Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase

A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC50 values. The most potent compound exhibited IC50 less than 10 nM against the genotype 1b HCV polymerase and EC50 of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.

Graphical abstract1,1-Dioxoisothiazole and benzo[b]thiophene-1,1-dioxide analogs were synthesized and tested as HCV NS5B polymerase inhibitors. Their PK properties were also evaluated.Figure optionsDownload full-size imageDownload as PowerPoint slide