Week 1 - Antiviral Agents - Acyclic Nucleoside Agents PDF

Antiviral Agents Pharmaceutical Chemistry III (PPC413) Dr. Shymaa Damfo [email protected] 1  Outline Classify the major drug classes of antiviral agents Define the structure-activity relationship (SAR) of antiviral agent Explain t...

Antiviral Agents Pharmaceutical Chemistry III (PPC413) Dr. Shymaa Damfo [email protected] 1  Outline Classify the major drug classes of antiviral agents Define the structure-activity relationship (SAR) of antiviral agent Explain the different modes of action and metabolic pathways ways of antiviral agent 2 Introduction nice replication maps a Viruses are non-cellular, infectious agents which take over a host cell in order to survive and multiply. Structure of viruses genam 3 Antiviral Agents I x̅ All viruses contain one or more molecules of either RNA or DNA, but not both. Antiviral agents: 1. Antiviral drugs acting against DNA viruses (interfering with Viral Nucleic Acid Replication) 2. Antiviral drugs acting against RNA viruses HIV (Nucleoside reverse transcriptase inhibitors, Protease inhibitors) Flu virus 4 Introduction The life cycle of viruses Animalorhuman virus 5 Antiviral drugs acting against DNA viruses 6  Ao purine Tec pyrimidine co.net g.EEing 7  1- Acyclovir DNAAntiviral O O N N HN HN N N H2N N H2N N 5' HO CH2 HO CH2 O Incomplete sugar O Acyclovir 4' 1' L Pro-drug inactive active Antimetabolite waswww.m 3' 2' OH Synthetic Analogue of deoxyguanosine Acyclic sugar moiety Deoxyguanosine Lacks the 3' OH of a cyclic sugar Metabolite (endogenous substance) as Poor bioavailability 15-30 % Cyclic sugar moiety 8 1- Acyclovir O O HN I N oniso.ie Viral Thymidine Kinase HN N Acyclovir Metabolism: N Virus H2N N O N H2N N HO CH2 HO P O CH2 O O OH 2 Acyclovir e Acyclovir Monophosphate nas Ki Inactive ate dyl st mi Ho thy O lar llu Ce N HN O O O N H2N N HO P O P O P O CH2 O OH OH OH Acyclovir Triphosphate (Active form) 9 2-Valacyclovir O O Valine si N N HN HN Hydrolysis Intestine, Liver H2N N N H3C N H2N N H HO CH2 CH C C O CH2 O O H3C NH2 O a 3 Acyclovir Valacyclovir t.IE Enaeaseoioananoiityoeacsaovir Viral Thymidine Kinase Valacyclovir: Amino acid ester Acyclovir monophosphate Pro-drug of Acyclovir r ie Y i.n Cellular thymidylate kinase Valine attached to the 5‘ OH group Increased GI absorption Higher Acyclovir levels Inexamwhatistheadvanofadding ester Acyclovir triphosphate increase and solubility absorption 3- Desciclovir (6-Deoxyacyclovir) woo is O N N N HN N oxygen H2N N Xanthine oxidase H2N N N HO CH2 O inexamcomplete HO CH2 1Purinebutnooxygeninco purine casenosine O Acyclovir 6-Deoxyacyclovir Viral Thymidine Kinase Pro-drug of Acyclovir Improved solubility properties Acyclovir monophosphate b caging lipomicity hydrophilicity solubility absorption Cellular thymidylate kinase Acyclovir triphosphate 11 4- Ganciclovir www.mmo O O N N 1purineguanosine HN HN 2Acyclicsuger 3 thereisnolaekof.su H2N N N Cellular Guanosine Kinase O H2N N N HO CH2 HO P O CH2 O O s OH OH OH Ganciclovir Monophosphate Ganciclovir Cellular kinase O N Prodrug HN Antimetabolite O O O N Acyclic deoxyguanosine analogue H2N N More toxic than Acyclovirnumaneneymepoaers.no HO P O P O P O CH2 O It does not require viral thymidine kinase OH OH OH intam choose structre Ganciclovir Triphosphate 12 OH  H 2N O 5- Famciclovir N N N HN O N N N H H 2N N H Adenine 2family Guanine N N HN HN Neutral bases N N H2N N 1) Hydrolysis H2N N H3C C O CH2 No oxygen 2) Oxidation HO CH2 O I rested Cellular Guanosine Kinase OH O CH3 C Penciclovir Famciclovir O Synthetic purine nucleoside analogue Related to guanine O O Diacetyl-6-deoxy ester of Penciclovir N N HN zester Guanosine Monophosphate Kinase HN O O O N O N H2N N H2N N HO P O P O P O CH2 HO P O CH2 OH OH OH OH Penciclovir Monophosphate Penciclovir Triphosphate OH OH 13  if Anti metabolites29 https://microbiologynote.com/mechanism-of-antiviral-drug/ 14 6- Cidofovir NH2 NH2 N Cytosine Monophosphate Kinase N O H2 N O HO P C O O O O Phosphonic acid H2 N O HO P O P O P C O OH OH OH OH Lc OH Cidofovir OH Cidofovir Diphosphate suger Synthetic acyclic pyrimidine nucleotide analogue of cytosine Phosphonic acid derivative does not requireios phosphates viral thymidine kinase Antimetabolite Phosphonic acid 15 7- Idoxuridine O O I H3C NH NH N O N O HO HO O O OH OH Idoxuridine Deoxythimidine I Nucleoside containing a halogenated pyrimidine and is an analogue of thymidine Competes with Deoxythymidine inhibit the replication of viral DNA Idoxuridine triphosphate is the active form It does not require viral thymidine kinase (phosphorylated equally well by viral and cellular thymidine kinases) say viral ws cellular 16 8- Trifluorothymidine O O F3C H3C NH NH N O N O HO HO O O OH OH Trifluorothymidine Deoxythimidine Pyrimidine nucleoside and is an analogue of thymidine Competes with Deoxythymidine inhibit the replication of viral DNA Bykinase Trifluorothymidine triphosphate is the active form nuclosite suger vacutise nosugar 17 9- Vidarabine NH2 NH2 N N N N N N N N HO HO OH O O OH OH Vidarabine Deoxyadenosine won sugar instead of ribose Natural adenosine nucleoside with arabinose Competes with Deoxyadenosine inhibit the replication of viral DNA Bykinase Vidarabine triphosphate is the active form 18 Antiviral drugs acting against RNA viruses: HIV 19 The HIV virus structure and the HIV life cycle 20 Nucleoside reverse transcriptase inhibitors (NRTI) 21  1- Ziduvudine t hymine resrimidine O O CH3 group CH3 HN HN O N O N HO HO O O N3 Fife Zidovudine OH 2'-deoxythymidine Analogue of thymidine Azido group substituted at 3'-carbon of the dideoxyribose moiety Ziduvudine-5'-triphosphate is the active form bykinase Ziduvudine-5'-triphosphate Incorporated into proviral DNA soanuaosisewax Phosphate.ms Prevents normal 5',3'-phosphodiester bonding SY S Termination of DNA chain elongation due to the presence of an azido group 22  1- Ziduvudine O O CH3 CH3 HN HN Cellular kinases O N O O O O N HO HO P P P O O O OH OH OH N3 N3 Zidovudine Zidovudine-5'-triphosphate 23  2- Didanosine O NH2 N N NH N inosine N N N N HO HO O O OH Didanosine Deoxyadenosine Purine dideoxynucleoside, analogue of inosine 2',3'-dideoxyinosine, differs from inosine by having a H atom in place of 3'-OH Didanosine is a pro-drug that is bioactivated by metabolism to dideoxyadenosine triphosphate (antimetabolite) Deoxyadenosine triphosphate is the metabolite Termination of DNA chain elongation due to the absence of 3'-OH 24 2- Didanosine NH2 O N N N NH Amination O O O N N Cellular kinases N HO P O P O P O N HO O OH OH OH O Didanosine Dideoxyadenosine triphosphate 25