Structure-activity relationship studies of a bisbenzimidazole-based, Zn2+-dependent inhibitor of HCVNS3 serine protease

A survey of isosteric replacements of the phosphonoalanine side chain coupl ed with a process of conformational constraint of a bisbenzimidazole-based, Zn2+-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease re sulted in the identification of novel series of active compounds with exten ded side chains. However, Zn2+-dependent HCV NS3 inhibition was relatively insensitive to the structural variations examined but dependent on the pres ence of negatively charged functionality. This result was interpreted in th e context of an initial electrostatic interaction between protease and inhi bitor that is subsequently consolidated by Zn2+, with binding facilitated b y the featureless active site and proximal regions of the HCV NS3 protein. (C) 2001 Elsevier Science Ltd. All rights reserved.