Antiviral agents-medicinal chemistry

Introduction, classification, their SAR and structure with its pharmacologolical properities.

1. GUIDED BY, Dr.T.PRABHA, M.Pharm, Ph.D. PROFESSOR, MEDICINAL CHEMISTRY NANDHA COLLEGE OF PHARMACY,ERODE . PRESENTED BY, J.NIKITHA III PHARM D NANDHA COLLEGE OF PHARMACY ,ERODE. ANTIVIRAL AGENTS

2. INTRODUCTION Antiviral drugs are class of medication used for treating viral infection. Unlike most antibiotics , drugs do not destroy their target pathogen ,instead they inhibit their development. Viruses are oligate intracellular parasites. They do not have metabolic machinery of their own-use host enzymes. Difficulty in obtaining selective toxicity against viruses.

3. STRUCTURE OF VIRUS: Virus particles (virions) consists of following parts: Nucleic acid core: DNA or RNA Contain virus – specific enzymes. Surronded by capsid An outer lipid envelope

4. LIFE CYCLE OF VIRUSES: ATTACHMENT of the virus to receptor on cell surface. ENTRY of the virus through the host cell membrane UNCOATING of viral nucleic acid REPLICATION synthesis of early regulatory proteins,eg: nucleic acid,polymerases. synthesis of new viral RNA or DNA. synthesis of late,structural proteins. ASSEMBLY of viral particles, RELEASE from the cell.

5. 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.amantidine.

6. CLASSIFICATION According to its MOA NUCLEOSIDE RT INHIBITORS : a.Purine nucleosides and nucleotides. Eg: aciclovir, ganciclovir, valaciclovir, vidarabine,penciclovir, famciclovir. b.Pyrimidines nucleosides and nucleotides. Eg: Iodoxuridine, Trifluridine, cidofovir c. Thiosemicarbazones Eg: methisazones d. Adamantane amines Eg: amantadine, rimantadine , somantadine.

7. NON NUCLEOSIDE RT INHIBITORS: Eg: Nevirapine, Delaviridine, Efavirenz, Emivirine, Loviride, Trovirdine. HIV PROTEASE INHIBITORS: Eg: saquinavir, Indinavir, Ritonavir, Nelfinavir. MISCELLANEOUS: Eg: Foscarnet sodium, Ribavirin. According to the enzyme inhibition: i. DNA polymerase inhibitors: Eg: Idoxuridine, Trifluridine, Vidarabine ii. RT inhibitors: Eg: Zidovudine, Zalcitabine, Didanosine, Stavudine.

8. According to treatment protocol: Treatment of respiratory virus infection: Adamantane derivatives: amantidine, rimantidine Treatment of herpes and cytomegalo virus infection . Purine nucleotides : acyclovir, gancyclovir Pyrimidine derivatives :Trifluouridine , Idoxuridine Phosphorus derivatives : Foscarnet sodium Treatment of HIV infection: a.RT inhibitors: i.purine derivatives : didanosine ii.Pyrimidine derivatives : Zidovudine, stavudine iii.Non nucleosides : Nevirapine, Delaviridine, Efavirenz b.Protease inhibitors : saquinavir, Indinavir,Ritonavir c.Integration inhibitors : Zintevir.

9. NUCLEOTIDES ANALOGUES: 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. Structure:

10. Synthesis:

11. Mechanism of action:

12. Dose: The administered dose for immuno- suppressed patients is upto 10mg/kg body weight every 8 h. ADR: headache, malaise, nausea, vomitting, dose dependent decrease in GFR. Uses: It treats cold sores around the mouth , shingles and chicken pox.

13. MECHANISM OF ACTION OF NNRTIs and NRTIs

14. Side effects: Granulocytopenia, Neutropenia, Bone marrow depression. Toxicity: Potential carcinogen, Teratogen , Spermatogenesis.

15. PYRIMIDINE NUCLEOSIDE ANALOG: Pyrimidine nucleoside analog mimics the pyrimidine nucleoside in their chemical structure and includes the following drugs.

16. MECHANISM OF ACTION : Pyrimidine nucleosides analogues substitute pyrimidine for thymidine, causing defective DNA molecule. In particular idoxuridine inhibits viral replication by substituing 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.

17. Contd…. 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, an enzyme responsible for DNA synthesis.

18. USES: IDOXURIDINE: In the treatment against herpesvirus infection of the superficial layers of the cornea (herpesvirus keratitis), and of the skin , but it is toxic when administered systemically. TRIFLURIDINE: In the treatment of herpesvirus keratitis in the humans. DOSE: IDOXURIDINE: 0.1% and 0.5% of opthalmic solution. TRIFLURIDINE: 75mg in 7.5ml sterile opthalmic solution.

19. THIOSEMICARBAZONES: Methisazone: Structure: Mechanism of action: It interferes with the translation of mRNA messages into protein synthesis on the cell ribosome producing a defect in protein incorporation into virus .

20. Dose: 1.5 to 3.0g twice daily for 4 days. Uses: Used as a prophylactic agent against smallpox . Active against poxvirus, including variola and vaccina.

21. ADAMANTANE AMINES Structure:

22. AMANTADINE: structure: Synthesis:

23. SAR of adamantane amines: Except glycyl derivatives, N-acyl derivatives shows decreased antiviral action and tormantadine possesses efficacy against clinical Herpes labialis and H.genitalis. Replacement of amino group with OH,SH,CN, or halogen produced inactive compounds. Optical isomers and the racemic mixture of rimantadine are equally active.

24. Mechanism of action: Amantadine (1-aminoamantane) inhibit the uncoating of viral RNA within the infected host cells thus preventing its replication. 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,drymouth, constipation.

25. NON NUCLEOSIDE RT INHIBITORS:

26. MECHANISM OF ACTION: They act by incorporating themselvesinto the DNA of the virus, therby 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.

27. THERAPEUTIC USES: Generally used in combination with other drugs to avoid development of resistance for HIV . HAART(highly active antiretroviral therapy): synergestic combinations of NRTIs and protease inhibitors.

28. HIV PROTEASE INHIBITORS: Viral proteases cut the longer chain polypeptide into its individual enzyme components which then facilitate the production of new viruses. They act at a late step of viral cycle, they are effective against both newly and chronically infected cells. Hence HIV produce non infectious viral progeny. Protease inhibitors were the second class of antiretroviral drugs developed.

29. MECHANISM OF ACTION: Protease enzyme cleaves HIV precusor 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.

30. Uses: These drugs are widely used to treat HIV/AIDS and Hepatitis caused by hapatitis C virus.

31. MISCELLANEOUS AGENTS: Foscarnet sodium: Structure: Mechanism of action: It directly inhibits the DNA and RNA polymerase and viral inverse transcriptase(it does not require phosporylation for antiviral activity).

32. Adverse effects: Hypocalcemia and Hypomagnesemia are common, Neurotoxicity, Nephrotoxicity. Therapeutic uses: It is an alternative drug for HSV infections (acyclovir resistant/immunocompromised patients) CMV retinitis(gancyclovir resistant/immunocompromised patient). Dose: 24mg /ml IV injection.

33. REFERENCE: Textbook of medicinal chemistry. Volume II by V Alagarasamy. An introduction to medicinal chemistry by Graham L.Patrick AIDSinfo-NIH