2-Hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic Acid with Inbuilt β-N-Hydroxy-γ-keto-acid Pharmacophore as HCV NS5B Polymerase Inhibitors

Author(s): R. R. Deore, G. S. Chen, C. -S. Chen, P. -T. Chang, M. -H. Chuang, T. -R. Chern, H. -C. Wang, J. -W. Chern

Journal Name: Current Medicinal Chemistry

Volume 19 , Issue 4 , 2012

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The inbuilt 2-N-hydroxy-1-oxo-3-carboxylic acid of isoquinolone was designed as pyrophosphate mimic for hepatitis C NS5B polymerase. Various 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives 11a-p were synthesized and evaluated as HCV NS5B polymerase inhibitors. Compound 11c exhibited moderate inhibitory potency based on the inorganic pyrophosphate generation (IC50 = 9.5 μM) and based on NTP incorporation by NS5B enzyme (IC50 = 5.9 μM). Compound 11c demonstrated antiviral activity (EC50 = 15.7 μM) and good selectivity in HCV genotype 1b replicon Ava.5 cells. Compound 11c reduced the interaction of NTP to NS5B polymerase. Docking model showed that 11c situated in similar orientation to the bound uridine triphosphate in the active site of NS5B polymerase. As a result, 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid was disclosed as a novel inbuilt γ-keto-acid pharmacophore for HCV NS5B polymerase inhibitors.

Keywords: Hepatitis C virus, non-structural protein 5B (NS5B) polymerase, α, γ-diketo acid, β-N-Hydroxy-γ-keto-acid, pyrophosphate mimic, metal chelation, structure-activity relationship, active site inhibitors, lead compound, pharmacophore

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Article Details

Year: 2012
Page: [613 - 624]
Pages: 12
DOI: 10.2174/092986712798918833
Price: $65

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