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Eur J Med Chem. 2011 Oct;46(10):5138-45. doi: 10.1016/j.ejmech.2011.08.028. Epub 2011 Aug 26.

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

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Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.


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 μM] to achieve more active NS5B inhibitors. This yielded compound 3a [IC(50) = 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 [IC(50) = 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 [IC(50) = 5.2 μM] and 24a [IC(50) = 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.

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