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

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Abstract:

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 &bgr-N-hydroxy- γ-keto-acid pharmacophore for HCV NS5B polymerase inhibitors.





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

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986712798918833

Publication date: February 1, 2012

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
ben/cmc/2012/00000019/00000004/art00009
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