[Studies in Natural Products Chemistry] Volume 42 || Natural Antiviral Compounds

Chapter 7

Natural Antiviral Compounds

A.E.D. Bekhit* and A.A. Bekhit{*Department of Food Science, University of Otago, Dunedin, New Zealand{Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University,

Alexandria, Egypt

Chapter OutlineIntroduction 195

Virus 198

Classes of Natural Antiviral

Compounds 199

Considerations for Antiviral

Activity of Compounds from

Natural Sources 217

Concluding Remarks 220

References 223

INTRODUCTION

Human relied on plants as medicine for centuries and their use for treatment

of ailments and diseases is practiced in many parts of the world despite the

widespread practice of modern medicine and the use of synthetic drugs world-

wide. Apart from their use in traditional medicine in many Asian, South

American, and African countries with an estimated 80% of the world’s popu-

lation using traditional medicine, plants contribute to about 25% of the pre-

scribed drugs worldwide [1]. Many natural products are used as adjuvant/

prophylactic or for therapeutic purposes. Several important synthetic drugs

have been isolated initially from plants (Table 1) and several other biologi-

cally active compounds are still obtained from cultivated or wild plants due

to limitations in synthesis techniques or economic viability [2].

The use of bioactive compounds from plants is attractive to many develop-

ing countries since the production cost is low compared to chemically synthe-

sized drugs rendering treatment to be affordable and accessible to all people.

Furthermore, the long history of medicinal plants in many societies has led to

improved understanding of the functions of certain plants and created a trust

and acceptability to herbal medicine. This knowledge is often treated as “heal-

ing art” and is often passed from one generation to another. The use of scien-

tific convention and systematic investigations to support the use of medicinal

Studies in Natural Products Chemistry, Vol. 42. http://dx.doi.org/10.1016/B978-0-444-63281-4.00007-0

© 2014 Elsevier B.V. All rights reserved. 195

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TABLE 1 Examples of Common Drugs Originated from Plants

Drug (Trade Name) Plant Use Structure

Digoxin (Lanoxin) Digitalis spp. (e.g.,Digitalis lanata)

Heart conditions

OH

OH

O

H

O

O

O

O

OO

O

HHHO

HHOHO

HO

Quinine Cinchona spp. (e.g.,Cinchona officinalis)

Antipyretic

N

OH

NOCH3

Antimalarial

Quinidine Analgesic

Anti-inflammatory

Vincristine Catharanthus roseus Cancerchemotherapy

N

N

O

OHH O

O

O

H

OO

NH

N

H

OH

OO

Vinblastine

TABLE 1 Examples of Common Drugs Originated from Plants—Cont’d

Drug (Trade Name) Plant Use Structure

Atropine Solanaceae (Atropabelladonna)

Anticholinergic

HO

HOO

NH3C

Lowers theparasympatheticactivity

Morphine Papaver somniferum Potent opiateanalgesic drug

O H

H

HO

N

HO

CH3

Codeine

Paclitaxel (taxol) Taxus brevifolia Anticancer agent

OHO

O

O

O

HOH

O O

O O

O

NHO O

OH

Salicin (aspirin) Salix alba Analgesic

O

OH

O

O

Antipyretic

Anti-inflammatory

plants or to screen new plants has attracted much research over the past five

decades. The antiviral activity of plant extracts has been a very active research

area. A database search for antiviral and extract as keywords, excluding books

and references, retrieved 14,930 titles (Fig. 1). Exponential increase in the

number of investigations on antiviral activity of extracts from natural sources

in the period between 1994 and 2012 reflects the scientific community vision

for prospecting natural materials for antiviral compounds and supports the

potential benefits of using natural resources for that purpose.

VIRUS

The word virus originated from Latin which means poison or toxic. A virus is

a small infectious agent which can trigger an immune response which can

control the virus in some instances (e.g., common flu) but can lead to lethal

and pathological effects in many other cases (hepatitis and human immunode-

ficiency viruses), especially in individuals with compromised immune system.

Unlike bacterial, fungal, and parasitic organisms causing infection, virus is

not an autonomous organism and can only replicate inside the host cell envi-

ronment of another organism [3] and therefore they are obligate intracellular

pathogens.

There are millions of different types of viruses found in almost every eco-

system on earth. In fact, viruses are the most abundant type of biological enti-

ties [4–6]. They contain little more than bundles of gene strands of either

RNA or DNA and may be enclosed by a lipid-containing envelope [3].

Viruses have several invasion strategies. Each strain of virus has its own

unique configuration of surface molecules that precisely fit the membranes

0

200

400

600

800

1000

1200

1400

1600

1800

2000

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

Num

ber

of p

ublic

atio

ns

Year

FIGURE 1 Number of publications between 1994 and 2012 for antiviral and extract as key-

words. The search was performed using Science Direct database on the November 15, 2012.

Studies in Natural Products Chemistry198

of target cells, which enable the entry of viruses into hosts [3]. These general

attributes lead to the success of viruses in evolution, genetic variation, variety

in means of transmission, efficient replication within host cells, and the ability

to persist in the host [4,5].

Viruses cause a range of structural and biochemical effects (cytopathic

effects) on the host cells. Most virus infections cause alterations to cell sur-

face membranes, cell lysis, and apoptosis (death to the host cell), though some

viruses result in no apparent changes to the infected cells [7]. Hundreds of

human-infecting viruses have been clinically investigated, but the majority

of natural antiviral extracts were tested against human immunodeficiency

virus (HIV), herpes simplex viruses (HSV), rhinoviruses, enteroviruses, hepa-

titis (Hep), and influenza viruses.

Classes of Natural Antiviral Compounds

Many crude and purified compounds have been reported to have antiviral

activity. The various classes of the majority of these compounds will be dis-

cussed below. It is worth noting that while the majority of these compounds

were examined using cell lines (i.e., in vitro), the beneficial effects reported

for these compounds should be used as indicator of the antiviral potential of

the examined compounds given that under metabolic in situ processes the

compounds may become inactive or higher concentrations will be required

for effective use in animal models which can be in some cases higher than

the toxic levels of compounds.

Photosensitizers

These are compounds which are expressed by plants and exhibit biological

activity under specific light wavelengths (Fig. 2). Based on their chemical

structure, the compounds can be alkaloids, furyl compounds or thiophenes,

and polyacetylenes, with the latter being the most potent against enveloped

viruses [7]. Photosensitizers are expressed in significant amounts (up to 1%

of the fresh weight) in plants belonging to Compositae (Asteraceae), Umbel-

liferae (Apiaceae), and Campanulaceae families. The compounds are also

found in several other organisms from marine ecosystems (e.g., algae, nudi-

branchs, sea hares, and sponges) as well as in fungi and insects [12]. These

compounds, as with most secondary metabolites, are suspected to be formed

as a defense mechanism against pests and are found in all plant parts. Several

reports documented the antiviral activity of plant photosensitizers, especially

thiophenes and polyacetylenes, which are activated by UV light [7,12] with

maximum activity observed at about 350–360 nm [7].

Several alkaloids (Fig. 2A) exhibit antiviral activity and some have been

shown to be active upon exposure to long-wave ultraviolet (UVA,

300–400 nm). Several alkaloids such as b-carbolines (Rutaceae), atropine

Chapter 7 Natural Antiviral Compounds 199

NH

N

NH3C

CH3

Brevicollin

N

N

O

6- Canthione

NH

N

CH3

H3CO

Harmine

NH

N

CH3

Harmane

NH

N

CH3

HO

Harmol

NH

N

CH3

HO

Harmalol

NH

N

CH3

H3CO

Harmaline

NH

NH

COOH

Harmane-1,2,3,4-tetra-hydro-3-carboxylic acid

Alkaloids (A)

O

O

OO

HNO

O

Colchicine

N

N

O

OH

O

O

O

O

HN

N

H

O

O

OH

H

Vinblastine

FIGURE 2—CONT’D


Furyl compounds (B)

OO O

OCH3

8-Methoxypsoralen

OO

OCH3

O

Visnagin

O OO

Angelicin

OO

OCH3

OOCH3

Khellin

N O

OCH3

Dictamnine

Thiophenes and polyacetylenes (C)

S S S

A-TerthienylS S

C C C C CH

CH2CCH3C

Thiarubrine-A

ACBP-Thiophene

C C C C CH

CH2CCH3CS

Thiophene-A

2,5-Bis(2-thienylethynyl)thiophene

C C C C C C CH3

Phenylheptatriyne

3(1-Phenylethyneyl)-2,2 bithiophene

CC

CH

H2C

OCC

CS

CH3C Cl

CH3C

O

SC C

SC C

S

S SC C

FIGURE 2—CONT’D


Hypericin and its dervatives (D)OH

HO

OH

CH3

O

OH

HO

OH

CH3

O

Hypericin

OH

O

OCH3OH

O

OH

O

OCH3

OH

O

Cercosporin

OHOCH3

O

O

OH

OHOCH3

O

O

OH

Isocercosporin

OCH3

OH

H3CO

O

OCH3

OH

H3CO

O

OH

CH3

COCH3

Hypocrellin A

OCH3

OH

H3CO

O

OCH3

OH

H3CO

O

COCH3

CH3

Hypocrellin B

OHOCH3

OH

H3CO

O

OHOCH3

OH

H3CO

O

Phleichrome

OH

O

O

OH

O

O

O

O

OH

PhS

O

OCH3OH

O

OH

PhS

O

OCH3

OH

O

OH

H3CO

OCH3OCOPh

O

OH

H3CO

OCH3

OCO2(o-OH-Ph)

O

Calphostin C

OCH3

H3CO

OCH3

CO2Me

O

OCH3

H3CO

OCH3

CO2Me

O

FIGURE 2 Structure of well-known photosensitizers reported to have antiviral activity [7–11].


(Atropa belladonna), camptothecin (Camptotheca acuminate), castanosper-mine (Castanospermum australe), colchicines (Colchicum autumnale), indoli-zidines swainsonine (Swainsona canescens), and vinblastine (Catharanthusroseus) were found to have antiviral activity [13]. Several natural alkaloids

(yohimbine, vincamine, scopolamine, atropine, colchicine, allantoin, trigonel-

line, octopamine, synephrine, and capsaicin) were recently evaluated for their

anti-HSV-1 and anti-RNA virus parainfluenza (type-3) [14]. High inhibitory

effect against HSV-1 was reported with cytopathogenic effect is in the con-

centration range of 0.05–0.8 mg/mL. On the other hand, only atropine and

octopamine demonstrated an inhibitory effect against parainfluenza (type-3)

with a cytopathogenic effect at concentration of 0.05 mg/mL for both com-

pounds. This selective activity against viruses was previously reported for

some isoquinoline alkaloids (protopine, fumarophycine, chelidimerine, ophio-

carpine, and (þ)-bulbocapnine) which were potent inhibitors of parainfluenza

(type-3) while they had negligible effects on HSV-1 [15]. Harmine (Peganumharmala) and some harmine b-carbolines compounds are available in many

plants, marine, and mammalian cells. These compounds demonstrated broad

virucidal activity which requires UVA activation. Castanospermine is effec-

tive against viruses with membranes and target glycoprotein maturation step

in the virus development cycle. Thalimonine and indole alkaloid from Thalic-trum simplex L. and Uncaria rhynchophylla, respectively, demonstrated

potent anti-influenza A activity [16,17]. Several mechanisms have been sug-

gested for their biological activities, such as interaction with nucleic acid

and targeting macromolecules.

Furyl compounds (Fig. 2B) after exposure to long-wave ultraviolet (UVA,

300–400 nm) exhibit broad efficacy against viruses [7]. Several reports on the

antiviral activity of furocoumarins (psoralens) and furanochromones (visna-

gin) from Rutaceae and Umbelliferae (Apiaceae) are available [13]. The com-

pounds require UVA for their activity and appear to inhibit virus replication

by disrupting viral gene target expression by forming photo-adduct with the

virus DNA.

Thiophenes and polyacetylenes (Fig. 2C) compounds occur as polyines,

allenes, phenyl and thiophenyl derivatives, thioethers, and spiroketal enol

ethers in Asteraceae, Apiaceae, Campanulaceae Panax ginseng (Korean gin-

seng roots), Bidens sp., and Chrysanthemum sibiricum. The mechanism of

action of thiophenes and polyacetylenes against viruses is thought to be

mediated by membrane damage caused by singlet oxygen attack which is

released upon exposure to light [7,8], but other mechanisms may be possible

since the compounds show strong activity against virus with no membranes

[7]. The virus integrity is not compromised by the damage caused to its mem-

brane and remains able to occupy cells but lose its capability to replicate [7].

The presence of thiophene rings and the acetylenic substituent is important for

the antiviral activity. The activity was not affected by the presence of halide

groups but it was decreased by the presence of phenyl groups.


Hypericin (Fig. 2D) is another photosensitizer commonly found in plants

belonging to the genus Hypericurn. Upon exposure to visible light, hypericin

produces singlet oxygen [9], which is suggested as the main mechanism for

the antiviral effects of the compound. A series of related compounds

(Fig. 2D) showed that the antiviral activity against Sindbis virus was linked

to the ability to generate singlet oxygen in some compounds. However, some

compounds (1, 2, and 6) which have high singlet oxygen generation capability

did not possess antiviral activity and vice versa, suggesting the involvement of

other mechanisms in the inhibition of virus.

Photosensitizers exhibit different antiviral activities against different

viruses [7–9]. Therefore, it is recommended to screen the potential of antiviral

activity of extracted compounds against wide range of viruses.

Phenolics

Polyphenol compounds, such as epigallocatechin gallate (ECGC), epicatechin

gallate (ECG), epigallocatechin (EGC), and theaflavin digallate, are widely

found in plants. Polyphenol from tea, grape products, berries, and other plant

sources exhibits several mechanisms which promote the prevention of the

virus infectivity, such as by binding to the hemagglutinin of influenza

virus [18] or by altering the physical properties of the viral membrane [19].

Viral inactivation in vitro is attributed to preferential binding of phenolics

to the protein coat of the virus thus arresting virus binding [20,21]. However,

the antiviral activity of polyphenol involves direct inactivation of the virus

and/or inhibition of the virus binding to the cells [22]. Several investigations

have drawn attention to possible antiviral activity attributable to other pheno-

lic compounds, such as proanthocyanidins, which are the oligomer or polymer

form of flavan-3-ol units, and resveratrol. Proanthocyanins (PACs) have been

shown to exhibit antiviral activity against poliomyelitis virus [23]. Three PAC

compounds existing in dimer, trimer, and tetramer form showed pronounced

antiviral properties against herpes simplex and coxsackieviruses [24,25]. Sev-

eral potential mechanisms have been reported for the antiviral activity of

PACs. For instance, PACs have been shown to inhibit enzymes involved in

the replication of rhinovirus and HIV virus [26]. Furthermore, PCAs A-1 pur-

ified from Vaccinium vitis-idaea had the ability to suppress HSV-2 infection

through the inhibition of viral attachment and penetration [27]. Several other

phenolics such as anthraquinone chrysophanic acid, caffeic acid, ellagitannin,

hypericin, tannins (condensed polymers); salicylates; and quinines (naphtho-

quinones, naphthoquinones and anthraquinones, in particular, aloe emodin)

have been reported to disrupt the synthesis of viral DNA [13]. Gallic acid,

chlorogenic acid, and quinic acid demonstrated good anti-HSV-1 and parain-

fluenza (type-3) inhibitory activity with cytopathogenic effect in the concen-

tration range of 0.05–0.4 mg/mL [14]. A selective effect was found for

caffeic acid which was effective against HSV-1 virus but had no effect on


parainfluenza (type-3). Grape extracts (skin and whole blue grapes), grape

juice, and wine were reported to inactivate various enteric viruses and HSV

type 1 [23]. More recently, wine residues were reported to have antiadenoviral

activity [28] and anti-influenza activity [29]. Pinot noir extracts exhibited pro-

tective effects of �50% against influenza A virus at concentrations

>1 mg/mL compared to virus alone. Pinot meunier pomace extracts had pro-

tective effects at concentration of 1 mg/mL, whereas both seed and skin

extracts were effective at 10 mg/mL.

Aqueous phenolic extracts from the Chinese plants Agrimonia pilosa, Pithe-cellobium clypearia, and Punica granatum showed anti-HSV-1 activity with

EC50 value ranging from 83.3 to 250 mg/mL, and selective indices (SI) ranging

from 3 to 12. In the same study, extracts from Blumea laciniata, Elephantopusscaber, Laggera pterodonta,Mussaenda pubescens, Schefflera octophylla, andScutellaria indica exhibited antihuman respiratory syncytial virus activity with

EC50 value ranging from 12.5 to 32 mg/mL and SI ranging from 11.2 to 40 [30].

The anti-HSV-1 activity (EC50) of A. pilosa aqueous extracts against standard,

acyclovir-resistant, and clinical strain was 125, 100, and 125 mg/mL, respec-

tively. Similarly, the EC50 of extracts from P. clypearia and P. granatumagainst the three strains varied (62.5, 125, and 100 mg/mL for P. clypeariaextract and 83.3, 62.5, and 50 mg/mL for P. granatum extract). This indicates

the need to examine the extracts on other strains in addition to standard virus

strains, especially those of clinical importance.

Resveratrol has been found to affect influenza virus replication both

in vitro and in vivo by several modes of action as follows: (1) by blockade

of the nuclear-cytoplasmic translocation of the viral ribonucleoprotein com-

plex, (2) by reducing the expression of late viral proteins, and (3) by the inhi-

bition of protein kinase C (PKC) activity and PKC-dependent pathways [31].

Resveratrol is able to inhibit the replication of HSV types-1 and -2 in a dose-

dependent and reversible manner [32]. Resveratrol also synergistically

enhances the anti-HIV activity of a number of nucleoside analogues for com-

bating infection in peripheral white blood cells [33]. In contrast to these

reports, Nakamura et al. [34] found resveratrol to increase the RNA replica-

tion in HepCV and the authors recommended that HepCV patients should

avoid supplements containing resveratrol. Resveratrol had anti-influenza

activity at low concentrations of 0.1–10 mg/mL and was the most effective

anti-influenza compound among several standards tested in our laboratory

(gallic acid, syringic acid, caffeic acid, b-coumaric acid, tannic acid, chloro-

genic acid, catechin, ECGC, keracyanin chloride, kuromanin chloride, delphini-

din chloride, cyanin chloride, cyanidin chloride, ideain chloride, pelargonidin

chloride, malvidin chloride, and quercetin) (unpublished data). It is worth

mentioning that resveratrol is very toxic at high concentration (only 11% viable

cells at 100 mg/mL).

Flavonoids demonstrated diverse antiviral activities against viruses includ-

ing HIV, respiratory and herpes viruses, and many others (adenovirus,


coxsackievirus, measles, pseudorabies virus, poliovirus, semliki forest virus,

and zoster virus). For example, amentoflavone, agathisflavone, robustafla-

vone, rhusflavanone, and succedaneflavanone from Rhus succedanea and

Garcinia multiflora [35], theaflavin from black tea [36], iridoids from Bar-leria prionitis [37], phenylpropanoid glycosides from Markhamia lutea [38],

chrysosplenol C from Dianella longifolia and Pterocaulon sphacelatum[39,40], morin from Maclura cochinchinensis [41], coumarins from Calophyl-lum cerasiferum [42], galangin from Helichrysum aureonitens [43], and baica-

lin from Scutellaria baicalensis [44] all have been shown to inactivate

different viruses at various levels depending on the virus type, concentration,

and the cell type used in the assay. Flavonoids exert their activity by blocking

RNA synthesis, protease inhibition, reverse transcriptase as well as direct

inhibition of viruses [13,45]. Some flavonoids exert their antiviral activity

through specific actions. For example, taxifolin (dihydroquercetin) from

Juglans mandshurica inhibited the cytopathic activity of HIV-1 virus [46], fla-

vonoid glucuronide from Chrysanthemum morifolium targeted integrase [47],

whereas Ginkgetin and tetrahydroxyflavone from Ginkgo biloba L. and

S. baicalensis, respectively, were targeting influenza virus sialidase [48,49].

The flavonoids glabranine and 7-O-methyl-glabranine were purified from the

Mexican plants Tephrosia madrensis, Tephrosia viridiflora, and Tephrosiacrassifolia and exhibited 70% inhibition of the dengue virus at a concentration

of 25 mM [50]. The efficacy of quercetin, apigenin, genistein, naringin,

silymarin, and silibinin was recently evaluated for their anti-HSV-1 and

anti-RNA virus parainfluenza (type-3) [14]. These compounds had high anti-

HSV-1 activity with cytopathogenic minimum inhibitory concentration

between 0.1 and 0.8 mg/mL with quercetin and silibinin being the most effec-

tive compounds. These compounds, however, were not effective against para-

influenza (type-3) except for genistein which had cytopathogenic minimum

inhibitory concentration of 0.2 mg/mL.

Water [51] and ethanolic [52] extracts of Brazilian propolis were effective

anti-influenza in several model systems. Shimizu et al. [52] investigated the

activity using A/PR/8/34 and A/WSN33 (WSN) strains in Madin–Darby

canine kidney (MDCK) cells and adapted influenza. The authors reported

wide range of effective and cytotoxic concentrations with one fraction at

10 mg/kg showing similar efficacy to oseltamivir (a standard anti-influenza

drug, 1 mg/kg). This antiviral activity is in agreement with strong documented

evidence for antiviral activity of propolis against HSV [53–56], poliovi-

rus [57], reovirus [58], HIV [59–61], and other viruses [62–65]. Several poly-

phenols, flavonoids, and phenylcarboxylic acids were identified from aqueous

and ethanolic extracts of propolis which exhibited very high antiviral activity

against HSV-1 with ethanolic extracts being about fivefold more effective

than aqueous extracts [55,56,63]. The extracts contained caffeic acid,

p-coumaric acid, benzoic acid, galangin, pinocembrin, and chrysin; however,

only galangin and chrysin demonstrated antiviral activity at concentrations


below their corresponding lethal levels and the extracts were far more effec-

tive as anti-HSV-1 compared to any of the individual compounds, suggesting

a synergistic effect among the various compounds. This is in contrast to the

findings reported for phenolic acids effects on HSV-1 and -2, and adeno-

viruses (3, 8, and 11) [66]. Aqueous extracts of Plantago major L. exhibitedweak inhibition on the viruses but pure compounds found in the extract of

the plant demonstrated potent activity. In particular, caffeic acid was the most

effective compound against HSV-1 and HSV-2 (EC50¼15.3 and 87.3 mg/mL,

SI¼671 and 118, respectively) and against adenovirus 3 (EC50¼14.2 mg/mL,

SI¼727). Chlorogenic acid exhibited the strongest antiadenovirus 11 activity

(EC50¼13.3 mg/mL, SI¼301). More, recently, Urushisaki et al. [51] reportedthe anti-influenza activity of aqueous extract of propolis and demonstrated

that the activity was mainly due to caffeoylquinic acids (Fig. 3). The authors

also found that the antiviral activity was due to a cytoprotective activity of the

cells since the extracts did not affect the viral RNA content per cell, suggest-

ing no direct effect on the influenza virus. The compound structure plays an

important role in determining the antiviral activity. For example, while 3,4-

dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, and 4,5-dicaffeoylquinic acid

have the exact molecular weight of 516.5 g/mol, their EC50 against influenza

A virus were 41.9, 107.3, and 144.9 mg/mL, respectively. The substitution of a

hydrogen group in chlorogenic acid by a caffeoyl group on R2 position

(Fig. 3) resulted in fourfold increase in the anti-influenza activity [51].

Terpenoids

Several sesquiterpene and triterpenoids (agastanol and agastaquinone from

Agastache rugosa, glycyrrhizin from Glycyrrhiza radix, moronic acid from

Rhus javanica, ursolic acid, maslinic acid, and saponin from Geum japoni-cum, Uvaol from Crataegus pinnatifida, Garciosaterpene A, C from Garciniaspeciosa, vaticinone from Vatica cinerea, and betulinic acid from many plants

spp.) demonstrated potent antiviral activities against HSV and HIV [67–75]

and improved the activity of synthetic drugs [76]. The antiviral activity was

attributed to: (1) a direct antiviral effect on the virus [76], (2) immunomodu-

latory effect through the production of interferon [21], (3) HIV-1 protease

R1O

OH OR2

OR3

HOOC

Quinic acid: R1 = R2 = R3 = H

O

(OH)HO

HO

Caffeoyl (caffeic acid)

Chlorogenic acid: R1 = caffeoyl, R2 = R3 = H4,5-Dicaffeoylquinic acid: R1 = H, R2 = R3 = caffeoyl3,5-Dicaffeoylquinic acid: R1 = R3 = caffeoyl, R2 = H3,4-Dicaffeoylquinic acid: R1 = R2 = caffeoyl, R3 = H3,4,5-Tricaffeoylquinic acid: R1 = R2 = R3 = caffeoyl

FIGURE 3 Chemical structures of several caffeoylquinic acids derived from propolis [51].


inhibition [77], and (4) interference with virus-cell binding [78]. Antiviral ter-

penoids can be found in marine sources. For example, Dolabelladienetriol

(Fig. 4) obtained from the marine brown alga Dictyota pfaffii inhibited

HIV-1 replication at EC50 of 8.4 mM through a noncompetitive inhibition of

reverse transcriptase [79].

Essential Oils

Essential oils (EOs) are mixtures of volatile compounds that can be isolated

from their original matrixes by distillation, solvent extraction, and expression

under pressure. These oils as mentioned above are complex mixture of various

compounds (Fig. 5), mostly terpenes (e.g., mono- and sesquiterpenoids) and

nonterpenes (e.g., benzoids and phenylpropanoids) and their composition

can vary depending on their source material. EOs with known biological

activities can be extracted from food plants (e.g., myristicin from nutmeg, cit-

ral from lemongrass oil, thymoquinone from black cumin, d-limonene from

orange, and b-myrcene from sweet fennel) but long list of food (dill seed, gar-

lic, basil, and so on) and nonfood materials (see below) has been reported as

sources of biologically active EOs extracts.

EOs have been used for therapeutic purposes and as cosmetics through

human history. Their antimicrobial effects and their use in skin formulations

have been known for centuries [82], which probably led to investigations of

their antiviral activities on viral skin diseases. Indeed, human herpes viruses,

for example, HSV-1 and HSV-2, are the most investigated viruses with EOs

[83–94]. Topical treatments containing extracts from lemon balm and sage

extracts are available for herpes labialis [80]. EOs obtained from Santolinainsularis [85], Melissa officinalis L. [82], Melaleuca species [87], Houttuyniacordata [88], Australian tea tree and eucalyptus [90], Mentha piperita [91],

and Salvia fruticosa [93] exhibited direct inactivation of HSV.

EOs from Artemisia arborescens L. (Asteraceae) exhibited potent inhibitory

activity against HSV-1 (EC50¼2.4 mg/mL) and HSV-2 (4.1 mg/mL) with a

CC50/EC50 ratio of 55 and 32.2, respectively, showing a good safety profile [95].

The antiviral activity was due to direct virucidal effects, which caused virus inac-

tivation and prevented cell-to-cell virus diffusion. EOs from Eugeniacaryophyllus and eugenol (the main EO in the obtained extract) inactivated

several herpes viruses at various levels directly and inhibited intracellular and

H

HO

OH

H

HO

FIGURE 4 Structure of Dolabelladienetriol [79].


Monoterpenes

α-Terpinene γ-Terpinene α-Pinene β-Pinene

OH

Terpinen-4-ol

OH

α-Terpineol

OH

OH

Thymol Carvacol

O

CHO

CHO

cis-Form trans-Form Citral p-Cymene

1,8-Cineole

H2C

OH

OH

Sabinene Geraniol Citronellol

Phenylpropanoids and sesquiterpenes

OCH3

trans-Anethole

OH

OCH3

Eugenol

OH

β-Eudesmol

HH

O

H

β-Caryophyllene β-Caryophyllene oxide

OH

Farnesol

CHOOH

OH

Cinnamaldehyde Cinnamyl alcohol Chavicol

OCH3 OCH3

O

O

Anethole Estragole Safrole

Isoprenoides

OO

OH

Ascaridole Menthol

FIGURE 5 Structure of various essential oils possesses antimicrobial and antiviral activities. Source: Refs. [80,81].

extracellular virus replication [96]. Direct virus inhibition of HSV-1 was reported

for several monoterpenes (a-terpinene, g-terpinene, a-pinene, p-cymene,

terpinen-4-ol, a-terpineol, thymol, citral, and 1,8-cineole), EOs from eucalyptus

(Eucalyptus sp., Myrtaceae), tea tree (Melaleuca alternifolia, Myrtaceae), and

thymol (Thymus sp., Lamiaceae) [81], and pure phenylpropanoids and sesquiter-

penes (trans-anethole, eugenol, b-eudesmol, farnesol, b-caryophyllene, and

b-caryophyllene oxide) and star anise oil [80]. Very high safety index of 160

and 140, for star anise oil and b-caryophyllene, respectively, was reported

(Table 2), suggesting a potential for practical application [80]. Furthermore, oils

from natural extracts (star anise oil and tea tree) had higher selectivity index and a

lower toxicity than their isolated pure compounds [80,81]. EOs from

A. arborescens demonstrated higher inhibition activity against HSV-1 compared

to HSV-2, EOs from E. caryophyllus were more effective against HSV-2 com-

pared with HSV-1 (EC50 was 42–74.4 mg/mL for HSV-2 compared with

62.0–153.0 mg/mL for HSV-1 depending on the virus strain) [96]. Therefore,

the source of EOs plays an important role in determining the efficacy of the

obtained extracts against various strains of the virus, which is related to the com-

position of EOs in the extracts and the sensitivity of the different strains to the

active compounds.

Investigations against other viruses have been reported but to a lesser extent.

For example, the EO of Lippia junelliana and Lippia turbinate showed a potent

inhibition against Junin virus [100]. EOs from Pectis odorata, Gaillardia mega-potamica, Heterothalamus alienus, Buddleja cordobensis, and L. turbinate werevery effective against arenavirus Junin with a virucidal concentration 50%

(VC50, the concentration required to reduce virus titer by 50%) of <50 ppm

[101]. Also, EOs from P. odorata and Jungia polita were effective against

dengue virus at concentrations of <50 ppm, whereas EOs from P. odorata,G. megapotamica, and B. cordobensis had VC50 of 71.5, 99.1, and 54.1 ppm,

respectively. The viral envelope was suggested as the potential target of EOs

giving the lipophilic nature of the oil, which enables it to penetrate membranous

structures, and consequently would control the virus entry. The effects of EOs

from Lippia alba Mill. (Verbenaceae), Lippia origanoides Kunth. (Verbena-

ceae),Oreganum vulgare L. (Lamiaceae), and Artemisia vulgaris L. (Asteraceae)were investigated for their inhibitory actions on yellow fever virus [102]. The oil

from L. origanoides was the most active against the virus (11.1 mg/mL caused a

100% reduction of virus yield) and best safety profile with CC50/minimum inhi-

bition concentration ratio of 26. The antiviral activity of M. alternifolia EO and

the main EOs available in its oil (a-terpinene, g-terpinene, a-pinene, p-cymene,

terpinen-4-ol, and a-terpineol) were investigated against influenza A/PR/8 virus

subtype H1N1, polio type 1, Enteric Cytopathic Human Orphan 9, Coxsackie B1,

and adeno type 2 [103]. All the compounds did not have antiviral activities against

polio 1, adeno type 2, Enteric Cytopathic Human Orphan 9, and Coxsackie B1.

Tree tea oil and terpinen-4-ol, terpinolene, and a-terpineol inhibited influenza

A/PR/8 virus subtype H1N1 with the tea tree oil possessing much higher activity

than any of the individual compounds available in its composition.


TABLE 2 Selectivity Indices of Essential Oils Against HSV-1 and HSV-2

[80,81,97–99]

Essential Oil/

Compound

Max. Noncytotoxic

Concentration

(mg/mL)�SD (%)

TC50 (mg/mL)�SD

(%)a

IC50 (mg/mL)�SD

(%)bSelectivity

Index

HSV-1

Eucalyptus oil 200�3.5 290�5.8 55�8.2 5.3

Tea tree oil 75�8.3 120�9.6 2�4.2 60.0

Thyme oil 50�16.2 70�2.1% 11�13.3 6.4

Star anise oil 100�8.0 160�30.7 1�0.1 160

a-Terpinene 50�11.2 55�8.1% 8.5�16.3 6.5

g-Terpinene 35�8.1 38�12.7 7�2.8 5.4

a-Pinene 50�3.2 80�5.1 4.5�10.4 17.8

p-Cymene 30�12.7 65�13.0 16�16.2 4.1

Terpinen-4-ol 250�11.7 650�13.3 60�17.7 10.8

a-Terpineol 150�16.5 400�19.9 22�14.9 18.2

Thymol 35�8.1 85�12.8 30�6.5 2.8

Citral 20�1.7 45�8.9 3.5�10.1 12.9

1,8-Cineole 1250�9.6 2000�8.4 1200�8.9 1.7

trans-Anethole 70�3.0 100�6.4 20�1.1 5

Eugenol 60�11.1 85�8.1 35�6.2 2.4

b-Eudesmol 9�1.3 35�5.4 6�0.3 5.8

Farnesol 10�0.4 40�3.7 3.5�0.1 11.4

b-Caryophyllene 10�0.1 35�2.3 0.25�0.0 140

b-Caryophylleneoxide

9�1.1 18�1.2 0.7�0.1 25.7

Ginger oil 0.004 0.0002 20

Thyme oil 0.007 0.001 7

Hyssop oil 0.0075 0.0001 75

Sandalwood oil 0.0015 0.0002 7

Lemon balm oil 0.002 0.003 0.0004 7.5

Continued


Lignans

Lignans are widespread compounds in plants and many lignans exhibited

antiviral activities [13,45]. For example, peltatins from Justicia procumbensand Podophyllum peltatum, schizarin B and taiwanschirin D from Kadsuramatsudai, and rhinacanthin E and rhinacanthin F from Rhinacanthus nasu-tus were shown to inhibit HIV, hepatitis B virus (HepBV), and influenza

A by blocking the virus replication [13,45,104]. Honokiol is a very potent

anti-HepCV compound obtained from Magnolia officinalis. Honokiol inhib-ited HepCV (EC50¼1.2 mg/mL, SI¼29.1) through the disruption of the

HCV life cycle [105]. A less effective lignan compound, 3-hydroxy carui-

lignan, is obtained from the stems of Swietenia macrophylla (Meliaceae).

This compound decreased the RNA and inhibited HepCV at EC50 of

10.5 mg/mL [106].

Proteins and Peptides

Antiviral protein and peptide compounds are classified into five categories:

(1) single chain ribosome-inactivating proteins, (2) dimeric cytotoxins, (3)

lectins, (4) antiviral factor, and (5) meliacine [13]. The single chain

ribosome-inactivating proteins are found in extracts from Clerodendruminerme, Dianthus caryophyllus, Gelonium multiflorum, Momordica charantia,Phytolacca americana, Saponaria officinalis, Trichosanthes kirilowii, and

TABLE 2 Selectivity Indices of Essential Oils Against HSV-1 and HSV-2

[80,81,97–99]—Cont’d

Essential Oil/

Compound

Max. Noncytotoxic

Concentration

(mg/mL)�SD (%)

TC50 (mg/mL)�SD

(%)

IC50 (mg/mL)�SD

(%)

Selectivity

Index

HSV-2

Anise oil 0.016 0.003 5

Hyssop oil 0.0075 0.0006 13

Thyme oil 0.007 0.0007 10

Ginger oil 0.004 0.0001 40

Camomile oil 0.003 0.00015 20

Sandalwood oil 0.0015 0.0005 3

Lemon balm oil 0.002 0.003 0.00008 37.5

aTC50 = half-maximal toxic concentrationbIC50 = half-maximal inhibition concentration


Triticum aestivum. These proteinous fractions exhibit their antiviral effects

through inhibiting the synthesis of viral protein and interfering with the ribo-

some function in the infected cell through their effects on N-glycosidases andthe depurination of RNA. Recently, a protein-enriched fraction obtained from

larvae of housefly Musca domestica L. (Diptera: Muscidae) showed strong

antiviral activity against influenza virus H1N1 which was the result of direct

virucidal activity as well as interference with the virus interaction with the

cell [107]. A group of protein fractions isolated from P. americana,M. charantia, and G. multiflorum coined as Pokeweed antiviral proteins

(MRK29, MAP30, and GAP31) have been shown to be potent compounds

inactivating infective HIV and HIV-infected cells [108–112]. Panaxagin from

Panax ginseng [113] and a- and b-antifungal proteins from Vigna unguiculatainhibited the HIV-1 reverse transcriptase [114]. The dimeric cytotoxins are

found in Ricinus communis, Abrus precatorius, and Adenia digitata and they

have similar mechanism of action to single chain ribosome-inactivating pro-

teins. Lectins are sugar-binding proteins which possess the ability to specifi-

cally bind to carbohydrate moieties including cells. Several lectins from

Canavalia ensiformis, Lens culinaris, Phaseolus vulgaris, and Triticum vul-garis were found to have strong antiviral activities through viral membrane

interactions [13]. Recently, lectins from plant sources have been proposed

to act as anti-HIV drugs where they target the glycans present on the surface

of the external envelope protein of HIV.

Lectins have the potential to inhibit HIV infection and prevent HIV trans-

mission from virus-infected cells to uninfected CD4T lymphocytes [115,116].

Meliacine, a protein isolated from Melia azedarach, demonstrated strong

activities against HSV-1 strain in mice, inhibited Junin hemorrhagic fever

virus in Vero cells, and foot and mouth disease virus in baby hamster kidney

cell [13]. Meliacine inhibits the virus replication cycle and interfere with the

virus penetration step into cells. The peptides mirabamides A, C, and D (Fig. 6)

were isolated from the sponge Siliquariaspongia mirabilis inhibited HIV-1

cell fusion (EC50¼0.21–6.1 mg/mL) through interaction with the virus enve-

lope glycoproteins [117].

A purified peptide from the seeds of Sorghum bicolor L. (MW¼2000 Da)

effectively inhibited the replication of HSV type 1 (HSV-1) in a dose-

dependent manner, at 40–90% of the control level, after incubation with

20–10 mg/mL of the peptide, with EC50 of 12.5 mg/mL and had an CC50 value

of 500 mg/mL against Vero cells [118]. The peptide was not only able to

inhibit the initiation and the spread of infection but also had an in vitro pro-

phylactic effect against HSV-1 infection. The virucidal activity was suggested

to be caused by the disintegration of the entire HSV particles; the solubiliza-

tion of the virus envelope; or the chemical modification, degradation, or

masking of some of the essential envelope proteins. The peptide had weak

activity against poliovirus type 1, a nonenveloped virus.


Polysaccharides

Extracts containing polysaccharides from Achyrocline flaccida, Aloe barba-densis, Bostrychia montagnei, Cedrela tubiflora, Prunella vulgaris, Sclero-tium glucanicum, Stevia rebaudiana, Rhizophora apiculata, and Rhizophoramucronata showed protective effects against several viruses [13]. The

mechanisms suggested for their effects were immunostimulation of antibody

production against capsid protein epitopes of nonenveloped picornavirus,

and prevention of the virus binding to the cell and the formation of syncytia.

Polysaccharides possessing antiviral activity from marine sources have been

reported. Talarico et al. [119] isolated an L-galactan hybrid C2S-3 (Fig. 7A)

from Cryptonemia crenulata, which exhibited a potent antiviral activity

(EC50¼0.8–16 mg/mL) against three clinical strains of dengue virus serotype 2.

NO

NH

NHOR1

OMe

NH

OO

O

O

O

R2

MeO

HN

NMe

OO

OH

HN

HN

NH2

O

O

O

HN

H2N

OHHN

NH

OO

O

HO

OH

Mirabamide A R1 = O

OH

HOHO

MeR2 = Cl

R2 = Cl

R2 = H

Mirabamide B R1 = H

Mirabamide C R1 =O

OH

HOHO

Me

FIGURE 6 Structure of the peptides mirabamides A, C, and D which were isolated from the

sponge Siliquariaspongia mirabilis.


A sulfated polymannuroguluronate (Fig. 7B) isolated from Laminaria japon-ica [120] and a sulfated xylomannan isolated from Scinaia hatei [121]

inhibited HIV and HSV, respectively. The compounds interfered with the

virus multiplication cycle.

Galactofucan, a sulfated polysaccharide obtained by aqueous extraction of

the seaweed Undaria pinnatifida, was evaluated for antiviral activity against

32 clinical strains of HSV in which 14 strains of HSV-1 and 18 strains of

HSV-2 were examined [122]. Among the investigated strains, 12 strains

(4 HSV-1 and 8 HSV-2) were resistant to acyclovir and 20 strains (10

HSV-1 and 10 HSV-2) were susceptible to acyclovir. The median EC50 of

galactofucan for the 14 strains of HSV-1 was 32 mg/mL, whereas the EC50

for the 18 strains of HSV-2 was 0.5 mg/mL and exhibited significantly higher

efficacy against clinical strains of HSV-2 than HSV-1. The mode of action of

the galactofucan was shown to be the inhibition of viral binding and entry into

the host cell. The cytotoxicity of galactofucan was >4.0 mg/mL, suggesting a

potentially high safety margin. Synthetic sugar analogues demonstrated that

the sugars interfere with glycosylation of influenza virus glycoprotein leading

to virus inhibition [123]. Sugars containing a benzyl group were able to

inhibit the virus and higher concentrations of 2-deoxy-D-glucose and

D-glucosamine promoted the disruption of the glycosylation step.

An extract obtained from the red marine alga Ceramium rubrum (Huds.) Ag.,

from the Bulgarian Black Sea, inhibited the replication of 11 strains of influenza

viruses’ type A and B in vitro and in vivo [124]. The extract induced a

O

HO OH

O3SO

O

O

O

O OSO3

HOHO

HO

O

OH

O

OSO3

O

OSO3

HOHO

n

D,L-Galactan hybrid C2S-3

OO

HO

HOOC

O

OSO3

OO

O3SO

HOOCOH

OO

O3SO

HOOCOH

OO

HO

HOOCOSO3

n

Sulfated polymannuroguluronate

A

B

FIGURE 7 Structure of polysaccharides obtained from seaweeds with high antiviral activity.


cytopathogenic effect at concentration range (0.12–1.1 mg/mL, depending on the

virus strain) and exhibited a selective virus-inhibitory effect in a dose-dependent

manner. The selectivity indices ranged 9.5–68.3 for the influenza viruses and the

activity was attributed to inhibition of virus adsorption as well as to inhibition of

the intracellular stages of viral replication. The extract also inhibited the

replication of HSV-1 and -2 in cell cultures with SI ranged from 4.9 to 10.8.

Chitosan is the deacetylated form of chitin, a polymer that is widely abundant

in nature (Fig. 8). Chitosan and its derivatives have been extracted from several

fungal, insect, and marine sources and their antiviral efficacies were evaluated

using various viruses [125–128]. Most of the available literature documents the

antiviral activity of chitosan against many plant viral infections [125–127] with

blocking the replication of the virus being described as the major mechanism

of action. Chitosan oligosaccharide lactate (MW¼5 kDa) and water-soluble

chitosan (MW¼53 kDa) were investigated at concentrations of 1.4%, 0.7%,

and 0.35% against murine norovirus 1, feline calicivirus F-9, and bacteriophage

MS2 [129]. Higher MW chitosan was more effective than oligosaccharide lactate

derivative and the highest antiviral activity was found at the concentration of

0.7%. The compounds were more effective against feline calicivirus F-9 than

bacteriophageMS2 but had no effect on murine norovirus 1. These results under-

pin the importance of elucidating the specificity of the tested antiviral compounds

toward certain viruses. The effects of chitosan appear to be linked to nonspecific

binding between the positively charged chitosan and the negatively charged virus

surface which causes weakening and disruption to the capsid structure [129].

Chitosan obtained from the larvae of houseflyM. domestica L. (Diptera: Musci-

dae) demonstrated effective antiviral activities against Autographa californicamulticapsid nucleopolyhedrovirus and Bombyx mori nuclear polyhedrosis virusin Spodoptera frugiperda 9 cell line and Silkworm larvae, respectively [128].

A 1 log reduction in virus titer and 30% reduction in larvaemortality after 20 days

were achieved at chitosan concentration of 1 mg/mL. The availability of several

functional groups and the cationic nature of chitosan render the compound as an

important template for the generation of several derivatives, whichmay have bet-

ter antiviral activity. Kulikov et al. [130] and Davydova et al. [126] using chemi-

cal and enzymatic hydrolysis techniques showed that the antiviral of chitosan

against tobacco mosaic virus was not affected by the compound deacetylation

OOO

OH

OH

CH2OH

NHCOCH3

CH2OH

OH

NHCOCH3

CH2OH

OH

NHCOCH3

OHOO

n

OOO

OH

OH

CH2OH

NH2

CH2OH

OH

NH2

CH2OH

OH

NH2

OHOO

n

Chitin Chitosan

FIGURE 8 Structure of chitin and its derivative chitosan.


degree but it was increased with the decrease in the degree of polymerization and

the molecular weight of the chitosan derivatives. Similar effects on human

viruses are yet to be investigated.

Considerations for Antiviral Activity of Compounds fromNatural Sources

Extraction Conditions

The successful evaluation of medicinal plants and the screen of novel natural

sources for antiviral activity are dependent on applying systematic procedures

to obtain the targeted compounds. Despite the availability of standard meth-

ods for the extraction of natural products [131], the reporting of extraction

procedures in the literature is normally not sufficient. The extraction temper-

ature is an important factor in successful extraction of bioactive compounds.

Aqueous extracts Agrimonia eupatoria, A. pilosa, and A. coreana pilosella

have been reported to possess antiviral activity against HepBV. Aqueous

extracts of A. eupatoria were extracted at 37, 45, 55, and 60 �C and investi-

gated for inhibition of HBsAg release against HepBV [132]. The extracts

obtained at 60 �C were found to have the greatest inhibition (104%, 41%,

and 32% decrease in production of HBsAg compared with 35, 45, and

55 �C, respectively). This is probably due to better extraction of active com-

pounds at 60 �C without compromising their activity. The study also high-

lighted the seasonal effects on the examined activity and the inhibitory

activity of A. eupatoria was highest at mid-July.

Furthermore, efficient use of extraction system to obtain the active

compound(s) is crucial for appropriate screening of materials. Methanol, hex-

ane, and chloroform extracts from Jatropha curcas were found to produce

moderate cytoprotective effect against HIV in cultured human lymphoblastoid

cells but not ethyl acetate or water extracts [133]. In the same study, methanol

extracts of Alchornea cordifolia, Maprounea africana, and Mangifera indicaexhibited weak cytoprotective effect against HIV but this activity was abol-

ished when other solvents were used, with the exception of chloroform when

was used to extract M. Africana. Similarly, Ben Sassi et al. [134] screened15 species of Tunisian traditional medicinal plants against HSV-1 using petro-

leum ether, acetone, methanol, or water as the extraction solvent and signifi-

cant effects from the solvent were evident. Generally, methanol produced

higher yields and in some instances better selectivity index which was depen-

dent on the material. Twenty-one Ethiopian medicinal plants were extracted

using various solvents and were screened for activity against HIV-type 1 and

type 2 [135]. Methanol extracts of Combretum paniculatum (Combretaceae)

and B. abyssinica (Melianthaceae) had SI of 4.7 and 3.8 against HIV-type 1

only, whereas the acetone extract of C. paniculatum only exhibited activity

against HIV-type 1 and type 2 with SI of 6.4 and 32, respectively. The antiviral

activity of seven Panamanian plant extracts (Hybanthus prunifolius, Ouratea


lucens, Trichilia cipo, Tetragastis panamensis, Piper cordulaturn, Alseis black-iana, and Aspidosperma megalocarpon) using dichloromethane, petroleum

ether, ethanol, or water as the extraction solvent indicated the poor efficacy of

dichloromethane and petroleum ether in extracting the active compounds from

the plants [136]. Generally, the extracts exhibited selective effects, with ethanol

extracts were more effective against HSV-1 than HSV-2 while the aqueous

extracts exhibited the opposite effect. Moreover, the extracts were more effec-

tive against HSV-1 compared with HSV-2, with the exception of O. lucensand T. panamensis extracts. The antiviral activity of the extracts were in the fol-lowing order: poliovirus>parainfluenza>vesicular stomatitis virus>HSV-1,

but this order was slightly affected by the cell line used in the assays.

Giving the various compounds that can be expressed differently in the

plant, the relationship between the best solvent to be used with a plant can

be complicated by the part of plant (leave, stem, root, or bark of these parts)

to be extracted from and this was reported in several studies [133–136]. Sev-

eral other factors need to be considered during the extraction and evaluation

of the compounds such as the distribution of the compounds in the plant,

extraction system (solvent, time, temperature, and solid:liquid ratio), the

effects of storage, chemicals used, dialysis, use of enzymes, pH, and

centrifugation.

Several reports compared the efficacy of plant crude extracts with their

active pure compounds [137,138]. These studies were generally reported a

higher antiviral activity of pure compounds compared with the crude extracts.

For example, the anti-HSV-1 activity of an ethyl acetate extract of Tanacetumvulgare was 0.008% the activity of its active compound, parthenolide [137].

Similarly, higher anti-HSV-1 was found in isolated ursolic acid and an active

fraction obtained from Mallotus peltatus compared to crude methanolic

extract of the plant [138]. While the purification of active compounds seems

to be a logical way to obtain active compounds with higher efficacy, several

disadvantages may be posed by carrying the purification step. For example,

active compounds are generally having low CC50 which can pose risk of

higher toxic effects at lower doses [138]. Also, the cost and technology asso-

ciated with the purification of these compounds can be prohibitive for certain

communities and reduce access and affordability of the treatment. Further-

more, some plant extracts may contain several active compounds which can

synergistically lead to higher antiviral activity or other component that can

lead to better bioavailability. For example, the anti-influenza activity of crude

grape extracts was equivalent (at the same concentration) to that found with

the most active antiviral compounds (catechin, ECGC, delphinidin chloride,

cyanidin chloride, or pelargonidin chloride) found in grapes [unpublished

data] despite the fact that they are available in much smaller concentrations

in the crude extract. The bioavailability of polyphenols is greatly enhanced

with natural compounds such as pectin [139] which will be lost during further

purification. Synergistic effects of active compounds in crude extracts have


been reported for J. curcas [140] and other medicinal plants [141] in other

medical conditions. Therefore, more research on the bioavailability of anti-

viral active compounds, the measurements of the compounds and their meta-

bolites, and their synergistic effects is needed.

Structure–Activity Relationships

A series of thyrsiflorin and scopadulane compounds (methyl thyrsiflorin A,

methyl thyrsiflorin B acetate, thyrsiflorin C, thyrsiflorin C diacetate,

13-scopadulanone, 13a-scopadulanol, 7b-hydroxy-13-scopadulanone, 7b-acet-oxy-13b-scopadulanol, 8(14)-scopadulen-13-one, 8(14)-scopadulen-13,15-

dione, 7a-hydroxy-8(14)-scopadulen-13-one, cyclopropane intermediate, 7a-hydroxy-8a-scopadulan-13-one, and a rearranged scopadulane-type diterpene

ketone) derived from the natural scopadulane-type diterpenes were investigated

for their in vitro anti-HSV-2 activity [142]. The activity of the compounds

indicated that a polar substituent at C-13 had a hydroxyl group in the case of

13a-scopadulanol, which is essential to improve the antiviral activity since the

presence of a carbonyl group at C-13 in 13-scopadulanone exhibited a lower

antiviral activity and a complete loss of activity when the hydroxyl group was

esterified in methyl thyrsiflorin A. The location of the substitution is important

since the substitution at C-7 with a polar group and the presence of a carbonyl or

ester group at C-13 in thyrsiflorin C resulted in a complete loss of the activity.

The antiviral activity of scopadulciol against HSV-1 increased when the substi-

tution at C-13 was with a hydroxyl group compared with acetyl group [142,143].

Indeed, the substitution with hydroxyl groups appears to improve the anti-

viral activity of some phenolic acids (Table 3) and improve their selectivity

toward the virus strain; however, the availability of hydroxyl groups do not

necessarily mean a better antiviral activity. The antiviral activity of flavonols

against HSV-1 was higher than flavones [144] and their activity was found to

decrease with the increase in the number of their hydroxyl substitution, that is,

galangin>kaempferol>quercetin (Table 4). The glycosides compounds of

kaempferol and quercetin (kaempferol 3-O-rutinoside, kaempferol 3-O-robi-nobioside, quercetin 3-O-rutinoside) had much higher antiherpes activity than

their aglycon (Table 4). This form has very high safety profile and exhibited a

much higher SI value compared to their aglycon [144]. It is worth mentioning

that this form is the natural form that can be found in many plants. Therefore,

particular attention should be given to the purification system to avoid the

activities of endogenous glucosidases which can catalyze the removal of the

sugar group.

The antiviral activities of three photosensitizer compounds (hypericin, tet-

rabromohypericin, and gymnochrome B) were evaluated against dengue

viruses [146,147]. Gymnochrome B exhibited higher anti-dengue 4 activity

while tetrabromohypericin had lower activity compared to hypericin

(EC50¼0.035, 0.91, and 2.31 mg/mL for gymnochrome B, hypericin, and


tetrabromohypericin, respectively). The antiviral activity of hypericin and

related analogues against herpes viruses was negatively correlated with the

level of substitution of chlorine in the hypericin structure in position 7 (7,70-dichlorohypericin) [148]. The substitution of functional groups on hypericin

can modify its nature and the antiviral mechanism becomes independent of

photoactivation [149].

CONCLUDING REMARKS

Antiviral compounds can be successfully obtained from various plants,

marine, insects, and animal sources. The compounds vary in their selective

nature and efficacy toward different viruses. The future of natural antiviral

compound is very promising since many of these compounds have multibio-

logical functions. Several health-promoting properties (anticancer, antioxi-

dant, immunomodulation, antibacterial, antiparasitic activities) have been

reported for many of the compounds discussed in this chapter (e.g., phenolic

compounds). The multifunctionality of these compounds makes them a very

appealing alternative to synthetic drugs. The economical advantage of obtain-

ing antiviral compounds from plants is obvious. Many of the reported

promising plants are cultivated in developing countries and can be beneficial

to their economies. Many plants have been reported to possess antiviral activ-

ities against plants viruses [150]. Some of those already shown to be effective

against human viruses such as Acacia arabica [151], Chenopodium

TABLE 3 The Structures of the Pure Compounds from Plantago major,

Their Anti-HSV Activities [66]

R3

O

R1

R2

Compound

Functional Group

Anti-HSV Activities

(EC50, mg/mL)

R1 R2 R3 HSV-1 SI HSV-2 SI

Caffeic acid dOH dOH dOH 15.29 671 87.25 118

Chlorogenic acid dOH dOH X* 47.6 83.9 86.44 46.2

Ferulic acid dOH dOCH3 dOH >100 – >100 –

p-Coumaric acid dOH dH dOH >200 – 32.78 14.9

X*: 1,3,4,5-tetrahydroxycyclohexane carboxylic acid.


TABLE 4 The Structure of Quercetin, Kaempferol, and Their Glycosides

Found in the Leaves of Ficus benjamina [145]

O

O

HO

OH

OH

O

O

HO

OH

OH

OHOH

OH

Galangin

OHO

OH

OH

OH

OO

H

OHOH

HO

O

O

O

H

OH

OH

HO

Quercetin 3-O-rutinoside

OHO

OH

OH

OO

H

OHOH

HO

O

O

O

H

OH

OH

HO

Kaempferol 3-O-rutinoside

OHO

OH

OH

OO

OH

HOH

HO

O

O

O

H

OH

OH

HO

HO

Kaempferol 3-O-robinobioside

O

O

HO

OH

OH

Kaempferol Quercetin

Continued


ambrosiodes L. [152], and Zingiber officinale [153] and the potential of other

plants is promising. The screening of pure compounds, such as in the case of

caffeic acid, resulted in different outcomes [29,56,66], which may be partially

explained by the differences in the antiviral screening system (i.e., the type of

virus and cells used in the assay). However, these compounds in their natural

sources will be complexed with other molecules and available in different

forms. The majority of available studies report the screening and evaluation

of natural antiviral compounds in in vitro systems. The inclusion of animal

models is encouraged where possible to determine any practical use. Any

extrapolation of antiviral activity obtained from pure compounds cannot be

extended to the composition of the extracts since the compounds will be in

different forms. The pure compounds, however, provide the template to syn-

thesize novel compounds and improve our understanding about structure–

activity relationship of antiviral drugs.

ABBREVIATIONS

CC50 the concentration causes the reduction of cell viability by 50%

EC50 half-maximal effective concentration

EOs essential oils

HIV human immunodeficiency virus

HSV herpes simplex viruses

Hep hepatitis

ppm part per million

SI selectivity index

VC50 the concentration required to reduce virus titer by 50%

TABLE 4 The Structure of Quercetin, Kaempferol, and Their Glycosides

Found in the Leaves of Ficus benjamina [145] —Cont’d

Compound

Anti-HSV-1

Activity (EC50,

mg/mL)

Plaques Number (% of

Control) During and After

Infection

HSV-1 SI HSV-1 HSV-2varicellazoster virus

Quercetin 3-O-rutinoside 0.92 266.7 18 28 100

Kaempferol 3-O-rutinoside 1.78 100 28 39 101

Kaempferol 3-O-robinobioside 1.38 666.7 6.1 10 102

Quercetin 18.12 7.1 – – –

Kaempferol 7.15 3.2 – – –


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[Studies in Natural Products Chemistry] Volume 42 || Natural Antiviral Compounds

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