Definition: Antiviral agents are substances used in the treatment and prophylaxis of disease caused by viruses. Classification: A] Agents involves the inhibition of early stage of viral replication (Adamantane derivatives) Admantane Amantadine Rimantadine Tromantadine B] Interferon: Tilorane ABPP (Bromopirimine) CP20,961

1. Antiviral Agents
NISHU SINGLA
ASSISTANT PROFESSOR
DEPT. OF PHARMACEUTICAL CHEMISTRY
ISF COLLEGE OF PHARMACY
WEBSITE: - WWW.ISFCP.ORG
EMAIL: NISHU131989@GMAIL.COM
ISF College of Pharmacy, Moga
Ghal Kalan,nGT Road, Moga- 142001, Punjab, INDIA
Internal Quality Assurance Cell - (IQAC)

2. ANTIVIRAL DRUGS
Definition: Antiviral agents are substances used in the treatment and prophylaxis of disease
caused by viruses.
Classification:
A] Agents involves the inhibition of early stage of viral replication (Adamantane derivatives)
Admantane
Amantadine
Rimantadine
Tromantadine
B] Interferon:
Tilorane
ABPP (Bromopirimine)
CP20,961
2

3. 3
C] Nculeoside analogue
a) Inhibitors of DNA Polymerase:
1. Purine analogue:
Acyclovir
Gancyclovir
Pencyclovir
Famcyclovir
Vidarabin
2. Pyrimidine analogue:
Idoxuridine
Trifluridine

4. 4
3. Phosphorous derivatives:
Foscarnet Sodium
D] Anti-retrovirus:
a) Nucleoside reverse transcriptase Inhibitors:
1. Thymine analogue:
Zidovudine
Stavudine
2. Cytosine analogue:
Lamivudine
Zalcitabine
3. Inosine
Didanosine

5. 5
b) Non-nucleoside reverse transcriptase Inhibitors
Nevirapine
Efavirenz
E) Protease Inhibitors:
Ritonavir
Indinavir
Nelfinavir
Saquinavir, Amprenavir, Lapinavir

6. 6
F] Miscellaneous:
1) Triazole Derivatives:
Ribavarin
2) Benzimidazole derivatives:
Delaviridine
Aleveridine

7. 7
A] Agents involves the inhibition of early stage of viral
replication
(Adamantane derivatives)
Admantane R= H
Amantadine R= NH2
R

8. 8Amantadine Hydrochloride:
IUPAC: 1-Adamantadine hydrochloride
Synthesis:
NH2
H
Admantane
Cl2/AlCl3
Cl
1-Chloro derivatives
NHCOCH 3
N-(1-Adamantanyl)-acetamide
Acetonitrile
CH3CN
+ H2SO4
1) HOH (Alkaline)
2) HCl
. HC
M.O.A.: Inhibition of transcription at an early stage between uncoating and viral specific RNA
synthesis

9. 9
Br
CH
CH3NH2
Rimantadine
CH2=CHBr
AlBr3
CH=CHBr
KOH
C CH
C
CH3O
NH2OH
C
CH3HON
LiAlH 4
Rimantadine
Synthesis

10. 10
Rimantadine M.O.A.
Rimantadine is thought to exert its inhibitory effect early in the viral replicative cycle, possible
by blocking or greatly reducing the uncoating of viral RNA within host cells.
Genetic studies suggest that a single amino acid change on the transmembrane portion of the
M2 protein can completely eliminate influenza A virus, susceptibility to rimantadine.

11. 11
Interferons are low-molecular weight glycoproteins produced in human or animal cells in exposure to
viruses.
They induce enzymes that inhibit synthesis of proteins and degrade viral RNA.
Type of interferon:
1. α-interferon = secreted by human leukocytes
2. β-interferon = secreted by human fibroblasts
3. γ-interferon = secreted by lymphoid cells
e.g.
Tilorane
ABPP (Bromopirimine)
CP20, 961
B] Interferon:

12. 12
O O
N CH3
CH3
O
N
CH3
CH3
N
NH
NH2
O
Br
[2-amino-5-bromo-6-phenyl-4-pyrimidone]
CH2 CH2 NN
H37C18
H37C18 CH2OH
CH2OH
Tilorane
ABPP (Bromopirimine)
CP20,961

13. 13M.O.A of interferons
It acts on viral infected cell by binding to specific cell surface receptor.
It inhibits translation and transcription of mRNA into viral nucleic acid and protein.
Uses:
For the treatment of
Herper zoster
Herpetic keratitis
Herpes genitalis
Chronic hepatitis
Common cold
Inflenza

14. 14
a) Inhibitors of DNA Polymerase:
1. Purine analogue:
N
NH N
NNH2
O
O
OH
Acyclovir
C] Nculeoside analogue
N
NH N
NNH2
O
O
OH OH
Gancyclovir

15. 15
N
N N
NNH2
OCOCH 3 OCOCH 3
Famcyclovir
N
NH N
NNH2
O
OH OH
Pencyclovir

16. 16
N
N N
N
NH2
OHOH
OH
Vidarabin
Adenine arabinosite

17. 17
N
NH
O
O
I
O
OH
OH
Idoxuridine
N
NH
O
O
CF3
O
OH
OH
Trifluridine
2. Pyrimidine analogue:

18. 18
P C
ONa
O
ONa
O
NaO
Foscarnet Sodium
3. Phosphorous derivatives:

19. 19
N
NH
O
CH3
O
OH
O
Stavudine
N
NH
O
O
CH3
O
N3
OH
Zidovudine
Azidothymidine (AZT)
D] Anti-retrovirus:
a) Nucleoside reverse transcriptase Inhibitors:
1. Thymine analogue:

20. 20
N
N
O
O
OH
NH2
Zalcitabine
2. Cytosine analogue:
N
N
O
O
S
OH
NH2
Lamivudine

21. 213. Inosine
N
NH N
N
O
O
OH
Didanosine

22. 22b) Non-nucleoside reverse transcriptase Inhibitors
N
N
H
N
N
O
CH3
Nevirapine
O
N
H
O
F3C C
Cl
C
Efavirenz

23. 23c) Protease Inhibitors:
Ritonavir (RTV)
Indinavir (IDV)
Nelfinavir (NFV)
Saquinavir (SQV)
Amprenavir (AMP)
Lapinavir (LPV)
S
N
N NH
NH
NH O
S
N
CH3
CH3
O
CH3
CH3CH3
O OH
O
Ritonavir

24. 24
1) Triazole Derivatives: Ribavarin
2) Benzimidazole derivatives: Delaviridine
Aleveridine
N
N
N
O
NH2
O
OHOH
OH
Ribavirin
E] Miscellaneous:

25. 25
N
H
O
N N
N
CH3 CH3
H3CO2SHN
Delaviridine
N
H
O
N N
N
C2H5
H3CO2SHN
Aleveridine

26. 26SYNTHESIS OF ACYCLOVIR
N
N N
N
H
NH2
OH
1. ((CH3)3Si)2N2
2. C6H5CO.O.CH2.CH2-O-CH2Cl
N
N N
NNH2
OH
CH2
O
CH2
CH2COO
H5C6NaOH
N
NH N
NNH2
O
O
OH
Acyclovir

27. 27
Acyclovir
Extracellular
IntracellularViral thymidine kinase
Acyclovir-MP
Acyclovir-DP
Acyclovir-TP
Cellular GMP Kinase
Cellular Phosphatase
Viral DNA Polymerase
deoxy guanosine triphosphate
(dGTP)
DNA ChainDNA Chain Termination
Non-functional complex
Acyclovir inhibit
thymidine kinase and
DNA Polymerase thus
it reduce significantly
reduce the DNA
synthesis in virus
infected cell without
affecting the active
replication of
uninfected cell.
M.O.A.

28. 28
N
NH
O
O
CH3
O
OH
OH
(C6H5)3C-Cl
Pyridine
N
NH
O
O
CH3
O
OH
(H5C6)3C-O
CH3SO2Cl
LiN3, DMF
100
0
C, N2, 3 hours
N
NH
O
O
CH3
O
N3
(H5C6)3C-O
Detritylation
HBr, 55%, H
+
N
NH
O
O
CH3
O
N3
OH
N
NH
O
CH3
O
O
(H5C6)3C-O
H3CO2S
O
SYNTHESIS OF ZIDOVUDINE

29. 29SAR (ANTIVIRALAGENTS)
Admantane Derivatives:
1. N-alkyl and N,N-dialkyl derivatives of amantadine exhibit antiviral activity
similar to that of amantadine hydrochloride.
2. N-acyl derivatives of amantadine show reduced antiviral activity except glycyl
derivatives.
3. Replacement of the amino group with OH, SH, CN or halogen produced
inactive compounds.
NH2

30. 30
 To improve the bioavailability of acyclovir side chain –OH converted to L-valylester (10 times
more than ACV) (Valacyclovir)VACV.
 It does not contains any free –OH group, so the molecules cannot
be phosphorylated prior to conversion.
 The prodrug (VACV) is rapidly converted to ACV in humanhydrolase present in liver and gut
wall. VACV has no intrinsic antiviral activity.
N
NH N
NNH2
O
O
OH
Acyclovir
N
NH N
NNH2
O
O
OCCHCH
NH2CH3
CH3 O Valacyclovir

31. 31
5. Addition of a –CH2 in the side chain of acyclovir give a opposite behavior. This addition
effects the activity spectrum and safety profile. E.g. Gancyclovir.
N
NH N
NNH2
O
O
OH OH
Gancyclovir

32. 32
6. Replacement of C=O with –NH2 in acyclovir afford good water solubility but poorly
adsorbed and are not metabolised efficiently.
E.g. Desciclovir
N
N N
NNH2
O
OH
NH2
Desciclovir

33. 33
8. Addition of a phosphonate group in the side chain of ACV reduces five times less active
compound than ACV against HSV invitro.
7. 2-substitution with 3,5-dichlorobenzyl group in amino gives inhibitory action of HSV-1
(Herpes Simplex virus), DNA synthesis, but display minimal antiviral selectivity and
effectively inhibit cell DNA.
N
NH N
NNH
O
O
OH
Cl
Cl

34. 34
9. Addition of a phosphonate group in the side chain of GCV equipotent and less toxic that
GCV but it causes renal tubular damage.
10. C=O of side chain by methylene groups (pencyclovir) give high selective activity agaist
herpes laboratory strain, it is far better substrate for enzyme than ACV but less potent that ACV.
N
NH N
NNH2
O
OH OH
Pencyclovir

35. 35
11. The diacetyl ester prodrug of 6-deoxy PCV (Femcyclovir) gives high blood level of PCV
(about 70% after oral administration.
N
N N
NNH2
OCOCH 3 OCOCH 3
Famcyclovir
12. Idoxuridine is the first pyrimidine nucleoside based antiviral agents.
N
NH
O
O
I
O
OH
OH
Idoxuridine

36. 36
13. Replacement of iodine at the position 5` with trifluridine can be administered at lower dose
frequency and gives metabolically stable product than Idoxuridine.
N
NH
O
O
CF3
O
OH
OH
Trifluridine