Département de chimie moléculaire

We have identified naturally occurring 2-benzylidenebenzofuran-3-ones (aurones) as new templates for non-nucleoside hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors. The aurone target site, identified by site-directed mutagenesis, is located in thumb pocket I of HCV RdRp. The RdRp inhibitory activity of 42 aurones was rationally explored in an enzyme assay. Mol. docking studies were used to det. how aurones bind to HCV RdRp and to predict their range of inhibitory activity. Seven aurone derivs. were found to have potent inhibitory effects on HCV RdRp, with IC50 below 5 $μ$M and excellent selectivity index (inhibition activity vs. cellular cytotoxicity). The most active aurone analog was (Z)-2-((1-butyl-1H-indol-3-yl)methylene)-4,6-dihydroxybenzofuran-3(2H)-one (compd. 51, I), with an IC50 of 2.2 $μ$M. Their potent RdRp inhibitory activity and their low toxicity make these mols. attractive candidates as direct-acting anti-HCV agents. [on SciFinder(R)]