Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition.

摘要

Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of alpha,gamma-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a IC(50) = 21.8 muM to achieve more active NS5B inhibitors. This yielded compound 3a IC(50) = 8.2 muM bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a IC(50) = 7.5 muM bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a IC(50) = 5.2 muM and 24a IC(50) = 2.4 muM. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization.