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

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 α,γ-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 microM] to achieve more active NS5B inhibitors. This yielded compound 3a [IC(50) = 8.2 microM] 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 microM] 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 microM] and 24a [IC(50) = 2.4 microM]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization.