medicinal chemistry of antiviral drugs with its chemical structures and how they chemically work Done by: Faten Al-Sadek , Pharmacy student at Mohammed Al-Mana college for Health Sciences -MACHS

1. Antiviral
Drugs
Faten Al-Sadek

2. • Viruses is a small infectious
agents that replicates only
inside the living cells of other
organisms.
• Viruses are lack both a cell wall
and cell membrane and they do
not carry out metabolic process

3. Viral particles consist of two to three parts :
1. Genetic material , either DNA or RNA
2. Protein coat (Capsid), which surrounds and
protects the genetic material
3. Envelope of lipid , lipid layer that surround the
protein coat when they are outside cell
• Viruses cannot reproduce on their
Own , they use host’s metabolic processes and
so few drugs are selective enough to prevent viral
replication

4. Viral attachment and
entry are blocked by:
• Enfuvirtide(HIV)
• Maraviroc(HIV)
• Docosanol(HSV)
• Palivizumab (RSV)
Uncoating are blocked by:
• Amantadine (influenza)
• Rimantadine(influenza)
Nucleic acid synthesis are
blocked by:
• Nucleoside reverse
transcriptase Inhibitors
NRTI (HIV,HBV)
• Non-Nucleoside reverse
transcriptase Inhibitors
NNRTI (HIV)
• Acyclovir (HSV)
• Foscarnet(CMV)
Protein processing are
blocked by:
• Protease inhibitors (HIV)
Viral release are blocked by:
• Neuraminidase
inhibitors(Influenzas)

5. Uncoating Inhibitors
• Amantadine and Rimantadine :
• They are hydrophobic amines
(weak organic bases) with clinical
against influenza A only.
• Their specificity stems from their
ability to bind to block the
proton channel formed by the
M2 matix protein.
• Can reduce severity of illness if
started within 48 hrs of onset of
symptoms .

6. Uncoating inhibitors
Amantadine :
Amantadine (1-aminoadamantane)
and its methyl derivative inhibit the
uncoating of the viral RNA within
the infected host cells thus
preventing its replication

7. Uncoating inhibitors
Rimantadine:
Interfere with virus uncoating by
inhibiting release of specific protein
also its more effective than
amantadine .

8. Synthesis of Amantadine

9. Synthesis of Rimantadine

10. •
The most common drugs that
prevent the virus from entering CD4
cells are:
-Maraviroc
-Enfuvirtide
-Docosanol
Entry Inhibitors:

11. Maraviroc:
-It is new class of antiretroviral agents that
targets a host protein, the chemokine
receptor CCR5, rather than a viral target.
-Binding to this cell-surface protein.
-block human immunodeficiency virus type
1 (HIV-1) attachment to the coreceptor and
prevents the virus from entering
CD4+ cells.
-Maraviroc is a substrate of cytochrome
P450 (CYP3A) and p-glycoprotein, and has
clinically significant interactions with other
drugs including efavirenz and rifampin.

12. Synthesis of
Maraviroc:

13. Metabolism:

14. Enfuvirtide
•New class of antiviral drug, fusion inhibitors, which interferate with penetration of
HIV-1 in the cells.
•Exhibits potent and selective inhibition of membrane of viral and cells.
•Showed significantly efficacy in the combination with other antiviral drugs in early
stadium of HIV infection and in patients with antiretroviral resistention

15. Protease inhibitors:
-the use of X-ray crystallography and molecular
modelling led to the structure-based design of a
series of inhibitors which act on the viral
enzyme HIV protease.
-They have a short-term benefit when they are
used alone, but resistance soon develops.
-When protease and reverse transcriptase
inhibitors are used together, the antiviral activity
is enhanced and viral resistance is slower to
develop.

17. Saquinavir
-the first PI to reach the
market
- it has high molecular
weight and peptide-like
character
- oral bioavailability

18. Metabolism:

19. Nucleic acid
Inhibitors
• These drugs usually act by
inhibiting the polymerases or
reverse transcriptase required for
nucleic acid synthesis. They are
usually analogues of the purine
and pyrimidine bases found in the
nucleic acids.

20. Inhibitors of viral DNA polymerase
Valaciclovir (prodrug of ACV)

21. Acyclovir
• is the prototypic antiherpetic therapeutic agent. Herpes
simplex virus (HSV) types 1 and 2,varicella-zoster virus (VZV)
(i.e. chickenpox and shingles).
• Acyclovir has 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, and so acyclovir is a
prodrug
• Acyclovir triphosphate prevents DNA replication in two ways.
Firstly, it can bind to DNA polymerase and inhibit it.
Secondly, the drug acts as a chain terminator

23. Valacyclovir
• The oral bioavailability of acyclovir is quite low (15– 30%).
• To overcome this, various prodrugs were developed to
increase water solubility. Valacyclovir is an l-valyl ester
prodrug absorbed from the gut far more effectively than
acyclovir.

24. Nucleoside reverse transcriptase inhibitors
(NRTI)
Zidovudine:
sugar 3′-hydroxyl
group
has been replaced by
an azido group
lamivudine and emtricitabine:
analogues of deoxycytidine
where the 3′ carbon has been
replaced by sulphur.
Didanosine:
nucleic acid base
present is inosine
base

25. • are analogs of native ribosides which all
lack a 3′-hydroxyl group.
• Once they enter cells, they are
phosphorylated to triphosphate analog
which is incorporated into the viral DNA
by Reverse Transcriptase . Because the
3′-hydroxyl group is not present, a 3′,5′-
phosphodiester bond between an
incoming nucleoside triphosphate and
the growing DNA chain cannot be
formed, and DNA chain elongation is
terminated

26. Non-nucleoside reverse transcriptase inhibitors
( NNRTI)

27. • are generally hydrophobic
molecules that bind to an
allosteric binding site
which is hydrophobic in
nature. Since the allosteric
binding site is separate
from the substrate binding
site, the NNRTIs are non-
competitive, reversible
inhibitors

28. Nevirapine
• Nevirapine has a rigid butterfly-like
conformation that makes it chiral. One
‘wing’ interacts through hydrophobic
and van der Waals interactions with
aromatic residues in the binding site,
while the other wing interacts with
aliphatic residues.

29. Metabolism of
Nevirapine

30. Release Inhibitors
• Drugs use to prevents the
Neuraminidase proteins on the
surface of IV removing sialic acid
from sialic aid-contanining
receptors .
• Viral budding and downstream
replication of IV are inhibited
when sialic acid remains on the
virion membrane and host cell.
• This segment will focus on the
synthesis of the anti-influenza
compound.
• available drugs : Zanamivir and
oseltamivir.

33. Oseltamivir
first orally active neuraminidase (NA) inhibitor.a prodrug
compound. Hydrolysis of the ester takes place in the body to
give the active carboxylic acid derivative of oseltamivir.
As a structural analogue of a key intermediate in sialic
acid/NA chemistry, oseltamivir serves as a competitive
inhibitor of viral NA by binding strongly to the active site of
NA. This interaction ultimately prevents the release of new
viral particles from the host cell.
Oseltamivir not a natural product but it is derived from
a natural product called shikimic acid.

34. Zanamivir
• Effective for both influenza A and B.
• Poor bioavailability and poor plasma portion
binding
• Use oral inhalation
4-guanidino-2,4-dideoxy-2,3-dehydro-N-
acetyl neuraminic aid

35. REFRENCES
• An Introduction to Medicinal Chemistry (5th
edition), Graham L. Patrick
• Fundamentals of Medicinal Chemistry,Gareth
Thomas
• Wilson and Gisvold’s Textbook of ORGANIC
MEDICINAL AND PHARMACEUTICAL CHEMISTRY
(12th edition)
• https://www.ncbi.nlm.nih.gov/pubmed/16134757
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC438
0148/