RESUMEN
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.
Asunto(s)
Ribavirina , Triazoles , Ácidos Carboxílicos , NucleósidosRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Antivirales/farmacología , Nucleósidos/farmacología , Triazoles/farmacología , Compuestos de Vinilo/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antivirales/síntesis química , Antivirales/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Hepacivirus/efectos de los fármacos , Humanos , Virus de la Influenza A/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Compuestos de Vinilo/síntesis química , Compuestos de Vinilo/químicaRESUMEN
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.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Ribavirina/análogos & derivados , Ribavirina/síntesis química , Triazoles/síntesis química , Catálisis , Isomerismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antivirales/síntesis química , Ribavirina/análogos & derivados , Animales , Antivirales/química , Antivirales/farmacología , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Hepacivirus/efectos de los fármacos , Herpesvirus Humano 1/efectos de los fármacos , Humanos , Virus de la Influenza A/efectos de los fármacos , Ribavirina/síntesis química , Ribavirina/farmacología , Células VeroRESUMEN
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.