The document discusses anti-HIV drugs and their mechanisms of action. It introduces that HIV causes AIDS and replicates using the reverse transcriptase enzyme. There are several classes of anti-HIV drugs that target different stages of the viral lifecycle including reverse transcriptase inhibitors like nucleoside analogs and non-nucleoside inhibitors, as well as protease inhibitors. Each drug class is described along with examples of drugs, their mechanisms of action, therapeutic uses, and common adverse effects. Modifications to drug structures are also discussed to improve potency and reduce toxicity.

1. Presented To: Mam Huma Rao
Presented By : M Sajid
M.phill Pharmaceutical Chemistry

2.  Introduction
 Designing of Anti-HIV Agents
 Drugs used for the treatment of HIV

3.  AIDS-Acquired Immunodeficiency Syndrome is a
fatal pathogenic disease caused by Human
Immunodeficiency Virus type-1(HIV-1).
 HIV-1 is a retrovirus; it releases the Reverse
Transcriptase (RT) when it enters the host cells.
The RT is important enzyme system in the
replication of DNA of HIV-1.

4.  To design a successful anti-HIV agent, it is important
to locate a target that is unique to the virus.
 The HIV is found mostly inside the cells, it is
essential for inhibitor to enter the host cell membrane
to reach the virus.
 Another challenge for the design of such inhibitors is
for the agent to be able to discriminate between a
virally infected cell and a non-infected cell.
 But it is difficult, because the cellular membranes of
virally infected cells differ only slightly from the
membranes of non-infected cells.

6.  Nucleoside Reverse Transcriptase Inhibitors
(NRTIs):Zidovudine, Stavudine, Lamivudine,
Abacavir, Zalcitabine, Emtricitabine, Didanosine
 Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs):Efavirenz, Nevirapine, Delaviridine
 Protease Inhibitors (PIs):Saquinavir, Indinavir,
Nelfinavir, Amprenavir, Fosamprenavir, Ritonavir,
Lopinavir,
 Nucleotide Reverse Transcriptase
Inhibitors(NNRTIs):Tenofovir

7.  NRTIs are analogs of native ribosides which all
lack a 3-hydroxyl group due to which growing
DNA chain cannot be formed and DNA
elongation is terminated.
 Most have activity against HIV-2 as well as HIV-
1.
 Example:Zidovudine, Stavudine, Lamivudine,
Abacavir, Zalcitabine, Emtricitabine, Didanosine.

8.  NRTIs inhibit RNA virus replication by reversible
inhibition of viral HIV reverse transcriptase, which
reverse transcribes viral RNA into DNA for insertion
into the host DNA sequence

11.  Therapeutic Uses
Generally used in combination with other drugs to
avoid development of resistance for HIV
 Adverse Effects
 Lactic acidosis
 severe hepatomegaly
 hepatic steatosis

12.  First antiviral drug used against HIV.
 It is a thymidine analogue that is effective
against HIV-1, HIV-2, and HTLV I and II
 Zidovudine, in combination with one or more
other antiretroviral agents, is approved for the
treatment of HIV infection in adults and children
and for post-exposure prophylaxis.

13.  It is used alone or in combination for the
prevention of prenatal and perinatal transmission
to the baby by HIV-infected pregnant women
Adverse effects
 Headache, nausea, vomiting, anorexia, fatigue,
confusion, insomnia.

15.  Many derivatives of AZT have been prepared by
modification of hydroxyl group at position 5′.
Solyev et al. synthesized 5′-O-carbamate prodrugs
of AZT and their anti-HIV activity was tested in
cell culture infected with HIV-I899A. These
compounds showed moderate activity and less
toxicity.
 Preparation of phosphate and phosphonate
derivatives is important because Nikavir, a new
anti-HIV drug, is a phosphonate derivative of
AZT.
 Azido group has been converted into triazole ring
and resultant compounds exhibited anticancer
activities in addition to antiviral activities.

16.  It is a thymidine nucleoside analogue
 Active against HIV-1 and HIV-2.
 It is approved for the therapy of HIV infection as
part of a multidrug regimen and is also used for
Postexposure prophylaxis
 Adverse effects
 Headache, diarrhoea, skin rash, nausea, vomiting,
insomnia, anorexia,
 Lactic acidosis occurs more frequently with
Stavudine than with other NRTIs

17.  It is a cytosine nucleoside analogue
 Activite against HIV-1, HIV-2, and hepatitis B
virus.
 It is approved as part of a multidrug regimen for
the therapy of HIV infection in adults and
children and has been used for HIV postexposure
prophylaxis.
 Lamivudine is the best-tolerated NRTI.
 Adverse effects: Headache, fatigue, insomnia.

18.  Example:Efavirenz, Nevirapine, Delaviridine
 Mechanism of Action
 Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) bind to and block HIV reverse
transcriptase (an HIV enzyme).
 HIV uses reverse transcriptase to convert its
RNA into DNA (reverse transcription).
 Blocking reverse transcriptase and reverse
transcription prevents HIV from replicating.

20. Therapeutic Uses
 All NNRTIs are active against HIV-1 reverse
transcriptase only.
 Their use with NRTIs or Protease Inhibitors
provide synergistic effects against HIV due to
sequential block at two different steps required
for viral replication.
Adverse Effects
 Skin rashes including Steven-Johnson syndrome
 Elevation of liver enzymes.

22.  It is approved for the therapy of HIV infection of
adults and children and is also used for post-
exposure prophylaxis.
 It is only NNRTI approved for once-daily dosing.
 Adverse Effects: Rash, elevated liver enzyme,
insomnia, headache, etc

23.  It is approved for the treatment of HIV
infection in adults and children as part of a
combination therapy.
 Dosage forms are supplied as a 50 mg/5 mL
oral suspension and a 200-mg tablet.
 Adverse Effect: Mild to moderate rash, fever,
nausea, fatigue, and elevated liver enzyme.

24.  Example:Tenofovir (TFV)
 Mechanism of action:
 First gets hydrolysed in liver
 Then gets phosphorylated to an active
Tenofovir diphosphate.
 This competitively inhibits HIV reverse
transcriptase enzyme and causes termination
of chain elongation after getting incorporate
into viral DNA

25. Therapeutic uses
 Used along with other anti-HIV drugs in the
treatment of HIV in adults.
Adverse effects
 Nausea, vomiting, diarrhea, Osteomalacia etc

26. Mechanismof action
 HIV protease is a viral enzyme responsible for the
cleavage of polyproteins into structural proteins
and certain enzymes that are required for the final
assembly of the new infectious virions.
 Protease inhibitors act by binding to the viral
protease,in this way preventing the correct
cleavage of viral proteins.

27.  Therapeutic Uses
 Combination therapy with PIs and other anti-
retroviral drugs significantly improve the clinical
efficacy by blocking HIV replication at different
stages in the intracellular life cycle
 Adverse effects
 Diarrhea, nausea, abdominal discomfort
 Hyperglycemia, fat distribution,hyperlipidemia

30.  Replacement of the side chain with the
conformationally constrained hexahydrofurofuranyloxy
P(2) ligand in combination with a
dimethylphenoxyacetate on the other end of the
ritonavir core diamine yielded highly potent HIV
protease inhibitors.
 Substituted groups on the P1 aromatic rings have
influence on their biological activity.
 Compounds having an alkyl or fluorine atom at the
meta or para position on their P1 benzene ring are good
inhibitors.
 Substitutions on the P2 ring is also important for good
antiviral property.

31.  Saquinavir is a potent inhibitor of HIV-1 and HIV-
2 protease.
 It is usually well tolerated and most frequently
produces mild gastrointestinal side effects.