Key Points
A wide variety of active phytochemicals have been found to have therapeutic applications against genetically and functionally diverse viruses. The antiviral mechanism of these agents may be explained on the basis of their antioxidant activities, scavenging capacities, the inhibition of DNA, RNA synthesis, or the blocking of viral reproduction, etc. Numerous epidemiological and experimental studies have revealed that a large number of phytochemicals have promising antiviral activities. Especially in the last decade, a number of promising leads have been identified by a combination of in vitro and in vivo studies using diverse biological assays.
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1 Introduction
Throughout the human history, man has been dependent on plant sources for his very basic needs (1). The use of medicinally active plants predates modern history. As per a World Health Organization estimate more than 80% of the world’s population is dependant on traditional plants to meet their health requirements (2). A large number of plants used in the traditional medicine have now become a part of the modern world health care system because of their unique ability to synthesize a wide array of compounds with diverse health-related benefits (3, 4). Most recently, the introduction of plant-based products in the form of nutraceuticals and dietary supplements have made a major impact in the drug industry market (5, 6). The isolation, structural elucidation, and evaluation of all major constituents of the plant-based products must occur efficiently in order to determine its pharmacological properties. A general isolation and evaluation procedure of plants-based active ingredients is depicted in Scheme 24.1. Plants provide compounds possessing a broad range of activities such as antimicrobial, antiviral, antioxidative, immunomodulatory and antitumor properties (7, 8). Because of the rapid advancement in modern day biology, drug discovery from natural sources has evolved into a highly multidisciplinary field utilizing various sophisticated methods of isolation, analysis, and evaluation. Over the last few decades, natural products have been studied for anti-infective and more specifically, antiviral activities. Basic researches in experimental models using various biological systems strongly suggest the protective role of plant-derived natural compounds against different viral infections (9, 10). Despite the substantial amount of progress made in the treatment and therapeutic strategies, the incidence, morbidity, and mortality of viral infections remain a major global challenge. The conditions are more complicated in the developing world due to the unavailability of relatively expensive medicines and widespread drug resistance (11). Unfortunately, many antiviral compounds presently in clinical use have a relatively narrow spectrum of activity, limited therapeutic usefulness, and variable toxicity. Whether natural antivirals can be developed as a viable alternative medicine or a synergistic combination therapy with pre-existing antiviral therapy will entirely depend on identifying broad-spectrum plant-based antivirals combined with a method of delivery and keeping in mind its stability and bioavailability. In addition, the development of a suitable in vitro pharmacodynamic screening technique could contribute to the rapid identification of potential bioactive plants and also to the standardization and/or pharmacokinetic–pharmacodynamic profiling of the bioactive components.
Originating from nucleosides or closely related carbon structure, the wellknown drugs face an emerging problem of development of resistant viral strains (12, 13). In addition, the emergence of many new and perhaps more deadly viruses such as Ebola and Marburg viruses and the possible threat of their use as arsenal for bioterrorism have enhanced our urgency to find new and potent antivirals as soon as possible. This need is further aggravated by the fact that viral infections are now recognized as the second most important known cause of human cancer (14). Viruses absolutely require host cell environment for survival. Besides the genetic variation, divergent invasion strategies pose a major challenge. Since medicinal plants have an endless variety of chemical constituents, it could be utilized to counter genetic and invasion divergence and thus inhibit the replication of both DNA and RNA virus. In fact, the world of ethnopharmacological knowledge increases the success probability of finding a new drug candidate (15, 16). In this article, we examine current developments on various naturally occurring antiviral compounds. The major advances in the field of virus growth inhibition have been summarized. In addition, the origin, mechanistic action, and phase trials of various plant-derived antiviral agents have been included in this chapter.
1.1 Antiviral Assays
In the process of drug discovery, the selection of an appropriate bioassay and its validation are the important steps to determine the activity of the products and extracts. The determination of antiviral efficacy is relatively complex because it is not possible to design a single assay for different viruses as they require different cell systems. The fact that so many so-called “exciting molecules” do not graduate to the next stage is primarily due to major flaws in the screening methodologies. Some of the major challenges include using high assays dosages, using improper test controls, and the wrong selection of targets and endpoints. In spite of the progress made, little attention has been given to the influence of various reaction parameters (17). The lack of standardization in methodologies produces highly inconsistent results posing a major obstacle in developing a novel entity as a drug molecule. More commonly, the evaluation of the antiviral is based on the capability to replicate in a particular cell system.
The efficiency of the plant extract can be evaluated by large number of methods. At a preliminary level, the in vitro efficacy is detected using markers such as cytopathic effect, plaque formation, or proliferative effects on diverse cell lines (Table 24.1). The detection of viral RNA and DNA do provide information about the viral replication. Although a number of assays have been developed there is still a need for more standardized assays to provide consistent results. The complexity in evaluation of viral inhibition is attributed to its efficient replication coupled with its genetic variation and diverse invasion strategy. Confluent monolayers of the cells are infected with virus in combination with a varied concentration of the plant extract and incubated followed by the calorimetric determination of viable cells. Radioactive-labeled viruses are employed to determine the mode of antiviral activity (18). Determination of the values of EC50 (reciprocal dilution required to prevent virus-induced cytolysis by 50%) and TCID50 (reduction of viral titer) are used as a measure to determine viral activity.
2 Classification of Antiviral Phytochemicals
2.1 Flavonoids
The flavonoid structure, basically a polyphenol consisting of 15-carbon atoms skeleton (C6–C3–C6 system) (1), constitutes the largest source of antiviral agents in the entire plant kingdom. In some compounds, the C2 carbon atom is directly linked to the oxygen as a result of which furan type molecule is formed called aurone (2). The further sub-classification of flavonoids is based upon the oxidation and the substitution pattern of the ring C. The biochemical effects of flavonoids are attributed to their ability to inhibit the number of enzymes such as aldose reductase, xanthine oxidase, phosphodiesterase, Ca+2-ATPase, lipoxygenase, cycloxygenase, etc., besides the regulatory role on different hormones like estrogens, androgens, and thyroid hormone (19, 20). Evaluating flavonoids for activity against herpes simplex virus (HSV), Thomas et al. reported that flavonols are more active than flavones (galangin > kaempferol > quercetin) (21). Flavonoid-based polymer (MW 2100 Daltons) has displayed substantial activity against HSV type-1 and type-2 strains (22). On the basis of the evaluation of a flavonoid subset, Gerdin et al. found that flavan-3-o1 was more effective in selective inhibition of human immunodeficiency virus (HIV)-1, -2, and similar immunodeficiency virus infections (23).
Chalcones, having general formula ArCH=CHC(=O)Ar forms the central core for a variety of important biological compounds. Considered as precursors of flavonoids and isoflavonoids, these compounds are abundant in edible plants, and display a diverse array of pharmacological activities. Deng et al. have reported excellent antiviral activity of chalcones 3 and 4 utilizing pharmacophore models to identify chemical signatures considered important for the antiviral activity (24, 25). Dihydrochalcones (5) (obtained by double bond reduction of chalcone) derived from Millettia leucantha KURZ (Leguminosae) showed anti-herpes simplex virus (HSV) activity (26). Flavones, structurally characterized by 2-phenylchromen-4-one backbone, are found in Lamiaceae, Apiaceous, and Astraea families. Likhitwitayawuid et al. described the isolation and anti-HSV activities of a series of phenolic compounds identified from the heartwood of Artocarpus gomezianus, including the new antiherpetic flavone artogomezianone (6) ( 27). Prendergast et al. have used 3′,4′-diacetoxy-5,6,7-trimethoxyflavone or naringin (7) in the treatment of viral (e.g., HCV, HIV, a picornavirus genus virus or a respiratory virus) or parasite (e.g., toxoplasmosis) infections (28). On the basis of molecular electrostatic potential (MEP) maps, Mishra et al. proposed that the anti-picornavirus activities of the flavones are related with negative MEP values in two regions, one near the 3-methoxy group and another in a diagonally opposite region near the substituent attached to the C7 atom of the molecules (29). We have synthesized and confirmed the antiviral activity of several novel analogs of flavanone Abyssinone II (8), a naturally occurring prenylated flavanone, in HeLa cells using a recombinant β-galactosidase expressing strain of HSV-1(Herpes simplex virus Type 1) (30). Characterized by hydroxyl group at position C3 of the flavonone molecule (9), flavanol mixture is applied for treating and preventing hepatitis B, mycotic infection, liver protection, inflammation disease, and autoimmune disease (31). The effect of several naturally occurring dietary flavonoids including quercetin (10) on the infectivity and replication of herpes simplex virus type 1 (HSV-I), polio-virus type 1, Para influenza virus type 3 (Pf-3), and respiratory syncytial virus (RSV) were studied in cell culture monolayers employing the technique of viral plaque reduction. Quercetin caused a concentration-dependent reduction in the infectivity of each virus. In addition, it reduced intracellular replication of each virus when monolayers were infected and subsequently cultured in a medium containing quercetin (10). Myricetin (11), a bioflavonoid whose occurrence in nature is widespread among plants showed excellent antiviral effect against hepatitis B virus, influenza virus, and/or coronavirus (32). Anthocyanidin (12) is an important group of plant pigments having free OH group which can co-ordinate with metal ions like Ca2+ and Mg2+ under alkali conditions. This coordination ability is one the major reasons for the bioactivity of molecule. Anderson et al. have reported the therapeutic effect of anthocyanidin in the treatment of diseases caused by viruses (33). Isoflavonoids is an important class of flavonoids with impressive biological activities formed as a result of migration of phenyl group from 2 to 3 as shown in 13 (Fig. 24.1). In contrast to most other flavonoids, isoflavones (14) have a rather limited taxonomic distribution and occur mainly within the Leguminosae family. Antiviral activity on Newcastle disease virus was examined and rotenone (15) showed significant inhibitory effects on the viral growth in cultured cells as determined by the plate and tube assay methods (34). Isoflavanones bear the same relationship to isoflavones as flavanones do to flavones. And, as in the case of flavanones, isoflavanones have a chiral center (C3 in isoflavanones). PMZ-1, a prenylated isoflavonone (16), isolated Bolusanthus speciosus (Bolus Harms) has exhibited excellent activity against HIV–having a broad therapeutic index (TI > 300) (35).
Structurally, one of the simplest members of these subclasses, the isoflavans, is characterized by the fact that they do not have the carbonyl group at C4 carbon, for example, 7,4′-dihydroxyisoflavan (17, equol). The effect of substituted isoflavans (18) (R and R1 = H, Cl, or Br) and isoflavenes (19) on human rhinovirus (HRV) 1B infection of HeLa cells was examined by Conti and coworkers who found that these compounds inhibited virus plaque formation in cell cultures with isoflavans being more effective than isoflavenes (36). It was found that the cells pretreated with compounds before challenge with HRV-1B exhibited resistance to the virus-induced cytopathic effect. Arylcoumarins related to flavonoids biogenetically are characterized by the presence of a carbonyl function at C2 and may or may not have oxygenation at C4. A large number of coumarins has been studied for antiviral activities (37). Calanolide A (20) first isolated from a tropical tree (Calophyllum lanigerum) in Malaysia is one of the novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent activity against HIV-1 (38).
Compounds belonging to the flavans class are normally devoid of carbonyl group at position 2. Although this class of compounds contains some common and comparatively simple compounds, catechin and epicatechin, in particular, the overall structural complexity of the group is impressive. Two new antiviral flavan derivatives were isolated from a methanol extract of leaves of Pithecellobium clypearia as guided by antiviral assays (7-O-galloyltricetifavan (21a) and 7,4-di-O-galloyltricetifavan (21b) (39). Neoflavonoids constitute a group of flavonoid derivatives that have their aryl group attached to C4 as opposed in flavonoids and C3 in isoflavonoids. A series of inophyllums 22–25 were isolated from the Malaysian tree Calophyllum inophyllum and evaluated for inhibitory activity against HIV-1 reverse transcriptase (RT). Among them, the most active compounds, inophyllum B and inophyllum P showed IC50 values against RT of 0.038 and 0.130 mM, respectively (40) (Fig. 24.2).
2.2 Alkaloids
Synthesized by plants from amino acids, alkaloids contain nitrogen in a heterocyclic ring. Some of the major nuclei found in various alkaloids have been shown in 26, 27, and 28. Thirty-six alkaloids isolated either from Catharanthus roseus or C. lanceus were evaluated for in vitro activity against vaccinia and polio type III viruses. Nine of these alkaloids were effective as antiviral agents, with pericalline (29) being the most effective (41). In an attempt to obtain SAR data, Houghton et al. tested several naturally occurring chromone alkaloids (derived from the rootbark of Schumanniophyton magnificum) for the inhibition of HIV and HSV infections in C8166 and Vero cells, respectively. The authors also synthesized acyl and methyl derivatives for screening. It was found that the presence of a piperidine ring and free hydroxyl groups on the molecules seems to favor the anti-HIV activity. Irreversible binding to gp 120 was considered to be responsible for the anti-HIV activity (42).
2.3 Terpenoids
The terpenoids, sometimes referred to as isoprenoids, are a large and diverse class of naturally occurring phytochemicals derived from five-carbon isoprene units, which are assembled and modified in thousands of ways. Numerous phytocompounds that were evaluated for activity against anti-severe acute respiratory syndrome-associated coronavirus (SARS-CoV) activities using a cell-based assay measuring the SARS-CoV-induced cytopathogenic effect on Vero E6 cells and compounds (30–32) showed excellent activities (43). More than 220 phytocompounds (including ten diterpenoids, two sesquiterpenoids, and two triterpenoids) were screened for activity against anti-SARS-CoV activities utilizing a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. The bioactive compounds with anti-SARS-CoV activity in the μM range included abietane-type and labdane-type diterpenes sesquiterpenes and lupane-type triterpenes.
2.4 Carotenoids
Carotenoids considered as the structural backbone of compound belong to the category of tetraterpenoids (hydrocarbons resulting from the association of several isoprene units). Majority of the carotenoids are derived from the 40 carbon polyene chain which is sometimes terminated by rings. Carotenoids can be Xanthophylls (molecules containing oxygen) such as lutein and zeaxanthin and carotenes (the unoxygenated or oxygen free carotenoids). The concentrations of plasma carotenoids (α-carotene (33), β-carotene (34), lutein/zeaxanthin (35) and lycopene (36) have been associated with the increased risk of death during HIV infection among infants in Uganda (44).
2.5 Organosulfur Compounds
Sulfur-containing compounds are present in all Brasicaceae family vegetables. In addition, plants belonging to the Allium family constitute an important class of antiviral agents (45). There a are number of representative examples of organosulfurs antivirals (37–40) that is, cauliflower, cabbage, kale, bok choy, brussels sprouts, radish mustard, and water garden cress that constitute the rich source of organosulfur compounds. Several unsymmetrical aralkyl disulfides, were synthesized and oxidized to study the relatively unexplored class of thiolsulfinate (46). The pungent odor, and chemical instability of these compounds make animal studies difficult; hence, structural modifications have been carried out. We have synthesized and screened several sulformates (based upon brassinin and sulfuraphane structures) derivatives for their HSV activities (47) (Fig. 24.3).
2.6 Vitamins
It has been shown that vitamin C (41) can increase the host immune response, and this may provide protection against infectious diseases (48). Vitamin E supplementation might be effective in the treatment of chronic hepatitis B (49). The name vitamin E covers a collection of eight fat soluble compounds, tocopherols (42) (methyl derivatives of tocopherol) and tocotrienols (43).
2.7 Selenium Compounds
A significant number of studies has indicated the importance of selenium compounds (44–46) as potent antiviral agents. The data generated from experimentation on various animal models and in vitro models demonstrate significant beneficial effects of selenium on different viral infections. Cermelli et al. studied the antiviral effects of three selenium compounds on the replication of Coxsackie virus B5 replication (50). Selenite was shown to reduce viral replication in Coxsackie virus B5 replication, but selenate and selenomethionine did not exhibit any substantial antiviral activity. Waotowicz et al. synthesized and tested different analogs of ebselen for their activity in in vitro antiviral assay. Some of the analogs tested had an appreciable inhibition of cytopathic activity of HSV-1 and encephalomyocarditis virus—EMCV (10) (Fig. 24.4).
2.8 Miscellaneous
Curcumin (47) derived from turmeric and a key constituent of food in the Indian subcontinent has shown potent activity against HIV-1 integrase (51). Chlorophyllin (CHLN) (48, 49), a synthetic derivative of chlorophyll has been assayed for its capacity to prevent nuclear fragmentation (NF) in HEp-2 cells infected with poliovirus (52). Carboxymethyl chitin, a polysaccharides polymer containing partially deacetylated aminosugar showed a significant inhibition of Friend murine leukemia helper virus (F-MuLV) and HSV (53). Seven ellagitannins isolated from Phyllanthus myrtifolius and P. urinaria (Euphorbiaceae) have shown to be active against Epstein–Barr virus DNA polymerase (EBV-DP) (54). Polyacetylenes (51, 52) are hydrocarbons that strongly absorb long-wave UV light. The medicinal activity of these compounds is altered upon exposure to light (photoactivation). The principal constituent in the leaf of Bidens pilosa, phenylheptatriyne (PHT), is one of the polyacetylenes that has been widely studied for its antiviral effects that is augmented by UV light exposure (55). The polyacetylenes are one of the few natural substances reported to inhibit CMV, a type of herpes virus that causes disease in immune-compromised individuals. Importantly, these polyacetylenes do not cause DNA changes (as do other herbal photoactivated substances, such as furanocoumarins found in the Umbelliferae plants), and the action appears to be mediated by cell surface activities, this implies a higher level of safety for their use (56).
Highly sulfated red algal polysaccharides (Cn(H2O)n (53)) extracted from Gelidium cartilagineum afforded protection against animal virus, influenza B, and mumps viruses (57). The cell-wall sulfated polysaccharide of the red microalga Porphyridium sp. has impressive antiviral activity against Herpes simplex viruses types 1 and 2 (HSV1,2) and varicella–zoster virus (VZV) (58, 59). Lignans are one of the major classes of phytoestrogens which are estrogen-like chemicals and also act as antioxidants (60). Nordihydroguaiaretic acid (NDGA) (54), a lignan present in the perspired resin of leaves of Larrea divaricata has displayed significant in vitro inhibition against several viruses, including HIV, HSV-1 and -2, and human papilloma (61). The pharmacokinetics and metabolism of retrojusticidin B, an anti-HIV reverse transcriptase agent isolated from Phyllanthus myrtifolius, have been studied in rats. Chrysophanic acid (56) (1,8-dihydroxy-3-methyl anthraquinone (55)), isolated from the Australian aboriginal medicinal plant Dianella longifolia, has been found to inhibit the replication of poliovirus types 2 and 3 (in vitro SARS-CoV spike (S) protein, a type I membrane-bound protein, is essential for the viral attachment to the host cell receptor angiotensin-converting enzyme 2 (ACE2) (62). Emodin (57), derived from genus Rheum and Polygonum, was shown to significantly block the S protein and ACE2 interaction in a dose-dependent manner. It also inhibited the infectivity of S protein-pseudotyped retrovirus to Vero E6 cells. These findings suggested that emodin may be considered as a potential lead therapeutic agent in the treatment of SARS (63). Gingerols (58) (derived from ginger, a typical south Asian spice) has traditionally been used to cure common colds and throat infections and form an important constituent of Ayurvedic formulations. There have been numerous studies on the efficacy of these compounds as antiviral agents (64). Salicylic acid ((59) C6H4(OH)CO2H) can stimulate the inhibition of all three main stages in virus infection: replication, cell-to-cell movement, and long-distance movement. There is evidence that SA may stimulate a downstream pathway, leading to the induction of mechanism of resistance based on RNA interference (65) (Fig. 24.5).
2.9 Activity of Extracts/Mixtures Preparation
Traditional medicine system (Egyptian, Ayurvedic, Chinese, Unani) have utilized the plant extracts/mixtures to cure infections. The underlying idea is to achieve the synergistic or combination benefits of the formulation. In addition, herbals offer a less toxic alternative to conventional therapies thereby encouraging patients to opt for this treatment. Semple and colleagues reported that Chrysophanic acid (1,8-dihydroxy-3-methylanthraquinone) (isolated from the Australian Aboriginal medicinal plant Dianella longifolia) inhibits the replication of poliovirus types 2 and 3 (Picornaviridae) in vitro (66). Terpenes and phenol esters from Plectranthus strigosus were screened against herpes viruses. The bioactivity study revealed herpetic inhibitory properties for ent-16-Kauren-19-ol ent-16-kauren-19-oic acid. The compound inhibited poliovirus-induced cytopathic effects in BGM (Buffalo green monkey) kidney cells at a 50% effective concentration of 0.21 and 0.02 g/mL for poliovirus types 2 and 3, respectively. Phellodendron amurense bark extracts were examined and substantial antiviral activity was reported against HSV-1 utilizing the plaque inhibition assay (67). Propolis, a crude extract of the balsam which contains terpenoids, flavonoids, benzoic acids, esters, phenolics, has been found to inhibit the hemagglutination activity of inflenza virus, acyclovir resistant HSV-1, adenovirus-2 VSV, and poliovirus (68). In a study, the Dryopteris crassirhizoma extract was used to inhibit the reverse transcriptase associated DNA polymerase and RNAse H activity (69). An extract derived from Asimina triloba, has been used for the treatment of oral herpes (HSV-1) (70). Sixty-five crude extracts from 51 selected endophytic fungi isolated from Garcinia species were tested for various bioactivities. Eighty percent of the fungal extracts from fermentation broths and mycelia displayed antiviral activity (71). In a related study, organosulfur compounds derived from garlic extract protected CD4 cells from HIV attack (72). Tertagalloyl glucopyranose obtained from Juglans mandshurica inhibited reverse transcriptase and RNAse H activity while extracts of Centella asiataca and magniferin of Magnifera indica have shown promising anti-herpes HSV activity (73). The crude extract of the roots from the Australian medicinal plant Dianella callicarpa (Liliaceae) displayed significant antimicrobial and antiviral activities (74). Meliacine (a partially purified extract (meliacine) from the leaves of Melia azedarach L) exhibits a potent antiviral effect against several viruses without displaying cytotoxicity (75). The in vitro antiviral activity of the Cuban-endemic plant Phyllanthus orbicularis against HSV-1 and -2 was confirmed and it was found that the drug acted at early stages of herpesvirus replication cycle (76). The concurrent use of natural health products (NHPs) with antiretroviral drugs (ARVs) is widespread among HIV-infected patients; however, extreme caution should be exercised since some NHPs are complex mixtures and are likely to contain organic compounds that may induce and/or inhibit drug metabolizing enzymes and drug transporters. It has been observed that St. John’s wort clearly induces cytochrome P450 3A4 and P-glycoprotein. This reduces protease inhibitor and non nucleoside reverse-transcriptase inhibitor concentrations, thereby increasing the likelihood of therapeutic failure (77).
2.10 Antiviral Mechanistic Aspects of Phytochemicals
One of the major steps in drug discovery is to identify and validate specific molecular targets. The advance of modern day biology has enabled us to identify microbial enzymes, receptors and molecular processes that facilitate drug action against a particular kind of virus. Studies have indicated that the antiviral action of plant-derived products may be attributed to a number of well-defined mechanisms (Table 24.2). It is possible that the antiviral effect of the compound may be explained on the basis of more than one mechanism and in some cases the action of mechanism may be unknown. Understanding the mechanistic pathways may help us to progress rapidly with more rational drug design and screening procedures.
2.11 Viral Studies
There have been numerous in vitro studies supporting the antiviral activity of phytochemicals. In order to further evaluate the modulation of several of these plant-derived compounds by components of tissue and body fluids, several in vivo studies have been carried out. However, the relative proportion of these studies is less for obvious reasons. There is tremendous amount of literature available regarding antiviral potential of phytochemicals. For the sake of clarity, the discussion has been classified into different sections with a focus on viral diseases.
2.12 AIDS
HIV is a retrovirus that can lead to acquired immunodeficiency syndrome (AIDS), a condition that is characterized by the failure of the immune system. According to a report by the World Health Organization, it has been estimated that 0.6% of the world’s population is infected with AIDS. Until the year 2006, AIDS has killed more than 25 million people, since it was first recognized in 1981 (107). With the recent advances in understanding the biology of HIV, there has been increased focus on the usage of phytochemicals as antivirals against HIV. Owing to the vast array of chemical entities in nature, effective therapies for HIV infection are being sought in the natural world. The scope of studies of anti-HIV plant extracts is too extensive. Owing to the size limitations of the present review, we have summarized some of the major studies in Table 24.3.
2.13 Poliomyelitis
Poliomyelitis, caused by a human enterovirus, damages the nervous system and causes paralysis. The disease is normally prevalent in less developed Asian and African countries where polio immunization for children is not very common in spite of the massive immunization by the governments and non-governmental organizations. A large number of plant-derived products have been evaluated for their activity against polio virus. Isoobtusitin (61), a prenylated coumarin showed substantial in vitro inhibitory activity against poliovirus (IC50 = 2.9 μM) (119). Isokaempferide (5,7,4′-trihydroxy 3-methoxyflavone) derived from Psiadia species was found to be an inhibitor of poliovirus type 2 replication (120). Tuli and colleagues examined the antiviral action of 3-methyleneoxindole (MO), a plant metabolite, in HeLa cells infected with poliovirus. On the basis of the experiments, authors suggested that the ability of MO to bind to ribosomes of HeLa cells may underlie the antiviral affect. Experiments showed that the poliovirus messenger RNA would not attach to those ribosomes that are already bound to MO. This resulted in the nonrecovery of virus-specific polysomes from infected cells treated with antiviral concentrations of MO (121) (Fig. 24.6).
2.14 Herpes
Herpes is caused by HSV-1 and -2. It is a painful infection mainly affecting skin, eyes, mouth, and genitals. There is no permanent cure for herpes but the treatment can certainly reduce the viral shedding. There have been efforts all around the globe to identify plant-based treatment for this infection. Lyu et al. performed anti-herpetic assays on 18 flavonoids in five classes and a virus-induced cytopathic effect (CPE) inhibitory assay, plaque reduction assay, along with yield reduction assay (122). EC, ECG, galangin, and kaempferol exhibited strong antiviral activity whereas catechin, EGC, EGCG (65), chrysin (66), BA (67) showed moderate activity against HSV-1. Among all the flavanols, it was found that EC and ECG displayed a high level of CPE inhibitory activity (2.5 µM [0.725 µg/mL]) and 5 µM (2.21 µg/mL), respectively), while among the flavanones naringenin expressed a strong inhibitory effect (5 µM [1.36 µg/mL]) against HSV-1. Similarly, among the flavonols, quercetin exhibited a high CPE inhibitory activity (5 µM [1.69 µg/mL]), and genistein which is an isoflavone also showed an inhibitory effect (5 µM [1.35 µg/mL]). Two dibenzocyclooctane lignans, Kadsulignan L, and Neokadsuranin were tested for their anti-HBV activities in vitro. These compounds at 0.1 mg/mL, exhibited moderate antiviral activities, inhibiting HBsAg and HBeAg secretions by 32.6 and 36.5%, and by 14.5, and 20.2%, respectively. From a structure-activity point of view, it was found that the introduction of an a-orientated AcO group enhances the antiviral activity (123). Chattopadhyay and colleagues reported substantial anti-HSV activity of Ophirrhiza nicobarica extract at 300 µg/mL. The alkaloid, flavonoid, and β-sitosterol isolated from bioactive parts had a dose-dependent therapeutic efficacy, justifying their use (124). Eugenol (4-allyl-1-hydroxy-2-methoxybenzene) was screened for efficacy against HSV-1 and HSV-2 viruses. The in vitro experiments revealed that the replication of HSV viruses was inhibited by eugenol. The inhibitory concentration 50% values for the anti-HSV effects of eugenol were 25.6 µg/mL and 16.2 µg/mL for HSV-1 and HSV-2, respectively, with 250 µg/mL being the maximum dose at which cytotoxicity was tested. In addition, it’s worth mentioning that eugenol showed no cytotoxicity at the concentrations tested. Furthermore, the eugenol–acyclovir combinations have synergistically inhibited herpesvirus replication in vitro (125). Nineteen compounds isolated from Ranunculus sieboldii and Ranunculus sceleratus were tested for inhibitory effects on hepatitis B virus (HBV) and HSV-1. The experiments revealed that apigenin 4′-O-α-rhamnopyranoside, apigenin 7-O-β-glucopyranosyl-4′-O-α-rhamnopyranoside, tricin 7-O-β-glucopyranoside, tricin, and isoscopoletin (18) possessed excellent antiviral activity against HBV replication. In addition, protocatechuyl aldehyde (19) also displayed substantial inhibiting activity on HSV-1 replication (126). Likhitwitayawuid et al. tested flavonoids, coumarins, phloroglucinol (68), and stilbenes (69) derivatives derived from Mallotus pallidus, Artocarpus gomezianin, and Triphasia trifolia. It was concluded that bis hydroxyphenyl structures are promising candidates for anti-HSV and anti-HIV drug development (127). The in vitro antiviral activity of galangin (3,5,7-trihydroxyflavone), the major antimicrobial compound isolated from the shoots of Helichrysum aureonitens, was investigated against herpes simplex virus type 1. The compound showed significant antiviral activity against HSV-1 (an enveloped double-stranded DNA virus) and Cox B1 (an un enveloped single-stranded RNA virus) at concentrations varying from 12 to 47 µg/mL (128). Epigallocatechin 3-O-gallate, samarangenin B derived from the roots of Limonium sinense had higher inhibitory activity than the positive control acyclovir. All of these were examined for inhibitory effect against the replication of HSV-1 virus in Vero cells (129). Du et al. isolated flavonoid leachianone from the root bark of Morus alba showing potent antiviral activity. A flavonoid moralbanone, having characteristic prenyl chain, along with seven other known compounds, was isolated from the root bark of Morus alba L. Among all the isolated compounds, Leachianone G showed potent antiviral activity (IC50 = 1.6 μg/mL) (130). Three new flavonol glycosides, namely, isorhamnetin 3-O-(6″-O-(Z)-p-coumaroyl)-β-d-glucopyranoside, quercetin 3-O-α-l-rhamnopyranosyl(1-2)-α-l-arabinopyranosyl(1-2)-α-l-rhamnopyranoside, and quercetin 3-O-α-l-arabinopyranosyl(1-2)-α-l-rhamnopyranoside, were isolated from the stems of Alphitonia philippinensis collected from Hainan Island, China. Some of the isolated triterpenoids and flavonoid glycosides showed cytotoxicity against human PC-3 cells and hepatoma HA22T cells, and the inhibition of replication on HSV-1 (131). Viral diseases, especially of skin, can be treated with a virucide encapsulated in multilamellar phospholipid liposomes. Rosmarinic acid (70), incorporated in phospholipid mixture demonstrated effectiveness in humans afflicted with HSV (132). Flavonol glycosides (from quercetin and isorhamnetin) derived from the stems of Alphitonia philippinensis have been reported to inhibit the replication of HSV-1. Isodihydrosyringetin, a new (2R,3S)-3,5,7,4′-tetrahydroxy-3′,5′-dimethoxyflavanone was extracted from the root of Limonium sinense (Girard) along together with nine other known compounds. Out of all the compounds examined for their inhibitory effects on HSV-1, replication in vero cells, epigallocatechin 3-O-gallate and samarangenin B exhibited potent inhibitory activities on HSV-1 replication. Comparison of the IC50 values indicated that these both compounds had higher inhibitory activities than the positive control acyclovir (38.6 ± 2.6 vs. 55.4 ± 5.3 μM, P < 0.001; 11.4 ± 0.9 vs.55.4 ± 5.3 μM, P < 0.0005) (129). Cedrus libani, widely used as traditional medicine in the middle east for the treatment of different infections was studied for its antiviral potential. The phytochemical components isolated himachalol (22.50%), β-himachalene (21.90%), and α-himachalene (10.50%) showed promising results against herpes simplex virus type 1 (HSV-1) (133). Harden et al. evaluated the antiviral activity of extracts from Undaria pinnatifida, Splachnidium rugosum, Gigartina atropurpurea, and Plocamium cartilagineum against HSV-1 and HSV-2. Different assays showed that the compounds had potent virucidal activity and were active at very low concentrations (134). There are already reports in literature regarding excellent anti-HSV activity of Maclura cochinchinensis in several in vitro experiments. The authors have carried out biologically-guided separation of the active component(s). Ethyl acetate and methanol extracts exhibited anti-HSV-2 activity at EC50 values of 38.5 μg/mL and 50.8 μg/mL, respectively. Biologically-guided chromatographic separation of the ethyl acetate extract yielded compound A, identified as morin using a spectroscopic method. Morin exhibited anti-HSV-2 activity at an EC50 value of 53.5 μg/mL. In order to test the activity of acetate derivative, morin penta acetate was synthesized; however, the compound did not show any activity. It was concluded that free hydroxyl groups were required for anti-HSV-activity, as demonstrated previously by other workers for the antiviral activity of other flavonoids (135).
2.15 Hepatitis
Hepatitis derives its name from the Greek words hepato and itis which literally stands for liver inflammation. There are several types of viral Hepatitis such as Hepatitis A, B,C,D,E,F,G. Hepatitis is also caused by mumps virus, rubella virus, and cytomegalovirus. A large number of herbal products have been screened to measure their efficacy as anti-hepatitis drugs. One of the coumarin derivative geranyloxy-8-methoxycoumarin, best known as collinin (71) obtained from Zanthoxylum schinifolium was shown to significantly inhibit the replication of hepatitis B virus DNA (IC50 = 17.1 μg/mL (109). Seven plant extracts from six different families were found to have antiviral activity against HSV-1, at a concentration non toxic to the cell line (Vero) used. It was shown that most of these extracts have partial activity at the low concentration used. The methanol extracts of the aerial parts of Hypericum mysorense and Hypericum hookerianum, exhibited detectable antiviral effect towards HSV-1 with an inhibitory concentration for 50% (IC^sub 50^) of 100 and 50 µg/mL respectively (135). The administration of concanavalin A (Con A) to mice induces cytokine-dependent hepatitis. Okamoto et al. examined the effect of glycyrrhizin on Con A-induced hepatitis and showed that glycyrrhizin inhibited Con A-induced hepatitis without affecting cytokine expression (136) (Fig. 24.7).
Constituents isolated from Ranunculus sieboldii and Ranunculus sceleratus were tested for inhibitory effects on hepatitis B virus (HBV) and HSV-1. It was shown that apigenin 4′-O-α-rhamnopyranoside, apigenin 7-O-β-glucopyranosyl-4′-O-α-rhamnopyranoside, tricin 7-O-β-glucopyranoside, tricin, and isoscopoletin possessed substantial inhibitory activity against HBV replication (126). Ellagic acid (73), isolated from Phyllanthus urinaria, has exhibited the blockage of HBeAg secretion in HepG2 2.2.15 cells. Since HBeAg is involved in immune tolerance during HBV infection, ellagic acid may be a new therapeutic candidate against immune tolerance in HBV-infected individuals (137).
2.16 Influenza
Influenza virus (an RNA virus belonging to the Orthomyxoviridae family) is the causative organism for influenza commonly known as viral flu. There are three types of viruses known to cause influenza: influenza virus A, B and C. As an integral part of traditional therapy in India and China, plant extracts have been routinely used to cure flu since old times. A number of active biological compounds have been found to possess excellent antiviral activity against the influenza virus. Antiviral flavonoid 2″-O-(2′″-methylbutanoyl) isoswertisin obtained from the flower of Trollius chinensis was found to be moderately active toward influenza virus A. Two new flavonoid-type C-glycosides, trollisin I (=(1S)-1,5-anhydro-1-[2-(3,4-dihydroxyphenyl)-5-hydroxy-7-methoxy-4-oxo-4H-[1]benzopyran-8-yl]-2-O-(2-methylbutanoyl)-d-glucitol) and its 2-O-benzoyl congener trollisin II, were isolated from Trollius chinensis, together with the two known compounds 2″-O-(2′″-methylbutanoyl) isoswertisin and vitexin galactoside. In antiviral assays, the compounds were found to be moderately active towards influenza virus A (138). The inhibiting effects of isoscutellarein-8-methylether (5,7,4′-trihydroxy-8-methoxyflavone, F36) obtained from Scutellaria baicalensis on the single-cycle replication of mouse-adapted influenza viruses A/Guizhou/54/89 (H3N2 subtype) and B/Ibaraki/2/85 was evaluated and it was reported that the flavone significantly suppressed the replication of these viruses in a dose-dependent manner. It was noticed that the agents suppressed the replication of these viruses from 6 to 12 h after incubation in a dose-dependent manner by 50% at 20 µM and 90% at 40 µM, respectively. Remarkably 5,7,4′-trihydroxy-8-methoxyflavone, at the concentration of (50 µM) reduced the release of B/Ibaraki virus in the medium by 90–93% when it was added to the MDCK cells at 0–4 h after incubation (139). In a series of experiments, the phenolic biopolymer SP-303 was tested for its efficacy against experimentally induced influenza A (H1N1) virus infections in mice. It was found that when 30, 10, or 3 mg/kg/day of SP-303 was administered intraperitoneally once daily for 8 days, beginning either 48 h before or 4 h after virus exposure, only lung consolidation was significantly reduced (140).
2.17 Common Cold
Common cold is caused by Rhinovirus, (derived from the Greek word rhin- denoting nose) belonging to the Picornaviridae family. Traditional forms of medicines have relied on plant preparations to cure common cold, especially in the Indian subcontinent. Employing a plaque reduction assay, several homo-isoflavonoids and chloro-substituted rac-3-benzylchroman-4-ones were evaluated for in vitro activity against selected picornaviruses. All homo isoflavonoids that were tested exhibited an inhibitory effect on rhinovirus replication with an activity depending on virus serotype and compound (141). Douglas and colleagues have reported antiviral activity of Vitamin C against rhinovirus (142). In another report, plants derived from the Echinacea family (family Asteraceae) have been shown useful for preventing and treating the common cold (143). The antiviral activity of different 2-styrylchromones was evaluated and almost all of them displayed activity against serotypes of human rhinovirus, 1B in a plaque reduction assay in HeLa cell cultures. Mechanistically, the compounds were found to interfere with HRV 1B replication. The antiviral activity of 2-styrylchromones and 3-hydroxy-1-(2-hydroxyphenyl)-5-phenyl-2,4-pentadien-1-ones, which are intermediates in the synthesis have been evaluated against two selected serotypes of human rhinovirus, 1B and 14, by a plaque reduction assay in HeLa cell cultures. It was found that al most all the compounds interfered with HRV 1B replication, with the exception of 3-hydroxy-1-(2-hydroxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadien-1-one which did not show any significant activity. It is worth mentioning that the majority of derivatives were found to be effective against serotype 14, often with a higher potency (144, 145).
2.18 Multiple Targets
A considerably large number of studies has reported the activity of various phytochemicals against multiple targets. Weber et al. used direct pre-infection incubation assays to determine the in vitro virucidal effects of fresh garlic extract, its polar fraction, and other garlic-associated compounds, that is, diallyl disulfide (37), diallyl thiosulfinate (39) (allicin), allyl Me thiosulfinate (74), ajoene (75), alliin (76), deoxyalliin (77), and diallyl trisulfide (146).
In an effort to determine the mechanistic action of garlic compounds to explain their antiviral action, direct pre-infection incubation assays were used to determine the in vitro virucidal effects against selected viruses including, HSV-1, HSV-2, Para influenza virus type 3, vaccinia virus, vesicular steatites virus, and human rhinovirus type 2. These results indicate that virucidal activity and cytotoxicity may have depended upon the viral envelope and cell membrane, respectively. However, activity against non-enveloped virus may have been due to the inhibition of viral adsorption or penetration. The order for virucidal activity generally was: ajoene (66) > allicin (39) > allyl Me thiosulfinate (74). Tait et al. showed marked antiviral activity of homoisoflavonoids against coxsackie virus B1, B3, B4, A9, and echovirus 30. The inhibition of viral replication was monitored on BGM cells. Out of the various tested compounds, 3-benzyl chroman-4-ones (79) have displayed substantial antiviral effect towards PI-3 (parainfluenza-3) in the range of 8–32 μg/mL of inhibitory concentration for cytopathogenic effect (CPE) in Madin–Darby bovine kidney and vero cell lines (146) Eugenol, (78) a traditional medicine has also been used against multiple viral targets (125). Singh et al. have investigated the interaction between chemokine receptor CXCR4 and flavonoids using in silico docking studies. On the basis of their studies, the authors concluded that flavonoids may also be useful as topical agents to inactivate virus, or may act as adjuvant with other antiviral drugs. Interaction network formed by disulfide bonds, hydrogen bonds, van der Waals force, and salt bridges between extracellular segments helped in maintaining the conformation of the docked complex (147). The moderate antiviral activity of the mixture of quercetin 3-O-β-glucoside and quercetin 3-O-β-galactoside derived from Chamaesyce thymifolia against HSV-1 and BVDV viruses was also reported (148). A number of substituted homo-isoflavonoids were synthesized in order to study their in vitro anti-picornavirus activity. Experiments were performed to determine the ability of non-cytotoxic concentrations to interfere with plaque formation by HRV 1B and 14 and poliovirus (PV) 2. Experiments suggested that serotype 1B was much more sensitive than 14 to the action of the compounds, and the presence of one or more chlorine atoms increased the antiviral effect in all homo isoflavonoids tested, confirming the positive influence of this substituent on activity (149). In an attempt to search for novel active agents from plant source pure flavonoids and aqueous extracts of Caesalpinia pulcherrima Swartz were screened to test their influence on a series of viruses, namely HSV-1, HSV-2, and adenoviruses (ADV-3, ADV-8, ADV-11). Results showed that the aqueous extracts of C. pulcherrima and its related quercetin possessed a broad-spectrum antiviral activity. The experiments have shown that fruit and seed extract showed the best activity (EC50 = 41.2 mg/L, SI = 83.2) as compared to stem and leaf (EC50 = 61.8 mg/L, SI = 52.1) and flower (EC50 = 177.9 mg/L, SI = 15.5). Quercetin derived from the plant possessed the strongest anti-ADV-3 activity (EC50 = 24.3 mg/L, SI = 20.4) (150). In the last decade, there has been a lot of focus on the amino sugar glucosidase inhibitors have selective antiviral activity against certain enveloped, mammalian viruses (151). It has been shown that deoxynojirimycins (DNJs) modified by reductive amination to attach a long chain to N atom (their N-DNJ derivative ) were shown to be, for example, at least 20 times more potent than the non-alkylated DNJ in inhibiting hepatitis B virus (HBV) and bovine viral diarrhea virus (BVDV) in cell based assays. These data suggested that the modification of the alkyl side chain could influence antiviral activity (152). De Almeida et al. reported strong inhibition of an infusion of Persea americana leaves against HSV-1, Aujeszky’s disease virus (ADV) and adenovirus type 3 (AD3) in cell cultures. An extract of Persea americana leaves (Lauraceae) strongly inhibited herpes simplex virus type 1 (HSV-1), Aujeszky’s disease virus (ADV) and adenovirus type 3 (AD3) in cell cultures. Its fractionation, guided by anti-HSV-1 and ADV assays, allowed the isolation and identification of two new flavonol monoglycosides, kaempferol and quercetin 3-O-α-d-arabinopyranosides, along with the known kaempferol 3-O-α-l-rhamnopyranoside (afzelin), quercetin 3-O-α-l-rhamnopyranoside (quercitrin), quercetin 3-O-β-gluco-pyranoside and quercetin. In the extract, the known quercetin 3-O-β-galactopyranoside was also identified. The authors have reported that afzelin and quercetin 3-O-α-d-arabinopyranoside showed higher activity against acyclovir-resistant HSV-1. Chlorogenic acid significantly inhibited the HSV-1 replication without any cytotoxicity. However, all the substances tested were less active than the infusion or fractions (153). A summary of major classes of antiviral phytochemicals along with their source and viral targets has been provided in Table 24.4.
2.19 Miscellaneous
There exists a huge volume of literature regarding the evaluation of plant-derived compounds against several other viral targets apart from the ones listed above. Substantial antiviral activity of 8-geranyloxypsoralen (80) (isolated in low yields from Citrus limon) was reported against tumor promoter TPA-induced Epstein–Barr virus activation (10 μM, the inhibitory activity was 79.3%) (111). Well-studied polyphenol Resveratrol (81) was found to inhibit varicella–zoster virus (VZV) replication in a dose-dependent and reversible manner. RT-PCR studies showed that protein and mRNA levels of IE62, an essential early viral protein, were reduced when compared to controls (205). Baicalin (BA) derived from Scutellaria baicalensis has shown substantial antiviral activities. Mechanistically, it was shown that BA inhibited the binding of a number of chemokines to human leukocytes or cells transfected to express specific chemokine receptors (206).
Antiviral activities of seven compounds belonging to kaempferol family were evaluated against human HCMV and it was confirmed that the presence of acyl group is important for the activity (207). A freshly prepared extract of Chelidonium majus was tested in vivo for anti-retroviral activity using highly susceptible C57Bl/6 strain in a mouse. The mice were infected intraperitoneally with 0.2 mL of the stock virus pool of defective murine leukemia retroviruses (MuLVs) LP-BM5. The animals were sacrificed (after 4 months) and a significant reduction in the weight of spleen and cervical lymph nodes was noticed in chronically infected mice treated with freshly prepared crude extract of Chelidonium majus (P = 0.0057 and P < 0.001) (208). In an effort to elucidate the action mechanism of 3-methyl quercetagetin, it was reported that the significant activity of the compound against tomato bushy stunt virus was attributed to the interference during the virus infection initiation (209). Sanchez and colleagues evaluated the possible antiviral effect of flavonoids obtained from Tephrosia madrensis, Tephrosia viridiflora, and Tephrosia crassifolia on dengue viruses and concluded that glabranine and 7-O-methyl-glabranine presented 70% inhibition on the dengue virus (210). 4-hydroxypanduratin A and panduratin chalcone derivatives derived from Boesenbergia rotunda displayed substantial inhibitory activities toward dengue 2 virus NS3 protease (Ki values of 21 and 25 µM, respectively) (211). The inhibitory effects of diosmin (82) and hesperidin (83) on the infectivity of rotavirus causing sporadic diarrhea in infants was evaluated and it was shown that both compounds were effective against rotavirus infection (212). Some of the phytochemicals have graduated to the clinical trials. Owing to the space constraints only the major clinical trials relating to the antiviral activities of phytochemicals have been summarized in Table 24.5.
3 Conclusions and Perspectives
Numerous epidemiological and experimental studies have revealed that a large number of the phytochemicals have promising antiviral activities. However, as discussed earlier, the development of new and better antiviral agents from plants pose a formidable challenge. One of the major challenges has been the relatively fewer number of in vivo studies coupled with inconsistency in results due to a lack of uniformity in the assays. Further, the data on the absorption metabolism and the excretion of phytochemicals in humans is contradictory and scarce. A highly interdisciplinary approach with meticulous planning and design needs to be followed for conducting the in vivo studies in a highly standardized environment. Consequently, the properly designed and rigorously executed clinical trial can help us to establish the efficacy and safety of the potential drug. In order to apply plant-based agents as an effective strategy, it is of extreme importance to understand the molecular and cellular mechanism of the compounds with proper understanding of metabolite retention process of the system. A greater emphasis on the use of combination of micro array and proteomics techniques is needed to define the molecular targets for various micronutrients. Various techniques such as the serial expression of gene expression, protein arrays, and the evaluation of the mechanism will not only enhance our understanding of antiviral action at molecular level, but also help in finding the most effective strategy. Rational synthesis of the diverse derivatives with a more favorable profile activity can be of immense value along with the development of agent-selective endpoint markers. There is immediate need for crafting and executing an aggressive strategy involving nongovernmental organizations, chemists, microbiologists, clinicians, and experts with indigenous knowledge, failing which there are high chances of losing several untapped resources due to the extinction of plants. Combination studies/synergism is another area that has remained neglected. Further detailed studies to specify the minimum quantity of the phytochemicals to be consumed since the dosage of pure compounds effective in animals may not stay realistic when extrapolated to human system. By covering all the above gaps, it would be possible to strike a balance between the toxicity and the activity of a particular agent, which is essential for developing a new drug.
References
Solecki RS (1975) Shanidar IV, a Neanderthal flower burial in northern Iraq. Science 190:880–881
International Symposium on Medicinal Plants, April 19–21, 1993, in Philadelphia, USA. The Morris Arboretum and the World Health Organization (WHO)
Fabricant DS, Farnsworth NR (2001) The value of plants used in traditional medicine for drug discovery. Environ Health Perspect 109(Suppl 1):69–75
Clardy J, Walsh C (2004) Lessons from natural molecules. Nature 432:829–837
Cardellina JH (2002) Challenges and opportunities confronting the botanical dietary supplement industry. J Nat Prod 65:1073–1084
Raskin I, Ribnicky DM, Komarnytsky S, Ilic N, Poulev A, Borisjuk N, Brinker A, Moreno DA, Ripoll C, Yakoby N, O’Neal JM, Cornwell T, Pastor I, Fridlender B (2002) Plants and human health in the twenty-first century. Trends Biotechnol 20:522–531
Pietta P, Gardana C, Pietta A (2003) Flavonoids in health. In: Rice-Evans C, Packer L (eds) Flavonoids in health and disease, 2nd edn. Marcel Dekker, New York, NY, p 43
Selway JWT (1986) Antiviral activity of flavones and flavans. In: Cody V, Middleton E, Harborne JB (eds) Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure–activity relationships. Liss, A.R, New York, NY
Martin KW, Ernst E (2003) Antiviral agents from plants and herbs: a systematic review. Antivir Ther 8(2):77–90
Naithani R, Huma L, Holland LE Shukla D, Mccormick DL, Mehta RM, Moriarty RM (2008) Antiviral activity of phytochemicals: a comprehensive review. Mini Rev Med Chem 8(11):1106
Okeke IN, Laxmaninarayan R, Bhutta ZA, Duse AG, Jenkins P, O’Brien TF, Pablos-Mendez A, Klugman KP (2005) Antimicrobial resistance in developing countries. Part 1: recent trends and current status. Lancet Infect Dis 5:481–493
Rose RE, Gong YF, Greytok JA, Bechtold CM, Terry BJ, Robinson BS, Alam M, Colonno RJ, Lin PF (1996) Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors. Proc Natl Acad Sci USA 93:1648
Balfour HH (1999) Antiviral drugs. N Engl J Med 340:1255
Kuper H, Adami HO, Trichopoulos D (2000) Infections as a major preventable cause of human cancer. J Int Med 48:171
Patwardhan B (2005) Ethnopharmacology and drug discovery. J Ethnopharm 100:50–52
Cordell GA, Colvard MD (2005) Some thoughts on the future of ethnopharmacology. J Ethnopharm 100:5–14
Hudson JB, Graham EA, Towers GHN (1994) Antiviral assays on phytochemicals: the influence of reaction parameters. Planta Med 60:329–332
Jensik SC, Northrop RL (1971) Incorporation of radioactive seleno-(75Se)-methionine into mumps virus. Appl Microbiol 21(3):451–455
Ververidis F, Trantas E, Douglas C, Vollmer G, Kretzschmar G, Panopoulos N (2007) Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I: chemical diversity, impacts on plant biology and human health. Biotechnol J 2(10):1214
Spencer JP (2008) Flavonoids: modulators of brain function? Br J Nutr 99:ES60–ES77
Thomas PRS, Nash GB, Dormandly JA (1988) White cells accumulation in dependent legs of patients with venous hypertension: A possible mechanism for trophic changes in the skin. Br Med J 296:1673
Loewenstein WR (1979) Junctional intercellular communication and the control of growth. Biochem Biophys Acta 560:1
Gerdin B, Srensso E (1983) Inhibitory effect of flavonoids on increased microvascular permeability induced by various agents in rat skin. Int J Microcir Clin Exp 2:39
Deng J, Kelley JA, Barchi JJ, Sanchez T, Dayam R, Pommier Y, Neamati N (2006) Mining the NCI antiviral compounds for HIV-1 integrase inhibitors. Bioorg Med Chem 14:3785
Nowakowska Z (2007) A review of anti-infective and anti-inflammatory chalcones. Eur J Med Chem 42:125
Phrutivorapongkul A, Lipipun V, Ruangrungsi N, Kirtikara K, Nishikawa K, Maruyama S, Watanabe T, Ishikawa T (2003) Studies on the chemical constituents of stem bark of Millettia leucantha: isolation of new chalcones with cytotoxic, anti-herpes simplex virus and anti-inflammatory activities. Chem Pharm Bull 51:187
Likhitwitayawuid K, Chaiwiriyaa S, Sritularaka B, Lipipunb V (2006) Antiherpetic flavones from the heartwood of Artocarpus gomezianus. Chem Biodivers 3:1138
Prendergast PT (2003) US Patent No 6555523
Santhosh C, Mishra PC (1996) Molecular electrostatic potential mapping and structure-activity relationship for 3-methoxy flavones. Indian J Biochem Biophys 33(6):458
Moriarty RM, Surve BC, Naithani R, Chandersekera SN, Tiwari V, Shukla D (2007) Synthesis and antiviral activity of Abyssinone II analogs. In: Abstracts of papers, 233rd ACS National Meeting, Chicago, IL, 25–29 March 2007
Zhao Yu, Wang F, Liu W, Bai H. (2007) Method for preparation and application dihydroflavanonol compounds. Faming Zhuanli Shenqing Gongkai Shuomingshu 34
Ren Q, Song X (2005) Use of a composition containing dihydromyricetin and myricetin in preparation of antiviral medicines. Faming Zhuanli Shenqing Gongkai Shuomingshu 20
Andersen, O. M, Helland, D. E, Andersen, K. J. (1997) Anthocyanidin and anthocyanidin derivatives, and their isolation, for treatment of cancer, diseases caused by lesions in connective tissues, and diseases caused by viruses. PCT Int Appl 121
Takatsuki A, Tamura G, Arima K (1969) Antiviral and antitumor antibiotics. XIV. Effects of ascochlorin and other respiration inhibitors on multiplication of Newcastle disease virus in cultured cells. App Microbiol 17:825
Mashava P (1996) PCT Int Appl 38
Conti C, Orsi N, Stein ML (1988) Effect of isoflavans and isoflavenes on rhinovirus 1B and its replication in HeLa cells. Antiviral Res 10:117
Yu D, Suzuki M, Xie L, Morris-Natschke SL, Lee K-H (2003) Recent progress in the development of coumarin derivatives as potent anti-HIV agents. Med Res Rev 23:322
Creagh T, Ruckle JL, Tolbert DT (2001) Safety and pharmacokinetics of single doses of (+)-calanolide a, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects. Antimicrob Agents Chem 45:1379
Li Y, Leung KT, Yao F, Ooi LSM, Ooi VEC (2006) Antiviral flavans from the leaves of Pithecellobium clypearia. J Nat Prod 69:833
Charles L, Laure F, Raharivelomanana P, Bianchini JP (2005) Sheath liquid interface for the coupling of normal-phase liquid chromatography with electrospray mass spectrometry and its application to the analysis of neoflavonoids. J Mass Spectrom 40:75
Farnsworth NR (2006) Biological and phytochemical screening of plants. J Pharm Sci 55(3):225
Houghton PJ, Woldemariam TZ, Khan AI, Burke A, Mahmood N (1994) Antiviral activity of natural and semi-synthetic chromosome alkaloids. Antiviral Res 25(3–4):235
Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS (2007) Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem 50:4087
Melikian G, Mmiro F, Ndugwa C, Perry R, Jackson JB, Garrett E, Tielsch J, Semba RD (2001) Relation of vitamin A and carotenoid status to growth failure and mortality among Ugandan infants with human immunodeficiency virus. Nutrition 17:567
Heldreth B, Turos E (2005) N-Thiolated beta-lactam antibacterials: effects of the N-organothio substituent on anti-MRSA activity. Curr Med Chem 4:295
Hunter R, Caira M, Stellenboom N (2005) Nat Prod Mol Ther 6:234
Moriarty RM, Naithani R, Surve BC, Tiwari V, Shukla D (2006) Synthesis and antiviral activity of Sulforamate derivatives. In: Abstracts-233rd ACS National Meeting Chicago, IL, 25–29 March 2006
Jariwalla R, Harakeh S (1996) Antiviral and immunomodulatory activities of ascorbic acid. In: Harris JR (ed) Subcellular biochemistry: ascorbic acid: biochemistry and biomedical cell biology, vol 25. Plenum, New York, p 215
Andreone P, Fiorino S, Cursaro C, Gramenzi A, Margotti M, Di Giammarino L, Biselli M, Miniero R, Gasbarrini G, Bernardi M (2001) Vitamin E as treatment for chronic hepatitis B: results of a randomized controlled pilot trial. Antiviral Res 49:75
Cermelli C, Vinceti M, Scaltriti E, Bazzani E, Beretti F, Vivoli G, Portolani M (2002) Selenite inhibition of Coxsackie virus B5 replication: implications on the etiology of Keshan disease. J Trace Elem Med Biol 16:41
La Colla P, Tramontano E, Musiu C, Marongiu ME, Novellino E, Greco G, Massa S, Di Santo R, Costi R, Marino A (1998) In vitro and in vivo antiproliferative activity of IPCAP, a new pyrazole. Antiviral Res 7:A57
Botelho MV, Orlandi JM, de Melo FL, Mantovani MS, Linhares RE, Nozawa C (2004) Chlorophyllin protects HEp-2 cells from nuclear fragmentation induced by poliovirus. Lett Appl Microbiol 39:174
Ishihara C, Yoshimatsu K, Tsuji M, Arikawa J, Saiki I, Tokura S, Azuma I (1993) Antiviral activity of sulfated chitin. Vaccine 11:670
Liu KC, Lin MT, Lee SS, Chiou JF, Ren S, Lien EJ (1999) Antiviral tannins from two Phyllanthus species. Planta Med 65:43
Hudson JB (1990) Antiviral compounds from plants. CRC, Boca Raton, FL
Wat CK, Biswas RK, Graham EA, Bohm L, Towers GH, Waygood ER (1979) Ultraviolet-mediated cytotoxic activity of phenylheptatriyne from Bidens pilosa. J Nat Prod 42:103
Neushul M (1990) Antiviral carbohydrates from marine red algae. Hydrobiologia 205:99
Gerber P, Dutcher JD, Adams EV, Sherman JH (1958) Protective effect of seaweed extracts for chicken embryos infected with influenza B or mumps virus. Proc Soc Exp Biol Med 99:590
Witvrouw M, DeClerq E (1997) Sulfated polysaccharides extracted from sea algae as potential antiviral drugs. Gen Pharmacol 29:497
Huleihel M, Ishanu V, Tal J, Arad SM (2001) Antiviral effect of red microalgal polysaccharide on Herpes simplex and Varicella zoster viruses. J Appl Phycol 13:127
Konigheim BS, Goleniowski ME, Contigiani MS (2005) Citotoxicity and antiviral activity of a lignan extracted from Larrea divaricata. Drug Des Rev 2:81
Wang CY, Sun SW, Lee SS (2004) Pharmacokinetic and metabolic studies of retrojusticidin B, a potential antiviral lignan, in rats. Planta Med 70:1161
Ho TY, Wu SL, Chen JC, Li CC, Hsiang CY (2007) Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Res 74:92
Chrubasik S, Pittler MH, Roufogalis BD (2005) Zingiberis rhizome: a comprehensive review on the ginger effect and efficacy profiles. Phytomedicine 12:684
Singh DP, Moore CA, Gilliland A, Carr JP (2004) Activation of multiple antiviral defence mechanisms by salicylic acid. Mol Plant Pathol 5:57
Semple SJ, Pyke GD, Reynolds SM, Flower RLP (2001) In vitro antiviral activity of the anthraquinone chrysophanic acid against poliovirus. Antiviral Res 49:169
Wang W, Zu Y, Fu Y, Reichling J, Suschke U, Nokemper S, Zhang Y (2009) In vitro antioxidant, antimicrobial and anti-herpes simplex virus type 1 activity of Phellodendron amurense China. Am J Chin Med 37(1):195–203
Amoros M, Simoes CMO, Girre L (1992) Synergistic effect of flavones and flavonols against herpes simplex virus type 1 in cell culture. Comparison with the antiviral activity of propolis. J Nat Prod 155:1732–1740
Min BS, Tomiyama M, Ma CM, Nakamura N, Hattori M (2001) Kaempferol acetylrhamnosides from the rhizome of Dryopteris crassirhizoma and their inhibitory effects on three different activities of human immunodeficiency virus-1 reverse transcriptase. Chem Pharm Bull 49:546–550
McLaughlin JL (2008) Paw paw and cancer: annonaceous acetogenins from discovery to commercial products. J Nat Prod 71(7):1311–1321
Phongpaichit S, Nikom J, Rungjindamai N, Sakayaroj J, Hutadilok-Towatana N, Rukachaisirikul V, Kirtikara K (2007) Biological activities of extracts from endophytic fungi isolated from Garcinia plants. FEMS Immunol Med Microbiol 51(3):517–525
Cos P, Maes L, Vander Berghe D, Hermen N, Pieters L, Vlietinck A (2004) Plant substances as Anti-HIV agents selected according to their putative mechanism of action. J Nat Prod 67:284–293
Yoosook C, Bunyapraphatsara N, Boonakiat Y, Kantasuk C (2000) Anti-herpes simplex virus activities of crude water extract of Thai medicinal plants. Phytomedicine 6:411–419
Dias DA, Silva CA, Urban S (2009) Naphthalene aglycones and glycosides from Australian medicinal plant, Dianella callicarpa. Planta Med 75((13)):1442–1447
Petrera E, Coto CE (2009) Therapeutic effect of meliacine, an antiviral derived from Melia azedarach L, in mice genital herpetic infection. Phytother Res 23(12):1771–1777
Alvarez AL, Del Barrio G, Kourí V, Martínez PA, Suárez B, Parra F (2009) In vitro anti-herpetic activity of an aqueous extract from the plant Phyllanthus orbicularis. Phytomedicine 16(10):960–966
Lee LS, Andrade AS, Flexner C (2006) Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects. Clin Infect Dis 43(8):1052
Ishitsuka H, Ohsawa C, Ohiwa T, Umeda I, Suhara Y (1982) Antipicornavirus flavone Ro 09-0179. Antimicrob Agents Chemother 22:611
Serkedjieva J (1995) Inhibition of influenza virus protein synthesis by a plant preparation from Geranium sanguineum L. Acta Virol 39(1):5–10
Malhotra B, Onyilagha JC, Bohm BA, Towers GHN, James D, Harborne JB, French CJ (1996) Inhibition of tomato ringspot virus by flavonoids. Phytochemistry 43:1271
Li BQ, Fu T, Dongyan Y, Mikovits JA, Ruscetti FW, Wang JM (2000) Flavonoid baicalin inhibits HIV infection at the level of viral entry. Biochem Biophysical Res Comm 276:534
Eversa DL, Chaoa CF, Wanga X, Zhanga Z, Huonga SM, Huang ES (2005) Antiviral Res 68:124
Castrillo JL, Carrasco L (1987) Action of 3-methylquercetin on poliovirus RNA replication. J Virol 61:3319
Takechi M, Tanaka Y (1981) Purification and characterization of antiviral substance from the bud of Syzygium aromatica. Planta Med 42:69
Sydiskis RJ, Owen DG, Lohr JL, Rosler KH, Blomster RN (1991) Inactivation of enveloped viruses by anthraquinones extracted from plants. Antimicrob Agents Chemother 35:2463
Kurokawa M, Hozumi T, Basnet P, Nakano M, Kadota S, Namba T, Kawana T, Shiraki K (1998) Purification and characterization of eugeniin as an anti-herpes virus compounds from Geum japonicum and Syzygium aromaticum. J Pharmacol Exp Ther 284:728
Bettega JMR, Teixeira H, Bassani VL, Barardi CRM, Simões MO (2004) Evaluation of the antiherpetic activity of standardized extracts of Achyrocline satureioides. Phytother Res 18:819
Spedding G, Ratty A, Middleton E (1989) Inhibition of reverse transcriptases by flavonoids. Antiviral Res 12:99
Salvati AL, De Dominicis A, Tait S, Canitan A, Lahm A, Fiore L (2004) Mechanism of action at the molecular level of the antiviral drug 3(2H)-isoflavene against type 2 poliovirus. Antimicrob Agents Chemother 48:2233
Song JM, Lee KH, Seong BL (2005) Antiviral effect of catechins in green tea on influenza virus. Antiviral Res 68:66
Lin YM, Flavin MT, Schure R, Chen FC, Sidwell R, Barnard DL, Huffman JH, Kern ER (1999) Antiviral activities of biflavonoids. Planta Med 65:120
Semple SJ, Nobbs SF, Pyke SM, Reynolds GD, Flower RL (1999) Antiviral flavonoid from Pterocaulon sphacelatum, an Australian Aboriginal medicine. J Ethnopharmacol 68:283
Yu YB, Miyashiro H, Nakamura N, Hattori M, Cheol PJ (2007) Effects of triterpenoids and flavonoids isolated from Alnus firma on HIV-1 viral enzymes. Arch Pharm Res 30:820
Hwanga DR, Wua YS, Changa CW, Liena TW, Chena WC, Tanb UK, Hsua JTA, Hsieh HP (2006) Synthesis and antiviral activity of a series of sesquiterpene lactones and analogues in the subgenomic HCV replicon system. Bioorg Med Chem 14:83
González ME, Alarcón B, Carrasco L (1987) Polysaccharides as antiviral agents: antiviral activity of carrageenan. Antimicrob Agents Chemother 31:1388
Talyshinsky MM, Souprun YY, Huleihe MM (2002) Antiviral activity of red microalgal polysaccharides against retroviruses. Cancer Cell Int 2:8
McMahon JB, Currens MJ, Gulakowski RJ, Buckheit RW Jr, Lackman-Smith C, Hallock YF, Boyd MR (1995) Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms. Antimicrob Agents Chemother 39:484
Renard-Nozaki J, Kim T, Imakura Y, Kihara M, Kobayashi S (1989) Effect of alkaloids isolated from Amaryllidaceae on herpes simplex virus. Res Virol 140:115
Bresnahan WA, Boldogh I, Chi P, Thompson EA, Albrecht T (1997) Inhibition of cellular Cdk2 activity blocks human cytomegalovirus replication. Virology 231:239
Schang LM, Phillips J, Schaffer PA (1998) Roscovitine, a specific inhibitor of cellular cyclin-dependent kinases, inhibits herpes simplex virus DNA synthesis in the presence of viral early proteins. J Virol 72:5626
Redfield DC, Oxman RDD, MN KLH (2001) Rapid serological technique for typing herpes simplex viruses. Infect Immun 32:1216
Durantel D, Branza-Nichita N, Carrouée-Durantel S, Butters TD, Dwek RA, Zitzmann N (2001) Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. J Virol 75:8987
Marles RJ, Hudson JB, Graham EA, Soucy-Breau C, Morand P, Compadre RL, Compadre CM, Towers GH, Arnason JT (1992) Structure-activity studies of photoactivated antiviral and cytotoxic tricyclic thiophenes. Photochem Photobiol 56:479
Stanberry LR, Bourne N, Bravo FJ, Bernstein DI (1992) Capsaicin-sensitive peptidergic neurons are involved in the zosteriform spread of herpes simplex virus infections. J Med Virol 38:142
Si X, Wang Y, Wong J, Zhang J, McManus BM, Luo H (2007) Dysregulation of the ubiquitin-proteasome system by curcumin suppresses coxsackievirus B3 replication. J Virol 81:3142
Dikici I, Mehmetoglu I, Dikici N, Bitirgen M, Kurban S (2005) Investigation of oxidative stress and some antioxidants in patients with acute and chronic viral hepatitis B and the effect of interferon-alpha treatment. Clin Biochem 38:1141
Joint United Nations Programme on HIV/AIDS (2006) Overview of the global AIDS epidemic. 2006 Report on the global AIDS epidemic, UNAIDS, Geneva, Switzerland
Paris A, Strukelj B, Renko M, Turk V, Pukl M, Umek A, Korant BD (1993) Inhibitory effect of carnosolic acid on HIV-1 protease in cell-free assays. J Nat Prod 56:1426
Chang CT, Doong SL, Tsai IL, Chen IS (1997) Coumarins and anti-HBV constituents from Zanthoxylum schinifolium. Phytochemistry 45:1419
Fortin H, Tomasi S, Jaccard P, Robin V, Boustie J (2001) A prenyloxycoumarin from Psiadia dentata. Chem Pharm Bull 49:619
Sakagami H, Asano K, Satoh K, Takahashi K, Kobayashi M, Koga N, Takahashi H, Tachikawa R, Tashiro T, Hasegawa A, Kurihara K, Ikarashi T, Kanamoto T, Terakubo S, Nakashima H, Watanabe S, Nakamura W (2007) Anti-stress, anti-HIV and vitamin C-synergized radical scavenging activity of mulberry juice fractions. In Vivo 21:499
Hsieh P-W, Chang F-R, Lee K-H, Hwang T-L, Chang SM, Wu YC (2004) A new anti-HIV alkaloid, drymaritin, and a new C-glycoside flavonoid, diandraflavone, from Drymaria diandra. J Nat Prod 67:1175
Lee JS, Kim HJ, Lee YS (2003) A new anti-HIV flavonoid glucuronide from Chrysanthemum morifolium. Planta Med 69:859
Olivero-Verbel J, Pacheco-Londono L (2002) Structure activity relationships for the anti-HIV activity of flavonoids. J Chem Inf Comput Sci 42:1241
Nishibe S, Ono K, Nakane H, Kawamura T, Noro Y, Tanaka T (1997) Inhibitory effects of flavonoids from Plantago species on HIV reverse transcriptase activity. Nat Med 51:547
Kim HJ, Woo ER, Shin CG, Park H (1998) A new flavol glycoside gallate ester from Acer okamotoanum and its inhibitory activity against human immunodeficiency virus (HIV-1) integrase. J Nat Prod 61:145
Critchfield JW, Butera ST, Folks TM (1996) Inhibition of HIV activation in latently infected cells by flavonoid compounds. AIDS Res Hum Retroviruses 12:39
Mahmood N, Pizza C, Aquino R, De Tommasi N, Piacente S, Colman S, Burke A, Hay AJ (1993) Inhibition of HIV infection by flavanoids. Antiviral Res 22:189
Schinazi RF, Chu CK, Babu JRB, Oswald V, Saalman DL, Erickson BF (1990) Anthraquinones as a new class of antiviral agents against AIDS. Antiviral Res 13:265
Robin V, Boustie J, Amoros M, Girre L (1998) In-vitro antiviral activity of seven Psiadia species. Pharmacol Commun 4:61
Tuli V (1974) Mechanism of the antiviral action of 3-methyleneoxindole. Antimicrob Agents Chemother 5(5):485
Lyu S-Y, Rhim JY, Park WB, Lyu SY, Rhim JY, Park WB (2005) Antiherpetic activities of flavonoids against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Arch Pharm Res 28:1293
Ma W, Ma X, Huang H, Zhou P, Chen D (2007) Lignans and triterpenoids from the stems of Kadsura induta. Chem Biodivers 4:966
Chattopadhyay D (2007) In: Ahmad I, Aqil F, Owais M (eds) Ethnomedicinal antivirals: scope and opportunity modern phytomedicine, p 313
Benencia F, Courrèges MC (2000) In vitro and in vivo activity of eugenol on human herpesvirus. Phytother Res 14:495
Li H, Zhou CX, Pan Y, Gao X, Wu X, Bai H, Zhou L, Chen Z, Zhang S, Shi S, Luo J, Xu J, Chen L, Zheng X, Zhao Y (2005) Evaluation of antiviral activity of compounds isolated from Ranunculus sieboldii and Ranunculus sceleratus. Planta Med 71:1128
Likhitwitayawuid K, Supudompol B, Sritularak B, Lipipun V, Rapp K, Schinazi RF (2005) Phenolics with anti-HSV and anti-HIV activities from Artocarpus gomezianus, Mallotus pallidus and Triphasia trifolia. Pharm Biol 43:651
El Sohly HN, El-Feraly FS, Joshi AS, Walker LA (1997) Antiviral flavonoids from Alkanna orientalis. Planta Med 63:384
Lin LC, Kuo YC, Chou CJ (2000) Anti-herpes simplex virus type-1 flavonoids and a new flavanone from the root of Limonium sinense. Planta Med 66:333
Du J, He ZD, Jiang RW, Ye WC, Xu HX, But PP (2003) Antiviral flavonoids from the root bark of Morus alba L. Phytochemistry 62:1235–1238
Jou S-J, Chen C-H, Guh J-H, Lee C-N, Lee SS (2004) Flavonol glycosides and cytotoxic triterpenoids from Alphitonia philippinensis. J Chin Chem Soc (Taipei, Taiwan) 51:827
Atta-ur-Rahman (ed) (1995) Studies in natural products chemistry, structure and chemistry, vol 17, Part D. Elsevier, Amsterdam
Loizzo M, Saab A, Tundis R, Statti G, Lampronti I, Menichini F, Gambari R, Cinatl J, Doerr H (2008) Phytochemical analysis and in vitro evaluation of the biological activity against herpes simplex virus type 1 (HSV-1) of Cedrus libani A. Phytomedicine 15:79–83
Harden EA, Falshaw R, Carnachan SM, Kern ER, Prichard MN (2009) Virucidal activity of polysaccharide extracts from four algal species against herpes simplex virus. Antiviral Res 83(3):282–289
Bunyapraphatsara N, Dechsree S, Yoosook C, Herunsalee A, Panpisutchai Y (2000) Anti-herpes simplex virus component isolated from Maclura cochinchinensis. Phytomedicine 6:421
Okamoto T, Kanda T (1999) Glycyrrhizin protects mice from concanavalin A-induced hepatitis without affecting cytokine expression. Int J Mol Med 4:149–152
Shin MS, Kang EH, Lee YI (2005) A flavonoid from medicinal plants blocks hepatitis B virus-e antigen secretion in HBV-infected hepatocytes. Antiviral Res 67:163
Cai SQ, Wang R, Yang X, Shang M, Ma C, Shoyama Y (2006) Antiviral flavonoid-type C-glycosides from the flowers of Trollius chinensis. Chem Biodivers 3:343
Nagai T, Suzuki Y, Tomimori T, Yamada H (1995) Antiviral activity of plant flavonoid, 5, 7, 4′-trihydroxy-8-methoxyflavone, from roots of Scutellaria baicalensis against influenza A (H3N2) and B viruses. Biol Pharm Bull 18:95
Sidwell RW, Huffman JH, Moscon BJ, Warren RP (1994) In vitro and in vivo sensitivity of a non-mouse-adapted influenza A (Beijing) virus infection to amantadine and ribavirin. Chemotherapy 40:42
Quaglia MG, Desideri N, Bossu E, Sgro R, Conti C (1999) Enantioseparation and anti-rhinovirus activity of 3-benzylchroman-4-ones. Chirality 11(5–6):495–500
Douglas RM, Chalker EB, Treacy B (2000) Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2:CD000980
Melchart D, Linde K, Fischer P, Kaesmayr J (2000) Echinacea for preventing and treating the common cold [Review]. Cochrane Database Syst Rev (2):CD000530
Desideri N, Conti C, Mastromarino P, Mastropaolo F (2000) Synthesis and anti-rhinovirus activity of 2-styrylchromones. Antivir Chem Chemother 11:373
Weber ND, Andersen DO, North JA, Murray BK, Lawson LD, Hughes BG (1992) In vitro virucidal effects of Allium sativum (garlic) extract and compounds. Planta Med 58:417
Tait S, Salvati AL, Desideri N, Fiore L (2006) Antiviral activity of substituted homoisoflavonoids on enteroviruses. Antiviral Res 72:252
Singh S, Malik BK, Sharma DK (2007) Targeting HIV-1 through molecular modeling and docking studies of CXCR4: leads for therapeutic development. Chem Biol Drug Des 69:191
Amaral ACF, Kuster RM, Goncalves JLS, Wigg MD (1999) Phytochemical investigation of an antiviral fraction of Chamaesyce thymifolia. Fitoterapia 70:293
Desideri N, Oliveri S, Stein ML, Sgro R, Orsi N, Conti C (1997) Synthesis and anti-rhinovirus activity of 2-styrylchromones. Antivir Chem Chemother 8:545
Chiang LC, Chiang W, Liu MC, Lin CC (2003) In vitro antiviral activities of Caesalpinia pulcherrima and its related flavonoids. J Antimicrob Chemother 52:194
Moriarty RM, Naithani R, Hirtopeanu A, Gao K, Kazerani S, Badlani R, Staszewski JP, Zitzmann, N, Dwek, RA, Jacob, GS, Picker D, Mehta A, Block TM. N-Alkyl deoxynojirimycins as antiviral compounds. In: Abstracts of papers, 224th ACS National Meeting, Boston, MA, 18-22 August 2002
Mehta A, Ouzounov S, Jordan R, Simsek E, Lu X, Moriarty RM, Jacob G, Dwek RA, Block TM (2002) Imino sugars that are less toxic but more potent as antivirals, in vitro, compared with N-n-nonyl DNJ. Antivir Chem Chemother 13:299
De Almeida AP, Miranda MMFS, Simoni IC, Wigg MD, Lagrota MHC, Costa SS (1998) Flavonol monoglycosides isolated from the antiviral fractions of Persea americana (Lauraceae) leaf infusion. Phytotherapy Res 12:562
Li Y, Ooi LS, Wang H, But PP, Ooi VE (2004) Antiviral activities of medicinal herbs traditionally used in southern mainland China. Phytother Res 18:718–722
Lipipun V, Kurokawa M, Suttisri R, Taweechotipatr P, Pramyothin P, Hattori M, Shiraki K (2003) Efficacy of Thai medicinal plant extracts against herpes simplex virus type 1 infection in vitro and in vivo. Antiviral Res 60:175–180
Arthan D, Svasti J, Kitaakoop P, Pittayakhachonwut D, Toem M, Thebtaranonth Y (2002) Antiviral isoflavonoid sulfate and steroidal glycosides from the fruits of Solanum torvum. Phytochem 59:459–463
Aspers S, Baronikova S, Sindambiwe JB, Witvrouwm M, De Clercqm E, Vanden Berghe D, Van Maeck E (2001) Antiviral, haemolytic and molluscicidal activities of triterpenoid saponins from Maesa lanceolata: establishment of structure-activity relationships. Planta Med 67:521
Sydiskis RJ, Owen DG, Lohr JL, Rosler KH, Blomster N (1999) Inactivation of enveloped viruses by anthraquinones extracted from plants. Antimicrob Agents Chemother 35:2463–2666
Jassim SA, Naji MA (2003) Novel antiviral agents: A medicinal plant perspective. J Appl Microbiol 95:412–417
Garcia CC, Talarico L, Almeida N, Colombres S, Duschatzky C, Damonte EB (2003) Virucidal activity of essential oils from aromatic plants of San Luis, Argentina. Phytother Res 17:1073–1075
Alche LE, Berra A, Veloso MJ, Coto CE (2000) Treatment with meliacine, a plant derived antiviral, prevents the development of herpetic stromal keratitis in mice. J Med Virol 61:474–480
Baermejo P, Abad MJ, Diaz AM, Ferenandez L, Santos JD, Sachez S, Vallaescusa L, Carrasco L, Irurzun A (2002) Antiviral activity of seven iridoids, three saikosaponins and one phenylpropanoid glycoside extracted from Bupleurum rigidum and Scrophularia scorodonia. Planta Med 68:106–110
Primo V, Rovera M, Zanon S, Oliva M, Demo M, Daghero J, Sabini L (2001) Determination of the antibacterial and antiviral activity of the essential oil from Minthostachys verticillata (Griseb.). Rev Argent Microbiol 33:113–117
Khan MT, Ather A, Thompson KD, Gambari R (2005) Extracts and molecules from medicinal plants against herpes simplex viruses. Antiviral Res 67:107–119
Chattopadhyay D, Arunachalam G, Mandal AB, Bhattacharya SK (2006) Dose-dependent therapeutic antiinfectives from ethnomedicines of bay islands. Chemotherapy 52(3):151–157
Cheng HY, Lin CC, Lin TC (2002) Antiherpes simplex virus type 2 activity of casuarinin from the bark of Terminalia arjuna Linn. Antiviral Res 55:447–455
Allahveridev A, Duran N, Ozguven M, Koltas S (2004) Investigation of the anticancerogenic effect of the essential oil of Melissa officinalis L. Phytomedicine 11:657
Ojo OO, Oluyege JO, Famurewa O (2009) Antiviral properties of two Nigerian plants African. J Plant Sci 3(7):157–159
Chiang LC, Cheng HY, Liu MC, Chiang W, Lin CC (2003) In vitro anti-herpes simplex viruses and anti-adenoviruses activity of twelve traditionally used medicinal plants in Taiwan. Biol Pharm Bull 26:1600–1604
Choi HJ, Song HJ, Park KS, Kwon DH (2009) Inhibitory effects of quercetin 3-rhamnoside on influenza A virus replication. Eur J Pharm Sci 3–4:329–333
Kernan MT, Amarquaye A, Chen JL, Chan J, Sesin DF, Parkinson N, Ye Z, Barrett M (1998) Antiviral phenylpropanoid glycosides from the medicinal plant Markhamia lutea. J Nat Prod 61:564–570
Wei F, Ma SC, Ma LY, But PP, Lin RC, Khan IA (2004) Antiviral flavonoids from the seeds of Aesculus chinensis. J Nat Prod 67:650–653
Rajbhandari M, Wegner U, Schopke T, Lindequist U, Mentel R (2003) Inhibitory effect of Bergenia ligulata on influenza virus. Pharmazie 58:268–271
Sokmen M, Angeova M, Krumova E, Peshova S, Ivancheva S, Sokmen A, Serkedijieva J (2005) In vitro antioxidant activity of polyphenol extracts with antiviral properties from Geranium sanguineum. Life Sci 76:2981–2993
Olila D, Olwa-Odyejk A, Opudo A (2002) Screening extracts of Zanthoxylum chalybeum and Warburgia ugandensis for activity against measles virus (Swartz and Edmonston strains) in vitro. J Afr Health Sci 2:2–10
Thyagarajan SP, Subramanian S, Thirunalasundari TN, Venkateswaran PS, Blumberg BS (1998) Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 2(8614):764–766
Thyagarajan SP, Jayaram S, Valiammai TT (1990) Phyllanthus amarus and hepatitis B. Lancet 336:949–950
Liu J, Zhu M, Shi R, Yang M (2003) Radix Sophorae flavescentis for chronic hepatitis B: a systematic review of randomized trials. Am J Chin Med 31:337–354
Ho TY, Wu SL, Lai IL, Cheng KS, Kao ST, Hsiang CY (2003) An in vitro system combined with an in-house quantitation assay for screening hepatitis C virus inhibitors. Antiviral Res 58:199
Sekine-Osajima Y, Sakamoto N, Nakagawa M, Itsui Y, Tasaka M, Nishimura-Sakurai Y, Chen CH, Suda G, Mishima K, Onuki Y, Yamamoto M, Maekawa S, Enomoto N, Kanai T, Tsuchiya K, Watanabe M (2009) Two flavonoids extracts from Glycyrrhizae radix inhibit in vitro hepatitis C virus replication. Hepatol Res 39(1):60–69
Esimone CO, Grunwald T, Nworu CS, Kuate S, Proksch P, Uberla K, Uberla K (2009) Broad spectrum antiviral fractions from the lichen Ramalina farinacea (L.) Ach. Chemotherapy 55:119–126
Manfredi KP, Vallurupalli V, Demidova M, Kindscher K, Pannell LK (2001) Isolation of anti-HIV diprenylated bibenzyl from Glycyrrhiza lepidota. Phytochemistry 58:153–157
Wu JH, Wang XH, Yi YH, Lee KH (2003) A potent anti-HIV chalcone and flavonoids from genus Desmos. Bioorg Med Chem Lett 13:1813–1815
Chang YS (2003) Woo ER (2003) Korean medicinal plants inhibiting to human immunodeficiency virus type 1 (HIV-1) fusion. Phytother Res 17:426–429
Balzarini JC, Daelemans BD, Meertens M, Cornier EG, Reinus JF, Peumans WJ, Van Damme EJM, Oki YIT, Schols D, Dragic T (2007) Carbohydrate-binding agents (CBAs) selectively target the glycoproteins of the HCV and HIV envelope to prevent viral entry. Antiviral Res 74:A43
Yogeeswari P, Sriram D (2005) Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem 12:657–666
Jay J, Lai B, Kiser P (2009) Multivalent synthetic lectin polymers against HIV. Antiviral Res 82:A63–A64
Gosse B, Gnabre J, Bates RB, Dicus CW, Nakkiew P, Huangg RC (2002) Antiviral saponins from Tieghemella heckelii. J Nat Prod 65:1942–1944
Ma CM, Nakamura N, Miyashiro H, Hattori M, Komatsu K, Kawahata T, Otake T (2002) Screening of Chinese and Mongolian herbal drugs for anti-human immunodeficiency virus type 1 (HIV-1) activity. Phytother Res 16:186–189
Shikishima Y, Takaishi Y, Honda G, Ito M, Takfda Y, Kodzhimatov OK, Ashurmetov O, Lee KH (2001) Chemical constituents of Prangos tschimganica; structure elucidation and absolute configuration of coumarin and furanocoumarin derivatives with anti-HIV activity. Chem Pharm Bull 49:877–880
Zhang HJ, Tan GT, Honag VD, Hung NV, Cuong NM, Soejarto DD, Pezzuto JM, Fong HH (2003) Natural anti-HIV agents. Part IV. Anti-HIV constituents from Vatica cinerea. J Nat Prod 65:1942–1944
Szlavik L, Gyuris A, Minarotvis J, Forgo P, Molnar J, Hohmann J (2004) Alkaloids from Leucojum vernum and antiretroviral activity of Amaryllidaceae alkaloids. J Planta Med 70:71–873
Ye XY, Ng TB (2001) Peptides from pinto bean and red bean with sequence homology to cowpea 10-kDa protein precursor exhibit antifungal, mitogenic, and HIV-1 reverse transcriptase-inhibitory activities. Biochem Biophys Res Commun 285:424–429
Min BS, Tomiyamam CM, Nakamura N, Hattori M (2001) Kaempferol acetylrhamnosides from the rhizome of Dryopteris crassirhizoma and their inhibitory effects on three different activities of human immunodeficiency Virus-I reverse transcriptase. Chem Pharm Bull 49:546–550
Jiratchariyakul W, Wiwat C, Vonsakul M, Somanabandhu A, Leelamanit W, Fujii I, Suwannoroj N, Ebizuka W (2001) HIV inhibitor from Thai bitter gourd. Planta Med 67:350–353
Notka F, Meier GR, Wagner R (2003) Immunodeficiency virus and reverse transcriptase inhibitor-resistant variants by Phyllanthus amarus. Antiviral Res 58:175–186
Park JC, Hur JM, Park JG, Hatano T, Yoshida T, Miyashiro H, Min BS, Hattori M (2002) Inhibitory effects of Korean medicinal plants and camelliatannin H from Camellia japonica on human immunodeficiency virus type 1. Phytother Res 16:422–426
Liu S, Jiang S, Wu Z, Lv L, Zhabg J, Zhu Z, Wu S (2002) Identification of an inhibitor of the HIV-1 gp41 six-helix bundle formation from extracts of Chinese medical herbs Prunella vulgaris and Rhizoma Cibotte. Life Sci 71:1779–1791
Choi KC, Jung MG, Lee YH, Yoon JC, Kwon SH, Kang HB, Kim MJ, Cha JH, Kim YJ, Jun WJ, Lee JM, Yoon HG (2009) Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. Cancer Res 69(2):583–592
Andres A, Donovan SM, Kuhlenschmidt MS (2009) Isoflavones and viral infections. J Nutr Biochem 20:563–569
Robin V, Irurzun A, Amoros M, Boustie J, Carrasco L (2001) Antipoliovirus flavonoids from Psiadia dentata. Antivir Chem Chemother 12:283–291
Hegde VH, Pu H, Patel M, Das PR, Butkiewicz N, Arreaza G, Gullo VP, Chan TM (2003) Two antiviral compounds from the plant Stylogne cauliflora as inhibitors of HCV NS3 protease. Bioorg Med Chem Lett 13:2925
Clark KJ, Grnat PG, Sarr AB, Belakere JR, Swaggerty CL, Phillips TD, Woode GN (1998) An in vitro study of theaflavins extracted from black tea to neutralize bovine rotavirus and bovine coronavirus infections. Vet Microbiol 63:147–157
Turan K, Nagata K, Kuru A (1996) Antiviral effect of Sanicula europaea L. leaves extract on influenza virus-infected cells. Biochem Biophys Res Commun 225:22–26
Docherty JJ, Sweet TJ, Bailey E, Faith SA, Booth T (2006) Resveratrol inhibition of Varicella-Zoster Virus replication in vitro. Antiviral Res 72:171
Li BQ, Fu T, Gong WH, Dunlop N, Kung HF, Yan Y, Kang J, Wang JM (2000) The flavonoid baicalin exhibits anti-inflammatory activity by binding to chemokines. Immunopharmacology 49:295
Mitrocosta D, Mitaku S, Axarlis S, Harvala C, Malamas M (2000) Evaluation of the antiviral activity of kaempferol and its glycosides against human cytomegalovirus. Planta Med 66:377
Gerencer M, Turecek PL, Kistner O, Mitterer A, Savidis-Dacho H, Barrett NP (2006) In vitro and in vivo anti-retroviral activity of the substance purified from the aqueous extract of Chelidonium majus L. Antiviral Res 72:153
Rusak G, Krajacic M, Plese N (1997) Inhibition of tomato bushy stunt virus infection using a quercetagetin flavonoid isolated from Centaurea rupestris L. Antiviral Res 36:125
Sanchez I, Gomez-Garibay F, Taboada J, Ruiz BH (2000) Antiviral effect of flavonoids on the Dengue virus. Phytother Res 14:89
Kiat TS, Pippen R, Yusof R, Ibrahim H, Khalid N, Rahman NA (2006) Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, Boesenbergia rotunda (L.), towards dengue-2 virus NS3 protease. Bioorg Med Chem Lett 16:3337
Bae EA, Han MJ, Lee M, Kim DH (2000) In vitro inhibitory effect of some flavonoids on rotavirus infectivity. Biol Pharm Bull 23:1122
Thamlikitkul V, Wasuwat S, Kanchanapee P (1991) Efficacy of Phyllanthus amarus for eradication of hepatitis B virus in chronic carriers. J Med Assoc Thai 74:381
Berk L, de Man RA, Schalm SW, Labadie RP, Heijtink RA (1991) Beneficial effects of Phyllanthus amarus for chronic hepatitis B, not confirmed. J Hepatol 12:405
Zhang JL, He WN, Ye P (1992) Clinical observation on Phyllanthus amarus for treating chronic hepatitis B virus infection 1992. Chin J Integr Tradit West Med Liver Dis 2:8
Milne A, Hopkirk N, Lucas CR, Waldon J, Foo Y (1994) A two-stage clinical trial of Phyllanthus amarus in hepatitis B carriers: failure to eradicate the surface antigen. N Z Med J 107:253
The University of Hong Kong Trial of Chinese Herbal Medicine in the Treatment of Upper Respiratory Tract Infections (URTIs) The Research Fund for the Control of Infectious Diseases of the Food and Health Bureau, the Government of the Hong Kong SAR 2009
Huang ZR, Zhong JP, Zhu GL, Chen YR, Wang GQ (1993) Therapeutic observation on Phyllanthus amarus for hepatitis B. Chin J Clin Hepatol 9:108
Zhu FM, Zhang JQ, Zhang XZ, Zhang XM (1992) Observation on the effect of Fujian’s Phyllanthus amarus in treatment of HBV infection. Chin J Integr Tradit West Med Liver Dis 2:10
Cao WZ, Liu JQ, Cao DY, Su F, Xu SG (1998) Clinical study on anti-HBV activity of Phyllanthus herb from Anhui, China. China J Chin Mater Med 23:180
Wang M, Cheng H, Li Y, Meng L, Zhao G, Mai K (1995) Herbs of the genus Phyllanthus in the treatment of chronic hepatitis B: observations with three preparations from different geographic sites. J Lab Clin Med 126:350
Su X, Chen H, Wang L, Jiang C, Liu J, Zhao M, Ma X, Zhao Y, Han D (1984) The protective effects of Glycyrrhiza glabra against Hepatitis. J Tradit Chin Med 4:127
Iino S, Tango T, Matsushima T, Toda G, Miyake K, Hino K, Kumada H, Yasuda K, Kuroki T, Hirayama C, Suzuki H (2001) Amino acid substitutions in S region of hepatitis B virus in the sera from patients with acute hepatitis. Hepatol Res 19:31
Doshi JC, Vaidya AB, Antarkar DS, Deolalikar R, Antani DH (1994) A two-stage clinical trial of Phyllanthus amarus on hepatitis B carriers: failure to eradicate the surface antigen. Indian J Gastroenterol 13:7
Tusenius KJ, Spoek JM, Kramers CW (2001) Iscador Qu for chronic hepatitis C: an exploratory study. Complement Ther Med 9:12
van Rossum TGJ, Vulto AG, Hop WCJ, Brouwer JT, Niesters HGM, Schalm SW (1999) Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double blind randomized placebo-controlled phase I/II trial. J Gastroenterol Hepatol 14:1093
Tsubota A, Kumada H, Arase Y, Chayama K, Saitoh S, Ikeda K, Kobayashi M, Suzuki Y, Murashima N (2002) Combined ursodeoxycholic acid and glycyrrhizin therapy forchronic hepatitis infection: a randomized control trial in 170 patients. Eur J Gastroenterol Hepatol 11:1077
van Rossum TGJ, Vulto AG, Hop WCJ, Schalm SW (2001) Glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis. Am J Gastroenterol 96:2432
Mehrotra R, Rawat S, Kulshreshtha DK (1990) In vitro studies on the effect of certain natural products against hepatitis B virus. Indian J Med Res 92:133
Stauder G, Kabil S (1997) Oral enzyme therapy in hepatitis C patients. J Immunother 13:153
Suzuki H, Ohta Y, Tekino T, Fujisawa K, Hirayama C (1983) Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitis-double blind trial. Asian Med J 26:423
Miyake K, Tango T, Ota Y, Mitamura K, Yoshiba M, Kako M, Hayashi S, Ikeda Y, Hayashida N, Iwabuchi S, Sato Y, Tomi T, Funaki N, Hashimoto N, Umeda T, Miyazaki J, Tanaka K, Endo Y, Suzuki H (2002) Efficacy of Stronger Neo-Minophagen C compared between two doses administered three times a week on patients with chronic viral hepatitis. J Gastroenterol Hepatol 17:1198
Vailaii A, Arista I, Sozze E (1993) Randomized open study of the dose-effect relationship of a short course of IdB1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64:219
Narendranathan M, Remla A, Mini PC, Satheesh P (1999) A trial of Phyllanthus amarus in acute viral hepatitis. Trop Gastroenterol 20:164
Parés A, Planas R, Torres M, Caballería J, Viver JM, Acero D, Panés J, Rigau J, Santos J, Rodés J (1998) Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 28:731
Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, Base W, Schneider B (1989) Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 9:105
Thom E, Zakay-Rones Z, Wollan T Wadstein J (2002) Randomised study on the efficacy and safety of an oral elderberry extract in the treatment of influenza A and B virus infection. In Proceedings of the 15th international conference on antiviral research, Prague, Czech Republic, March 2002.
Zakay-Rones Z, Varsano N, Zlotnik M, Manor O, Regev L, Schlesinger M, Mumcuoglu M (1995) Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L) during an outbreak of influenza B Panama. J Altern Complement Med 1:361
Melchoir J, Palm S, Wikman G (1996) Controlled clinical study of standardized Andrographis paniculata extract (Kan-Jang tablet) in common cold a pilot trial. Phytomedicine 3:315
Caceres DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK (1999) Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardised Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind placebo study. Phytomedicine 6:217
Hancke J, Burgos R, Caceres D, Wikman G (1995) A double-blind study with a new monodrug Kan Jang: decrease of symptoms and improvement in the recovery from common colds. Phytother Res 9:559
Josling P (2001) Preventing the common cold with a garlic supplement: a double-blind placebo-controlled survey. Adv Ther 18:189
Phillpotts RJ, Wallace J, Tyrrell DA, Freestone DS, Shepherd WM (1983) Failure of oral 4′, 6-dichloroflavan to protect against rhinovirus infection in man. Arch Virol 75:115
Tanamly MD, Tadros F, Labeeb S (2004) Randomised double-blinded trial evaluating silymarin for chronic hepatitis C in an Egyptian village: study description and 12-month results. Dig Liver Dis 36:752
Gordon A, Hobbs DA, Bowden DS (2006) Effects of Silybum marianum on serum hepatitis C virus RNA alanine aminotransferase levels and well-being in patients with chronic hepatitis C. J Gastroenterol Hepatol 21:275
Melhem A, Stern M, Shibolet O, Israeli E, Ackerman Z, Pappo O, Hemed N, Rowe M, Ohana H, Zabrecky G, Cohen R, Ilan Y (2005) Treatment of chronic hepatitis C virus infection via antioxidants: results of a phase I clinical trial. J Clin Gastroenterol 39:737
Strickland GT, Tanamly MD, Tadros F (2005) Two-year results of a randomised double-blinded trial evaluating silymarin for chronic hepatitis C. Dig Liver Dis 37:542
El-Zayadi AR, Attia M, Badran HM (2005) Non-interferon-based therapy: an option for amelioration of necro-inflammation in hepatitis C patients who cannot afford interferon therapy. Liver Int 25:746
Koytchev R, Alken RG, Dundarov S (1999) Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis. Phytomedicine 6:225
Wobling RH, Leonhardt K (1994) Local therapy of herpes simplex with dried extract from Melissa officinalis. Phytomedicine 1:25
Syed TA, Cheema KM, Ashfaq AS, Holt AH Jr (1996) Aloe vera extracts 0.5% in a hydrophilic cream versus Aloe vera gel for the management of genital herpes in males. A placebo-controlled, double-blind, comparative study. J Eur Acad Dermatol Venereol 7:294
Syed TA, Afzal M, Ashfaq AS, Holt AH, Ali AS, Ahmad SH (1997) Management of genital herpes in men with 0.5% Aloe vera extract in a hydrophilic cream: a placebo-controlled double-blind study. J Dermatol Treat 8:99
Jayavasu C, Balachandra K, Sangkitporn S, Maharungraungrat A, Thavatsupa P, Bunjob M, Chavalittumrong P, Dechatiwongse N, Ayudhaya T, Sittisomwong N (1992) Clinical trial in the treatment of genital herpes patients. Commun Dis J 18:152
Carson CF, Ashton L, Dry L, Smith DW, Riley TV (2001) Melaleuca alternifolia (tea tree) oil gel (6%) for the treatment of recurrent herpes labialis. J Antimicrob Chemother 48:450
Saller R, Buechi S, Meyrat R, Schmidhauser C (2001) Combined herbal preparation for topical treatment of Herpes labialis. Forsch Komplementarmed Klass Naturheilkd 8:373
Sangkitporn S, Chaiwat S, Balachandra K, Na-Ayudhaya TD, Bunjob M, Jayavasu C (1995) Treatment of herpes zoster with Clinacanthus nutans (bi phaya yaw) extract. J Med Assoc Thai 178:624
Charuwichitratana S, Wongrattanapasson N, Timpatanapong P, Bunjob M (1996) Herpes zoster: treatment with Clinacanthus nutans cream. Int J Dermatol 35:665
Calabrese C, Berman SH, Babish JG, Ma X, Shinto L, Dorr M, Wells K, Wenner CA, Standish LJ (2000) A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytother Res 14:333
Durant J, Chantre G, Gonzalez G, Vandermander J, Halfon P, Rousse B, Guedon D, Rahelinirina V, Chamaret S, Montagnier L, Dellamonica P (1998) Efficacy and safety of Buxus sempervirens L. Preparation ( SPV-30) in HIV infected asymptomatic patients randomized, double-blind, placebo-controlled trial. Phytomedicine 5:1
Gotoh Y, Tada K, Yamada K, Minamitani M, Negishi M, Fujimaki M, Ikematsu S, Hada M, Mori K, Ito M, Shigeta S, Nakashima H, Yamamoto N, Shiokawa Y (1987) Administration of glycyrrhizin to patients with human immunodeficiency virus infection. Igaku no Ayumi 140:619
Gaspar-Marques C, Simões MF, Valdeira ML, Rodríguez B (2008) Terpenoids and phenolics from Plectranthus strigosus, bioactivity screening. Nat Prod Res 22(2):167–177
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Naithani, R., Mehta, R.G., Shukla, D., Chandersekera, S.N., Moriarty, R.M. (2010). Antiviral Activity of Phytochemicals: A Current Perspective. In: Watson, R., Zibadi, S., Preedy, V. (eds) Dietary Components and Immune Function. Nutrition and Health. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-061-8_24
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