Computer based design, synthesis and biological evaluation of novel indole derivatives as HCV NS3-4A serine protease inhibitors

Abstract

A series of novel indoles were designed and their molecular modeling simulation study including fitting to a 3D pharmacophore model using CATALYST program and their docking into the NS3 active site was examined as HCV NS3 protease inhibitor. Several compounds showed significant high simulation docking score and fit values. The designed compounds were synthesized and biologically evaluated in vitro using an NS3 protease binding assay, where compounds 10a– k showed significant inhibitory activity (⩾67% inhibition at 100 μg/mL). Of these, compounds 10c and 10f demonstrated potent HCV NS3 protease inhibitors with IC 50 values of 15 and 13 μM, respectively. Enantio-selective Michael addition of an indole derivative in the presence of catalytic amount of AlCl 3 and quinine at room temperature afforded the adduct 7e in excellent yield with 73% ee. The product was converted into 10l, which showed lower activity than the mixture of the corresponding diastereoisomers.