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Atta-ur-Rahman (Ed.

) Studies in Natural Products Chemistry, Vol24'
2000 Elsevier Science B.V.

473

NATURAL PRODUCTS AS ANTIVIRAL AGENTS
KHALID A. EL SAVED
Medicinal Aromatic and Poisonous Plants Research Center,
College of Pharmacy, King Sand University, P,0, Box 2457, Riyadh 11451,
Saudi Arabia

ABSTRACT: Since the ancient times, natural products have served as a major source of
drugs. Aboutfiftypercent of today's pharmaceutical drugs are derived from natural origin.
Interest in natural products as a source of new drugs is growing due to many factors that
will be discussed in this article. Viruses have been resistant to therapy or prophylaxis
longer than any other form of life. Currently, there are only few drugs available for the
cure of viral diseases including acyclovir which is modeled on a natural product parent.
In order to combat viruses which have devastating effects on humans, animals, insects,
crop plants, fungi and bacteria, many research efforts have been devoted for the discovery
of new antiviral natural products. Recent analysis of the number and sources of antiviral
agents reported mainly in the annual reports of medicinal chemistry from 1984 to 1995
indicated that seven out often synthetic agents approved by FDA between 1983-1994,
are modeled on a natural product parent. It has been estimated that only 5-15% of the
approximately 250,000 species of higher plants have been systematically investigated for
the presence of bioactive compounds while the potential of the marine environment has
barely been tapped. The aim of this review is to provide an overview on the central role
of natural products in the discovery and development of new antiviral drugs by
displaying 340 structures of plant, marine and microbial origin that show promising in
vitro antiviral activity.
INTRODUCTION
Natural Products as a Source for New Drugs: Merits and Obstacles
Since the ancient times, natural products have served as a major source of
drugs. About fifty percent of today's pharmaceutical drugs are derived
from natural origin [1]. The growing interest in natural products as a
source of new drugs can be attributed to many factors including urgent
therapeutic needs, the wide range of both chemical structures and
biological activities of natural secondary metabolites, the adequacy of
bioactive natural products as biochemical and molecular probes, the
development of recent techniques to accurately detect, isolate and
structurally.characterize the bioactive natural products and advances in
solving the demand for supply of complex natural products [1].
Historically, the majority of the natural product-based drugs including
cyclosporine, paclitaxel and camptothecin derivatives were first discovered

* Present address: Department of Pharmacognosy, School of Pharmacy, University of
Mississippi, P.O. Box 7624, University, MS 38677, U.S.A.

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KHALID A. EL SA^ ED

by traditional cell-based in vitro assays before their real molecular
biological targets were identified [2]. These cellular biological responses of
natural products are likely to be associated with the inherent properties of
secondary metabolites for the defense of their producing organisms [2],
Infectious viral diseases remain a worldwide problem. Viruses have
been resistant to therapy or prophylaxis longer than any other form of life
due to their nature because they totally depend on the cells they infect for
their multiplication and survival. This peculiar characteristic has rendered
the development of effective antiviral chemotherapeutic agents very
difficult. Currently, there are only few drugs available for the cure of viral
diseases including acyclovir (1), the known antiherpetic drug which is
modeled on a natural product parent. In order to combat viruses which
have devastating effects on humans, animals, insects, crop plants, fungi
and bacteria, many research efforts have been devoted for the discovery of
new antiviral natural products. Although the search for naturally occurring
products which can interfere with viral infections began with the
successful isolation of antibiotics from microorganisms but it has not been
as intensive as that of synthetic antiviral agents [3]. This is mainly due to
the tendency of most virologists who adopt a rational design of antiviral
agents rather than toward empiricism especially with the progress in
knowledge of viral replication [3]. Moreover, there are some problems
arising from the screening of crude extracts, as well as with the purification
and identification of the antiviral components from these crude extracts.
These problems became less intense with the recent advances in different
chromatographic and spectroscopic technologies. Many natural and
synthetic compounds were found to show in vitro antiviral activity but
were much less effective when tested in vivo. This could be attributed to
difficulty in drug transportation to the cells of the infected tissue
especially if these tissues become inflammed due to infection. Many
antivirally active compounds are too toxic for therapeutic applications.
However, natural products remain the best resource for chemically
diversed new lead entities that could serve for future development as
potent and safe antiviral agents. Recent analysis of the number and sources
of antiviral agents reported mainly in the annual reports of medicinal
chemistry from 1984 to 1995 indicated that seven out often synthetic
agents approved by FDA between 1983-1994, are modeled on a natural
product parent [4]. These drugs are: famciclovir (2), ganciclovir (3),
sorivudine (6), zidovudine (7), didanosine (8), zalcitabine (9) and
stavudine (10) [4].
The aim of this review is to provide an overview on the central role of
natural products in the discovery and development of new antiviral drugs.

ANTIVIRAL AGENTS

475

History and Definition of the Word "Virus"

The original Latin meaning of "virus" is "poison", "venom" or "slime" [5].
The word "virus" was also used figuratively in the sense of "virulent or
bitter feeling", "stench" or "offensive odor" [3]. In the late 1800s, the term
"virus" was bestowed on a newly discovered class of pathogens, smaller
than bacteria being studied by Louis Pasteur and others of that era [6]. As
late as 1907, "virus" was defined as "the poison of an infectious disease
especially found in the secretion or tissues of an individual or animal
suffering from infectious diseases [5]. In the early decades of the twentieth
century, viruses were identified as infectious agents that were filterable
and invisible in the light microscope which superficially distinguished
them from most familiar microorganisms [5]. Today, viruses are defined as
noncellular infectious agents that vary in size, morphology, complexity,
host range and how they affect their hosts [7]. However, they share three
main characteristics in common: a) A virus consists of a genome, either
RNA or DNA core (its genetic material) which is surrounded by a
protective protein shell. Frequently this shell is enclosed inside an
envelope (capsid) that contains both proteins and lipids, b) A virus can be
replicated (multiplied) only after its genetic material enters a host cell.
Viruses are absolutely dependent on the host cells' energy-yielding and
protein-synthesizing machineries and hence they are parasites at the
genetic level, c) A virus's multiplication cycle includes the separation of
its genomes from its protective shells as an initial step [7]. When a virus is
outside the host cell, it is considered no more alive than a chromosome [6].
The Multiplication Cycle

The interval between successive mitosis of the individual cell is divided
into three periods [7]:
123-

The Gl period precedes DNA replication. Its average duration is 12
hours.
The S period during which DNA replicates. Its average duration is 8
hours.
The G2 period in which the cell prepares for the next mitosis. Its
average duration is 4 hours.

RNA and protein are not synthesized while mitosis proceeds, i.e.,
during the metaphase which is between 02 and Gl periods but are
otherwise synthesized throughout the multiplication cycle [7]. Nongrowing cells are usually arrested in the Gl period; the resting state is
referred to as GO. Under normal grov^h conditions, cells of a growing
culture multiply in an unsynchronized manner, hence cells at all stages of
the cycle are present. The aging of cells starts after about 50 passages by

complex polypeptide binding sites are involved. Generally viruses replicate through the following stages [3. In all cases. The chromosomal complement changes from normal diploid to aneuploid pattern.7]: 1- 2- 3- The virus chemically recognizes and attaches to appropriate host cell. All protein synthesis proceed in the cytoplasm. contains DNA-s. supernumerary chromosomes and it finally fragmented and the cell dies. the viral DNA or RNA is copied repeatedly. Patterns of Macromolecular Biosynthesis The main feature of normal animal cell is its compartmentalization [7]. The organs of cell attachment of some viruses are protrusions from their outer surface which called spikes. The synthesis of RNA occurs in the nucleus and most of it remains there.and proteinsynthesizing systems of their own [7]. A virus may have different penetration mechanisms in the host cell. The mitochondria. but messenger RNA and transfer RNA migrate to the cytoplasm. Most viruses are introduced into the cell by a kind of phagocytosis named viropexis. Malignant tissues give rise to aneuploid cell lines that have infinite life spans and are known as continuous cell lines. Viral Replication Viruses replicate in different ways. This step is very specific. RNA. Virus particles are transported along the network of cytoplasmic microtubules to a specific cell site where subsequent replication takes place. The amount of time they spend in GO after each mitosis gradually increases. Uncoating results in the liberation of viral nucleic acids into the cell which makes them sensitive to nucleases.e.476 KHALIDA. which is located only in the cytoplasm.ELSAYED slowing their growth rate. the two ribosomal subunits are partly assembled in the nucleolus and nucleus then migrate to the cytoplasm. specific virus sites will bind to appropriate cellular receptor sites which are presumably glycoproteins. In viruses lacking spikes. fusion of membrane sometimes occurs.. The whole virus or its genetic material alone (DNA or RNA) enters the ceirs cytoplasm (penetration and uncoating). Information contained in the viral DNA or RNA directs the host cell to replicate viral nucleic acids and synthesizes viral enzymes and . Viral proteins are synthesized inside a suitable host cell where many new viral particles are assembled [6]. For enveloped virus. The DNA of the animal cell is restricted to the nucleus at all cell cycle stages except during metaphase when no nucleus exists. i. Ribosomal RNA is synthesized in the nucleolus.6.

the major component of envelopes and also they are associated with the nucleic acids of many viruses as core proteins [7]. 8. Proposed targets of some specific antiviral chemotherapy are illustrated in Figure 1 and can be summarized as [3]: 123- Attachment (adsorption) of the viral particle to the host cell. damage to the DNA or some other event may activate transcription of the viral genes therefore new viral particles can be produced and infected cells are destroyed [6].Morphogenesis and assemblage of viral capsids and precursors. In temperate pathways. The newly formed viral particles are released from the infected cell. Glycoproteins: Viral envelopes usually contain glycopoteins in the form of oligomeric spikes or projections. ruptures and dies after loss of its contents. 11.Release. Viral proteins also vary in number. In the lytic pathway. The carbohydrate moieties of . 13. some viruses posses as few as three species while others contains up to 50 protein species. 6.000 daltons. In some cases of latency the viral genes become integrated into the host's DNA. 10.Translation of m-RNA to polypeptides which are early proteins.000150. replicated along with it and passed along to all daughter cells. 7. enzymes and capsid proteins are assembled into new viral particles (genomes) together with their associated RNA or DNA polymerase. Particles uncoating. in which viral genes remain inactive inside the host cell. All members of the same virus family display almost the same highly characteristic electrophoretic protein patterns [7]. Viral proteins have a wide range of molecular weight ranging from 10. Viruses usually replicate by lytic or temperate pathways.Replication of nucleic acids.ANTIVIRAL AGENTS 45- 477 capsid proteins. release and transport of viral nucleic acid and core proteins.Nucleic acid polymerase release and/or activation.Viral polypeptides cleavage into useful polypeptides for maturation.Protein synthesis (late proteins). 4.Envelopment. which are incorporated into the host's plasma membrane. the virus does not kill the host cell but the infection enters a period of latency. 9. Proteins are the sole constituent of capsids. These viral nucleic acids.Encapsidation of nucleic acid. In time. stages 1-4 from above proceeds quickly and the virus is released as the host cells undergo lysis.Transcription of m-RNA. 5. Viral Proteins Proteins represent the main viral component. 12. Penetration of the host cell by infectious viral particles.

These enzymes are virus-specific. Apoptosis can be induced*by a variety of stimuli. The consequences of apoptosis are the fragmentation of nuclear DNA. or energy metabolism [9]. the zeiosis (boiling) of the cytoplasm associated with the blebbing and increased granularity of the plasma membrane and fracturing of the cell into subcellular DNA-containing apoptotic bodies. steroids. Enzymes: Animal viral particles often contain enzymes (Table 1). Among them are the enzymes that modify both ends of m-RNA molecules synthesized by their capping enzymes and poly(A) polymerases. e.g. In addition to the enzymes summarized in Table 1. deoxyribonucleases. the swelling of the cell and the actual rupture of the plasma membrane. Viral hemagglutinins could be used in their quantitative measurement [7]. Example of some viral proteins with specialized functions are: Hemagglutinins: Many animal viruses (e. Protein kinases. generalized protein synthesis. the breakdown of the nucleus and alteration of the cell shape and the plasma membrane permeability.g. can inhibit apoptosis and allow for cell transformation. It is divided into two stages namely. EL SAVED glycoproteins are formed of oligosaccharide (10-15 monosaccharide units) which are linked to the polypeptide backbone through N. growth factor withdrawal and in case of T or B cells. This means that these red cells contain receptors for certain surface components of viral particles that act as cell attachment proteins which are glycoproteins and known as hemagglutinins. antigen-receptor engagement.478 KHALID A. mannose and sialic acid which always occupies a terminal position [7]. DNA-dependent phosphohydrolases and topoisomerases are also often present in viruses [7]. Apoptosis is a process by which cells undergo physiologic death in response to a stimulus and it is a predictable series of morphologically defined events. Many viruses can induce apoptosis in infected cells while many other viruses especially transforming viruses. fucose. glucose and glucoseamine. The nuclear changes during apoptosis induce chromatin . Apoptosis in Viral Infections [8] Homeostasis of cell numbers in multicellular organisms is maintained by a balance between cell proliferation and physiologic (programmed) cell death. viruses often contain other enzymes. ortho. Their main components are: galactose and galactosamine. cytokines. Necrosis is often induced by agents that affect membrane integrity.. DNA-damaging agents. Apoptosis process is different from necrotic cell death by involvement of lysosomal enzyme leakage into the cytoplasm.and O-glycosidic bonds involving asparagine and serine or threonine. Apoptosis is also a mechanism by which cytotoxic lymphocytes kill their targets. respectively..and paramyxoviruses) agglutinate the red blood cells of certain animal species.

ANTIVIRAL AGENTS Table 1. 479 Enzymes in Animal Viruses [7] Virus Enzyme 1 DNA-Dependant RNA polymerase Messenger-RNA capping enzyme Poly(A) polymerase Nucleasess DNA-Dependant nucleotide phosphohydrolase Topoisomerase Protein kinase 1 DNA Viruses: Poxyvirus 1 Herpesvirus None Adenovirus None Papovavirus None Hepatitis virus DNA Polymerase Parvovirus None 1 Picomavirus None 1 Calicivirus None 1 Togavirus None 1 Flavivirus None 1 Coronavirus None 1 Reo virus RNA-Dependant RNA polymerase Nucleotide phosphohydrolase Messenger-RNA capping enzyme | Rhabdovirus RNA-Dependant RNA polymerase | 1 Paramyxovirus Neuraminidase RNA-Dependant RNA polymerase | Neuraminidase RNA-Dependant RNA polymerase | RNA Viruses: 1 Orthomyxovirus 1 Bunyavirus RNA-Dependant RNA polymerase | 1 Arenavirus RNA-Dependant RNA polymerase | 1 Retrovirus RNA-Dependant DNA polymerase (reverse transcriptase) Ribonuclease H Endoribonuclease Protein-cleaving enzyme Protein kinase .

tumors on roots and color change in flowers. Examples of some common RNA viruses and their target plants are: Closterovirus (Beet). reducing the yield of a variety of crops including tobacco. Hordeivirus (Barley). Species that are apparently genetically similar are grouped into genera. Classification of Viruses Viral strains that are distinctly different in more than one gene. Replication of bacteriophages can proceed by either lytic or temperate pathways [6]. Plant Viruses Viruses cause several hundred infectious diseases to many plants after successfully penetrating their cell walls. . Therefore. as well as many other vegetables. Outward symptoms of infection include mottled and blistered leaves. Comovirus (Cowpeas). Potaxvirus (Potatoes) and Tobamovirus (Tobacco mosaic virus. Most plant viruses are RNA viruses. This process involves the activation of endogenous endonuclease(s) in the cell programmed to die. misshapen or abnormally small fruits. excluding mutants and variants. Viral particles may be clinging to these insects' piercing or sucking devices and when these devices penetrate plant cells. An increase in intracellular calcium ions is observed in cells undergoing apoptosis.480 KHALID A. potatoes. Despite bacteriophages could have adverse effects on the host cell. Viruses are classified into four major different classes: Bacteriophages A class of viruses that infect bacterial cells. Cucumovirus (Cucumber). infection occurs. tomatoes. Tobacco) [6]. These genera are grouped into families based on morphology. inducing serious economic damages. they could also be used as research tools in early experiments designed to reveal whether DNA or proteins are the molecules of inheritance and in genetic engineering. physical and chemical nature of viral component and on molecular strategies used by viral genomes to express themselves and replicate [6]. The nuclear DNA is fragmented into oligonucleosomal-sized pieces [8]. Changes in accessibility of DNA to nucleases is mediated by topoisomerases which can induce conformational changes in DNA by making strand cuts. Some insects that feed plants assist in viral infection. are designated species. EL SAVED condensation into several segments. The endonucleases associated with DNA fragmentation are Ca"^"^ dependent. extracellular calcium-chelating agents can block a variety of apoptotic forms. Examples of DNA viruses and their plant targets are: Caulimovirus (Cauliflower) and Geminivirus (Maize) [6].

hepatitis A (infectious hepatitis) 1 Rhinoviruses Common cold 1 Togaviruses Encephalitis. 481 Classification of Animal Viruses [6. intestinal infections 1 Retroviruses: 1 HTLVI.7.ANTIVIRAL AGENTS Table 2. yellow fever 1 Paramyxoviruses measles. dengue fever. non-B Hepatitis Post transfusion hepatitis 1 Delta hepatitis virus (HDV) Hepatitis (requires HBV as a helper virus) 1 Chronic infectious 1 agents (CHINAs) Kuru and Creutzfeldt-Jacob in human. simplex type I Oral herpes. aggravates sickle-cell anemia Poxyviruses Smallpox. 1 1 Adenoviruses Respiratory infections 1 H. implicated in some cancer 1 Herpesviruses: Papovaviruses Benign and malignant warts Parvoviruses Roseola (fever. shingles 1 Epstein-Barr Infectious mononucleosis. ARC 1 Filoviruses: 1 Marburg virus Marburg hemorrhagic fever 1 Ebola virus Ebola hemorrhagic fever 1 Mi^ggliangpus virvisgs. 11 Associated with cancer 1 HIV AIDS. simplex type II Genital herpes 1 Varicella-zoster Chickenpox. hemorrhagic eye disease. cold sores 1 H. cowpox 1 1 RNAVirw^es. mumps 1 Rhabdoviruses Rabies 1 Coronaviruses Respiratory infections 1 Orthomyxoviruses Influenza 1 Arenaviruses Hemorrhagic fevers 1 Reoviruses Respiratory. Picomaviruses: Enteroviruses Polio. 1 The Norwalk group of viruses Gastroenteritis 1 Non-A.10] Viruse Disease 1 PNA Yirytg^g. scrapie in sheep neuropathic 1 . rash) in children.

.ELSAYED Animal Viruses Many animal viruses infect humans and animals causing several serious diseases. Apparently. multiply and produce progeny or as viral particles. potatoes and other crop plants.482 KHALIDA. Prions might be synthesized according to information in mutated genes. Agar is frequently incorporated in the medium to ensure that the liberated progeny virus particles in the medium do not diffuse away and initiate separate or secondary plaques. in terms of their ability to infect. i. Areas of infected cells develop plaques that can be seen with a naked eye. regardless of their function as infectious agents [7]. progeny virus particles are produced. Whenever viral particles infect cells. Viroids and Otiter Unconventional Agents Viroids are plant pathogens which consist of naked strands or circles of RNA with no protein coat. Measurement of Animal Viruses Viruses are either measured as infectious units. Titration of Viruses as Infectious Units Titration means the measurement of the amount of virus in terms of the number of infectious unites per unit volume. avocados. released and immediately infect adjoining cells.. i. Table 2 presents a summary of some animal viruses and the diseases they induce. tentatively named prions.e. This process is repeated until after 2-12 incubation days or more. The infected cells must differ in some recognizable manner from non infected ones. they must .e. Some unidentified infectious agents cause some rare fatal diseases of the nervous system including Scrapie in sheep and Kuru and Crutzfeldt-Jacob (mad cow) disease in humans. have isolated the gene coding for altered forms of a protein in infected cells [6]. enzymes already present in a host cell synthesize viroid RNA then use this new viroid RNA as a template for building new viroids. Viroids are mere snippets of genes smaller than the smallest known viral DNA or RNA molecule and they can have damaging effects on citrus. Plaque Formation [7] Monolayers of susceptible cells are inoculated with small aliquots of serial dilutions of the virus suspension to be titrated. Researchers studying scrapie. Probably these diseases are caused by infectious protein particles.

Each viral particle is a multivalent. Plaque formation is the most desirable method of viral titration because it is economic and technically simple. which is analogous to plaque formation assay.e. it can adsorb more than one cell at a time. not all viruses can be measured this way due to lack of host cells that can develop the desired cytopathic effects (CPE). become detached from the surface on which they grow or possess staining properties different from those of normal cells. the maximum number of cells with which any particular virus can combine is two since RBCs are bigger than viral particles. Enumeration of the Total Number of Viral Particles (Hemagglutination Assay) Many animal viruses get adsorbed by red blood cells (RBCs) of various animal species. i. the small number of cell dimer that may be formed is generally undetectable. Virus stocks derived from single plaques are named "plaque purified" which is important in isolating pure virus strains. In a virus-cell mixture in which the number of cells exceeds the number of viral particles. Colonies of the transformed cells are developed into large foci which are visible by naked eye. They induce morphological changes and faster multiplication rate in the infected cells which are known as transformed cells. In practice.ANTIVIRAL AGENTS 483 be completely destroyed. These viruses are titrated by serial dilution end point method. Focus Formation [7] Many tumor viruses do not destroy cells in which they multiply and hence produce no plaques. Serial dilutions of virus suspensions are inoculated into cell monolayers which are then incubated until the cell sheets show clear signs of cell's destruction. Assay by focus formation depends on counting the number of focus-forming units (FPU). Titers are expressed in terms of number of plaque-forming units (PFU) per milliliter. There is a linear relationship (linear dose-response curve) between the amount of virus and the number of plaques produced which indicates that each plaque is produced by a single viral particle. The end point is the dilution that gives a positive (cell-destroying) reaction and originally contains at least one infectious unit. However. The virus progeny in each plaque are clones.. If the number of viral particles exceeds the number of cells. a lattice of agglutinated cells is formed that settles out . The most common method to visualize plaques is to apply neutral red or crystal violet to the infected cell monolayers and then counting the number of non stained areas [7]. Serial Dilution End Point [71 Some viruses destroy cells they infect but do not produce the necessary CPE for visible plaque formation.

484

KHALIDA.ELSAYED

in a characteristic readily distinguishable manner from the settling pattern
exhibited by unagglutinated cells [7]. Hemagglutination assay is the
determination of the virus that will exactly agglutinate a standard number
of RBCs. Because the number of viral particles required for this is readily
calculated (slightly higher than the number of cells), hemagglutination is a
highly accurate and rapid assay.
In Vitro Antiviral Screening Assays [11,12]

The viral infectivity in cultured cells is determined during virus
multiplication in the presence of a single tested compound or extract or
after extracellular incubation.
1-

2-

345-

Plaque inhibition or reduction assays: Only for viruses which form
plaques in suitable cell systems. Titration of a limited viruses
number or residual viruses infectivity after extracellular action of the
tested compound. The tested compound must be in a non-toxic dose
or cytotoxicity should be eliminated by dilution or filtration before
the titration.
Inhibition of viral-induced CPE: For viruses that induce CPE but do
not form plaques in cell cultures. Determination of virus-induced
CPE in monolayers cultured in a liquid medium, infected with a
limited dose of virus and treated with a non-toxic dose of tested
sample.
Virus yield reduction assay: Estimation of a virus yield in tissue
cultures, infected with a given amount of virus and treated with a
non-toxic dose of tested sample.
End point titration assay: Determination of viral titer reduction in
the presence of two-fold dilutions of tested sample.
Assays based on measurements of specialized functions and viral
products: For viruses that do not form plaques or induce CPE in cell
cultures. Determination of virus specific parameters, e.g.,
hemagglutination and hemadsorption tests, inhibition of cell
transformation and immunological tests detecting antiviral antigens in
cell cultures. Reduction or inhibition of the synthesis of virus
specific polypeptides in infected cell cultures, e.g., viral nucleic
acids, viral genome copy numbers or the uptake of radio labeled
precursors.

Current Antiviral Chemotherapy [13,14]

Research in antiviral chemotherapy started around early 1950's when the
search for anticancer drugs revealed several new compounds that inhibit
viral DNA synthesis, e.g., the pyrimidine analog idoxuridine which was

ANTIVIRAL AGENTS

485

later approved as a topical treatment for herpes keratitis. Since then,
research efforts were focused on both purine and pyrimidine nucleoside
analogs [13]. With the emergence of AIDS epidemic, research on antiviral
generally and specifically anti-HIV became highest priority. Many of
these retrovirus proteins have been purified and characterized for the sake
of designing drugs that would selectively inhibit some critical enzymes of
HIV such as reverse transcriptase and protease which are required for the
final packaging of this virus particle. Most current antiviral agents (purine
and pyrimidine derivatives) target reverse transcriptase inhibition to block
the transcription of HIV RNA genome to DNA and hence preventing
synthesis of viral mRNA and proteins (Figure 1). Protease inhibitors
affect the synthesis of late proteins and packaging (Figure 1). No currently
available drugs target the early protein synthesis.

o
oo
(Viral Release)

Fig (1). Major sites of action of current antiviral drugs.

486

KHALID A. EL SAVED

Antiherpetic Drugs

1-

2-

3-

4-

5-

6-

Acyclovir (1) is an acyclic guanosine derivative which is very
effective against Herpes simplex viruses (HSV)-l, -2 and Varicellazoster virus (yZW). It also shows in vitro inhibitory activities
against Epstein-barr virus (EBV), cytomegalovirus (CMV) and
human herpes virus (HHV)-6. Acyclovir requires three
phosphorylation steps for activation. It is first converted by the
virus-specific thymidine kinase to monophosphate derivative (hence
it is selective to the infected cells). Acyclovir monophosphate is
then converted by the host's cellular enzymes to di- followed by
triphosphate derivatives. Acyclovir triphosphate inhibits viral DNA
synthesis by competitive inhibition of GTP for the viral DNA
polymerase, irreversibly binding to DNA template and chain
termination after incorporation to the viral DNA. Valacyclovir is the
L-valyl ester of 1 which is rapidly transformed after ingestion to
acyclovir. Resistance to acyclovir can be developed in HSV and VZV
through alteration of viral thymidine kinase or DNA polymerase.
Famciclovir (2) is the diacetyl ester prodrug of 6-deoxy penciclovir,
an acyclic guanosine analog. Famciclover is rapidly converted to its
prodrug after oral ingestion. The latter is similar to 1 in the margin of
activity. It is also active in vitro against HSV-1, -2, VZV, EBV and
hepatitis virus B (HVB). Activation by phosphorylation is also
accomplished by the virus-specific thymidine kinase. Unlike 1,
Penciclovir does not induce DNA chain termination. There is a cross
resistance between 1 and penciclovir.
Ganciclovir (3) is a guanosine analog which also requires
triphosphorylation for activation prior to inhibiting the viral DNA
polymerase. Monophosphorylation is catalyzed by the virusspecific protein kinase phosphotransferase UL97 in CMV-infected
cells and by thymidine kinase in HSV-infected cells. Ganciclovir is
active against CMV, HSV, VZV and EBV. Its activity against CMV
is 100 fold more than 1 [13].
Foscamet (4) is an inorganic pyrophosphate derivative that inhibits
viral DNA, RNA polymerases and HIV reverse transcriptase (RT)
directly without the need of any activation steps. It is in vitro active
against HSV, VZV, CMV, EBV, HHV-6, HBV and HIV. Resistance
is developed due to mutation in the DNA polymerase gene [13].
Cidofovir (5) is a cytosine nucleotide analog which is active in vitro
against CMV, HSV-1, -2, VZV, EBV, adenovirus and human
papillomavirus. Phosphorylation of 5 is independent of viral
infection [13].
Sorivudine (6) is an investigational pyrimidine nucleoside analog
with an in vitro activity against VZV, HSV-1 and EBV. It requires
activation through phosphorylation by the virus-specific thymidine

Incorporation of trifluridine phosphate into both viral and cellular DNA prevents its systemic use but not its topical use. It is incorporated into both viral and cellular DNA and shows some animal teratogenicity [13].0 3Na^ CAN O /Ml ^^. It is in vitro active against HSV-1. AZT) is a deoxythymidine analog that also requires anabolic phosphorylation for activation. -2. It competitively inhibits DNA polymerase but does not incorporate into viral DNA.O'^ HO O P(OH)2 HO Foscamet (4) OH Cidofovir (5) 7- 8- HO Sorivudine (6) Trifluridine is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis. It also acts as a chain terminator in the synthesis of pro viral DNA. vaccinia virus (VV) and some advenoviruses. H2N N OAc Acyclovir (1) OH Ganciclovir (3) Famciclovir (2) Br O NH . HIV-2 and the . It is phosphorylated intracellularly by host enzymes to form ara-ATP which inhibits viral DNA polymerase. Vidarabine is an adenine arabinoside which shows in vitro activity against HSV. VZV and CMV.ANTIVIRAL AGENTS 487 kinase. It competitively inhibits deoxythymidine triphosphate for the RT. Antiretroviral Drugs [13] 1- Zidovudine (7) (previously azidothymidine. It is active against HIV-1.

High level of resistance is developed by mutation at codon 184.3-dideoxyadenosine-5-triphosphate which inhibits viral replication as 7.ELSAYED human T cell lymphotropic viruses. It requires metabolic phosphorylation as that of 7. 3- HO HO N3 Zalcitabine (9) Didanosine (8) Zidovudine (7) NHo NHo HO L 45- Stavudine (10) Lamivudine (11) Stavudine (10) is a thymidine analog that also requires a metabolic activation as that of 7. Mutation at codon 65 induces resistance which is associated with the decrease in susceptibility to 8 and 9. Resistance to 7 occurs due to mutation in RT gene. Lamivudine (11) is a nucleoside analog which in vitro inhibits HIV-1 and HBV. Zalcitabine (9) is a pyrimidine nucleoside that inhibits replication of HIV-1 in a similar mechanism to 7.488 KHALIDA. Didanosine (8) is a synthetic analog of deoxyadenosine. It is active against HIV-1. It is anabolically activated to 2. It inhibits HIV-RT and shows synergistic effect with 7 against HIV-1. Resistance is typically associated with mutation at codon 74. .

Systemic INF-a is currently approved in US for the treatment of chronic HBV and HBC infections. Unlike the rest of the other INFs. six of them are probably pseudogenes. immunomodulatory and antiproliferative agent. Saquinavir is a synthetic peptide-like analog that inhibits the activity of HIV-1 protease and prevents the cleavage of viral polyproteins. There are four laiown varieties of INFs: INFa. They are effective in prevention and treatment of influenza A infection in high risk individuals [13]. five of them are pseudogenes and a single INF-p gene. . uncoating. INF-y is encoded in a single copy gene with three introns and is designated as type II INF. which inhibits peptide initiation. Other Antiviral Agents 1- 2- Amanatdine and Rimantadine are the 1-aminoadamantane hydrochloride and its a-methyl derivative. These three INF subtypes are designated as members of a super family of type I (or oc/p) INFs. INFs are not direct antiviral agents but they act by causing elaboration of effector proteins in infected cells which inhibits the viral penetration. There are six INF-co genes. It is also clinically approved for the treatment of AIDS-associated Kaposi's sarcoma and laryngeal papillomatosis.Phosphodiesterase. It is metabolized by the hepatic P450 cytochrome oxidase system and hence suffers from several drug interactions. which degrades the terminal nucleotides of tRNA and thus inhibiting peptide elongation.ANTIVIRAL AGENTS 489 Protease Inhibitors [13] 123- Indinavir is a specific inhibitor of HIV-1 protease which is essential for the production of mature and infectious virions. Three known enzymes are induced by INFs: 1Protein kinase that leads to phosphorylation of elongation factor 2. INF. the INF-a family is composed of eighteen genes. In humans. Both compounds are cyclic amines that inhibit the uncoating of the influenza A viral RNA within the infected host cell and hence prevent its replication. Ritonavir is an inhibitor of HIV protease with high bioavailability. Their immunomodulatory effect may be additive to their antiviral effect. Each type acts as a potent complex antiviral. 3.Oligoisoadenylate synthase. mRNA synthesis and translation or virion assembly and release. which leads to activation of RNAase and degradation of viral mRNA. 2. It is currently clinically approved for treatment of HIV-1 infections.CO. Interferones (INFs) are a family of multifunctional endogenous polypeptides that exerts non-specific antiviral activities through cellular metabolic processes involving the synthesis of both RNA and proteins [13-15]. INF-p and INF-y.

the therapeutic index in a given viral system is calculated. Selection of the In Vitro Assays for Antiviral Screening of Natural Products Different cell culture-based assays are currently available and can be successfully applied for plant extracts and pure compounds. The therapeutic index is defined as a ratio of the maximum drug concentration at which 50% of the normal cells grovrth is inhibited to the minimum drug concentration at which 50% (sometimes 90 or 99%) of the virus is inhibited. respiratory syncytial virus (RSV).Literature-based follow up of the existing leads. The key factors that determine the selection of the assay system are: simplicity. Its triphosphate derivative inhibits the replication of a wide range of RNA and DNA viruses including influenza A and B. 3. paramyxovirus. After evaluation of the antiviral potency of a tested compound along with its cytotoxicity. The random approach usually affords more novel compounds with antiviral activity. PLANTS AS ANTIVIRAL AGENTS Introduction Selection of Plants for Antiviral Screening Four basic approaches are conducted for plant selection for antiviral screening assays: 1. The second and third approaches are the most favored ones because of their cost-effective applicability. reproducibility. The selection based on folkloric use proved five times higher percentage of active leads than other approaches. EL SAVED Ribavirin [13] is a guanosine analog that is intracellularly phosphorylated by the host cell's enzymes. HCV and HIV-1. Virucidal agents that extracellularly inactivate virus infectivity are rather candidates as antiseptics. selectivity and specificity [12]. Combining ethnomedical.Ethnomedical approach. parainfluenza. Antiviral agents that interfere with one or more viral biosynthetic dynamic processes are good candidates as clinically useful drugs.490 3- KliALID A. 2. Despite its mechanism is not yet fully elucidated. 4. . The relative potency of a new antiviral agent should be compared with an existing approved drug. phytochemical and taxonomical approaches is considered the best compromise.Random collection of plants followed by mass screening. it apparently interferes with the synthesis of guanosine triphosphate to inhibit capping of viral mRNA and some viral RNA-dependent polymerases.Chemotaxonomic approach [12]. accuracy.

Two useful animal models are usually employed: heterologus or homologus. To study a human CMV-induced disease in an animal model. it is uncertain whether animal models can be developed for all human viral infections. However. For example CMV infection is host specific. National Cancer Institute [2]. In heterologus systems. In vitro studies of 12 demonstrated activity against HIV-1 including AZT and other nonnucleoside RT inhibitors-resistant strains. Testing if the compound is reachable to the target organ without stability problems. phase la clinical trial of 12 was started to assess its safety and .e. HSV-l in rodents including mice. the homologus virus of that animal must be used. Examples of such systems are Herpes encephalitis induced by a human virus.16-23].ANTIVIRAL AGENTS 491 In Vivo Testing of Antiviral Agents In vivo testing of any new in vitro active antiviral agent is considered the key step before any human clinical trials. (-f)-Calanolide A (12) is a C22 coumarin isolated from the Malaysian rainforest tree. Several reviews have been published dealing with natural productsderived antiviral compounds [11. a homologus system is conducted. there are only two plant-derived compounds under clinical development [2]. Checking if the compound is well excreted and does not interfere with an animal's metabolic processes. rats and hamsters as well as genital herpes induced by HSV-2 in mice. Calophyllum langigerum by the U. a disease is induced by a virus from an animal origin in an experimental animal that mimics the human disease. Proving that the compound will resist and will not adversely affect the immune system [12]. The therapeutic index of any antiviral agent to be in vivo tested should be adequate so that appropriate. It also shows synergistic antiHIV activity in combination with nucleoside RT inhibitors: 7.12. It shows a potent HIV-RT inhibitory activity [2]. e. clinical development of 12 was started as a potential drug for treatment of AIDS. its total chemical synthesis was accomplished [2].S. Animal models are useful in: 1234- Detecting the effectiveness of the candidate compound as a viral inhibitor without inducing a viral resistance. Presently. This model should predict efficacy in human and should mimic the natural disease as close as possible. To overcome the difficulty of supply of 12. guinea pigs and monkeys.. non-toxic dose for the animal could be considered. i. human CMV only infects humans and mice CMV only infects mice. 8 and 9 [2]. In June 1997.S.. Some viruses are without convenient models. HBV and human papilloma virus which can be studied in non-human mammals only. A single -center 7-month U.g. In case of host specific viruses.

Provir.492 KHAUDA. the oral formulation of SF-SOB. These trials were later suspended as they proved virend to have no additional benefit over using oral acyclovir alone. SP-303 (13) is a mixture of natural oligomeric proanthocyanidins up to a molecular weight 2100 daltons. which is the topical formulation of 13. Virend. It shows potent in vitro activity against HSV and other varieties of DNA and RNA viruses. Many .ELSAYED tolerability [2]. However. ^OH J 9-11 OH (+)-Calanolide A (12): a-CHg P-CH3 H-CalanolideA(67): P-CH3 a-CHg Plant-Derived Antiviral Compounds Alkaloids Alkaloids are heterogeneous group of compounds linked by the common possession of a basic nature. It is isolated from the latex of a Latin American plant Croton lechleri [2]. Their precursors are usually amino acids and they exert certain biological activities. containing one or more nitrogen atoms usually in combinations part of heterocyclic system [11]. provir was proved effective in symptomatic treatment of traveler's diarrhea through restoration of normal bowel function and prevention of recurrences [2]. is evaluated in phase II clinical trials for the treatment of genital herpes in combination with acyclovir. is proved to be safe and well tolerated in phase I trials but ineffective in phase II for the treatment of RSV since there was no adequate absorption by patients.

1 Atalaniia monophylla Citrus sp. 10-OMe-camptothecin Schumaniophyton magnificum HIV Irreversible binding to gpl20 [12] Buchenavia capitata HIV Cytotoxic [30] Camptotheca acuminata HSV Cytotoxic DNA topoisomerase [12. Harmol (28) About 26 families MCMV Chroming: Schumannificine (29) FlavQiioid: O-Demethyl-buchenavianine (30) Indole: Camptothecin (31).25. 16] ApQrphing. Fagaronine (22). Pretazettine (17) Clivia miniata Narcissus tazetta HSV Cytotoxic Protein synthesis [24. 31] Castanospermum australe HIV Alexia leiopetala Glucosidase I [3234] HIV HIV-induced cell killing HlV-RT Indoliziding: Castanospermine (32). HSV Virus-coded riboucleoside reductase Viral DNAsynthesis [12] Lycorine (16). Oliverine (18). Harmane (27). Table 3. Table 1 illustrates various alkaloids with activity against many animal viruses. Pachystaudine (19). 1 36] . Harmine (26). PgnzQphgnanthriding: Chelidonine (21). B (33). Nitidine (23) Chelidonium majus Fagara xanthoxyloides Xanthoxylium sp. Alexine Naphthylisogviffoling: 1 Michellamincs A. P-Carboline: BrevicoUin (24). Citrusinine I (15) Source rence 1 Amaryllidaggag. Oxostephanine (20) Polyalthia oliveri HSV Pachypodanthium staudi Stephania Japonica Late protein synthesis Assembly of virions [26] HSV HIV-RT Cytotoxic/ Cell protein synthesis [2729] sv. 6-Canthinone (25). C Ancistrocladus korupensis [35.ANTIVIRAL AGENTS 493 alkaloids are also found in animals and humans where they could exert a profound pharmacological activity [11]. Late protein synthesis Viral replication [H] Acridone: Atalaphillidine (14). Antiviral Plant-Derived Alkaloids Alkaloid: Type & Name Activity Against Mechanism/ Inhibition Refe.

ELSAYED (Table 3). 39] Castanospermum australe HIV Glucosidase I [12] Cephalis ipecacuanha Haplophylum tuberculatum Euodia oxburghiana HSV HIV-RT HIV-RT Cytotoxic/Prote in synthesis HIV-RT HIV-RT [16. Columbamine 1 (42). Psychotrine (46). Scopolamine (49) OH OCH3 Atalaphillidlne (14) Citrusinine I (15) Lycorine (16) . 1-Deoxynojirimycin (38). Codeine (35).. contd. Alkaloid: Type & Name Source Activity Against Mechanism/ Inhibition Reference 1 Papaver somniferum HSV Non-specific at subtoxic concentration [16] Boehmeria cylindhca HSV Cytotoxic/ cell protein synthesis [37] Omphalea diandra HIV Corydalis cava HIV-RT HIV-RT [29. Buchapine (47) Trpp^n^: 1 Atropine (48). 41] Opium. 38] Protoberberine: Berberine (41).494 KHALIDA. Morphine (34). lDeoxymannojirimycin (39). 40] Atropa belladona Datura stramonium HSV Viral protein glycosylation Non-specific at subtoxic concentration [16. a-Homonojirimycin (40) Glucosidase I Mannosidase I [12. Palmatine (43) Pvrrolizidine: 1 Austral ine (44) Ouinoline/Isoquinoline: 1 Emetine (45). Papaverine (36) Phenantl iroquinozolizidine: Cryptopleurine (37) Pipgriding. 29.

= H: R2 = CH3 Nitidine (23) Ri = R2 = CH2 Chelidonine (21) BrevicoUin (24) 6-Canthinone (25) Harmine(26) R = OCH3 Harmane (27) R = H Harmol (28) R = OH HO. Rg = OCH3 HQ OR2 CH3 Fagaronine (22) R. OH O Schumannlflcine (29) O-Demethylbuchenavianlne (3(» Camptothecin (31) .ANTIVIRAL AGENTS 495 H3CO4 ••IN—CHq \ HO" Pretazettine (17) Oliverlne (18) Ri = H. R2 = H Pachystaudine (19) Rj = OH.

R2 = a-OH l-Deoxymannojirimycin (39): R. R2=P-OH a-Homonojirimycin (40): Ri = CH20H.496 KHALIDA. = H.ELSAYED OH OH HQ HO Castanospermine (32) OH = Michellamine (33) HX HN—CH3 H3CO' OCHo HO Morphine (34) R = H Codeine (35) R = CH3 Papaverine (36) OCH3 OH nr ^fi' 1-Deoxjmojirimyclne (38): Ri = H. I\j=a-OH Cryptopleurine (37) .

HIV-RT. R2 = -CHgColumbamine (42) Rj = CH3.ANTIVIRAL AGENTS 497 RiO. = R2 = CH3 H3CO. . R2 = Epoj^ Carbohydrates Many plant-derived carbohydrates exhibited in vitro inhibitory activities against HIV. H3CO' H3CO' oa: Emetine (45) Psychotrine (46) H3C—N^^^ -\J 8 k"^ O—C-CH' ^OH Buchapine (47) Atropine (48) Ri = R2 = H Scopolamine (49) Rj. OH OH RoO' OCHo OCHq Australine (44) Berberine (41) Rj. H3CO. Table 4 summarizes the antiviral activity of plant and some non-plant carbohydrates. CMV and HSV. R2 = H Palmatine (43) R.

Hippeastrum hybrid. [12] [46] Reference Monosaccharides: Glucosamine (50) Polysagcharidgs. Prunellin. & Dahlia sp. Gigartina sp. Chondrus crispus. Epipactis helleborine. Immunostimulation: Acemannans [12] [18] [4345] Cymbidium hybrid. Viola yedoensis HIV HIV Interaction with gpl20. pacifica. Schizymenia dubyi.ELSAYED Table 4. Arabinoxylans: MGN-3 (51) Syiphatg(j pQlysaggharicJgs. Increase T & B cell mitogen response [42] Aloe sp. Mannan sulphate (58) Lectins: Mannose specific lectins \ L> ^ L „ ^ L . Dextran sulphate (55). Sea algal extract (SAE) y-carragenan.. Syncytium formation. Prunella vulgaris. Dextrin sulphate (56). Syncytia formation. M. Syncytium formation. HSV Gylycolipid glycoprotein syntheses and [18] Rice bran enzymatically modified with Hyphomycetes mycelia HIV HIV replication.498 KHALIDA. 1 r e" ^^y^^Xi^ HO^"^ 5. Gerardia savaglia HIV CMV Cell fusion of HIV replication. Acemannan. Curdlan sulphate (52) Fucoidan (53) NON PIANT ORIOINS: Heparin (54). Alternanthera philoxeroides.. Listeria ovata. Antiviral Plant-Derived Carbohydrates Carbohydrate: Name Type & Source Activity Against Mechanism/ Inhibition Glycine max. S. lunatus. Blocking the binding of gpl20 to CD4 receptor. Virus attachment. Pentosan polysulphate (57). Machaerium biovulatum.OH 0- OH "^VTN NH2 Glucosamine (50) _ [-X„" K^^ OR 1 OR Curdlan sulphate (52) R = H or SO3 0- MGN-3 (51) _ n I r TSL/l\ RO 1 1/ OR Fucoidan (53) R = H or SO3- | | .

coumarins and flavonoids. Coumarins are specifically abundant in the families Rutaceae and Umbelliferae [11]. Heparin (5^ Dextran sulphate (55) R = HorS03- I—OR I OR Dextrin sulphate (56) R = H or SO3" OR Pentosan polysulphate (57) R = H or SO3- OR Mannan sulphate (58) R = H or SO3- Chromones. The yield could sometimes reach up to 1% of the dry plant weight.ANTIVIRAL AGENTS 499 ^y OR oso. R2 KheUln(59) Visnagin(60) R2 Ri I^ OCH3 OCH3 H OCH3 Ri R2 Psoralen (61) H H Isopimplnellln (62) OCH3 OCH3 Angelicin (63) OH Coriandrin (64) Glycycoumarin (65) . Coumarins and Flavonoids Chromones. furanocoumarins and flavonoids are common constituents in many plant families. Table 5 illustrates various antiviral activities of chromones.

500

Table 5,

KHAL1DA,ELSAYED

Antiviral Plant-Derived Chromones, Furanocoumarins and Flavonoids

Type & Name

Source

Activity
Against

Mechanism/ Inhibition

Reference

Ammi species
(Umbelliferae)
Coriandrum
sativum

DNA, RNA
viruses and
Bacteriophages
HIV

Cross linking viral
DNA
Adds
to
viral
pyrimidines (in DNA)
and uridines (in RNA),
forming cycloadduct

[11]
[21]

Glycyrrhiza
glabra

HIV

Giant cell formation

[47]

Calophyllum
langigerum
C. teysmannii
C. inophyllum

HIV-RT

HIV-RT

[48]
[49]
[50]
[12]

FiavpoQidg;
Anthocyanins: Cyanidin
(71), Pelargodin (72)

Many sp.

HSV

Virucidal

[12]

Catechins: Catechin (73)

Many sp.

HSV

Virucidal

[12]

Many sp.

HSV

Virucidal

[12]

HSV
HIV-RT
Picornavirus,
e.g., rhino &
coxsackie V.
HSV-1, CMV
& Poliovirus
HIV
HIV
HIV-RT

Virucidal
HIV-RT

[12,
21]
[51]

ClirQmQngg m i Cownarins;
Khellin (59), Visnagin (60),
Psoralen (61), Isopimpinellin
(62), 8-Methoxypsoralen,
Angelicin (63),
Coriandrin (64)
Glycycoumarin (65),
Licopyranocoumarin (66)
Calanolides A (12), B (67)
(Costatolide), Soulattrolide
(68), Inophyllums A (69), B,
C, D(70)and E

Flavanones/
Dihydroflavano-ls: Naringin
(74), Hesperetin (75),
Taxifolin (76),
Dihydrofisetin

Flavones/Flavonols:
Apigenin (77), Luteolin Many sp.
Plantago sp.
(78),
Luteolin-7-glucoside, Morin, Euphorbia
grantii
Quercetin (79),
Agasiache
Quercetagistrin,
rugoza
Quercimeritrin, Quercetrin,
3-Methoxyflavones, 4',5- Callicarpa
japonica
Dihhydroxy-3,3\7Glycyrrhiza
trimethoxyflavone (80)
glabra
5,6,7-Trimethoxyflavone
Many sp.
Glycyrrhizoflavone (81)
Myricetin ('<2), Kaempferol Many sp.
(83), & their 3-O-glucosides
Baicalein (84),
6-Hydroxyluteolin (85),
Pedalitin (86),
Scutellarein (87), Quercetagetin (88), Gossypetin (89),
6-Hydroxykaempferol (90)
Isoflavones/Isofalvonols:
5-0-Methylgenistein-7glucoside (91)
Isolicoflavonol (92)

Ulex europaeus HSV
HIV
Glycyrrhiza
glabra

Giant cell formation
Viral
replication,
synergistic
with
acyclovir
Selective interaction
with gpl20
HIV-RT

Uknown
Giant cell formation

[52]
[53]
[54]
[55]
[56]
[57]
[47]
[12,
21]
[58]

[59]
[47]

ANTIVIRAL AGENTS

501

(Table 5). contd...

Type & Name
Chal cones:
Licochalcone A (93)
Flavans:
(-)-Epicatchin-3-0-gallate
1 (94), Epicatchin (95),
Biflavones:
Amentoflavone (96)
Flavanone-Xanthone:
Swertifrancheside (97)

Source

Activity
Against

Mechanism/ Inhibition

Reference

Glycyrrhiza
glabra

HIV

Giant cell formation

[47]

Many sp.

HIV

Selective interaction
with gp 120

[12]

Viburnum
prunifolium

HIV-RT

HIV-RT

[12]

Swertia
franchetiana

HIV-RT

HIV-RT

[60]

HO

Ucopyranocoumarin (66)
Ri

SoulattroUde (68)
Inophyllum A (69)
Inophyllum D (70)

Ro

Ro

OH H a-CHo
OH H P-CH,
H
OH P-CH3

OH
OH
OH
HO
HO,

OH
Cyanidin (71) OH
Pelargodin (72) H

502

KHALIDA.ELSAYED

HO.

Ri

Naringin(74)
H
Hesperetin (75) H
Taxifolin (76)
OH

H
^
OH
OH

OH
OCH3
OH

4'. 5-Dihydroxy-3.3'. 7tiimethoxy flavone (80)
5- O-Methylgenlsteln-7glucoside (91)

HO,
OH

OH

Quercetin (79)
Myricetin (82)
Kaempferol (83)
Quercetagetin (88)
Gossypetin (89)
6-Hydroxykaerapferol (90)

Glycyrrhizoflavone (81)

Ri
H
H
H
OH
H
OH

R2
OH
OH
H
OH
OH
H

HO,

OH
Apigenin (77)
Luteolin (78)
Baicalein(84)
6-Hydroxyluteolin (85)
Pedalitin (86)
Scutellareln (87)

Ri
H
H
OH
OH
OH
OH

R2
H
OH
H
OH
CH3
H

R3
OH
OH
H
OH
OH
OH

OH
HO,

Ucochalcone A (93)

(-)-Epicatchln-3-0-gallate(94) o c '
(-)-Epicatchln (95)

R3
H
OH
H
H
OH

resin and bark trees [11]. Benzoic acid derivatives: 1 Woodorien (108) Source Activity Against Podophyllum HSV HIV peltatum Influenza A Amanoa oblongifolia HIV-1 Forsythia intermedia VSV Ipomea cairica Pinus sp. There is an evidence that lignans play a major role in plant-plant. Suppression of integration of proviral DNA into cellular genome. Podophyllotoxin (99) & its deoxy analog (-)-Arctigenin (100). Wt. Phenolics. nucleic acid metabolism. B.1 Cytotoxic. D. (-)Trachelogenin (101). They are also found in many roots. Replication/microtubule formation. Compounds KS-6 & KS-7-Rhinacanthins F (102) &E(103) Termilignan (10 4 ) . Diphyllin aposide PbgnQlJgs. P. parvijlora Rhinacanthus nasutus Terminalia bellerica Justicia procumbens Woodwardia orientalis HSV Mechanism/ Inhibition Refe. Antiviral Plant-Derived Lignans. Swertlfrancheside (97) Amentoflavone (96) Llgnans. fruits and seeds [61]. 67] [68] [69] [70] Uknown [59] rence . Diphyllin. They occur in many parts of plants especially wood.ANTIVIRAL AGENTS 503 OH HO. Thannilignan (105). flowers. C and their 6'-0-gIucosides. Anolignan (106) Justicidin A (107). 3-0Demethylarcetagenin. early stage of replication. Phenolic. HIV-RT Unkown [62] [63. High M. The chemical structures of Table 6. leaves. plantinsect and plant-fungus interactions [11]. Quinone/Xanthones and Phenyipropanoids LIgnan/: Type & Name Phenolic/qulnone/Xan-thone Lignans: a-Peltatin (98). Qulnone/Xanthone and Phenylpropanold Compounds Lignans are widespread secondary metabolites in plant kingdom. disruption of cellular microtubules. 64] [65] [66.

73. HIV Virucidal [71. Mallotusjaponicus 1 Mallotochromene (121). 1 Balanocarpol (125) Ouinones/Xanthones: 1 Anthraquinones/ 1 xanthones: 1 Aloe-emodin (126). B. Eucalyptus grandis 1 Mallotojaponin (122) Macrocarpal A (123).74] [75.000) Synthesis in presence of peroxidase & H202 HIV Virucidal Binding of gp 120 to CD4 HIV-RT Unknown 1 1 1 1 Combretum micranthum HIV Viral penetration [12] Potomorpha peltata HIV Unknown [77] HSV HSV HIV HIV Cytotoxicity Cytotoxic HIV-RT HIV-RT [78. 72] Many sp.504 KHALIDA.5-Di-O acid. Synapoic acid Gallic acid derivatives: Methylgaltate(113) 3. 3.Eucalyptus grandis 1 chromanol (117).4. Chinesin II Hypericum Chinese (120). Methoxyresorc. Sessili.C 1 Phloroglucinol derivatives: 1 Sessiliflorene (115). HSV Topically used [84] 1 acid Catechinic derivatives: Alkaline auto-oxidised catechinic acid Comps.B.Meiicope sessiliflora 1 inol analogs. Isomalloto. Euglobal 03 (118) polycephaloides.Syzygium 1 chroman.4. 1 Mangiferin (127) . Binding of gp 120 to CD4 HIV-RT [16. caffeoylquinic acid. Securidaca longipedunculata HSV HIV Virucidal.Mallotusjaponicus 1 florol (116). Lignan/: Type & Name Phenolic/quinone/Xan-thone Binaphthalenes: (-)-GossypoI (109) & its analogs Caffeic acid derivatives: Caffeic acid (110). Butyrylmalloto. Chlorogenic acid (111) & its butyl ester. Rosmarinic acid (112). (ACK^A) Catechols: PeltatolsA(114).5-Tri-(9-caffeoyl-quinic 4. 79] [80. KOP (Caffeic acid oxidised polymer). Syzygiol (119).. contd.5-Tri-O-gaHoylquinic Source Activity Against Mechanism/ Inhibition Reference Gossypium sp. C.ELSAYED (Table 6). E 1 Oligostilbenes: 1 Dibalanocarpol (124). 76] Dehydrogenation polymers 1 of cinnamic derivatives (MW 1 800-150. Cellular DNA metabolism. 76] HSV Sabium sebiferum Guiera senegalensis HIV [12] [75. 712] 1 D. 81] [12] [82] Hopea malibato HIV Unknown [83] Many sp.

Plumbagin (131). benzoquinones. Presently. naphthoquinones. Phenolics. monoepoxylignans (tetrahydrofuran derivatives).ANTIVIRAL AGENTS 505 (Table 6). lignanolicles (butanolides). Table 6 illustrates the reported antiviral activities of these plant secondary metabolites.3. cyclolignans (tetrahydronaphthalenes) and cyclolignans based on naphthalene [11]. P2 5 H3C HaC H3CO' 0R3 R2 R3 a-Peltatin (98) H OH H CH3 Podophyllotoxln (99) OH H OCHq R H (-)-Arctigenin (100) (-)-Trachelogenin (101) OH . contd. H. anthraquinones and phenylpropanoids are abundant secondary metabolites in plants. p-lapachone (132) Conocurvone (133) Isoeleutherol (134). B (136). Isoverbascoside (139) Markhamia lutea RSV lignans are diverse and complex despite they are essentially dimers of phenylpropanoid units (C6-C3) linked by the central carbons of their side chains [11]. bisepoxylignans (3. Eleutherin americana Non-specific at subtoxic doses No virucidal effects Unknown Uknown [16] Intracellular mechanism [89] [87] [88] PhgpylprQpanQJds: Luteosides A (135).0)-octane derivatives). Verbascoside (138). C (137). Isoeleutherin Source Activity Against Mechanism/ Inhibition Reference Hypericum triquetrifolium. Lignan/: Type & Name Phenol ic/quinone/Xan-thone Naphthodianthrones: Hypericin (128). HIV Conospermum sp. Photosensitizers Viral & virion assembly [12] [85] [86] HSV Juglans regia HIV Drosera sp.7-dioxabicyclo(3. HSV HIV Non-specific union with viral & cellular Memberanes. perforatum Hypericin sp. there are six lignan subgroups: butane derivatives.. Pseudohypericin (129) Naphthoquinones: Juglone (130).

A 7 .ELSAYED Ri Termilignan (104) OH Anolignan B (105) H Rg OCH3 OH Rhinacanthin-F (102) Rhinacanthin-E ( 1 0 3 ) . 8 E H3C OH ^<?^ ^OCHq H3CO' HO' Thannllignan (106) Justicidin A (107) OH / OH ^ ^ CHO OH OH CHO OH HO' COOCH3 Woodorien (108) (-)-Gossypol(109) HOOC HO H COOH Caffeic acid (110) HO' txx.506 KHALIDA. f OH Chlorogenlc acid (111) .

ANTIVIRAL AGENTS 507 COOH HO ""-Ki^^y^ HO Rosmarinic acid (112) Methylgallate (113) SessiliHorene (115) OH PeltatolA(114) OH O HO HO H3CO Butyrylmallotochromanol (117) SessilifloroKllG) O O H3CO OH EuglobalG3(118) Syzygiol(119) OH .

OCHq OH Mallotochromene (121) Chinesin 11 (120) CHO OH OHC OCHo Macrocarpal (12^ Mallotojaponin (122) OH OH HO' HO Dibal£inocarpol (124) .508 KHALIDA.ELSAYED HO.

ANTIVIRAL AGENTS 509 OH HO O OH OH Aloe-emodln (126) OH HO' HO^ ^^ ^O^ OH Glc Balanocarpol (125) HO OH O Mangiferln (127) OH I : OH I O Juglone (130) H Plumbagin (131) CH3 P-lapachone (132) OH O OH R Hypericin (128) CH3 Pseudohypericin (129) CH2OH OCH3 OH Isoeleutherol (134) Conocurvone (133) .

pentagalloylglucose. dry weight of tannins which are mainly constructed from caffeic acid. Geraniin (142). Leaves of this plant contain about 5%. Glycohydrolase (gene transcriptase) HIV-RT [91] [92] [93. Camellin B (148). The condensed type is similar to flavonoids. which is linked to sugar. Hepta & Octagalloylglucoses Ellagic acid (152).g. Agrimoniin (150).3. Pavetannins. Gemin D (146). Antiviral Plant-Derived Tannins. Cinnamtannins. Trapanin B(149) Gallitannins & Ellagitannins: 143. Terpenoids are also abundant secondary metabolites Table 7. Coriarin A (151). Galloylated epicatechin oligomers. Camellia japonica Trapajaponica Many sp. Punicaliin (144 ). Terminalia chebula Geum japonicum Tibouchina semidecandra. Genothein B (143). Coriariin.4-Tri-O-gaIloylquinic 3. Punicallagin (145). Eugeniin (141). Steroids and Iridoids Tannin/: Type & Name Terpene Source Activity Against Mechanism/ Inhibition Refe. gallic acid.. Sanguin. e.510 KnALIDA. Comberetum micranthum. Agrimoniin. Punica granatum . The known medicinal tannin-containing plant lemon balm (Melissa officinalis. Nobotanin B (147). Labiatae) is extensively studied as antiviral agent [11]. Terpenes.g. Pavetta owariensis. Basically. galoylated (-)-epicatechin 4.ELSAYED Tannins. Digallic acid (153). Hy4rQ|ysql?lg tftunins: Chebulagic acid (140). Cas-uarictin. 94] [95] [12] [17] [96] [97] [98] [99] [100] HSV HIV-RT HSV-2 Virucidal Penteration in the cell HIV-RT Virucidal [91] [101] [102] [103] [104] [105] rence 1 Tanning. Galloyl catechin and epicatechin. galloylshikimic acid (155) 1 1 1 1 Condensed tannins: CatgghinJg acid (156) condensed tannins. Many sp. e. Terpenes. Hydrolysable type which usually consists of simple phenolic acids. The effect of this cream in the topical treatment is statistically significant as proven by clinical studies [90]. This is a decisive indication that constituents and /or extracts of plants could serve as useful leads for developing the antiviral drugs for the future. 140.1 HSV HIV HIV-RT Virucidal Attachment to CD4 rece-ptor. Procyanidin B2 (157). 1. A cream containing 1% of a specially prepared dried extract from lemon balm leaves has been introduced to the German market for local therapy of herpes infection of the skin [90].. Steroids and Iridoids Tannins are phenolic compounds that are abundant in plant kingdom. there are two types of tannins. Cinnamomum sp. Galloylgeraniin. Poly (ADP-ribose).8trimer(158) Many sp.5-Di-O acid (15 4).

Gleditsia saponin C (173). Betulinic acid (178) & its analogs. Calcium eienolate. Saikosaponin G (163). triterpenes. These are classified into: monoterpenes (CIO).. Glycyrrhiza glabra Glycine max. Terpenoids are essentially derived from the basic 5-carbons isoprene unit. Scopadulin Tritgrpgng sapQnins: Aescin. Topical treatment [107] [108. contd. 2a. Ursonic acid (164). Geum japonicum Syzygium claviflonim Panax ginseng Rosa woodsii & Hyptis capitata Tritgrpgng §tgr<?i4s: 1 1 1 1 Digitoxin. Dammarenediol 11 (161). its sulphate & analogs Soya saponin Bl. Glycyrrhizin (162). Pomolic acid (182) & other related triterpenoids Anagallis arvensis HSV Dipterocarpaceae HIV Gierocarpus HSV-1 inthcatus HIV Glycyrrhiza glabra Bupleiirum falcatum Woodwardia ohentalis Maesa lanceolata Myrsine sp. 22-Hydroxyhopanone (169). Isofouquierol (168). . Nigranoic acid (185). 113] [114] [115] [116. Ecdysterone (172). Oleanane glycosides. Protoprimulagenin (165) & its glycosides. Ursolic acid (176). Maslinic acid (177). Pterosterone (171).19a-dihydroxy-3-oxo-12ursen-28-oic acid (175). 162. Gleditsia japonica Gymnocladus chinensis. Tannin/: Type & Name Terpene Source Activity Against Mechanism/ Inhibition Reference Sulphated tannins: Semi-synthetic HIV Attachment to CD4 receptor [106] Cannabis sativa Olea europaea Scoparia dulcis HSV Virucidal membrane effect. diterpenes (C20). 122] [123] [124] [125] Digitalis HSV purpurea HIV-RT Maprounea ajricana Shisandra sphaerandra. 1 59] [117] [118] [43] [12] [116] [119] [120] [121. Cyclobuxamine H(187) 1 Iridoids: Fulvoplumerien (188) HIV-RT in plant world. 109] [110] Viral DNA synthesis Viral capsidation Virus absorption Protein kinase C Virucidal. sesquiterpenes (CI5). Digitoxigenin (183) 1-p-Hydroxyaleuritolic acid 3-/?hydroxybenzoate (184).ANTIVIRAL AGENTS 511 (Table 7). Ponasterone A (170). Chikusetsusaponin III (180) Oleanolic acid (181). Platanic acid (179). late proteins synthesis Unknown [12] [111] [16] [112. Gymnocla-dus saponin G (174). Buxamine E (186). Buxus sempervirens Uknown HIV-RT [16] [50] [126] Plumeria rubra HIV-RT [29] Terpencs: Mono & Diterpenes: A^-Tetrahydrocannabinol (159). saponins. sterols. Eichlerianic acid (166) Shoreic acid (167). Scopadulcic acid 1 B (160).

ELSAYED cardiac glycosides (basically all are C30) and carotenoids (C40). terpenes and iridoids are reported in table 7. Iridoids are also common plant secondary metabolites. The antiviral activities of tannins. RjO '"^^"^^XY HO LuteosideA(135) Luteoside B (136) Luteoside C (137) Verbascoside (138) Isoverbascoside (139) Ri H Caf Ac Caf Fer R2 Caf H Caf H H R3 H H Api Api Api X o—c S^OH HO HOH2C OH Api = Apiosyl Caf=Caffeoly. R: CH3 OH OH OH OHHO OH HO ^= 0= C C=:0 HOO( Chebulagic acid (140) .512 KHALIDA. R:H Fer = Feruloyl.

/r-i^ ' 0=:C HO^I I HO Geraniin (142) hw 'O L.0 OH -O OR2N O 6 / OH HO OHHO OH OH HO OH Eugeniin (141) OH HO OHHO OH HO OHHO OH HO OH I I OH -7.^CY OH t=o / ^ N OH OH .ANTIVIRAL AGENTS 513 OH OH R.

ELSAYED OH Punicallin (144) I J OH Gemin D (146) Oenothein B (143) o Np=o .514 KHALIDA.

515 ANTIVIRAL AGENTS OH OH "V^ Nobotanin (147) "O OH HO OH HO Trapanin B (149) OH OH OH O OH .

>^„ HO O^ OH OH HO OH OH HO—/ "^ \ ^ ^—OH OH HD ^ ^^^ OH 'HO^Q^HO-M HO OH OH HO CoriarinA(151) HO COOH OH HO HO HO Digallic acid ( 1 5 ^ EUagic acid (152) COOH Galoyll-O^^ ^COOH HO^ G A GaloylO^ OGaloyl OGaloyl 1.3.5-Di-O-galloylshikimic acid (155) .4-Tri-O-galloylquinic acid ( 1 5 ^ ^ ^ ^OGatoyl OH 3.KHALIDA.ELSAYED 516 OH HO HO HO OH H3 OH OHHO OH Agrimonlin (150) OH OH O HO OH .

8-tiimer (158) ''COOH OCOCeHs A-Tetrahydrocannabinol (159) HO Dammairenediol II (161) Scopadulcic acid B (160) .517 ANTIVIRAL AGENTS OH OH OH HO. O-Galoyl OH Galoylated (-)-epicatechin 4. OH OH OH Catechinlc acid (156) 'OH OH Procyanidin B2 (157) OH CgH.

A^^*^ Protoprimulagenln (164) R = OH Glycyrrhlzln (162) COOH HO- Ursonic acid (165) Elchlerlanlc acid (166) Shoreic acid (167) -C(CH3)20H H H -C(CH3)20HJ OH HO Isofouquierol (168) 22-Hydroxyhopanone (169) .KHALIDA.ELSAYED 518 HOOQ COOH I ^ ''' CHpH HO^ 1 I OH OH '^^COOH Saikosaponin G (163) R = H.

Ponasterone A (170) Pterosterone (171) Ecdysterone (172) H H OH H H OH •tr> V HOH2 ^^ *''' HO^**^^ Gleditsia saponin C (173) Gymnosladus saponin G (17^ . R .ANTIVIRAL AGENTS 519 HO^ Ij ^" HO^ H 11 R.

ELSAYED COOH COOH HO. 2a. 19a-dihyclroxy-3-oxo.520 KHALIDA.12-ursen28-oic acid (175) Ri UrsoUc acid (176) P O H Masllnic acid (177) a-OH PomoUc acid (182) p-OH R2 H OH OH HO Betulinlc acid (178) R = H2 latanic acid (179) R = 0 .X Digitoxigenin (183) HO COOH HO l-p-Hydrojgraleuritolic acid 3-p-hydro^benzoate (184) Nigranoic acid (185) \ H Buxamine B (186) .

phenyl. Bidens spp. lactones. Antiviral Plant-Derived Thiophenes. Phosphatidylethanolamine. . polyacetylenes.^^^^ H Cyclobuxamine H (187) Fulvoplumerien (188) 1 Thiophenes. thiophenyl. Umbelliferae and Campanulaceae [11]. Pofyacetylenes. The antiviral activities of thiophenes. Polyacetylenes occur principally as straight chain polyines. Polyacetylenes. Butenolides and Phospholipids Compound: Type & Name Thiophenes & Polvacetvlene: la-Terthienyl (a-T) (189) Thiarubrine A (190) Thiophene-A (191) Phenylheptatriyne (192) |ACBP-Thiophene(193) Source Chenactis douglasii Tagetes sp.1 rence Photo-oxidative damage (UVA. Activity Against HIV CMV HSV Mechanism/ Inhibition Refe. Lactones. butenolides and phospholipids show antiviral activity. Butenolides and Phospholipids About seven hundred polyacetylenes have been isolated so far mainly from plants belonging to the family of Asteraceae..%NH2 COOCH3 y^'^ 0 i 1 . 1 1 1 •LJi 1 1 1 ^ Jl 1 ^2^ s v. Phosphatidyl inositol (196) . HIV Accumulation of toxic metabolic products into the HIV memberanes [12] [128] Phosphlipids: Phosphatidylcholine..521 ANTIVIRAL AGENTS f V . Few plant-derived lactones. Lactones. thioether and spiroketal-enoether derivatives in a quite high yield. Thiophenes and related sulfur compounds are usually grouped together with the polyacetylenes because of their common biosynthetic pathways [11]. Table 8. butenolides and phospholipids from plant origin are reported in table 8. 320-400 nm)of viral unsaturated membranelipids and associated proteins [11] Protolichesterinic acid (194) Citraria islandicm HIV-RT HIV-RT [50] Cochinolide (195) Homalium cochinchinensis HSV-1 & 2 Unknown [127] Many sp. allenes.

KHALIDA. Several groups of plant proteins exhibit fairly non-specific antiviral activity. These constitute: .ELSAYED 522 r\-f\-r\ ^^^nv^^% a-Terthienyl (a-T) (189) Thiarubine A (190) ^4>^-^ 0 ^ ^ ^ Phenylheptatriyne (192) Thiophene-A(191) —^^-^xc ACBP-Thiophene (193) HO^ "^^ Protolichesterinic acid (194) "O" ""'0 CochinoUde (195) Phosphatidylinositol (196) HO Proteins and Peptides Plants are endowed with a multitude range of proteins and peptides.

the A and B chains. inactivates ribosome function. bryodin 2 from Bryonia dioica [129] and Bougainvillea antiviral protein I (BAP I) from Bougainvillea spectabilis root [130]. Additional proteins (PAP-II and PAPs) were found in relative smaller amounts. other RIPs were found in other plants and exhibit similar antiviral activity. Lectins These cell-agglutinating proteins have been reported active against certain membrane-containing viruses.ANTIVIRAL AGENTS 523 Single-chain (Homologous) Ribosome-Inactivating Proteins fRIPs> Since 1925. enters its cell cultures and inactivate its ribosomes [11]. Other examples for these toxins are: lentil lectin . extracts of the pokeweed plant {Phytolacca americand) were shown to selectively reduce the infectivity of tobacco mosaic virus (TMV) without demonstrable effect on the host cell. PAP also shows activity against the mammalian viruses HSV and poliovirus. PAP also was found to have anti-HIV activity through the inhibition of translation topisomerase [131-133]. Chain A.000 dalton molecular weight. These three toxins inhibit the TMV in a similar manner to PAP-related RIPs [11]. Dimeric Ribosome-inactivating Proteins These cytotoxic glycosylated proteins consist of two distinct polypeptide groups. The B chain is responsible for initiating the cytotoxicity. each constitutes about 30. tricosanthin from Trichosanthes kirilowii [11]. Ricin (from Ricinus communis seed). Unlike the single chain RIPs. momordin from Momordica charantia seed. which seems to be homologous to the single chain RIPs. A protein of molecular weight 29. On the other hand. Ricin was shown to decrease the latent HSV-1 infection in trigeminal ganglia of HSVimmunemice [11]. saporin from Saponaria officinalis seed. dianthin from Dianthus caryophyllus leaf. from Canavalia ensiformis) was found to inactivate HSV. southern bean mosaic virus and cucumber mosaic virus in plants. Subsequently. tritin from Triticum aestivum seed. Concanavalin A (con A. The antiviral spectrum of PAP includes: TMV.000 daltons designated poekeweed antiviral protein (PAP) was purified from the leaf extract [11]. The possible mechanism of RIPs by which they inhibit viral growth is through inactivating the large subunit of eukaryotic ribosomes (except for the donor plant ribosomes).g.. influenza virus and CMV infectivity and also found to interfere with the viral replication [11]. vesicular stomatitis virus (VSV). abrin (from Abrus precatorius seed) and modeccin (from Adenia digitata root) are examples of these toxins. Both chains are attached to each other by a disulfide bond. e. this dimeric type is equally toxic to uninfected and virus-infected cells. PAP was found to bind irreversibly to poliovirus. gelonin from Gelonium multiflorum seed.

AVF Is a glycoprotein which is terminally phosphorylated with 22. phytothemagglutinin (from Phaseolus vulgaris) and wheat germ agglutinin (from Triticum vulgaris). which all shown to abolish HIV-linfectivity[ll]. The mechanism of action of AVF is not yet established. Oligopeptides Many plant-derived di. Aportinine is known to be a protease inhibitor. It acts by interfering with the essential step of cleavage of the precursor Hao into subunit polypeptides and hence prevents the viral infection [11]. Aprotinine Aprotinine is another plant-derived antiviral polypeptide which specifically inhibit myxoviruses especially influenza A.and tri-peptides were proved to be active against HSV and measles virus (MV). isolated from the leaves of Melia azedarach (Meliacea) [11. prophylactic . Cationic peptides and proteins are now proceeding through clinical trials as topical antibiotics and antiendotoxins [136]. polio virus. In most cases.134].524 KIULID A. Meliacin Meliacin is an antiviral glycopeptide of molecular weight 5000-6000 daltons. These peptides consist mainly of carbobenzoxy derivatives of phenylalanine [11].000 daltons molecular weight. Antiviral Factor (AVF) Some varieties of Nicotiana glutinosa produce a protein called AVF which afford some protection against TMV by restricting its lesions in an analogy manner to interferons [11]. Cationic peptides are used as nature's antibiotics. the assay methods are designed to detect virucidal. HSV-1. Plant Extracts Several thousand plant extracts have been shown to possess in vitro antiviral activity with little overlap in species between studies. being produced in response to an infection in virtually most organisms including plants and insects. The activity of this glycopeptide is displayed against VSV. EL SAVED (from Lens culinaris). SV and foot and mouth disease virus (FMDV). Its mechanism of action was proposed recently through the prevention of uncoating process of virus and not through the virucidal or inhibition of viral penetration [135].

C. lechleri. palanostigma. Pseudorabies virus (PRV). HSV. cannabinum VV. C. MCMV Virucidal [11] 1 Apocynum sp. C. Poliovirus-1 Postinfection treatment [H] Thchilia glabra SV. 525 Antiviral Plant Extracts Plant Name Activity Against Mechanism/ Inhibition Refe. Polio Postinfection treatment [11] 1 Asarium canademe HSV. P. 1 J. VV. orbiculatus. VSV. B. VV Preinfection treatment "[H] Zingiber capitatum NDV. gossypiifolia. 139] Phyllanthus amarus. urinari HBV MCMV. Pseudoconami. HSV-2 Virucidal [147] Veratrum patulum HSV-l. notosergila VSV Postinfection treatment [11] Geranium sanguineum Influenza. VSV. Poliovirus-l Postinfection treatment [11] Baccharis crispa. HSV-2 Virucidal [147] Veratrum viride HSV-l Unknown [148] Rooibos tea leaves HIV Unknown [149] Croton cuneatus.SV mRNA transcription [140142] Larrea tridentata HSV Protein synthesis [143] Persea americana HSV Virucidal [144] Acanthospermum hispidum HSV Virucidal [145] [11] HIV gp-I20-CD4 [146] Sedum sarmentosum HIV gp-120-CD4 [146] Caraganae Radix HSV-l. Potato virus Y Preinfection treatment Inhibits transmission [137] Cedrela tubijlora SV. HSV-2 Virucidal [147] 1 Osmundae japonica 1 Callicarpajaponica HSV-l. PRV Postinfection treatment [11] 1 Asclepias incarnata Polio Postinfection treatment [11] 1 Campanula trachelium HSV Postinfection treatment [11] . P. Polio Postinfection treatment [11] 1 Thevetia nerifolia VV. Weberbaueri SV. HIV-1 Postinfection treatmen [138. trinitatis SV. P. HSV. MCV Virucidal [11] Jatropha curcas. 1 A.1 rence Agalia roxburghiana Newcastle disease virus (NDV) Preinfection treatment Cassiafistula NDV & VV Preinfection treatment Hemidesmus indicus NDV. 1 J. VV Postinfection treatment [11] Nerium oleander VV. HSV. VV Preinfection treatment Melia azedarach Neem seed oil SV. Polio.ANTIVIRAL AGENTS Table 9.VSV. MCMV Virucidal [11] Hevea brasiliensis SV..

Many of active extracts may turn out to be identical or related to the previously described structure classes.526 KHALIDA. Polio Postinfection treatment [11] Aster patens Measles Postinfection treatment [11] Coreoptis tripteris Polio Postinfection treatment [11] Eupatorium purpureum HSV Postinfection treatment [11] Hieraceum aurantiacum Polio Postinfection treatment [11] Solidago sempervirens HSV Postinfection treatment [11] Satureja vulgaris VV Postinfection treatment [11] Scilla campanulata PRV. The marine macrofauna represents a broader range of taxonomic diversity than found in terrestrial evironment [150].. Further characterization of the active constituents in these active extracts should reveal some useful compounds. the global marine macrofauna are the source of 2.000 genes. . Table 9 summarizes some of the most active extracts in the literature. With a typical eukaryote possessing 50. there also may be a possibility for some novel phytochemicals.5 x 10^^ -1.. Yet.5 x 101^ primary products and an associated extensive range of secondary metabolites [150]. Presently.. Marine-Derived Antiviral Compounds With marine species comprising approximately one half of total global biodiversity for which estimates range between 3-500 x 10^ species of prokaryote and eukaryote organisms. Plant Name Activity Against Mechanism/ Inhibition Reference Tradescantai virginiana VV. Polio Postinfection treatment [11] Xartthium sp.ELSAYED (Table 9). HSV Postinfection treatment [11] Lycopodium obscurum HSV Postinfection treatment [11] Nuphar advena VV Postinfection treatment [11] Chelidonium majus Measles Postinfection treatment [11] Piper methysticum Polio Postinfection treatment [11] Lysimachia quadrifolia VV Postinfection treatment [11] 1 Gerardia pedicularia Polio. Coxsackie Postinfection treatment [11] 1 Sium suave PRV Postinfection treatment [11] activities and to define extracts that interfere w^ith viral replication in cultured cells. contd.. PRV Postinfection treatment [in Artemisia sp. Aqueous and organic extracts have generally been proved equally fruitful and hence it is not feasible to assert that any one method of extraction is preferable.

B (214). Sponge. D (219) Sceptrin (220). 157. Coronavirus Cytotoxicity Cytotoxicity [161] Cytotoxicity Unknown Unknown Unknown Cytotoxicity [162] Protein synthesis Protein synthesis Viral replication Viral replication Unknown Cytotoxicity Unknown Binding of gp 120 toCD4 Unknown Unknown Unknown [164] [165] [166] Pgptite. Mycale sp. Agelas coniferin & A.527 ANTIVIRAL AGENTS Only few thousand novel compounds from marine origin have been identified. HSV-2 HSV-1. Dichothrix baueriana Sponge. 844 (231) & 800 (232) Hennoxazole A (233) 6-Cyano-5-methoxy-l2methylindolo[2. Kirkpatrickia variolosa Sponge. cf. Acaranus erithacus Tunicate. B (198). Antiviral Marine-Derived Peptides. Sponge. Elysia rufescens Sponge. album. Aikaloids & ^-Containing ConipQUn(j$. E (205) K (206). VSV HSV-l HSV-1 HSV-1 HSV-l.2 HSV-1 HIV HSV-2 HSV HIV-1 [163] [167. Ptilocaulis spiculifer & Hemimycale sp. E. mauritiana Sponge. C (199) and other didemnins Kahalalide E (202) Callipeltin A (203) Tunicate. Sponge. Polyfibrospongia sp. E. VSV & Coronavirus CMV HIV HSV-1. Dercitus sp. However. Dibromosceptrin (222). Topsentia genithx & Spongosohtes sp. RNA synthesis Protein synthesis Unknown Protective [156. Oxysceptrin (223). 830 (230). 169] [170. Eudistoma olivaceum. B (237) Bauerine A (238). Blue-green alga. Eudistomin C (204). Trididemnum Mollusk. Sponges. sp. Apiidiasphingosine (235) Batzelladine A (236). Poliovirus HSV-1. C(240) Variolin B (241) Trikendiol (242) Tunicate. B (217). Nostoc sphaericum Tunicate. 3A]carbazole (234) & its 12-Demethyl deiv. only few promising therapeutic leads Table 10. 158] [159] [160] HSV-1. C (215) Polyandrocarpidine A (216). B (226) Onnamide A (227) Ptilomycalin A (228) Crambesscidins 816 (229). Blue-green alga. Debromosceptrin (221). VSV. 171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] . These compounds have been revealed unique in chemical and pharmacological terms. Nucleosides and Other JV-Containing Compounds Compound: Type & Name Source Activity Against Mechanism/ Inhibition Reference HSV-1 & 2 & other RNA viruses HSV-2 HIV-1 DNA. Tubastrea aurea Sponge. Trikentrion loeve A59 HSV-1 HSV-1 HSV-I HSV. glaucus. Didemnin A (197). 168. Sponge. Crambe crambe Sponge. B (239). Theonella sp. L (207) Topsentin (208) Bromotopsentin (209) 4. ApUdium sp.5-dihydroxy-6"deoxybromotopsentin (210) Dercitin(211) Tubastrine (212) Acarnidine A ( 2 1 3 ) . Sponge. C (218). Sponges. Ageliferin (224) Mycalamide A (225). Batzella sp. Proteins. Polyandrocarpa sp. Callipelta sp. Alkaloids. Softcoral.

Didemnin B (198) was found to inhibit cell cycle progression at Gl and binds to elongation factor l a in the presence of GTP [151]. 183] [184] Anemone. Both compounds 197 and 198 inhibited the replication of HSV-1 and HSV-2 v^ith ID50 < 1. rhinovirus 9 [182. B (198) and C (199) are a group of cyclic depsipeptides isolated from the Caribbean marine tunicate Trididemnum solidum.ELSAYED 528 (Table 10). Venezuelan equine encephalovirus and yellow fever virus [154.£'w/7/ce//flf cavolini HSV-1 & -2. 3'-0Acetylara-A Activity Against Mechanism/ Inhibition Reference HSV-1 & -2. Similar efficacy v^as show^n against cosxackie virus A21. Compound: Type & Name 1 Nyglg9?idgs: Spongothymidine (ara-T. vaccinia.KHALIDA. contd. crypta Cryptotethia 1 Prptging. Anemonia sulcata Sponge. BDS-1 Niphatevirin Cyanovirin-N [185] [186] [187] have been reported to display antiviral activity.155]. v^hich has been extensively studied for its antitumor and antiviral activities. gp 120 binding Source Sponge. Didemnins A (197). 243). Nephates erecta Blue-green alga.5 |Llg/mL [153]. didemnins are cytotoxic and inhibit cellular JL-o^ >" o' Didemnin A (197) R = H 7**^ ^'xi ^ Didemnin B (198) R = CH3 Didemnin C (199) R = 0 = / V—OH . equine rhinovirus. preventing gpl20 binding Viral replication. Cytotoxicity Cytotoxicity Gorgonian. Rift Valley fever virus. It is clinically evaluated in the early 1980s in a large phase I/II and w^as proved interesting antitumor activities [152]. Spongouridine (244) Ara-A ( 2 0 0 ) .. Nostoc ellipsosporum mouse hepatitis virus MSV-A59 HIV HIV Unknown Bind to CD4. Despite their significant antiviral activities. parainfluenza virus 3.

ara-A (9P-Darabinofuranosyladenin. (Table 10) [155]. 201) are related to the arabinosides isolated in the early 1950s from the marine sponge Cryptotethia crypta. Ara-A (20(9 OH Ara-C (201) ^r^yt^iy Eudlstomin Eudistomin Eudistomin Eudistx)min C (204) E (205) K (206) L (207) Ri H Br H H R2 OH OH H Br ^ Br H Br H R4 H H H ^ CallipeltinAC203) iM . Some improvements in the therapeutic index have been achieved through structural modifications [156]. 200) and ara-C (l-|3-D-arabinosyl-cytosine. RNA and protein synthesis at concentrations close to those at which viral growth was inhibited and hence they have both low antiviral selectivity and therapeutic index. Two synthetic antiviral agents are currently under clinical use.ANTIVIRAL AGENTS 529 DNA.

5-dih)n-oxy-6"-deo3Qrbromotopsentin (210) Acamidine A (213) CO(CH2)ioCH3 Acamidine B (214) CO(CH2)^H=CH(CH2)5CH3(2) Acamidine C (215) COC13H21 NHo Br O HN ^ Nl \=/ R2 (CH2)nNHCNH2 II NHo NH Polyandrocarpldlne A (216): n = 5.KHALIDA. * Cis Isomer PolyandrocarpldlneB (217): n s 5: •trans Isomer Polyandrocarpldlne C (218): n = 4: *Cte Isomer Polyandrocarpldlne D (219): n = 4. < Topsentin (208) Bromotopsentin (209) H Br HgC^ CH3 Dercitin (211) HO OH Tubastrine (212) 4.ELSAYED 530 H.C x>. *trans Isomer Sceptrln (220) Debromosceptrin (221) Dlbromosceptrln (222) Rj H H Br R2 R3 Br H H H Br Br .

ANTIVIRAL AGENTS 531 NHo O "NHa H N ^ N Ageliferin (224) Oxysceptrin (223) NHg OCHo OCHo OH Mycalamide A (225): R = Mycalamide B (226): R = OH O L-Arg-OH Onnamlde A (227): R = Ptilomycalln A (228) Crambesscidin816(229) Crambesscidln 830 (230) Crambesscidin 844 (231) Crambesscldin 800 (232) Ri H OH OH OH H Ra H OH OH OH OH n 13 13 14 15 13 .

7. Batzelladine A (236) Batzelladlne B (237) R n a-CHg 8 (major).24 NH CI Bauerine A (238) H Bauerlne B (239) CI CHq O Bauerine C (240i .24: a-Oriented CH3 6 (major). SAJcarbazole (234) OH OH OH NH2 Aplidiasphingosine (235) NH (CH2)6 R HoN^ N g '(CH2)nCH3 ^N. 10 23.532 KHALIDA. 8 A32. 9.ELSAYED OH H3CO H Hennoxazole A (233) OCHo 6-Cyano-5-methoxy-12-methylindolo[2.

Alkaloids. 244) Marine-Derived Antiviral Peptides. proteins. Steroids and Carotenoids The antiviral activities of various marine-derived terpenoids. 243) OH Spongouridine (ara-U. Marine-Derived Antiviral Terpenoids. Table 10 illustrates these activities. Proteins. Nucleosides and Other NContaining Compounds Many marine-derived peptides. nucleosides and other A^-containing compounds were shown to be active against several viral species. .ANTIVIRAL AGENTS 533 Variolin B (241) Trikendiol (242) OH Spongothymidine (ara-T. steroids and carotenoids are summarized in Table 11. alkaloids.

ELSAYED Marine-Derived Antiviral Terpenoids. Sponge. Solenopodium sp. Y (264). HIV-RT [194] Unknown [195] Sponge. Avarone (247) Chamigrene derivative (248) Sesquiterpene isocyanide (249) 1 Strongylin A (250) (-)-Frondosin A (255). polyanthes Rhinovirus. HSV Unknown [201] Sponge. B. Jrcinia sp. Ann Arbor. Dysidea avara Coronavirus A59 Gland of the sea hare. HSV-1 Unknown Unknown [197] [198] Halitunal (266) Alga. Rhinovirus A59 Unknown [200] Sponge. Epispongiadiol (258). VSV Sponge. Spongiadiol (257). Peyssonnelia sp. reiswigi HSV-1. D (261).Influenza PRora hartmani 8 Unknown Viral replication Uknown Virucidal [188] Unknown [192] 15-CyanopuupehenoI (251) Verongida sponge Unknown [193] Peyssonol A (252). B (270) Sesterterpenes: Variabilin (271) Tritgrpgpgs. Bubahs sp. Hyatella intestinalis Sponge. Semliki Forest Coronavirus A59. Z(265) Red alga. Maryland. Laurencia venusta 1 Holothurinoside A (275).VSV HIV HSV. Halimeda tuna Coronavirus A59 Unknown [199] Reiswigin A (267).1 HSV-1. VSV. Mycale sp. Polio III. Gorgonian. & Sarcotragus sp. Holothuhaforskahi HSV . Halogenated cyclohexadienone(245) Sggqviitgrpgngs: Avarol (246). Desholothurin A (276) Sea Cucumber. HSV-1 Cytotoxicity [196] Gorgonian. Coronavirus A59. Isospongiadiol (259) Solenolide A (260). HSV-1 Cytotoxicity [203] Unknown [204] Compound: Type & Name Source Activity Against rence 1 IMonQferpgng. Spongia sp. Steroids and Carotenoids Mechanism/ Inhibition Refe. B (253). E(262) Brianthein V (263).534 Table 11. HSV. Thyrsiferol 1 Acetate (273). HIV Sponge. Aplysia dactylomela Sponge. B (268) Sponge. KHALIDA. Hyatellaquinone (254) Alga. Venustatriol (274) Red alga. Euryspongia HIV sp. Strongyloph. D (256) Pitgrpgpg?. Desmia hornemanni Epipolasis HSV-2 [189] [190] [191] Norsgstgrtgrpengs. Thyrsiferol (272). Briareum asbestinum. HSV Cytotoxicity [202] VSV. Mycaperoxide A (269).

weinbergi Petrosia Feline leukemia virus. 1 Usneoidols Z (289). [211] CI OAc ^ Halogenated cyclohexadienone (245) )Ac phamigrene derivative (248) CN Sesquiterpene isocyanide (249) Strongylin A (250) . B (285) Sponge. 25-Demethylhalistanol trisod1 ium sulfate (283) MgrQtgrpgpgg. HSV-1. Topsentia. HIV-l Uknown [208] Orthosterol disodium sulfates A (286). Sea Cucumariaxanthin C (291) Cucumariajaponica Epstein-Barr virus Uknown Compound: Type & Name 1 Crossasteroids B (277). coronaviruse A59 Uknown [209] Brown seaweed. HSV2.ANTIVIRAL AGENTS 535 (Table 11). Influenza PR8. D (278) herpes Steroids: Secosteroids: Calciferol D (279) Sulfated sterols: Ibisterol trisodium sulfate (280).. Cystoseira usneoides HSV Uknown [210] Carotgn9i<3g. contd. E (290) Cucumber. weinbergi Petrosia Feline leukemia. C (288) Sponge.. mooreiy Pseudaxinyssa digitata HIV-1. Source Activity Against Mechanism/ Inhibition Reference Starfishes Suid virus Cytotoxicity [205] Gorgonian. HIV-2 Cytotoxicity. Halistanol trisodium sulfate (281). Poliovirus Uknown [206] Sponge Spp. B (287). Halichondria cf.26-Methylhalistanol trisodium sulfate (282). HIV-RT [207] Weinbersterols disodium sulfate A (284). Kfuricella sp.

ELSAYED 536 CH2CO2CH3 OH Peyssonol B (253) Peyssonol A (252) 15-Cyanopuupehenol (251) Hyatellaquinone (254) (-)-Frondosin A (255) (.Frondosln D (256) CgHu HO' Ri Spongiadiol (257) Epispongiadiol (258) Isospongiadiol (259) R2 =0 ~o H OH R3 H OH R4 OH H =0 SolenoUde A (260) OAc ''CI AcO SolenoUde D (261) SolenoUde E (262) .KHAL1DA.).

19S . 19R Venustatriol (274) H 18R. R2 Mycaperoxide A (269) P-CH3 a-OH Mycaperoxide B (270) a-OH P-CH3 OH R Thyrsiferol (272) H 18S.o^< Reiswigin A (267) CH2CH(CH3)2 Reiswigin B (268) CH=C(CH3)2 ^COOH R. 19R Thyrsiferol Acetate (273) Ac 18S.ANTIVIRAL AGENTS 537 RiO' CHO Brianthein V (263 Briantheln Y (264) Brianthein Z (265) Ri Butyroyl Ac Ac R2 Butyroyl Butyroyl Ac .

KIIALIDA.ELSAYED 538 Desholothurin A (276) OH Holothurinoside A (275) QB2 Ha OH R. Crossasteroids B (277) H R2 HO 4-O-Me-Xyl(l-2)-3-0-Me-Xyl Crossasteroids D (278) OH Xyl-(l-2)-3-0-Me-Xyl Calciferol D (279) .

NaOaSO^ NaOgSO' OSOaNa 26-Methylallistanol sulfate (282) OSOgNa 25-Demethylallistanol sulfate (283) NaOgSq NaOaSa R.539 ANTIVIRAL AGENTS NaOgSO^ NaOaSO' OSOgNa NaOgSO^' Ibisterol sulfate (280) OSOgNa Halistanol sulfate (281) NaOgSO. NaOgSO^ Orthosterol disulfate A (286) Orthosterol disulfate B (287) Orthosterol disulfate C (288) C (CHMcj )=CHMe Q CHEtCHMe2 . ^2 Welnbersterol disulfate A (284) H OH WeinbersteroldisulfateB(285) OH H NaOsSQ.

Agardhiella tenera and Euchema cottonii inhibited the activity of yellow fever virus by up to 25. A commercial sample of carrageenan (Sigma Co. isolated from the red algae (Rhodophyta) is constructed from galactose with varying amounts of sulfate substituents.ELSAYED 540 OH OH Usneoidols Z (289) Usneoidol E (290) Cucumariaxanthin C (291) Marine-Derived Antiviral Polysaccharides The cell wall polysaccharide carrageenan.) inhibited HSV-1 cell growth in Hela cells without becoming cytotoxic when concentrations were up to 200 |j. Samples collected in Senegal include: Hypnea musciformis. The activity against HIV of water soluble .KHALIDA.8% [212].g/mL [213]. Anatheca montagnei.

Acid hydrolysis of this polysaccharide revealed the presence of arabinose.215]. respiratory syncytial virus and measles virus without displaying cytotoxicity or inhibition of blood coagulation of host cells [222]. isolated from the Pacific tunicate Didemnum molle shows in vitro anti-HIV activity. composed of mannose.3-disulfated mannose units joined through p (1. Marine-Derived Antiviral Polyacetylenes. rhamnose.ANTIVIRAL AGENTS 541 compounds extracted from Schizymenia California was also observed and carrageenan was reported to be one of the constituents which inhibits HIV-RT [214. uronic acid and sulfate groups (7-8% wt/wt) was obtained from the marine microalga Cochlodinium polykrikoides show potent inhibitory activities against: influenza viruses type A and B. influenza viruses A and B. Quinones/Pyrones. A polysaccharide from the green marine alga Ulva lactuca inhibited the reproduction of many human and avian influenza viruses. glucose.3-glucanase from marine invertebrates transformed p-l. Macrolides and Prostaglandins Table 12 illustrates the reported antiviral activities of the common marine secondary metabolites polyacetylenes. Sulfated derivatives of a polysaccharide prepared by chlorosulfonic acid treatment of a fucosamine-containing polysaccharide from a marine Pseudomonas sp. No cytotoxic effects on Vero cells were detected up to 1000 |Lig/mL [216]. was prepared from a marine Pseudomonas. respiratory syncytial viruses type A and B. galactose. displayed antiviral activities against HIV-1 and -2. quinones/pyrones.72 |Lig/mL. Treatment of laminarin isolated from the marine alga Laminaria cichorioides by endo-p-l. Another study indicated the inhibition of HIV-1 replication in MT-4 cells by a sulfated derivative of fucosamine-containing polysaccharide obtained from a marine Pseudomonas strain HA-318 and also showed no cytotoxicity [217].6) glycosidic linkages [221]. zidovudine-resistant HIV-1. Polysaccharides. showed strong anti-HSV-1. HIV-1. HSV-1. xylose. This sulfated polysaccharide inhibited the CPE of HSV-1 at 0. The NMR data of this polysaccharide reveals that it consists of a sequence of 2. A natural sulfated mucopolysaccharide (OKU40). extracted from a marine plant Dinoflagellata and an artificial sulfated polysaccharide (0KU41).3:l. mannose and glucose in ratio of 1:1:9:5:2:5:16.6-glucan into a highly efficient preparation against tobacco mosaic virus named antivir [219]. No cytotoxicity nor inhibition to the blood coagulation were observed up to 100 |Lig/mL [220]. HSV-1 and parainfluenza viruses type 2 and 3. An unusual sulfated mannose homopolysaccharide. macrolides and prostaglandins. respectively along with an unidentified sugar [218]. galactose. .

13. l7-triene5. Marine-Derived Antiviral Polyacetylenes.15£)hexadeca-9.7. HE)octadeca-9. Sponge.B r o m o .15triynoic acid (298) Petrosynol (299) 1 Petrosolic acid (300) Source Activity Against Sponge. Quinones/Pyrones. Teles to nisei VCV. Macrolides and Prostaglandins Compound: Type & Name 1 PQJyaggtylgngs: 16-Bromo-(7£.7.ELSAYED 542 Table 12. II (302) 2-Hexaprenylhydroquinone Magroiidgg. Soft coral.( 9 £ .15-triynoic acid (293) 18-Bromo. 17£)octadeca-7. 13£. 17£)octadeca-9.(7£.17-diene-5.VSV sp.(9£. Petrosia sp. 13E. Onchidium sp.7.11.15-diene-5. Clavularia viridis Octacoral. Misakinolide A (303) Clavulone II (304) Punaglandin-1 (305) Mollusc. 15-diene-5. HSV HIV-1. Theonella HSV-1. 11£. 15£)octadeca-9. 17-triene5. Mechanism/ Inhibition Refe.15-diynoic acid (294) 18-Bromo-(9£:.13diynoic acid (296) 1 8 .15triynoic acid (295) 16-Bromo-(9£. Ircinia sp. 15-triene5.1 HIV protease HIV-RT [223] rence [224] Qyinongg/Pyrongs: Onchitriol 1(301). HIV Xestospongia muta HIV-1 Sponge. 15£)hexadeca-7.KHALIDA. \1E)octadeca-9.13-diynoic acid (292) 18-Bromo. murine leukemia virus Sponge.EMC HSV Cytotoxicity HIV-RT [225] [226] Cytotoxicity [227] Uknown [155] [155] .17-diene-5. -2.7 -diynoic acid (297) 18-Bromo-(9£:.13.

13§) . 13i^ O Onchltriol II (302): (lOR.543 ANTIVIRAL AGENTS COOH 294 Br' COOH 295 COOH 296 COOH 297 Bi COOH 298 Bi OH OH Petrosynol (299) OH DH OH .(CH2)8 COOH Petrosolic acid (300) O Onchitriol I (301): (IDS.

Examples of secondary . which is approved for clinical investigation. The use of microbes to modify synthetic compounds or to accomplish specific desired reaction is common in pharmaceutical industry. Adenine arabinoside (Ara A.544 KlULID A. 200). several microbial-derived metabolites show promising activity. is also produced by a Streptomyces sp [19]. However. EL SAVED H3CO Misakinolide A ( 3 0 9 OCHq \ ^ ^ ^ > ^ ^ ^ ^ ^ ^ ^ CI COOCH3 HO Clavulone II (304) Punaglandin-1 (305) m Microblal-Derived Antiviral Compounds The human dream of finding an antiviral antibiotic from microbial origin which selectively affects the viral but not the host cell in a similar manner to the regular antibiotics has not become a reality.

antitumor and antifungal effects [18]. Addition of diethylbarbituric acid to the fermentation medium results in the production of 306 only. Of these. e. Gliotoxin acetate inhibited the CPE of poliovirus in monkey kidney cell cultures due to the early stage inhibition of RNA viral replication [18].ANTIVIRAL AGENTS 545 metabolites from microbial origin that show antiviral activities are presented below. Arantonins are related compounds.. The streptovaricins and tolypomycins resemble rifamycins in RT-inhibitory activity [18]. These activities are apparently due to inhibition of the early step of viral morphogenesis which affects the assembly of immature viral particles. obtained from the soil of the pine forests of southern France [18]. The inhibitory activity of rifamycins on retroviruses is also reported [18]. VV activities [18]. as the case of 308. Many natural and semisynthetic rifamycins inhibit the virion RNA-dependent DNA polymerase (RT) [18]. Rifamycin B (306) was reported active against murine sarcoma virus (MSV) due to its RT. Rifampicin is the C3hydazone semisynthetic derivative of rifamycins.g. rifamycin B (306) is the least toxic. The Ansamycin Antibiotics Streptovaricin B (307). isolated from Arachniotus aureus diXidi Aspergillus terreus and show RT inhibitory activity [19]. Gliotoxin and Related Compounds Gliotoxin (308) is a fungal metabolite. focus formation and cell transformation inhibitory activities [18]. Gliotoxin also inhibits influenza virus-induced RNA polymerase. Rifamycins show in vitro and in vivo anti-poxyviruses. isolated from Aspergillus terreus and found to have antibacterial. Rifamycin antibiotics also inhibit the RT of Rauuscher leukemia virus. tolypomycin and geldanamycin are examples of ansamycins which are chemically related to rifamycins. The activity is attributed to the epidithiapiperazinedione moiety. preventing its leukomogenic activity [18]. Rifamycins Rifamycins are microbial-derived macrolides that were isolated in 1957 from the actinomycete Streptomyces mediterranei. Streptovaricin B inhibits the replication of poxviruses by inhibiting early stages of mRNA synthesis [18]. They also inhibit the . Inhibition of focus formation of MSV by streptovaricins is also reported [18]. Sporidesmin and its metabolites were isolated from Chaetomium cochliodes and show structural similarity to 308.

Example of DNA viruses inhibited by this group are vaccinia virus and HSV-1.KHALIDA.ELSAYED 546 RNA-containing viruses but with remarkable toxicity which prohibited their therapeutic applicability. isolated from Streptomyces distallicus that inhibits transcription and replication of DNA viruses along with its other related semisynthetic analogs [18]. . Distamycin A also shows inhibitory activity for RT of retroviruses [18]. HQ HO. HaCO.^^ Streptovaricin B (307) OH Gliotoxin (308) Distamycins (Pyrrole Amidines) Distamycin A (309) is an oligopeptide..

isolated from Streptomyces peucetius [18]. R COCHa COH^^H ^ . It interacts with cellular DNA and inhibits the replication of mammalian viruses that depend on cellular functions. rabies virus [18]. e. Cordyceptin (3'-Deoxyadenosine). . Actinomycin D and Mithramycin Actinomycin D is a peptide antibiotic. INHo I OH N N HO' R2 Daunomycin (310) DoxorubLn.3XI. . Mithramycin is a related compound that inhibits influenza and pseudorabies viruses probably due to inhibition of host cell RNA polymerase II [18].o-. Toyocamycin and Sinefungin Cordyceptin (313) is a fermentation product of the fungi Aspergillus nidulans and Cordyceps militaris. ^. Cordyceptin inhibits the synthesis of mRNA and hence the replication of both RNA and DNA viruses [18]. produced by Streptomyces parvulu. isolated from Streptomyces verticillus..o^ S j S y ' ^ S OH 5^ w^ ^N S H Bleomycins Bleomycins are glycopeptide antibiotics. Bleomycins interact With DNA and induce breakage of DNA with a concomitant release of free bases.ANTIVIRAL AGENTS 547 Daunomycin and Doxorubicin Daunomycin (310) and doxorubicin (311) are anthracycline glycosides. Both compounds inhibit RT and production of murine leukemia virus [18]. Bleomycin A (312) inhibits the replication of W [18].g. These compounds are used in cancer chemotherapy due to their ability to bind DNA.

548 KHALIDA.ELSAYED CX)NH2 NB NH.?N^^^^S^^N^?^^^^ 1 OH Filipin (315) A H OH OH CgHn Cytochalasin OH 1 B (316) 1 . Filipin and Amphotericin B Filipin (315) is a polyene antibiotic that is capable of interaction with sterols in liposomes and biological membranes. Toyocamycin (314) is another adenosine derivative produced by Streptomyces toyocaensis [18]. rhinovirus. HSV. The synthesis of adenovirusspecific mRNA is also inhibited by 314 [18]. poliovirus and MSV [18]. This compound selectively inhibits the ribosomal RNA synthesis in fibroblasts. leading to alteration of / OH OH OH OH ^OH HO"^ v^^^ 0:h ^ 0 ^ 0 S^. HoN Bleomycin A (312) . isolated from Streptomyces griseolus and it effectively inhibits VV mRNA (guanine-7Jmethyltransferase and hence inhibits methylation of its mRNA [18]. adenovirus.i HO O—CXDNHa This effect displayed by activity of 313 against VV. Sinefungin is an adenine derivative.

It shows potent inhibitory activity against HSV-1 and -2 apparently due to the inhibition of viral glycosylation [19]. -2. The mechanism of this compound is not yet established.ANTIVIRAL AGENTS 549 bilayer structure. Semliki forest. VV and herpetic keratitis of rabbit [19]. VV. Its effect is probably due to cytotoxicity [19]. influenza A viruses and coxsackievirus. SV and VSV with less cytotoxicity and improved water solubility [18]. Its methyl ester is active against HSV-1 and -2. and shows inhibitory activity against HSV-1 and -2. Aphidicolln Aphidicolin is a tetracyclic diterpenoid. It inhibits hexose transport in cells and hence it is used for the study of virus-specific glycoprotein synthesis. Filipin shows activity against VSV and to less degree against influenza and Rauscher leukemia virions [18]. Cytochalasins Cytochalasin B (316) is a metabolite of the mold Helminthosporium dermatoideum [19]. VV. Cytochalasin D is a closely related compound that shows activity against adenovirus but it enhances the infectivity of poliovirus and parainfluenza [19]. . It has the ability to inhibit HSV-1. Amphotericin B is another related antifungal antibiotic. Mycophenolic Acid (317) It is a phenolic acid. produced by the fungus Cephalosporium aphilicola. isolated from a Penicillium sp.

E. Human CMV WC76599 HCMV Protease [228] Delitschia confertaspora Influenza virus Endonuclease [229] Bacillus sp. G Bacillus pumilus HSV-1 Unknown [239] 1 Lanthiopeptin Streptoverticillium HSV-1 cinnamoneum Unknown [240] Bu. 2'-Methylsattazolin Source Activity Against Mechanism/ Inhibition Reference Streptomyces sp.B2. 0(325) Fenalamide I (326) 1 Thiangazole (327) 1 FluvirucinsAl. VV Ara-A Synergistic Adenosine deaminase [243] Avian myeloblastosis virus RTII [244] HSV Unknown 1 Adechlorin (331) 1 Chromostin 1 Virantmycin (332) Unidentified 1 actinomycete Streptomyces nitrosporeus j [245] 1 . F.ELSAYED Additional antiviral microbial-derived metabolites are summarized in Table 13. Sattazolin 1 (320). B3. Microbial-Derived Antiviral Compounds Compound: Type & Name 1 N'QonXmm. C. B1. Table 13. D. Protein and Pgptidg Compotfnds. B (324). B. Unidentified actinomycetes 1 B4. HSV-2 Protein synthesis [230] Kistamicin A and B Microtetraspora Influenza A parvossata ATCC 55076 Uknown [231] Caprolactin A (321) and B (322) Unidentified gm+ve marine bacterium HSV-2 Cytotoxicity [232] Lycogala epidendrum HSV-1 Uknown [233] Myxococcus stipitatus HIV-1 Replication [234] Gliding bacteria HIV-1 Cytotoxicity [235] Influenza A Unknown [236] Parainfluenza-1 and 2 Unknown [237] HIV-1 Cytotoxicity [238] 1 Lycogarubin A (323).A2. 1 Briodionen (318) Flutimide (319) 4-Hydroxysattabacin. HSV-1.550 KHALIDA.2231 Streptoalloteichus HSV-1 hindustanus Unknown [241] Oxetanocin A (330) Bacillus megaterium HSV-2 Protein synthesis [242] Actinomadura OMR-37 HSV.B5 Actinomadura MM46115(328) pelletieri 1 Phenoxan (329) Polygonium PI V019 1 Pumilacidin A.

. Moloney murine leukemia Protein synthesis [253] Brlodlonen (318) N I OH Flutimlde (319) 1 . A3 (340) Podoscyphic acid KibdelosporangiumHSV-1 albatum Amycolatopsis orientalis HSV-1 Cytotoxicity [252] Podoscypha sp. Avian myeloblastosis. Coxsackie 86 Protein synthesis [250] Unknown [251] MagrQiidgs: Cycloviracins Bl (337).ANTIVIRAL AGENTS 551 (Table 13).2. B2 Quatromicins Al (338). HCV Proteinase [248] Pradimicins Actinomadura AA085 HIV Unknown [249] Mutactimycin A (336) Mutated Streptomyces HSV-1. A2 1 (339). contd.1836C (333) Streptomyces zaomuceticus Influenza Replication [246] 1 Sattabacin (334) Bacillus sp. HSV-1. Compound: Type & Name Source Activity Against Mechanism/ Inhibition Reference 1 SF. Influenza A3. HSV. HSV-2 Unknown [247] AH-1763 Sch 68631 (335) Streptomyces sp. HSV-2 Protein synthesis [230] Streptomyces cyaneus HSV-1.

OH J3 Thlangazole (327) MM46115(328) OH .ELSAYED Caprolactin A (321) Caprolactln B (322) R Lycogarubin A (323) OH Lycogarubin B (324) OH Lycogarubin C (325) H CHgCHMea CHMe2 R OH H H .552 KHAL1DA.

ANTIVIRAL AGENTS 553 NHo Phenoxan (329) OH Oxetanocin A (330) X)H OH NHa COOH Vlrantmycln (332) SF-18360(333) OH CI Adechlorin (331) OH Sch 68631 (335) Sattabacin (334) Mutactlmycin A (336) H3CO OH .

... 1 „ ^ ^.--rA Na* \^ 1 CHO K-^ CH2OH Ca** 0%H .5 .-'r^ OHl ^"Y^ M+ '^ ^ fl JLi T O o=/ o 0 \/o-/ ^ = 0 1 >X \ / ^0^^0 M* A 1 ^2 y^ ' 1 o iT o ^ ^ ^ M* ^ 0 Quatromicln Al (338) CHO Quatromicln A2 (339) CH2OH Quatromicln A3 (340) CHgOH V R2 CHO Ln-X^^''" M* HoA.ELSAYED ^ V / \ o (H^)-^ / HO^>^CH3 y OH (CH2).^OH cT HOT ^ / ^ HO '^^ Y (CH2)i3 OH 1 O y ^(c^ «So>^»»c=^o„ ..554 KIIALIDA.OH nio Cycloviraclns Bl (337) Ha\.

H. Nadia E. Napro Biotherapeutics. School of Pharmacy. Out of ten synthetic approved drugs between 1983-1994. for his continuous support and introducing me to Pharmacognosy science.ANTIVIRAL AGENTS 555 CONCLUSIONS There is an urgent need to identify novel active chemotypes as lead for effective antiviral chemotherapy. structurally define and automated assay the bioactive natural products will result in more lead of antiviral agents. University of Mississippi. Farouk S. University of Mississippi. Dr. Hashish. for offering me the opportunity to explore the fascinating world of marine natural products. I am indebted to The Department of Pharmacognosy. is acknowledged for his valuable editorial assistance. Ms. Halim. for informative literature and valuable discussions. Recent years have witnessed great advances in this area. Mark Hamann. 000 species of higher plants have been systematically investigated for the presence of bioactive compounds while the potential of the marine environment has barely been tapped [4]. ACKNOWLEDGMENTS I am grateful to Dr. This is represented by the FDA's approval for clinical investigation of two plantderived compounds. James D. It has been estimated that only 5-15% of the approximately 250. El-Feraly. McChesney. King Saud University. The development of recent techniques to dereplicate. for his continuous support and encouragement. Dr. for the data base search facilities. Muhammad A. in addition to one compound of marine origin and one microbial-derived compound.J. Dr. natural products represent potential antiviral leading resources for imaginative discoverers. isolate. The enormity of natural products as antiviral agents started to be expressed in the area of antiviral chemotherapy. University of Minnesota. Mr. Consequently. for his valuable editorial guidance. accurately detect. Mansoura University. LIST OF ABBREVIATIONS AVF BAP CMV CPE EBV FMDV HBV = = = = = = = Antiviral Factor Bougainvilla Antiviral Protein Cytomegalovirus Cytopathic Effect Ebstein-Barr Virus Foot and Mouth Disease Virus Hepatitis B Virus . Ahmed F. Research Institute of Chemistry. Yaqoob. seven were modeled on a natural product paren [4].E.

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