ABSTRACT
Ribavirin analogs substituted at position 5 of the heterocyclic base are interesting for their biological activity. This protocol describes a synthetic route to several such ribavirin analogs with a wide range of substituents.© 2021 Wiley Periodicals LLC. Basic Protocol 1: Synthesis and purification of 5-substituted ethyl 1,2,4-triazole-3-carboxylates - synthetic precursors of nucleobases Basic Protocol 2: Synthesis and purification of protected 1,2,4-triazole nucleoside analogs Basic Protocol 3: Synthesis and purification of 5-substituted ribavirin analogs.
Subject(s)
Ribavirin , Triazoles , Carboxylic Acids , NucleosidesABSTRACT
Some 5-substituted ribavirin analogues have a high antiviral and anticancer activity, but their mechanisms of action are obviously not the same as their parent compound. The SAR studies performed on 3 (5)-substituted 1,2,4-triazole nucleosides have shown a high dependency between the structure of the 3 (5)-substituent and the level of antiviral/anticancer activity. The most active substances of the row contain coplanar with the 1,2,4-triazole ring aromatic substituent which is connected by a rigid ethynyl bond. However, the compounds with the trans-vinyl linker also had antiviral activity. We decided to study the antitumor activity of ribavirin analogues with alkyl/aryl vinyl substituents in the 5th position of the 1,2,4-triazole ring. Protected nucleoside analogues with various 5-alkylvinyl substituents were obtained by Horner-Wadsworth-Emmons reaction from the common precursor and converted to the nucleosides. Arylvinyl nucleosides were synthesised according the reported procedures. All compounds did not show significant antiproliferative activity on several tumour cell lines. Coplanar aromatic motif in the 5-substituent for the anticancer activity manifestation was confirmed.
Subject(s)
Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Nucleosides/pharmacology , Triazoles/pharmacology , Vinyl Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hepacivirus/drug effects , Humans , Influenza A virus/drug effects , Microbial Sensitivity Tests , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Vinyl Compounds/chemical synthesis , Vinyl Compounds/chemistryABSTRACT
The chemical ribosylation pathways of 5-substituted-1,2,4-triazole-3-carboxylates are discussed. For the products of the chemical synthesis of the 3(5)-alkyl- or 3(5)-aryl-substituted ribavirin analogues the anomer configuration and isomer composition were determined.
Subject(s)
Carboxylic Acids/chemical synthesis , Ribavirin/analogs & derivatives , Ribavirin/chemical synthesis , Triazoles/chemical synthesis , Catalysis , Isomerism , Molecular Structure , Structure-Activity RelationshipABSTRACT
The novel isosteric ribavirin analogues were synthesized by two different ways. Some of them showed significant antiviral action against hepatitis C virus (HCV), herpes simplex (HCV-1) and influenza A virus comparable to that of ribavirin itself. The data obtained confirm the proposed theory of the ribavirin possible antiviral activity mechanism related with bioisosterism.
Subject(s)
Antiviral Agents/chemical synthesis , Ribavirin/analogs & derivatives , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , Hepacivirus/drug effects , Herpesvirus 1, Human/drug effects , Humans , Influenza A virus/drug effects , Ribavirin/chemical synthesis , Ribavirin/pharmacology , Vero CellsABSTRACT
A new pathway to synthesis of arylvinyl ribavirin analogues is developed which makes it possible to obtain not only trans- but also cis-isomers at vinyl bond. By this route eight ribavirin 5-arylvinyl analogues are synthesized and their antiviral activity is evaluated.
