title: Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition.
abstract: 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.
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.
authors: Aaditya
authors: A
authors: Bhatt
authors: K R
authors: KR
authors: Gurukumar
authors: Amartya
authors: A
authors: Basu
authors: Maulik R
authors: MR
authors: Patel
authors: Neerja
authors: N
authors: Kaushik-Basu
authors: Tanaji T
authors: TT
authors: Talele
mesh_terms: D000143:Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000143:Acids; D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase