Development of benzidine and diaminofluorene prolinamide derivatives as potent hepatitis C virus NS5A inhibitors

Abstract

To come up with hepatitis C virus (HCV) NS5A inhibitors, we designed a series of highly potent inhibitors based upon the modification of known inhibitor structures. We synthesized symmetrical prolinamide derivatives of benzidine and diaminofluorene. The structure-modification allowed us to form a library of potent HCV NS5A inhibitors. After optimizing the benzidine prolinamide skeleton, we developed novel inhibitors possessing meta-substituted benzidine core structures that presented the most potent anti-HCV activities. Furthermore, through a battery of studies including hERG ligand binding assay, CYP450 binding assay, rat plasma stability test, human liver microsomal stability test, and pharmacokinetic studies, the identified compounds 12, 14, 15, 28 and 29 are found to be nontoxic, and are expected to be effective anti-HCV therapeutic agents.