Synthesis and evaluation of hexahydropyrimidines and diamines as novel hepatitis C virus inhibitors

In order to identify novel anti-hepatitis C virus (HCV) agents we devised cell-based strategies and screened phenotypically small molecule chemical libraries with infectious HCV particles, and identified a hit compound (1) containing a hexahydropyrimidine (HHP) core. During our cell-based SAR study, we observed a conversion of HHP 1 into a linear diamine (6), which is the active component in inhibiting HCV and exhibited comparable antiviral activity to the cyclic HHP 1. In addition, we engaged into the biological characterization of HHP and demonstrated that HHP does not interfere with HCV RNA replication, but with entry and release of viral particles. Here we report the results of the preliminary SAR and mechanism of action studies with HHP. [Display omitted] •Hexahydropyrimidine (HHP) was identified by phenotypic HTS using infectious HCV.•HHP is converted into a linear diamine inhibiting HCV in cell culture.•HHPs and diamines interfere with entry and release of viral particles.