Synthesis, biological evaluation and in silico modeling of novel pan-genotypic NS5A inhibitors.

Bioorg Med Chem

Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia; ChemDiv, 6605 Nancy Ridge Drive San Diego, CA 92121, United States; Avisa Pharmaceuticals LLC, 1835 E. Hallandale Beach Blvd, #442, Hallandale Beach, Fl 33009, United States.

Published: October 2020

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Article Abstract

A series of novel small-molecule pan-genotypic hepatitis C virus (HCV) NS5A inhibitors with picomolar activity containing 2-[(2S)-pyrrolidin-2-yl]-5-[4-(4-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}buta-1,3-diyn-1-yl)phenyl]-1H-imidazole core was designed based on molecular modeling study and SAR analysis. The constructed in silico model and docking study provide a deep insight into the binding mode of this type of NS5A inhibitors. Based on the predicted binding interface we have prioritized the most crucial diversity points responsible for improving antiviral activity. The synthesized molecules were tested in a cell-based assay, and compound 1.12 showed an EC value in the range of 2.9-34 pM against six genotypes of NS5A HCV, including gT3a, and demonstrated favorable pharmacokinetic profile in rats. This lead compound can be considered as an attractive candidate for further clinical evaluation.

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http://dx.doi.org/10.1016/j.bmc.2020.115716DOI Listing

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