Antiviral Agents.pptx A virus is a small infectious agent that replicates inside the living cells of organisms.

A virus is a small infectious agent that replicates inside the living cells of organisms.
Viruses can infect all types of life forms, from animals and plants to microorganisms.
Viruses are found wherever there is life and have probably existed since living cells first evolved.
Viruses are much simpler organisms than bacteria and they are made from protein substances and nucleic acid.

1. Antiviral Drugs B. Pharmacy III Year II sem Medicinal Chemistry-III By Dr. Rakam Gopi Krishna Associate Professor MLRIP

2. Introduction A virus is a small infectious agent that replicates inside the living cells of organisms. Viruses can infect all types of life forms, from animals and plants to microorganisms. Viruses are found wherever there is life and have probably existed since living cells first evolved. Viruses are much simpler organisms than bacteria and they are made from protein substances and nucleic acid.

3. virus Viruses have no cell wall and made up of nucleic acid components Viruses containing envelope – antigenic in nature Viruses are obligate intracellular parasite They do not have a metabolic machinery of their own – uses host enzymes 7/9/2024 3

4. Understanding Viruses They are different from other Microbes Viral replication A virus cannot replicate on its own It must attach and enter into a host cell It then uses the host cell’s energy to synthesize protein, DNA and RNA 7/9/2024 4

5. Understanding Viruses Viruses are difficult to kill because they live inside the cells Any drug that kills a virus may also kill cells 7/9/2024 5

6. Structure of viruses Virus particles (virions) consist of following parts : Nucleic acid core: DNA or RNA Often contain virus-specific enzymes Surrounded by protein: “capsid” sometimes an outer lipid “envelope”

7. 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 - Just as in cells, 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. Fig1 .Structure of virus Fig2. 2

8. Virus Certain viruses multiply in the cytoplasm but others do in the nucleus Most multiplication take place before diagnosis is made 7/9/2024 8

9. The Life Cycle of Viruses Attachment of the virus to receptors on the host cell surface Entry of the virus through the host cell membrane Uncoating of viral nucleic acid Replication Synthesis of regulatory proteins , eg , nucleic acid polymerases Synthesis of new viral RNA or DNA Synthesis of structural proteins 5. Assembly (maturation) of viral particles 6. Release from the cell

10. Antiviral drugs Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics, specific antivirals are used for specific viruses. Viruses cause more diseases than any other group of parasites. They can cause blindness, deafness, paralysis, mental retardation, various birth defects and in at least a few plants and animals, cancer.

11. Of all the most well-known viral diseases, the ones that should be stated are Measles, Mumps, Smallpox, Chicken Pox, Influenza, Poliomyelitis and Yellow Fever. Viruses are one of the great mysteries of biology.

12. Measles is a highly contagious infection caused by the Measles virus. Initial signs and symptoms include fever, often greater than 40 °C. Mumps , also known as epidemic parotitis , is a viral disease caused by the mumps virus. Initial signs and symptoms often include fever, muscle pain and headache. 

13. Drugs for treating AIDS They have limited clinical use because of their narrow therapeutic index (ratio of effective and lethal doses). These drugs have a direct effect on viral replication however, they also inhibit certain host cell functions. Later Amantadine, Acyclovir, Ribavirin And Zidovudine were suggested. Currently, a number of new drugs have been suggested for treating acquired immunodeficiency syndrome (AIDS)— Ribavirin, Ampligen , Dideoxycytidine .

14. Mechanism of Action These drugs act by inhibiting the process of virus cell multiplication. Antiviral agents are most active when viruses are replicating.

15. Classification of Drugs Drugs used to treat viral infections are known as antiviral drugs. These are classified based on the type of viral enzyme inhibited. Classification of Antiviral drugs Inhibitors of DNA polymerases :- Inhibitors of HIV Reverse Transcriptases :- Inhibitors of Penetration & Uncoating of Influenza virus :-

16. Inhibitors of DNA polymerases :- Purine Analogues- Acyclovir, Ganciclovir, Vanciclovir and Peniciclovir Pyrimidine Analogues- Idoxuridine and Trifluridine Non-nucleoside Analogue - Foscarnet sodium Inhibitors of HIV Reverse Transcriptases :- Purine Nucleoside- Didanosine Pyrimidine Nucleoside- Zalcitabine, Lamivudine and Zidovudine. Inhibitors of Penetration & Uncoating of Influenza virus:- Amantidine Amines- Amantidine and Rimantidine

17. DNA POLYMERASE INHIBITORS-STRUCTURES 12

18. Classification of Antiviral Drugs CLASSES DRUGS 1. Ant i -Herpes virus Idoxuridine, Trifluridine Acyclovir, Valacyclovir, Famciclovir, Ganciclovir, Valganciclovir Cidofovir, Foscarnet, Fomivirsen, Idoxuridine, Trifluridine 2. Ant i -infl u en z a virus Amantadine, Rimantadine Oseltamivir, Zanamivir 3. Anti-Hepatitis virus/Nonsele c tive antiviral drugs a. Primarily for Hepatitis B Lamivudine , Adefovir dipivoxil, Tenofovir b. Primarily for Hepatitis C Ribavirin , Interferon α Department of Pharmaceutical Chemistry

19. CLASSES DRUGS 4. Ant i- retrovirus a. Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine ( AZT), Didanosine , Stavudine, Lamivudine, Zalcitabine, Abacavir, Emtricitabine Tenofovir (Nt RTI) b. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine, Efavirenz, Delavirdine, Loviride c. Protease inhibitors Ritonavir , Atazanavir, Indinavir, Nelfinavir Saquinavir , Amprenavir, Lopinavir d. Entry (Fusion) inhibitor Enfuvirtide e. CCR5 receptor inhibitor Maraviroc f. Integrase inhibitor Raltegravir Department of Pharmaceutical Chemistry

20. Antivirals Available for many viral infections Viruses controlled by current antiviral therapy Cytomegalovirus (CMV) Hepatitis viruses Herpes viruses Human immunodeficiency virus (HIV) Influenza viruses (the “flu”) Respiratory syncytial virus (RSV) 7/9/2024 20

21. Acyclovir 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6 H -purin-6-one 1 2 3 4 5 6 7 8 9

22. Acyclovir The first successful antiviral drug is Acyclovir , it is a nucleoside analog and is effective against herpes virus infections. The first antiviral drug to be approved for treating HIV, Zidovudine(AZT) , is also a nucleoside analog.

23. Guanine derivative 1 3 4 8 5 Guanine is a Purine derivative, consisting of fused Pyrimidine and Imidazole ring system.

24. Synthesis of Acyclovir Acyclovir: is synthesized by alkylating Guanine with 1-benzoyloxy-2-chloromethoxyethane in trimethylamine. The hydroxyl and amino groups of guanine are previously protected with a trimethylsilyl group by being treated with hexamethyl disilazane . After hydrolysis the resulting product with water, 9-(2-benzoyloxyethoxymethyl)guanine(36.1.4) is isolated.

25. Treating this with a methanol solution of ammonia removes the benzoyl protecting group from the hydroxyethoxymethyl fragment, giving Acyclovir.

26. Synthesis of Acyclovir 1-benzoyl oxy-2-chloro Methoxy ethane Methanol solution of Ammonia Guanine benzoyl group is removed Or NaoH Acyclovir Ester H 2 O Alkaline hydrolysis Trimethyl silyl amine + Benzoic acid

27. Synthesis: Department of Pharmaceutical Chemistry

28. Mechanism of Action of Acyclovir An acyclic guanosine derivative Phosphorylated by viral thymidine kinase Di-and tri-phosphorylated by host cellular enzymes Inhibits viral DNA synthesis by: 1) competing for viral DNA polymerase 2) chain termination

29. Mechanism of action Competitive Inhibition of Herpes Virus DNA polymerases. Acyclovir gets incorporated into the viral DNA and results in termination of DNA strand lengthening. This ultimately results in irreversible inhibition of DNA polymerase. Thus the replication of viral DNA is prevented by Acyclovir.

30. Mechanism of action: Acyclovir Herpes virus specific thymidine kinase Acyclovir monophosphate Cellular kinases Acyclovir triphosphate Inhibits herpes virus DNA polymerase competitively Gets incorporated in viral DNA and stops lengthening of DNA strand; the terminated DNA inhibits DNA- polymerase irreversibly Department of Pharmaceutical Chemistry

31. Uses and adverse effects Uses :- Used for Herpes simplex virus infections In chicken pox, the drug prevents visceral complications and reduces fever and eruptions. Varicella zoster viral infections. Adverse effects :- Anorexia, itching and skin rashes.

32. Herpes keratitis is a viral infection of the eye caused by the herpes simplex virus.

33. Ganc y clovir Used to treat cytomegalovirus (CMV), HSV and V esicular s t om a ti t i s viru s . ( V SV) Department of Pharmaceutical Chemistry

34. Mechanism of Action Department of Pharmaceutical Chemistry

35. A Amantadine hydrochloride 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. Amantadine is a primary amine derivative of adamantane. structure activity relationship 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 adamantadine 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. Mechanism of action It inhibits penetration of RNA viral partcles 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. 25

36. Amantadine hydrochloride Clinical application-Uses Amantadine is clinically effective in preventing and treating all types of strains of influenza , particularly type A2 strains of Asian influenza virus , and to a lesser extent , German measles (rubella) or atoga virus. It is also used for parkinsonism Side effects Generally, at therapeutic levels may cause severe CNS symptoms, such as nervousness, confusion, headache, drowsiness, insomnia, depression, and hallucinations. The GI side effects include nausea, diarrhea, constipation, and anorexia . Convulsions and coma occur with high doses and in patients with cerebral arteriosclerosis and convulsive disorders. 26

37. Rimantadine HCl Methyl derivative of amantadine. Side effects is lower More potent, longer acting (t½ 30 hours) and better tolerated. It Interferes with virus uncoating by inhibiting the release of specific protein. Oral bioavailability is higher and it is largely metabolized by hydroxylation followed by glucuronide conjugation. Metabolites are excreted in urine Department of Pharmaceutical Chemistry

38. Idoxuridine Idoxuridine is an analog of timidin —and iodinated derivative of deoxyuridin . Moa: Idoxuridine acts as an antiviral agent by  inhibiting viral replication by substituting itself for thymidine in viral DNA. This in turn inhibits thymidylate phosphorylase and viral DNA polymerases from properly functioning

39. Idoxuridine Uses: It is used primarily for ophthalmology for herpetic infections of the eye (keratitis). Adverse effects Since this drug also affects mammalian cells and also possess theratogenic , mutagenic, and immunosuppressive action, its use is limited to external use .

40. Structure of zidovudine

41. Zidovudine Zidovudine (ZDV), also known as Azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. Zidovudine is a deoxythymidine analog. It is the first licensed antiretroviral agent. It is the first drug approved for treatment of HIV It reduces the replication of the virus and leads to improvements in both symptoms and blood tests.

42. Mechanism of action Zidovudine is phosphorylated in vivo by cellular kinase enzymes to the corresponding deoxynucleoside triphosphate.

43. Phosphorylation is an important mechanism by which the activity of proteins can be altered after they are formed. A phosphate group is added to a protein by specific enzymes called kinases. This phosphate group is usually provided by ATP, the energy carrier of the cell.

44. Mechanism of action The active triphosphate metabolite inhibits viral RNA-dependent DNA polymerase (reverse transcriptase, RT). This enzyme is essential for the life cycle of the retrovirus. Zidovudine triphosphate has greater selectivity affinity for reverse transcriptase (Virus) than for human DNA polymerase. This causes chain termination and reverse transcriptase inhibition.

45. Uses and adverse effects Uses:- used in the treatment of HIV-1, HIV-2 and T-cell lymphotrophic viral infections. Combination of zidovudine with other drugs are used for better effects. Adverse effects :- High dose may result in anxiety and confusion. Long term therapy leads to Anemia and bone marrow depression. Insomnia and myalgia.

46. DI D ANOSINE Is a purine nucleoside analogue which after intracellular conversion to didanosine triphosphate competes with ATP for incorporation into viral DNA, inhibits HIV reverse transcriptase and terminates proviral DNA. Antiretroviral activity of didanosine is equivalent to AZT. Use has declined due to higher toxicity than other NRTIs Department of Pharmaceutical Chemistry

47. Zalcitabine Zalcitabine (2′-3′-dideoxycytidine, ddC ), also called dideoxycytidine, is a pyrimidine nucleoside analog reverse-transcriptase inhibitor (NRTI) sold under the trade name Hivid. Department of Pharmaceutical Chemistry

48. Lamivudine Lamivudine , commonly called 3TC , is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. Department of Pharmaceutical Chemistry

49. Lamivudine An inhibitor of both hepatitis B virus (HBV) DNA polymerase and human immunodeficiency virus (HIV) reverse transcriptase First line drug for chronic hepatitis B Chronic treatment decreased plasma HBV DNA levels, improved biochemical markers, and reduced hepatic inflammation Mechanism of action: It must be phosphorylated by host cellular enzymes to the triphosphate (active) form This compound competitively inhibits HBV DNA polymerase at concentrations that have negligible effects on host DNA polymerase Department of Pharmaceutical Chemistry

50. Used in combination with other anti-HIV drugs, and appears to be as effective as AZT Synergises with most other NRTIs for HIV, and is an essential component of all first line triple drug NACO regimens for AIDS Side effects are few—fatigue, rashes , abdominal pain Pancreatitis and neuropathy are rare Hematological toxicity does not occur Department of Pharmaceutical Chemistry

51. Lo v iride Loviride is a non-nucleoside inhibitor of reverse transcriptase. It inhibits virion and recombinant reverse transcriptase of HIV-1. Department of Pharmaceutical Chemistry

52. Delavirdine (brand name Rescriptor ) It is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It is used as part of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) type 1. Department of Pharmaceutical Chemistry

53. Ribavirin Ribavirin consists of a ribose sugar moiety attached to a structure that resembles a purine nucleotide. Ribavirin is a synthetic analog of nucleosides. It is effective against many DNA and RNA viruses, such as viral influenza and herpes. The mechanism of its action is not completely known. However, it is highly likely that it is not the same for all viruses. It has been tried on a number of AIDS patients with various results. A synonym of this drug is virazoll .

54. Saquinavir Mechanism of action It is specifically designed to inhibit HIV protease, thus preventing post translational format ion of viral proteins. It contains a hydroxyethylamine moiety rather than the Phe -Pro scissile bond (Covalent chemical bond broken by enzyme) present in the normal substrate for HIV protease. Clinical application Saquinavir is used in the treatment of advanced HIV infection in selected patients. Side effects GI disturbances, Headache Rhinitis Diarrhea. Saquinavir was the first PI approved by the U.S. FDA in December 1995. It is a carboxamide derivative. 32

55. Saquinavir Saquinavir ( SQV ), sold under the brand names Invirase and Fortovase , is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. It is taken by mouth. Department of Pharmaceutical Chemistry

56. Retroviral protease inhibitors (PIs) INDINAVIR Indinavir ( IDV ; trade name Crixivan , made by Merck) 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. Department of Pharmaceutical Chemistry

57. Indinavir (IDV) Is to be taken on empty stomach g.i. intolerance is common excess fluids must be consumed to avoid nephrolithiasis Hyperbilirubinaemia occurs less frequently used now Department of Pharmaceutical Chemistry

58. Ri t on a vir Ritonavir brand ( R TV ), name s ol d u n de r t he Norvir , is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination t r e a tme n t i s known as highly active antiretroviral therapy (HAART). Often a low dose is used with other protease inhibitors. It may also be used in c ombin a tion w ith o ther medications for hepatitis C. Department of Pharmaceutical Chemistry

59. Is potent Drug interactions, nausea, diarrhoea, paresthesias, fatigue and lipid abnormalities are prominent more commonly employed in a low dose Department of Pharmaceutical Chemistry

60. Antivirals: Adverse Effects Acyclovir Burning when topically applied, nausea, vomiting, diarrhea and headache. Amantadine and Rimantadine Anticholinergic effects, insomnia, light headedness, anorexia, nausea Didanosine ( ddl ) Pancreatitis, peripheral neuropathies, seizures

61. Antivirals: Side Effects Zidovudine (AZT) Bone marrow suppression, nausea, headache Foscarnet ( Foscavir ) Headache, seizures, acute renal failure, nausea, vomiting, diarrhea Ganciclovir ( Cytovene ) Bone marrow toxicity, nausea, anorexia, vomiting

62. Agents used in AIDs treatment

63. Viruses are difficult to kill because they live inside our cells. Any drug that kills a virus may also kill our cells.

64. Anti- HIV Drug Targets Three types of drugs are currently in clinical use: Nucleoside And Nucleotide Reverse Transcriptase (RT) Inhibitors (NRTI) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) Protease Inhibitors ( Pis )

65. Current Medications NRTI Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine NNRTI Efavirenz Etravirine Nevirapine PI Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir Fusion Inhibitor Enfuvirtide CCR5 Antagonist Maraviroc Integrase Inhibitor Raltegravir Fixed-dose Combinations Zidovudine/ lamivudine Zidovudine/lamivudine/abacavir Abacavir/lamivudine Emtricitabine/ tenofovir Efavirenz/emtricitabine / tenofovir

66. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors These were the first type of drug available to treat HIV infection . NRTIs interfere with the action of an HIV protein called Reverse Transcriptase . (Reverse transcriptase changes viral RNA to DNA)

67. Act by competitive inhibition of HIV reverse transcriptase; incorporation into the growing viral DNA chain results in premature chain termination due to inhibition of binding with the incoming nucleotide .

68. NRTIs Common Adverse Effects Zidovudine Fatigue, bone marrow suppression Didanosine , Zalcitabine Stavudine: peripheral neuropathy, pancreatitis Abacavir hypersensitivity zenofovir , Lamivudine : (generally well-tolerated) vomiting, flatulence

69. Non nucleoside Reverse Transcriptase Inhibitors (NNRTI) Bind directly to HIV reverse transcriptase, prevents viral RNA from conversion to the viral DNA that infects healthy cells, by causing conformational changes in the enzyme. The binding site of NNRTIS is near to but distinct from that of NRTIS.

70. Drug resistance develops quickly if NNRTIs are administered as monotherapy and therefore NNRTIs are always given as part of combination therapy. Delavirdine Efavirenz Nevirapine

71. NNRTI’s: Adverse Effects Side effects are worst during the first 1 to 2 weeks of therapy. NNRTI agents are associated with varying levels of GI intolerance and skin rash. CNS effects (e.g. sedation, insomnia, and confusion)

72. Protease Inhibitors Prevent the processing of viral proteins into functional conformations, resulting in the production of immature, noninfectious viral particles . Do not need intracellular activation.

73. Atazanavir Indinavir Lopinavir Nelfinavir Saquinavir Ritonavir Darunavir Fosamprenavir Tipranavir contain sulfonamide

74. PI Class Side Effects Metabolic Disorders Hepatotoxicity Hyperglycemia Lipid abnormalities (increases in triglyceride and LDL levels) Bone Disorders GI Intolerance 77

75. Nucleoside Analogs There are currently 7 FDA-approved NRTI’s and one nucleotide analog. The first anti-HIV drug approved was the NRTI known as AZT or Zidovudine (1987). AZT was discovered as a treatment of AIDS during a screening process for the identification of effective AIDS treatments. Antiviral selectivity due to higher affinity for HIV RT than human DNA polymerases.

76. Non-Nucleoside Analogs Non-nucleoside analog reverse transcriptase inhibitors (NNRTI’s) inhibit viral DNA replication by binding at the allosteric non-bonding site of RT, causing a conformational change of the active site. NNRTI’s do not require bioactivation by kinases. Three NNRTI’s are currently approved for clinical use in combination therapy: Nevirapine , Delavirdine and Efavirenz

77. Non-Nucleoside Analogs Delavirdine Benzoxazinone Nevirapine

78. Combination Therapy The combination of drugs chosen is based on the history of each individual patient and synergistic drug interactions. Some drugs compete with each other for binding sites or enzymes. Example: zidovudine and stavudine . Both nucleoside analogs compete for the same kinase.

79. Drug Toxicity and Side Effects All available antiretroviral drugs are toxic. Side effects of nucleoside analogs are lactic acidosis and severe hepatomegaly with steatosis (enlarged fatty liver). Other side effects of anti-HIV drugs include pancreatitis, myopathy, anemia, peripheral neuropathy, nausea and diarrhea.

80. Reducing Drug Toxicity The use of combination therapy: Combining agents with favorable synergistic properties allows a decrease in dose or dosing frequency Ritonavir alone cause gastrointestinal side effects but when used in combination with other PI’s it can be administered at a lower dose.

81. Some HIV Facts HIV – the H uman I mmunodeficiency V irus is the retrovirus that causes AIDS HIV belongs to the retrovirus subfamily lentivirus . HIV attaches to cells with CD4 receptors (T4 cells and macrophages).

82. Antivirals Key characteristics of antiviral drugs: Able to enter the cells infected with virus. Interfere with viral nucleic acid synthesis and/or regulation. Some agents interfere with ability of virus to bind to cells. Some agents stimulate the body’s immune system.

83. Antivirals: Mechanism of Action Inhibit viral replication Inhibit viral attachment Prevent genetic copying of virus Prevent viral protein production

84. Zidovudine Zidovudine is an analogue of thymidine in which the 3-hydroxyl group is replaced by an azido group. IUPAC Systematic Name : 3′-Azido-3′-deoxythymidine. Synonyms : Azidothymidine, 3′-azidothymidine, AZT, 3′-deoxy-3′-azidothymidine, ZDV

85. Structure of zidovudine

86. Zidovudine Zidovudine (ZDV), also known as Azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It reduces the replication of the virus and leads to improvements in both symptoms and blood tests.

87. Synthesis of Zidovudine Zidovudine is 3-azido-3-deoxytimidine (36.1.26), It is synthesized from 1-(2-deoxy-5-O-trityl-β-D- lyxosyl )thymine, which is treated with methanesulfonyl chloride in pyridine to make the corresponding mesylate 36.1.24. Replacing the methyl group with an azide group using lithium azide in dimethylformamide makes the product 36.1.25 with inverted configuration at C3 of the furanosyl ring. Heating this in 80% acetic acid removes the trityl protection, giving zidovudine.

88. Synthesis of Zidovudine Lithium azide Dimethyl formamide Methane sulfonyl chloride in Pyridine Mesylate . Zidovudine Heating 1-(2’-deoxy-5’-O-trityl- β -D- lyxosyl )thymine,

89. Structure of ribose 2-deoxy-D-ribose is a deoxypentose that is D-ribose in which the hydroxy group at position C-2 is replaced by hydrogen.

90. Trityl group- triphenyl methane. Triphenylmethane is the hydrocarbon with the formula (C 6 H 5 ) 3 CH.

91. Lyxose is an aldopentose — a monosaccharide containing five carbon atoms, and including an aldehyde functional group.

92. Scheme 2

93. Mechanism of action Zidovudine is an antiretroviral drug that is clinically active against HIV-1 and is intended to treat HIV-infected patients. Zidovudine is an analog of thymidine that inhibits replication of the AIDS virus. It also turned into mono, di and triphosphates by the same cellular enzymes that catalyze phosphorylation of thymidine and thymidine nucleosides. Zidovudine-triphosphate is then included in the terminal fragment of the growing chain of viral DNA by viral reverse transcriptase, thus causing the viral DNA chain to break apart in cells infected with the virus.

94. Uses and adverse effects Uses:- used in the treatment of HIV-1, HIV-2 and T-cell lymphotrophic viral infections. Combination of zidovudine with other drugs are used for better effects. Adverse effects :- High dose may result in anxiety and confusion. Long term therapy leads to anemia and bone marrow depression.

95. Zidovudine has been authorized for treating patients with AIDS . It significantly prolongs the life of the patient, although it has a number of toxic effects. Synonyms of this drug are azidothymidine and retrovir .

96. Conclusions An effective anti-HIV therapy is still needed. Several possible targets are being studied and tested. The area of anti-HIV drugs has more room for growth and the future for the discovery of new effective drugs is promising.