Discovery, Synthesis, and invitro Evaluation of West Nile Virus Protease Inhibitors Based on the 9,10-Dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one Scaffold

Abstract

West Nile virus (WNV), a member of the Flaviviridae family, is a mosquito-borne pathogen that causes a great number of human infections each year. Neither vaccines nor antiviral therapies are currently available for human use. In this study, a WNV NS2B-NS3 protease inhibitor with a 9,10-dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one scaffold was identified by screening a small library of non-peptidic compounds. This initial hit was optimized by solution-phase synthesis and screening of a focused library of compounds bearing this scaffold. This led to the identification of a novel, uncompetitive inhibitor (1a40, IC 50=5.41±0.45μM) of WNV NS2B-NS3 protease. Molecular docking of this chiral compound onto the WNV protease indicates that the Senantiomer of 1a40 appears to interfere with the productive interactions between the NS2B cofactor and the NS3 protease domain; (S)-1a40 is a preferred isomer for inhibition of WNV NS3 protease. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.