RESUMEN
In ongoing studies towards novel hepatitisâ C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.
Asunto(s)
Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Línea Celular , Permeabilidad de la Membrana Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Perros , Evaluación Preclínica de Medicamentos , Farmacorresistencia Viral , Hepacivirus/metabolismo , Humanos , Enlace de Hidrógeno , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
As part of a project to generate a library of nucleosides as potential antiviral agents, a small subset of novel acyclic phosphonic acid nucleosides was prepared. Practical synthetic routes are described for three targets, which were then tested against HIV, hepatitis C virus (HCV), and Dengue virus.