit strong inhibitory activity in viruses-infected 293T cells. Compound 3 (echinantin) and oseltamivir proved synergistic effects against NA of H274Y virus [99] .

From the EtOAc extract of Thalassodendron ciliatum, Thalassodendrone (dihydrochalcone diglycoside), and 5 known phenolic compounds, namely asebotin, quercetin 3,7 diglucoside, protocatechuic acid, ferulic acid, and phydroxybenzoic acid were isolated and identified. These compounds were evaluated for anti-influenza activity against H1N1 (influenza A virus /WSN/33) and revealed asebotin (IC 50 2.00μg/mL, CC 50 3.36 μg/mL) inhibition and cytotoxic concentration were more than those of thalassodendrone (IC 50 1.96 μg/mL, CC 50 3.14 μg/mL) [147] .

Liu et al. isolated six NA inhibitor compounds that are brazilein, brazilin, protosappanin A, 3-deoxysappanchalcone, sappanchalcone, and rhamnetin from Caesalpinia sappan and evaluated their anti-influenza activity against A/PR/8/34 (H1N1), A/Guangdong/243/72 (H3N2), and B/Jiangsu/10/ 2003 viruses. The results disclosed that the chalcone compounds 3-deoxysappanchalcone (IC 50 1.06) and sappanchalcone (IC 50 2.06 μg/mL) explained the highest inhibition activity against H3N2-infected MDCK cells [79] .

Isoflavonoid compounds build great attention in healthprotecting and health-promoting effects preferable to use in human medicine [188] . This class includes pterocarpans [189] and homoisoflavonoids [190] .

From the methanol extract of Sophora flavescens, three pterocarpans and six flavanones were isolated and their NA inhibitory activity disclosed all the isolated compounds excluded the compound 3, showing inhibitory effects between 12 and 20 μM. Among these, pterocarpan 1 with IC 50 1.4 μM displayed the best inhibition activity. Moreover, molecular docking studies of pterocarpan 1 with the receptor neuraminidase (PDB 1L7F) show the binding region nearer to the active site of the receptor [142] .

Homoisoflavonoids are a rare class of flavonoids present in few plant families like Fabaceae, Asparagaceae, Portulacaceae, Cucurbitaceae, and Polygonaceae [191] . Recently, it is reported in Caesalpinia sappan of the Fabaceae family disclosing potential anti-influenza activities.

Jeong Homoisoflavonoids with an unsaturated group like sappanone A (2) and brazilin (12) unveiled higher NA activity than saturated sappanone B (3). Hence, the investigators conclude that the α, βunsaturated carbonyl group in the A-ring is the main factor needed for NA inhibition [80] . Ginkgetin acts as a sialidase inhibitor but it exerts a cytotoxic effect in MDCK cells, while the conjugates 8R and 8S are empowered with low cytotoxic effect and high sialidase inhibition. The intranasal application of 8R and 8S to the H1N1-infected mice reflected an increased survival rate of 75-78% at day 10 and 62.5-56% at day 21 [98] .

In the study by Chiou et al., was isolated from the roots of Sophora flavescens and added into MDCK cells infected with H1N1 (A/PR/8/34) which significantly reduced RANTES accumulation along with nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF-3) nuclear translocation in a dose-dependent manner. The investigators revealed the fact that both NF-κB and IRF-3 were essential for H1N1 RANTES production. The influenza virus-activated PI3K pathway and Akt phosphorylation were also attenuated along with the prevention of IκB degradation by 8-PK. This PI3K-Akt pathway was essential for NF-κB-and IRF-3-mediated RANTES production [143] . 50 43.9 μM) which produced moderate inhibitory activity [144] .

Lignans are the polymers of lignin comprising a large number of compounds. Compounds include arctiin, arctigenin in Arctium lappa, clemastanin B, and lariciresinol-4-O-β-D-glucopyranoside from Isatis indigotica which played a predominant role to restrict influenza viral infections.

Hayashi et al. explored two lignan components, arctiin and arctigenin, isolated from the fruits of Arctium lappa which exerted strong inhibitory effects on the replication of the H1N1 (A/NWS/33) virus. Further ongoing investigation reveals that arctigenin exhibited a 6-to 8-fold lower IC 50 value (IC 50 3.8-2.9 μM) with minimum cytotoxic effect (CC 50 45 μM) than arctin (IC 50 24-22 μM, CC 50 290 μM) in virus-infected MDCK cells. Thus, it will be interesting to investigate and characterize arctigenin through the time of addition assay and progeny release assay. Surprisingly, arctigenin's best inhibitory effect was noted within immediate addition of virusinfected MDCK cells suggesting that it interacted with the early stage of viral replication but did not inhibit its cellular penetration. The addition of arctigenin, even after 8 h p.i. gives a scope that it inhibits viral progeny and release. The investigator's in vivo study explicitly explains that the oral administration of (H1N1, H3N2, H6N2, H7N3, H9N2 , and influenza B) with IC 50 0.087-0.72 mg/mL. A distinct reduction of virus titer was observed only when the compound was added after viral incubation in the MDCK cell. The time course assay was performed using H1N1 (A/PR/8/34) and prominent inhibition was observed when clemastanin B treated 0-2 h after virus adsorption in the cell line, which suggested the compound target was at the early stage of replication. Moreover, this cell line unveiled the presence of viral RNP in their nucleus, which implies clemastanin B interferes with RNP export. Through a multi-passage experiment, the authors identified clemastanin B did not create drug resistance by the virus [107] .

Phenolic acids are derivatives of benzoic acid and cinnamic acids. Benzoic acid derivatives include p-hydroxybenzoic acid, gallic acid, and ellagic acid, whereas cinnamic acid derivatives include rosmarinic acid [192] .

The benzoic acid derivative compound 3, 4dihydroxybenzoic acid of Chaenomeles speciosa shows significant dose-dependent DPPH radical scavenging and NA inhibition activities against H1N1. It also significantly inhibits TNF-α and NO production [88] .

The water-soluble polyphenol tannin is found in various plants and brings antiviral activity. Theisen found that gallic acid (phenolic acid), hamamelitannin (gallic acid derivative), tannic acid, and pentagalloylglucose (tannin) are the active part. The bark extract fractionated by ultrafiltration (UF) segregates low-and highmolecular-weight compounds. The low-molecularweight compounds of less than 500 g/mol are gallic acid, epigallocatechin gallate, or hamamelitannin which exhibit neuraminidase inhibition but not hemagglutination, whereas high-molecular-weight tannin-containing extracts and tannic acid (1702 g/mol) show inhibition of viral binding and neuraminidase [101] . Ellagic acid of Aronia melanocarpa inhibits replication without cytotoxic effect in HIN1 (A/Korea/01/2009)adapted MDCK cells and increased the 37.5% survival rate of rPR8-GFP virus-infected mice [75] .

Perilla frutescens seeds contain rosmarinic acid, a cinnamic acid derivative, which shows potent NA activity with IC 50 of 46.7 μM and proved as noncompetitive inhibitors [118] .

Resveratrol, a low-molecular-weight stilbene compound isolated from the ethyl extract of Polygonum cuspidatum act as NA inhibitors with IC 50 values of 129.8 [124] .

Kurokawa et al. selected six antipyretic compounds, 7hydroxycoumarin (coumarin), 4-allylanisole, cinnamic acid ethylester, acetic acid cinnamylester, 2Xhydroxyacetophenone, and 2-hydroxycinnamic acid (cinnamyl derivatives) from the organic solvent-extractable fractions of Cinnamomum cassia and examined their antipyretic effects in H1N1 (A/PR/8/34)-infected mice that showed a remarkable reduction in rectal temperature. Further, four compounds, 7-hydroxycoumarin, 4-allylanisole, cinnamic acid ethylester, and acetic acid cinnamylester, suppressed the rise of interleukin-1α production to the basal level and reduced its circulation in the serum. The presence of the ester bond is the main determiner for both antipyretic and interleukin-1α suppression [90] .

The above study brings out the fact that the coumarin compound, 7-hydroxycoumarin (7HC), reduced the proinflammatory cytokines along with antipyretic and interleukin suppression activities. The author Kurokawa and other investigators investigate 7HC in detail and explore 30 mg/kg oral administration of 7HC significantly reduces weight loss and virus production in the lung bronchoalveolar lavage fluid (BALF) of influenza-adapted mice. The author identified the suppression of proinflammatory and Th1 cytokine (IL-12 and interferongamma) results in the reduction of virus titer [91] .

The coumarin glycyrol of Glycyrrhiza uralensis with IC 50 3.1 μM showed strong inhibition on rvH1N1 NA and proved to be a non-competitive inhibitor [100] .

The hydrolyzable tannins strictinin found in Camellia sinensis comprised about 0-1.0% dry weight. The study of Saha et H3N2) ), and B (B/Harbin/07/94) viruses, which shows drastic proliferation inhibition without cytotoxicity in virus-adapted MDCK cells. H3N2induced agglutination of chicken is inhibited by PPE suggesting the target was viral attachment. PPE showed direct inhibitory and virucidal effects on the H3N2 virus which are observed through the RT-PCR technique. The single-cycle and multiple-cycle growth conditions indicated PPE affects viral replication but did not alter vRNP entry and translocation in the host cell. To identify active potential components from the extract, four polyphenol compounds, ellagic acid, caffeic acid, luteolin, and punicalagin, were selected and examined. Surprisingly, the tannin compound punicalagin plays similar activities, like PPE, and mimics the same effect. In addition to that, PPE produces a synergic effect when combined with oseltamivir [126] ..

The tannin-rich components tannic acid and pentagalloylglucose of Hamamelis virginiana of 1702 g/mol show inhibition of viral binding and neuraminidase [101] .

Hydroxytyrosol (HT) is one of the main phenolic components of Olea eurolaea belonging to the class of catechols produced a virucidal effect which was revealed in the study of Yamada et al. Hydroxytyrosol inactivates enveloped viruses including influenza A/Hokkaido/30/ 2000 (H1N1), A/Hokkaido/52/98 (H3N2), A/chicken/ Yamaguchi/7/04 (H5N1), and A/chicken/Yokohama/ aq55/01 (H9N2). HT did not show any cytotoxic effect on MDCK cells; it affected H9N2 virus NP protein synthesis and suppressed mRNA synthesis at 24 h.p.i. Electron microscopic analysis detects the structural disruption of the H9N2 virus by HT [113] .

Aloe vera is a widely used herb of economical importance. In this study, two new anthraquinones, namely aloesaponarin-I (1) and aloesaponarin-II (2), were isolated from the roots. From aloesaponarin-I (1), six derivatives were obtained by the consecutive process like methylation (3), acetylation (4), and O-glycosyl (5, 6). As well as from aloesaponarin-II (2), a new derivative termed Tetra-O-acetyl-β-D-glucopyranosyl derivative obtained and these entire compounds experimented against H1N1 (A/Yucatán/2370/09, A/Mexico/ InDRE797/10) infection. All these compounds (CC 50 > 90 μM) did not exert any cytotoxic effect in MDCK cells. Virus replication inhibition analyzed by cytopathic effect reduction assay (CPE) noted compounds 3-(2′,3′,4′,6′tetra-O-acetyl-β-D-glucopyranosyl-aloesaponarin-I (5) and

3-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosylaloesaponarin-II (7) against A/Yucatán/2370/09 (IC 50 of 30.77 and 13.70 μM) and A/Mexico/InDRE797/10 (IC 50 of 62.28 and 19.47 μM) reduction effect. Since other derivatives did not exhibit any antiviral effect, compounds 5 and 7 were taken for further studies. Plaque inhibition test using A/Yucatán/2370/09 strain noted the dosedependent addition of compound 5 (50 and 100 μM) had significantly reduced the virus titer more than compound 7. The time-of-addition experiment appraising the efficacy of two compounds yielded a 70% reduction of virus titer at 6-10 h post-treatment [69] .

Glycosides are active biological compounds reported in Albizia julibrissin, Panax quinquefolium, and Panax ginseng proved effective anti-influenza compounds.

Sun et al. isolated total saponin from the stem bark of Albizia julibrissin (AJSt) and fractionated it into AJS30, AJS50, AJS75, and AJS95. These compounds hemolytic activities and their adjuvant effect was reviewed. The compound AJSt, AJS50, AJS75, and AJS95 experienced minor hemolytic effects. The adjuvant effect of the compounds in the mice immunized with ovalbumin (OVA) and recombinant fowlpox virus vector-based avian influenza vaccine (rFPV) unveiled AJSt, AJS50, and AJS75 potent activities like enhancing concanavalin A (Con A), lipopolysaccharide (LPS), antigen-stimulated splenocyte proliferation, and serum antigen-specific IgG, IgG1, IgG2a, and IgG2b antibody titers. In-depth analysis of adjuvant action revealed AJS75 was the most potent adjuvant by inducing cellular and humoral response through stimulating cytokines and chemokines [68] .

Dong et al. selected ginseng extracts (GE) and ginsenosides against the 2009 pandemic virus (A/Nanchang/ 8002/2009 H1N1 (NC2)) and observed the effect in both in vitro and in vivo study. The mice infected with GE-NC2 showed an increased survival rate and minimum weight loss. Similarly, the pretreated ginsenoside-and NC2 (Rb1-NC2)-received mice show a remarkable survival rate. Meanwhile, the mice at 3 d.p.i. show a reduction in viral titer which revealed ginsenoside action against lethal lung damage. Hemagglutination assay confirms the interaction of ginsenoside with the HA, thereby interfering with the virus attachment. The authors explore sugar moieties of ginseng play a crucial role in the interaction with HA of the virus. Oligosaccharide binding assay confirms that ginsenoside prevents virus attachment with α 2-3′ sialic acid receptors on the host cell surface. Subsequently, it minimizes virus entry and thereof decreases the infection [116] . Chan et al. chose special types of ginsenoside (Re, Rg1, and PPT) of Panax ginseng and studied the effect of inflammation and apoptosis induced by the H9N2 (A/ Quail/Hong Kong/G1/97) virus. Human umbilical vein endothelial cells (HUVECs) were infected with H9N2 produce inflammation by inducing the chemokine IP-10 production. Ginsenoside PPT inhibits IP-10 production by regulating the micro RNA, miR-15b. Post-treatment of ginsenoside Re (50 μM) partially reduced the virusadapted apoptosis which denotes its cytoprotection and increased cell viability effect [115] .

Diarylheptanoids are structurally distinctive compounds with diverse biological and pharmacological effects [193] . Recently, its anti-influenza effects have been reported in Alpinia officinarum and Curcuma longa.

From the rhizome of Alpinia officinarum, ten diarylheptanoids were isolated and their anti-influenza efficiency against H1N1 (A/PR/8/34) examined which provide the EC 50 value of diarylheptanoids was lower than CC 50 and MNCC (maximum non-cytotoxic concentration). The diarylheptanoids 7-4″-hydroxy-3″methoxyphenyl)-1-phenyl-4E-hepen-3-one (3) and (5S)-5-hydroxy-7-(4″-hydroxyphenyl)-1-phenyl-3-heptanone (8) show the EC 50 values 2.9 ± 0.3 μg/mL and 0.7 ± 0.3 μg/mL were lower than the control ribavirin EC 50 16 .7 ± 0.4 μg/mL. Hence, the authors suggested diarylheptanoids 3 and 8 as a potent source of anti-influenza activity [70] .

The authors continued the study by orally administering these two compounds 7-4″-hydroxy-3″-methoxyphenyl)-1-phenyl-4E-hepen-3-one (AO-0002) and (5S)-5-hydroxy-7-(4″-hydroxyphenyl)-1-phenyl-3-heptanone (AO-0011) three times daily to the H1N1 (A/PR/8/34)infected mice for 6 days after infection. AO-0002 (100 mg/kg) effectively reduced the bodyweight loss and enhanced the survival period of infected mice. AO-0002 (30 mg/kg, 30 and 100 mg/kg) notably reduced the virus titer in the lung BALF of infected mice on days 3 and 6 after infection. AO-0011 did not exhibit the above activities; hence, the author selected AO-0002 for further in vitro analysis. AO-0002 effectively inhibited the infec- Chen et al. evaluated the efficiency of curcumin against H1N1 (A/Puerto Rico/8/34) and H6N1 (A/ chicken/Taiwan/NCHU0507/99) which revealed no cytotoxic effect in virus-infected MDCK cells. Dosedependent addition of curcumin reduced viral replication. Specifically, 30 μM of curcumin lessened 90% of virus yield. Time-of-addition experiments verified the direct inhibitory effect of curcumin. The mechanism was revealed by plaque reduction assay, which showed the early stage of inhibitory activity includes attachment prevention but not penetration. HA assay demonstrated curcumin possesses HA inhibition activity by interacting and interrupting the link between viruses HA and host cell receptors but not with the host RBC cell. In comparison with amantadine, curcumin did not evoke viral resistance [93] .

Curcuma longa empowers a broad spectrum of antiviral activities. This creates interest for the investigators to investigate the presence of the substance in the herb. Recently, Dao et al. isolated 3 new (1-3) and 10 known (4-13) curcuminoids from the rhizome of Curcuma longa and performed neuraminidase inhibition assays against H1N1 (A/California/08/2009, A/Sw/Kor/CAH1/ 04, H274Y mutant) and H9N2 (A/Chicken/Korea/ O1310/2001). From the study, all compounds are proven as non-competitive inhibitors with significant NA activity, of which compounds 4, 5, and 13 showed the best potent ability [94] .

Isothiocyanate is one of the active ingredients of Wasabi japonica which shows a significant virucidal effect against the influenza virus when treated with the composition of O.1SmL isothiocyanate in addition to 0.05 mL virus. The content of isothiocyanate differs in different parts of the plant where the rhizome (0.80 mol·mL −1 ) had a high amount compared with the fibrous root and petiole [148] .

Influenza remains a global threat. Even though it is under control, handling the pandemic situation remains a great challenge. Vaccine development and drug resistance coupled together to create a massive crisis in the difficult condition. To combat the problem, new drugs are necessary to practice. Keeping this view, alternative and traditional medicines provide new insights into the arrival of new drugs. This paper emphasizes an overview of the active ingredients of plants and their promising scientifically validated activity of the anti-influenza characteristics. Therefore, shortly, these active ingredients can be promoted for use as a new safe drug. A successful attempt can be claimed only when the clinical trial is appreciable.

Devi and Sarala Future Journal of Pharmaceutical Sciences (2021) 7:120 Page 27 of 33

Adenovirus 3; AL-1: 14-a-Lipoyl andrographolide; AMPK: 5′ adenosine monophosphate-activated protein kinase

AJSt: Total saponin from the stem bark of Albizia julibrissin

BALF: Bronchoalveolar lavage fluid; BCPS: Bupleurum chinense polysaccharides; BeA: Betulinic acid; CC 50 : Half maximal cytotoxic concentration; CDC: Centers for Disease Control and Prevention; CEF: Chick embryo fibroblasts

CPE: Cytopathic effect reduction assay

Direct analysis in real time mass spectrometry; diTPSs: Diterpene synthases; EC 50 : Half maximal effective concentration

EGC: Epigallocatechin; EGCg: (−) Epigallocatechin gallate

EGCG: Epigallocatechin-3-gallate; EHext: Extract of Ephedra herba

ELS: Endosome and lysosome; ELISA: Enzyme-linked immunosorbent assay

FDA: Food and Drug Administration; GE: Ginseng extract; GP: Panax ginseng polysaccharides; GTE: Green tea extract; HA: Hemagglutinin

HEF: Hemagglutinin esterase fusion; HeLa: Human epithelioid cervical carcinoma; HI: Hemagglutination inhibition assay; HIV: Human immunodeficiency virus; HPLC: High-performance liquid chromatography

HT: Hydroxytyrosol; HUVECs: Human umbilical vein endothelial cells; IAV: Influenza A virus; IBV: Influenza B virus; IC: Inhibitory concentration; IC 50 : Half maximal inhibitory concentration; ICV: Influenza C virus; IDV: Influenza D virus

IRF-3: Interferon regulatory factor 3; IRPS: Isatis indigotica root polysaccharides; LAIV: Live attenuated influenza vaccines; LC: Liquid chromatography; LPS: Lipopolysaccharide; M1: Matrix protein; MDBK: Madin-Darby bovine kidney cells; MDCK: Madin-Darby bovine canine kidney cells

MeOH: Methanol; MNCC: Maximal non-cytotoxic concentration

MxA: Myxovirus resistance gene A; MS: Mass spectroscopy; MTT assay: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NA: Neuraminidase; NEML: National essential medicines list; NF-κB: Nuclear factor-κB; NI: Neuraminidase inhibition assay; NIC: National Influenza Centers

NO: Nitric oxide; NP: Nucleoprotein or nucleocapsid protein; nsLTPs: Fetuinbinding non-specific lipid transfer protein; NTL: Narcissus tazetta lectin

OAS: 2-5′ oligoadenylate synthetase; OSMIP: Oseltamivir molecularly imprinted polymer; OVA: Ovalbumin; 8-PK: 8-Prenylkaempferol; PA: Patchouli alcohol; PDB: Protein Data Bank; p.i.: Post-infection

PPE: Pomegranate polyphenol extract

QIV: Quadrivalent inactivated vaccine; qRT-PCR: Real-time quantitative reverse transcription PCR; RANTES: Regulated upon Activation, Normal T cell Expressed and Secreted; rFPV: Recombinant fowlpox virus vector-based avian influenza vaccine; RSV: Respiratory syncytial virus; SAR: Structure-activity relationship; SIV: Swine influenza virus; SRB method: Sulforhodamine B assay (SRB); T&CM: Traditional and Complementary medicine

TOA: Time-of-addition assay; UF: Ultrafiltration; vRNP: Nuclear export of viral ribonucleoprotein

Sporadic occurrence of zoonotic swine influenza virus infections

The global impact of influenza on morbidity and mortality

Virus taxonomy, classification and nomenclature of viruses: ninth report of the International Committee on Taxonomy of Viruses

A divergent Articulavirus in an Australian gecko identified using meta-transcriptomics and protein structure comparisons

Inactivated influenza vaccines

Influenza Vaccines-Are They Efficacious or Not?

Host and viral determinants of influenza A virus species specificity

Basics of virology

Influenza D virus in animal species in Guangdong Province, southern China

Serologic evidence of exposure to influenza D virus among persons with occupational contact with cattle

Emerging influenza D virus threat: what we know so far

Overview of the WHO Global Influenza Programme

Mapping of the US domestic influenza virologic surveillance landscape

Traditional medicines in the world: where to go next? Evid Based

The biology of influenza viruses

Antiviral Activity and Molecular Targets of Plant Natural Products Against Avian Influenza Virus

Preparation and immunogenicity of a purified influenza virus haemagglutinin and neuraminidase subunit vaccine

Back to the Future for Influenza Preimmunity-Looking Back at Influenza Virus History to Infer the Outcome of Future Infections

A seven-segmented influenza A virus expressing the influenza C virus glycoprotein HEF

The influenza C virus CM2 protein can alter intracellular pH, and its transmembrane domain can substitute for that of the influenza A virus M2 protein and support infectious virus production

Genetic lineage and reassortment of influenza C viruses circulating between 1947 and 2014

Influenza C and D viruses package eight organized ribonucleoprotein complexes

Novel influenza D virus: epidemiology, pathology, evolution and biological characteristics

Antigenic variation of influenza viruses

Antigenic Variation

Encyclopedia of Virology

Infectious Diseases

Is there evidence for antigenic drift of influenza C virus?

Influenza vaccine-outmaneuvering antigenic shift and drift

Immunization: The Basics definition of terms

Vaccine manufacturing: challenges and solutions

Making better influenza virus vaccines?

Advances in the development of influenza virus vaccines

Epidemiology of influenza B in Australia: 2001-2014 influenza seasons. Influenza Other Respir Viruses

Safety and Immunogenicity of Full-Dose Trivalent Inactivated Influenza Vaccine (TIV) Compared With Half-Dose TIV Administered to Children 6

Through 35 Months of Age

Immunogenicity of H5N1 influenza vaccines in elderly adults: a systematic review and meta-analysis

Seasonal Flu Shot

Traditional and new influenza vaccines

Fluzone® High-Dose Influenza Vaccine

Advances in the vaccination of the elderly against influenza: role of a high-dose vaccine

Sometimes, more is better

Live Attenuated Influenza Vaccine [LAIV] (The Nasal Spray Flu Vaccine) Available at

Genetics of the influenza virus

Prospects and challenges in the development of universal influenza vaccines

Nextgeneration influenza vaccines: opportunities and challenges

Influenza vaccines: challenges and solutions

The 2015 global production capacity of seasonal and pandemic influenza vaccine

Recommendations for the prevention and treatment of influenza using antiviral drugs based on cost-effectiveness

Development of effective anti-influenza drugs: congeners and conjugates -a review

Influenza (flu) antiviral drugs and related information (2020) US Food and Drug Administration

Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients

The use of antiviral drugs for influenza: recommended guidelines for practitioners

Baloxavir marboxil for uncomplicated influenza in adults and adolescents

Anti-influenza treatment: drugs currently used and under development

Antiviral agents active against influenza A viruses

Pandemic (H1N1) 2009: antiviral drug resistance

Published sequences do not support transfer of oseltamivir resistance mutations from avian to human influenza A virus strains

Herbal medicine: current status and the future

Herbal plants and plant preparations as remedial approach for viral diseases

Prevention and treatment of influenza, influenza-like illness, and common cold by herbal, complementary, and natural therapies

Herbal medicine

Potential of complementary and alternative medicine in preventive management of novel H1N1 flu (Swine flu) pandemic: thwarting potential disasters in the bud

Adjuvant-active fraction from Albizia julibrissin saponins improves immune responses by inducing cytokine and chemokine

at the site of injection

In vitro evaluation of anthraquinones from Aloe vera (Aloe barbadensis Miller) roots and several derivatives against strains of influenza virus

Antiviral activities of diarylheptanoids against influenza virus in vitro

In vitro and in vivo anti-influenza virus activity of diarylheptanoids isolated from Alpinia officinarum

Activity of andrographolide and its derivatives against influenza virus in vivo and in vitro

14-Deoxy-11, 12-dehydroandrographolide exerts anti-influenza A virus activity and inhibits replication of H5N1 virus by restraining nuclear export of viral ribonucleoprotein complexes

Therapeutic effect of arctiin and arctigenin in immunocompetent and immunocompromised mice infected with influenza A virus

Aronia melanocarpa and its components demonstrate antiviral activity against influenza viruses

Astragalus polysaccharide enhances immunity and inhibits H9N2 avian influenza virus in vitro and in vivo

Designing and screening of universal drug from neem (Azadirachta indica) and standard drug chemicals against influenza virus nucleoprotein

Immuno-pharmacological effects of Bupleurum chinense polysaccharide

In vitro antiinfluenza viral activities of constituents from Caesalpinia sappan

Homoisoflavonoids from Caesalpinia sappan displaying viral neuraminidases inhibition

Effects of green tea catechins and theanine on preventing influenza infection among healthcare workers: a randomized controlled trial

Additional inhibitory effect of tea extract on the growth of influenza A and B viruses in MDCK cells

Antiviral effect of catechins in green tea on influenza virus

Broad and potent anti-influenza virus spectrum of epigallocatechin-3-O-gallate-monopalmitate

Inhibition of the infectivity of influenza virus by tea polyphenols

Identification of suitable natural inhibitor against influenza A (H1N1) neuraminidase protein by molecular docking

Antiviral effect of strictinin on influenza virus replication

Antioxidant, anti-inflammatory and anti-influenza properties of components from Chaenomeles speciosa

Inhibitory effect of cinnamaldehyde, derived from Cinnamomi cortex, on the growth of influenza A/PR/8 virus in vitro and in vivo

Antipyretic activity of cinnamyl derivatives and related compounds in influenza virus-infected mice

Modulation of cytokine production by 7-hydroxycoumarin in vitro and its efficacy against influenza infection in mice

Germacrone inhibits early stages of influenza virus infection

Curcumin inhibits influenza virus infection and haemagglutination activity

Curcuminoids from Curcuma longa and their inhibitory activities on influenza A neuraminidases

Anti-influenza A virus activity of dendrobine and its mechanism of action

Anti-influenza virus activities of flavonoids from the medicinal plant Elsholtzia rugulosa

Inhibitory effect of (+)-catechin on the growth of influenza A/PR/8 virus in MDCK cells

Anti-influenza virus activity of biflavonoids

Chalcones as novel influenza A (H1N1) neuraminidase inhibitors from Glycyrrhiza inflata

Inhibition of neuraminidase activity by polyphenol compounds isolated from the roots of Glycyrrhiza uralensis

Tannins from Hamamelis virginiana bark extract: characterization and improvement of the antiviral efficacy against influenza A virus and human papillomavirus

Virucidal effects of the steam distillate from Houttuynia cordata and its components on HSV-1, influenza virus and HIV

Houttuynia cordata polysaccharides ameliorate pneumonia severity and intestinal injury in mice with influenza virus infection

Inhibitory effects of quercetin 3-rhamnoside on influenza A virus replication

Effects of Isatis root polysaccharide in mice infected with H3N2 swine influenza virus

Inhibition of RANTES expression by indirubin in influenza virus-infected human bronchial epithelial cells

Antiviral activity of Isatis indigotica root-derived clemastanin B against human and avian influenza A and B viruses in vitro

Amaryllidaceae alkaloids inhibit nuclear-to-cytoplasmic export of ribonucleoprotein (RNP) complex of highly pathogenic avian influenza virus H5N1

Amaryllidaceae alkaloids exhibit anti-influenza activity in MDCK cells, an investigation of Amaryllidaceae Alkaloids and MDCK cells insight

Antiviral activity of Chinese medicine -derived phytochemicals against avian influenza A ( H5N1 ) virus

Narcissus tazetta lectin shows strong inhibitory effects against respiratory syncytial virus, influenza A (H1N1, H3N2, H5N1) and B viruses

Isolation, characterization, molecular cloning and modeling of a new lipid transfer protein with antiviral and antiproliferative activities from Narcissus tazetta

Mechanism of the antiviral effect of hydroxytyrosol on influenza virus appears to involve morphological change of the virus

Protective effect of ginseng polysaccharides on influenza viral infection

Dual functions of ginsenosides in protecting human endothelial cells against influenza H9N2-induced inflammation and apoptosis

Inhibition of influenza A virus infection by ginsenosides

Purification and characterization of a new antiviral protein from the leaves of Pandanus amaryllifolius

rvH1N1 neuraminidase inhibitory activities of phenolics from Perilla frutescens (L.) and their contents in cultivars and germplasm

Anti-influenza effect and action mechanisms of the chemical constituent gallocatechin-7-gallate from Pithecellobium clypearia Benth

Inhibition effects of patchouli alcohol against influenza a virus through targeting cellular PI3K/ Akt and ERK/MAPK signaling pathways

Oral administration of patchouli alcohol isolated from Pogostemonis Herba augments protection against influenza viral infection in mice

Inhibitory effect and possible mechanism of action of patchouli alcohol against influenza A (H2N2) virus

Active neuraminidase constituents of Polygonum cuspidatum against influenza A(H1N1) influenza virus

Bakuchiol Is a Phenolic Isoprenoid with Novel Enantiomer-selective Anti-influenza A Virus Activity Involving Nrf2 Activation

Pomegranate (Punica granatum) purified polyphenol extract inhibits influenza virus and has a synergistic effect with oseltamivir

Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities

Anti-influenza virus activity of crude extract of Ribes nigrum L

Activity of anthocyanins from fruit extract of Ribes nigrum L. against influenza A and B viruses

Elderberry flavonoids bind to and prevent H1N1 infection in vitro

Antiviral triterpenoids from the medicinal plant Schefflera heptaphylla

Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase

Inhibition of influenza virus sialidase and anti-influenza virus activity by plant flavonoids

In vivo antiinfluenza virus activity of plant flavonoids possessing inhibitory activity for influenza virus sialidase

4′-trihydroxy-8-methoxyflavone, from the roots of Scutellaria baicalensis against influenza A (H3N2) and B viruses

Mode of action of the anti-influenza virus activity of plant flavonoid

Wogonin, a flavonoid isolated from Scutellaria baicalensis, has anti-viral activities against influenza infection via modulation of AMPK pathways

Baicalein, ethyl acetate, and chloroform extracts of Scutellaria baicalensis inhibit the neuraminidase activity of pandemic 2009 H1N1 and seasonal influenza A viruses

Anti influenza virus activity of a redfleshed potato anthocyanin

Identification and synthesis of quinolizidines with anti-influenza A virus activity

A non-biological method for screening active components against influenza virus from traditional Chinese medicine by coupling a LC column with oseltamivir molecularly imprinted polymers

Pterocarpans and flavanones from Sophora flavescens displaying potent neuraminidase inhibition

8-Prenylkaempferol suppresses influenza A virus-induced RANTES production in A549 cells via blocking PI3K-mediated transcriptional activation of NF-κB and IRF3. Evid Based Complement Alternat Med

Prenylflavanones isolated from Sophora flavescens

An extract from Taxodium distichum targets hemagglutinin-and neuraminidase-related activities of influenza virus in vitro

Anti-H5N1 virus new diglyceride ester from the Red Sea grass Thallasodendron ciliatum

Anti-influenza A virus activity of a new dihydrochalcone diglycoside isolated from the Egyptian seagrass Thalassodendron ciliatum (Forsk.) den Hartog

Extraction of isothiocyanate in Wasabi Japonica Matsum and its effects to influenza virus

Promising Anti-influenza Properties of Active Constituent of Withania somnifera Ayurvedic Herb in Targeting Neuraminidase of H1N1 Influenza: Computational Study

Anti-influenza activity of betulinic acid from Zizyphus jujuba on influenza A/PR/8 virus

Inhibiting H5N1 hemagglutinin with samll molecule ligands

Plants: A rich source of herbal medicine

Carbohydrates in plant immunity and plant protection: roles and potential application as foliar sprays

In: Freeman WH (ed) Monosaccharides are aldehydes or ketones with multiple hydroxyl groups. Biochemistry, 5th edn

Pharmaceutical applications of natural polysaccharides

Approaches for Prodrugs

In: Habtemariam S (ed) Introduction to plant secondary metabolites-From biosynthesis to chemistry and antidiabetic action

Production of shikimic acid

Shikimic acid: review of its analytical, isolation and purification techniques from plant and microbial sources

Bioactive Molecules as Regulatory Signals in Plant Responses to Abiotic Stresses

From central to specialized metabolism: an overview of some secondary compounds derived from the primary metabolism for their role in conferring nutritional and organoleptic characteristics to fruit

Tilting Plant Metabolism for Improved Metabolite Biosynthesis and Enhanced Human Benefit

A Review Article: The Importance of the Major groups of Plants Secondary Metabolism Phenols, Alkaloids, and Terpenes

Plant terpenes: defense responses, phylogenetic analysis, regulation and clinical applications

Introductory Chapter

Dictionary of terpenoids

Terpenoids as therapeutic drugs and pharmaceutical agents

De novo synthesis of high-value plant sesquiterpenoids in yeast

Diterpenoids: Types, Functions and Research

Diterpene synthases of the biosynthetic system of medicinally active diterpenoids in Marrubium vulgare

Analysis of triterpenes and triterpenoids

Chapter Two -Application of LC-MS and LC-NMR Techniques for Secondary Metabolite Identification

Phenolic compounds: introduction

Modern plant metabolomics for the discovery and characterization of natural products and their biosynthetic genes

Phenolic compounds: from plants to foods

Nomenclature of flavonoids (IUPAC recommendations 2017)

Chemistry of himalayan phytochemicals

Biochemical pharmacology of biflavonoids: implications for anti-inflammatory action

A systematic review on biological activities of prenylated flavonoids

Cancer chemoprevention through dietary flavonoids: what's limiting?

Flavonoids: promising natural compounds against viral infections

Flavonoids: an overview

Inhibition of sialidase activity as a therapeutic approach

Recent patents on antibacterial, antifungal and antiviral properties of tea

Beneficial effects of green tea: a literature review

Green tea consumption In: World Green Tea Association Available at

Green tea consumption is inversely associated with the incidence of influenza infection among schoolchildren in a tea plantation area of Japan

Chapter 11-Health Perspectives of an Isoflavonoid Genistein and its Quantification in Economically Important Plants

Isoflavonoids. In: Justino J (ed) Flavonoids -From Biosynthesis to Human Health. UK IntechOpen Ltd

Natural Products. Heidelberg

A Comprehensive Review on Chemotaxonomic and Phytochemical Aspects of Homoisoflavonoids, as Rare Flavonoid Derivatives

Nutritional quality of fruits and vegetables

Diarylheptanoid: A privileged structure in drug discovery

Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations

Not applicable.

Authors' contributions BDA collected and analyzed the data and wrote the manuscript. SR gave proper suggestions and approved the submission. Both authors contributed significantly to bring out this review and they have read and approved the manuscript.

Not applicable.Availability of data and materials All information provided in the manuscript is obtained from the references.

Ethics approval and consent to participate Not applicable.

Not applicable.

The authors declare that they have no competing interests.Received: 29 December 2020 Accepted: 20 May 2021