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.

Abstract 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 IC 50 values. The most potent compound exhibited IC 50 less than 10 nM against the genotype 1b HCV polymerase and EC 50 of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.