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

Hepatitis C virus (HCV) is a major cause of end-stage liver diseases like 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 acts as a critical target for the development of anti-HCV therapeutics. Based on these essential requirements for the 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 developed. Interestingly, all compounds displayed low cellular cytotoxicity in Huh 7.5 cells (CC50 > 100) and proper EC50 values against HCV replication. Docking studies revealed that compounds with metal coordinating groups may be able to prevent the binding of the natural substrate of NS5B, which is a nucleotide, via binding to the metal cations present in the enzyme. In agreement with the biological studies, most of the designed compounds have considerable affinity to the active site in comparison with sofosbuvir. Compound 3z with EC50 of 6.0 mu M, and an appropriate affinity to the active site could be considered as a new hit for the design of novel HCV inhibitors.