Discovery of novel HCV inhibitors: design, synthesis and biological activity of phthalamide derivatives

Abstract

Hepatitis C virus (HCV) is a major cause of end-stage liver diseases like cirrhosis and hepatocarcinoma, posing a serious worldwide threat when left untreated. Nowadays, direct-acting antivirals (DAAs) constitute core components of anti-HCV treatment. Nonetheless, some DAAs are associated with a growing level of drug resistance as well as adverse reactions. That is why introducing new anti-HCV drugs with higher potency and lower toxicity is so essential. NS5B polymerase is an HCV non-structural protein that acts as a critical target for the development of anti-HCV therapeutics. Based on the necessary pharmacophores for inhibition of HCV NS5B polymerase, a novel series of phthalamide analogs that harbor the potential of NS5B polymerase inhibition to stop HCV proliferation in a cell-based assay were designed, synthesized, and in-vitro evaluated. Interestingly, all compounds displayed low cellular cytotoxicity in Huh 7.5 cells (CC 50 > 100). Compound 28 with EC 50 of 6.0 µM, and an appropriate a nity to NS5B polymerase active site could be considered as a new hit compound, providing useful information for the design of novel HCV inhibitors.