Antiviral Agents,Medicinal Chemistry •Introduction to Viruses •Structure of Virus •Types of Viruses. •The viral Life cycle. •Classification of Antiviral Agents

1. ANTIVIRAL AGENTS
Medicinal Chemistry- III
Presented by,
Vedant Balasaheb Bhor
T.Y. B. pharmacy
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2. CONTENT
 Introduction to Viruses
 Structure of Virus
 Types of Viruses.
 The viral Life cycle.
 Classification of Antiviral Agents
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3. INTRODUCTION TO VIRUSES
 Viruses are obligate intracellular parasites.
 Virus can be defined as sub microscopic entity
consisting of a single nucleic acid surrounded by a
protein coat and capable of replication only within the
living cells.
 Viruses are much smaller than prokaryotes, ranging in
size from about 20– 300 nanometers.
 The infective, extracellular (outside the cell) form of a
virus is called the virion.
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4. STRUCTURE OF VIRUS
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5. STRUCTURE OF VIRUS
 Capsid - The capsid is the protein shell that encloses the nucleic
acid; with its enclosed nucleic acid, it is called the nucleocapsid. This
shell is composed of protein organized in subunits known as
capsomers.
 Envelope - Many types of virus have a glycoprotein envelope
surrounding the nucleocapsid. The envelope is composed of two lipid
layers interspersed with protein molecules (lipoprotein bilayer) and
may contain material from the membrane of a host cell as well as that
of viral origin.
 Nucleic acid -the nucleic acid of each virus encodes the genetic
information for the synthesis of all proteins. While the double-stranded
DNA is responsible for this in prokaryotic and eukaryotic cells, only a
few groups of viruses use DNA. Most viruses maintain all their genetic
information with the single stranded RNA. 5

6. TYPES OF VIRUSES
 DNA-viruses:
Contain mostly double-stranded DNA. DNA virus enters
directly into the cell.
e.g.-poxviruses, herpes, adenoviruses papilloma viruses.
 RNA-viruses-
Contain largely single-stranded RNA (ss-RNA).
RNA viruses do not enter the cell nucleus (except the
influenza virus).
RNA retroviruses uses the viral reverse transcriptase to make
a DNA copy of the viral RNA, which is then integrated into the
host genome.
e.g.- Influenza, measles, Mumps , Polio virus, Retroviruses
(AIDS)
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7. 7

8. THE VIRAL LIFE CYCLE
 1. Attachment-The virus
recognizes and binds to a host
cell via a receptor molecule on the
cell surface.
 2. Entry-The virus or its genetic
material enters the cell.
 3. Genome replication and
gene expression-The viral
genome is copied and its genes
are expressed to make viral
proteins.
 4. Assembly-New viral particles
are assembled from the genome
copies and viral proteins.
 5. Release-Completed viral
particles exit the cell and can
infect other cells. 8

9. ANTIVIRAL DRUGS
 Antiviral drugs are a class of medication used for
treating viral infections.
 In 1963, idoxuridine became the first antiviral
compound to be licensed by the US Food and Drug
Administration (FDA) for the topical treatment of
herpes simplex virus (HSV) keratitis.
 Most of the antiviral drugs currently available are used
to treat infections caused by HIV, herpes viruses,
hepatitis B and C viruses, and influenza A and B
viruses.
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10. ANTIVIRAL DRUGS WORK BY
 Altering the cells genetic material so that the virus
cannot use it to multiply.
i.e, Acyclovir (inhibiting viral enzymes, host
expression of viral proteins and assembly of viral
proteins)
 Preventing new virus formed from leaving the cell ,
i.e. amantadine.
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11. CLASSIFICATION
 Nucleoside RT Inhibitors-
A .Purine nucleosides and nucleotides.
E.g.: Acyclovir*, Gancyclovir.
B .Pyrimidine nucleosides and nucleotides.
E.g.: Iodoxuridine, Trifluridine, Lamivudine.
C. Adamantane amines.
Eg: amantadine HCL, Rimantadine HCL
 Non Nucleoside RT Inhibitors:
E.g.: Delaverding, Loviride
 HIV Protease Inhibitors:
E.g.: Indinavir, Ritonavir, saquinavir.
 RT inhibitors:
E.g.: Zidovudine , Zalcitabine, Didanosine, Stavudine .
 Miscellaneous:
E.g.: Ribavirin. 11

12. CLASSIFICATION OF ANTIVIRALS
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13. A. PURINE NUCLEOTIDES AND NUCLEOSIDES
 ACYCLOVIR :-
 Acyclovir is a nucleoside like structure. It lacks the
complete sugar ring.
 In virally infected cells, it is phosphorylated to form a
triphosphate which is the active agent, so acyclovir is a
prodrug. 13

14. SYNTHESIS OF ACYCLOVIR
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15. MECHANISM OF ACTION
 It is sufficiently similar to the
"normal” nucleosides, so that
it can serve as substrate for
the viral DNA polymerases.
Since the sugar lacks the
3’hydroxyl group it act as
chain terminators.
 Acyclovir is prodrug, that can
only be converted into the
phosphorylated form by the
viral thymidine kinase and
hence do not interfere with
DNA synthesis in non-
infected cells.
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16. SAR OF ACYCLOVIR
 1.The length of acyclic side chain attached at N-9 is
essential for the anti viral activity.
 2.When the acyclic side chain containing hydroxy
methylene group was replaced by other substituents,
inactive analogues are obtained. This implies that –
CH2OH group is essential for anti viral activity.
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17. SAR
 3.The 9-alkoxy derivative was obtained when a
slight modification was brought in the acyl side
chain which is highly active against herpes simplex
and varicella zoster viruses.
 4.Several structural modifications have been
brought to acyclovir to obtain high potent drugs.
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18.  Dose:
The administered dose for immuno-
suppressed patients is up to 10mg/kg body
weight every 8 hrs.
 Adverse Drug Reactions:-
headache, malaise, nausea, vomiting, dose
dependent decrease in GFR.
 Uses:-
It treats the cold sores around mouth,
shingles, chicken pox. 18

19. 19

20.  Gancyclovir:-
 It is a DNA polymerase inhibitor used to treat
cytomegalovirus and herpetic keratitis of the eye.
 Gancyclovir is a prodrug that is structurally similar
to acyclovir.
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21. MECHANISM OF ACTION
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22.  Adverse Drug Reactions:-
Nausea, vomiting, Diarrhea, constipation, stomach pain,
belching, loss of appetite.
 Dose(Capsules):-
Adults and teenagers-
1000 milligrams (mg) three times a day with food; or
500 mg six times a day, every three hours with food,
during waking hours.
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23. B. PYRIMIDINE NUCLEOSIDES AND
NUCLEOTIDES
 Pyrimidine nucleoside analog mimics the pyrimidine
nucleoside in their chemical structure.
Idoxuridine Trifluridine
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24. MECHANISM OF ACTION
 Pyrimidine nucleosides analogues substitute
pyrimidine for thymidine, causing defective DNA
molecule.
 In particular idoxuridine inhibits viral replication by
substituting itself for thymidine in viral DNA.
 This in turn inhibits the function of thymidylate
phosphorylase and viral DNA polymerases
resulting in inability of the virus to reproduce and
infect tissue
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25. MECHANISM OF ACTION
 The MOA of trifluridine has not been fully
determined, but it is thought to inhibit the viral
replication.
 It does this by incorporating into viral DNA during
replication and forms defective proteins and cause
an increased mutation rate.
 Also reversibly inhibits thymidylate synthesis
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26.  Uses:-
IDOXURIDINE: In the treatment against herpes virus
infection of the superficial layers of the cornea (herpes
virus keratitis), and of the skin , but it is toxic when
administered systemically.
TRIFLURIDINE: In the treatment of herpes virus keratitis
in the humans.
 Dose:-
IDOXURIDINE: 0.1% and 0.5% of ophthalmic solution.
TRIFLURIDINE: 75mg in 7.5ml sterile ophthalmic
solution
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27. MARKETED PREPARATIONS
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28.  Structures:-
Zalcitabine Stavudine Zidovudine
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29. MECHANISM OF ACTION
 Zalcitabine is a nucleoside reverse transcriptase
inhibitor (NRTI) with activity against Human
Immunodeficiency Virus Type 1 (HIV-1).
 Within cells, zalcitabine is converted to its active
metabolite, dideoxycytidine 5'-triphosphate (ddCTP), by
the sequential action of cellular enzymes. ddCTP
interferes with viral RNA-directed DNA polymerase
(reverse transcriptase) by competing for utilization of the
natural substrate deoxycytidine 5'-triphosphate (dCTP),
as well as incorporating into viral DNA.
 Due to it's lack of a 3'-OH group, the formation of a 5' to
3' phosphodiester linkage that is necessary for DNA
chain elongation is inhibited, thus leading to the
termination of viral DNA growth. 29

30.  Uses:- Zalcitabine is an oral medication that
is used for the treatment of infections with the
human immunodeficiency virus (HIV).
 Side Effects:-
Nausea, vomiting ,stomach or abdominal pain ·
diarrhea ,constipation ,headache ,fatigue.
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31. C. ADAMANTANE AMINES
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32. AMANTADINE:
 Structure:-
It inhibits penetration of RNA viral particles into the host
cell . It also inhibits the early stages of viral replication by
blocking the uncoating of the viral genome and the transfer
of nucleic acid into the host cell.
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33. RIMANTADINE HCL
 Rimantadine is antiviral agent which is used to treat
the peoples infected with life-threatning influenza
virus.
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34. MECHANISM OF ACTION
 It inhibits penetration of RNA viral particles into the
host cell . It also inhibits the early stages of viral
replication by blocking the uncoating of the viral
genome and the transfer of nucleic acid into the
host cell.
 Adamantane derivatives block the migration of
protons into the interior of the virions within
endosomes, thereby preventing the pH shift
required for uncoating. They act by blocking the M2
(matrix 2) channel.
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35. SAR OF ADAMANTANE AMINES
 Amantadine is a adamantane amine.
 α –amino derivative of adamantane is amantadine .
 N-Alkyl and N,N- dialkyl derivatives of
adamantadine exhibit antiviral activity similar to that
of amantadine HCl.
 Except glycyl derivatives, N–acyl derivatives shows
decreased antiviral action.
 Replacement of the amino group with OH, SH, CN,
or halogen produced inactive compounds.
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36.  Dose: 100mg twice daily.
 Uses:
Effective against influenza type-A virus, parainfluenza
and some RNA virus.
 Adverse effects:
Blurred vision, Nausea, LOA, Drowsiness,
lightheadedness, headache, dry mouth, constipation.
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37. NON NUCLEOSIDE RT INHIBITORS:
Loviride Delaverdine
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38.  Loviride is a non-
nucleoside inhibitor of
reverse transcriptase. It
inhibits virion and
recombinant reverse
transcriptase of HIV-1.
 It is given in the
combination for the
therapy of HIV infection
with other anti-HIV
agents.
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39.  Delavirdine is a
synthetic,non-nucleoside
reverse transcriptase
inhibitor. In combination
with other anti-retroviral
drugs, this agent has
been shown to reduce
HIV viral load and
increase CD4 leukocyte
counts in patients.
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40. MECHANISM OF ACTION:
 They act by incorporating themselves into the DNA
of the virus, thereby stopping the process of
transcription from RNA to DNA . The resulting DNA
is incomplete and cannot create a new virus.
 Block the HIV replication, block the infection of new
cells .
 No effect on already infected cells.
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41. MECHANISM OF ACTION
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42.  Therapeutic uses:
1)Generally used in combination with other drugs to
avoid development of resistance for HIV.
2)HAART(highly active antiretroviral therapy):
synergistic combinations of NRTIs and protease
inhibitors.
 Side effects:-
nausea, loss of appetite, upper stomach pain
,tiredness ,fever ,unexplained muscle pain ,dark urine
,jaundice.
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43. HIV PROTEASE INHIBITORS:
 Protease cleave the viral polyproteins into individual
functional HIV proteins and enzymes. The various
structural components then assemble to produce a
mature HIV virions which is capable of infecting
another cell .
 Drugs that inhibit HIV protease are designed as
transition-state mimetic that align at the active site of
HIV-1 protease.
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44. STRUCTURE
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45. INDINAVIR
 Indinavir is a protease
inhibitor used as a
component of highly
active antiretroviral
therapy to treat
HIV/AIDS.
 It is soluble white
powder administered
orally in combination
with other antiviral
drugs.
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46. RITONAVIR
 Ritonavir, sold under
the brand name Norvir,
is an antiretroviral
medication used along
with other medications
to treat HIV/AIDS. This
combination treatment
is known as highly
active antiretroviral
therapy.
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47. MECHANISM OF ACTION
 Protease enzyme
cleaves HIV precursor
proteins (gag/pol
proteins) that are
needed to assemble a
new, mature HIV virus.
 PIs bind to protease
preventing the
cleavage and inhibiting
the assembly of new
HIV viruses.
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48.  Uses:
These drugs are widely used to treat HIV/AIDS and
Hepatitis caused by hepatitis C virus.
 Side effects :-
GI disturbances, Headache ,Rhinitis ,Diarrhea.
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49. MISCELLANEOUS AGENTS
 Ribavirin, also known
as tribavirin, is an
antiviral medication
used to treat RSV
infection hepatitis C
and some viral
hemorrhagic fevers For
hepatitis C.
 It is also been used in
Hanta virus infection.
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50. MECHANISM OF ACTION
 Ribavirin inhibits the of RNA and DNA viruses.
 The drug is first phosphorylated to the 5’ phosphate
derivatives. the major product being the compound
ribavirin triphosphate, which exerts its antiviral
action by inhibiting guanosine triphosphate
(GTP)formation, preventing viral messenger RNA
(mRNA) capping, and blocking RNA-dependent
RNA polymerase.
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51. SAR OF RIBAVIRIN
 1,2,4-triazole ring, carboxamide group and ß-D-
ribofuranosyl moiety are important for antiviral activity.
 3-carboxamide derivatives and thiocarboxamide
derivatives are only active against DNA viruses.
 5’ imidazole riboside derivatives show antiviral activity
with hydrogen or halide. Larger substitutions shows
lesser activity.
 Substitution of the 5’ carbon with hydroxyl group results
in a compound with antibacterial as well as antiviral
properties, but is having unacceptable toxicity.
 Replacement of the 5’ carbon with amino group results
in activity only against viruses. [1]
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52.  Uses:-
1)ribavirin is used in treating immunosuppressed infants
and young children with severe RSV infections.
2)Ribavirin is also effective in chronic hepatitis C infections
when used in combination with interferon-α.
 Adverse effects:-
Side effects of ribavirin include dose-dependent transient
anemia, Elevated bilirubin .
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53. MARKETED PREPARATION
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