Potent Hepatitis C Virus NS5A Inhibitors Containing a Benzidine Core

Abstract

Here we report the discovery of a series of potent hepatitis C virus (HCV) NS5A inhibitors based on the benzidine prolinamide backbone. Taking a simple synthetic route, we developed a novel inhibitor structure, which allows easy modification, and through optimization of the capping group, we identified compound 6 with highly potent anti-HCV activity. Compound 6 is nontoxic and is anticipated to be an effective HCV drug candidate.

Keywords: HCV; NS5A inhibitor; antiviral agent; benzidine; structure−activity relationship.

Scheme 1. Synthesis of Benzidine Prolinamide Skeleton

Reagents and conditions: (a) N-Boc-l-proline, EDC, DCM, 94%; (b) TFA, DCM; (c) capping group, EDC, DIPEA, DCM 22–49% (2 steps).

Figure 1

Effect of cotreatment of compound 6 and sofosbuvir on the HCV replicon system. All measurements were made in triplicate.