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 [IC50 = 21.8 μM] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 μM] 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 [IC50 = 7.5 μM] 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 [IC50 = 5.2 μM] and 24a [IC50 = 2.4 μM]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization.

Optimization of specificity domain of α,γ-diketo acids (DKAs) resulted in identification of low micromolar NS5B polymerase inhibitor 24a [IC50 = 2.4 μM]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization.Figure optionsDownload as PowerPoint slideHighlights
► HCV NS5B polymerase is an attractive target for intervention of HCV infection.
► Specificity aryl/heteroaryl domain in α,γ-diketo acids influences NS5B inhibition.
► 2,4-difluorophenyl as the specificity domain resulted in potent inhibition of NS5B.
► Docking model of most active analog suggests clues for future SAR optimization.