Antiviral Drugs

Antiviral agents are substances used in the treatment and prophylaxis of diseases caused by viruses.
Viral diseases include influenza, rabies, yellow fever, poliomyelitis, ornithosis, mumps, measles,
ebola, human immunodeficiency virus (HIV), herpes, warts, and smallpox.
 Viruses are not proper living things, but consist of a genome; they are smaller in size with
simple chemical composition, sometimes a few enzymes stored in a capsule made up of
protein and rarely covered with a lipid layer.
 The viruses only replicate within the host cell and the viral replication depends primarily
on the metabolic processes of the invaded cell.
 Viruses do not possess cell walls, but they have RNA or DNA enclosed in a shell of protein
known as capsid. The capsid is composed of several subunits known as capsomers.
 In certain cases, the capsid may be surrounded by an outer protein or lipoprotein envelope.
One group of RNA virus that deserves special mention are retroviruses. They are
responsible for acquired immuno deficiency syndrome (AIDS) and T-leukaemias.
Retroviruses contain reverse transcriptase (RT) enzyme activity that makes a DNA copy
of the viral RNA template. Then, the DNA copy is integrated into the host genome, at
which it is referred to as provirus and is transcribed into both the genomic RNA and mRNA
for translocation into the viral proteins, giving generation to new virus particles. The viral
life cycle varies according to the species, but they all share a general pattern that can be
sequenced as follows

Classification:
Classification According to the Treatment Protocol
 Treatment of respiratory virus infection
 Adamantane derivatives: Amantadine, Rimantadine
 Treatment of herpes and cytomegalovirus infection.
o Purine nucleotides: Acyclovir, Ganciclovir, Vidarabine,
o Pyrimidine nucleosides: Trifl uouridine, Idoxuridine.
o Phosphorus derivatives: Foscarnet sodium.
 Treatment of HIV infections
o RT inhibition.
 Purine derivatives: Didanosine.
 Pyrimidine derivative: Zidovudine, Stavudine.
 Non-nucleosides: Nevirapine, Delaviridine, Efavirenz.

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 o Protease inhibition: Saquinavir, Indinavir, Ritonavir, Nelfinavir, Amprenavir,
Lopinavir.
o Integration inhibition: Zintevir
Classification According to the Enzyme Inhibiton
 DNA polymerase inhibitors: Idoxuridine, Trifluridine, Vidarabine
 RT inhibitors: Zidovudine, Zalcitabine, Didanosine, Lamivudine, Abacavir.

Acyclovir

Mechanism of Action:
Acyclovir is selectively taken up by cells infected with HSV or VZV. This selective uptake is due
to the viral thymidine kinase (TK) enzyme, which has a much higher affinity for acyclovir than
the host cell's TK. Once inside the infected cell, acyclovir is phosphorylated by the viral TK to
acyclovir monophosphate. The acyclovir monophosphate is then further phosphorylated by
cellular kinases to its active triphosphate form, acyclovir triphosphate (ACV-TP). Acyclovir
triphosphate acts as a competitive inhibitor of viral DNA polymerase. It competes with
deoxyguanosine triphosphate (dGTP) for incorporation into the viral DNA strand. When acyclovir
triphosphate is incorporated into the viral DNA, it lacks a 3'-hydroxyl group, which is essential for
continuing DNA chain elongation. This results in chain termination and prevents further viral
DNA synthesis.

Therapeutic Applications
Acyclovir is used to treat infections caused by certain types of viruses:
 It treats cold sores around the mouth caused by Herpes simplex.
 Shingles caused by Herpes zoster.
 Chicken pox.
 used to treat outbreaks of Genital herpes.
 Varicella zoster virus infection.
Synthesis

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Structure-Activity Relationship:
1. At position number 2, the amino group is essential and unsubstituted. If we replace this
with any other group or if we change the position with any other position, the therapeutic
activity will be terminated.
2. At position 9, there is ethoxy methyl (Ether) is essential and unsubstituted. If we change
this with any other group the therapeutic activity will be terminated.
3. Imidazole ring, pyrimidine ring purine, and guanine are essential and unsubstituted.
4. At position number 2 of ethoxy methyl the hydroxyl can be substituted. If we substitute
this hydroxyl with valine it is converted into valacyclovir which is a prodrug and converted
to acyclovir in the body after absorption.

Tromantadine
Tromantadine is an antiviral drug used to treat Herpes Simplex virus.
Mechanism of Action:
Tromantadine inhibits the early and late stages of the viral replication cycle. It changes the
glycoproteins of host cell, therefore impeding the absorption of virus. It inhibits penetration of
virus and prevents its uncoating as well.
Synthesis:
STEP 1: In the 1st step of synthesis of tromantadine, there’s amination at position no. 1 of
adamantane and forms 1 amino adamantane or amantadine.

STEP 2: In the 2nd step, there’s the acetylation of amino group of amantadine (an electrophilic
substitution reaction) and forms 1 amino adamantine acetamide or 1 amino adamantyl acetamide
or N-1 adamantane

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STEP 3: In the next step there’s Halogenation, which is chlorination at position no. 2 of the
acetamide group.

STEP 4: In the next or last step there is a reaction of 2-dimethyl amino lithium ethoxide with the
above compound 1 amino adamantine 2 chloro acetamide. The product formed is 1-amino
adamantine-2(2-dimethyl amino ethoxide) acetamide,

Structure-Activity Relationship:
1. In the structure of tromantadine, the main ring is amantadine which is essential and
unsubstituted then other functional group.
2. Acetamide is essential and unsubstituted.
3. The NH2 group is essential and unsubstituted. If we substitute it with any amine,
therapeutic activity will be terminated.

Ribavirin
It is used in the treatment of influenza type A and -B, hepatitis, genital herpes, and Lassa fever.

Mechanism of Action:

1. Ribavirin is a guanosine analog that gets incorporated into viral RNA. This incorporation
leads to defective RNA synthesis by inhibiting viral RNA polymerase.
2. Ribavirin induces mutations in the viral RNA genome, increasing the mutation rate to a
level that is detrimental to the virus (lethal mutagenesis).
3. By inhibiting IMPDH, ribavirin decreases the synthesis of guanosine triphosphate (GTP),
which is essential for viral RNA synthesis.

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Synthesis:

Ribavirin is synthesized by reacting methyl ester of 1,2,4-triazol-3-carboxylic acid with O -2,3,5-

triacetyl-β-D-ribofuranose to make methyl ester of 1- O -2,3,5-triacetyl-β-D-ribofuranosyl-1,2,4-
triazol-3-carboxylic acid, which is treated with an ammonia solution of methanol to simultaneously
deacylate the carbohydrate part and amidation of the carboxyl part of the product to afford
ribavirin.
Structure-Activity Relationship:
1. The structure of ribavirin contains 2 rings, oxolan ring and a triazole ring. These are
essential and unsubstituted. When we substitute these rings with any other ring or change
their position, their therapeutic activity will be lost.
2. At position 3 carboxamide is present. If we substitute this group with any other group or
change the position of this group to any other position, the therapeutic activity of ribavirin
will be terminated.

References
 Lectures by Dr. Mohsin Abbas Khan
 Textbook of Medicinal Chemistry—V. Alagarsamy.
 Medicinal Chemistry— Ashutosh Kar.
 Medicinal Chemistry—D. Sri Ram

M. Awais Fareed Pharm D IUB (2019-24)