Discovery of 2-iminobenzimidazoles as potent hepatitis C virus inhibitors with a novel mechanism of action

•Iminobenzimidazole (IBI) was identified by phenotypic HTS using infectious HCV.•IBI showed strong inhibitory activity against infectious HCV.•IBI exhibited antiviral activity on both early and late steps of the viral cycle.

In this report we describe 2-iminobenzimidazole (IBI) analogs, identified during the course of a phenotypic high-throughput screening campaign, as novel hepatitis C virus (HCV) inhibitors. A series of IBI derivatives was synthesized and evaluated for their inhibitory activity against infectious HCV. Among the IBIs derivatives studied in this work, we identified promising compounds with high antiviral efficacy, high selectivity index and good microsomal stability. Noteworthy, the IBI series exhibited inhibitory activity on early and late steps of the viral cycle, but not in the HCV replicon system demonstrating a mechanism of action distinct from clinical-stage and approved anti-HCV drugs. Overall, our results suggest that IBIs are predestinated for further exploration as lead compounds for novel HCV interventions.

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