Abstract: Hepatitis C virus (HCV) is a human pathogen with high morbidity. The HCV NS3/4A protease is essential for viral replication and is one of top three drug targets. A number of drugs have been developed but drug resistant mutant strains emerged. Here we screened and synthesized of novel class of small molecules of Formula I or Formula IA based on tryptophan derivative scaffold as HCV NS3/4A protease inhibitors that is active against both wild type and mutant form of the protease. Only the docking hits with a binding pose that is not affected by the most frequent mutations in the active site were selected for experimental validation. The antiviral activities were evaluated by replicon and enzymatic assays. Twenty-two compounds in this series were found to inhibit HCV with EC50 values ranging between 0.64 to 63 ?M with compound 22 being the most active of this series. In protease assays, 22 had a comparable inhibition profile for the common mutant HCV GT1b D168A and the wild type enzyme.

Abstract: Hepatitis C virus (HCV) is a human pathogen with high morbidity. The HCV NS3/4A protease is essential for viral replication and is one of top three drug targets. A number of drugs have been developed but drug resistant mutant strains emerged. Here we screened and synthesized of novel class of small molecules of Formula I or Formula IA based on tryptophan derivative scaffold as HCV NS3/4A protease inhibitors that is active against both wild type and mutant form of the protease. Only the docking hits with a binding pose that is not affected by the most frequent mutations in the active site were selected for experimental validation. The antiviral activities were evaluated by replicon and enzymatic assays. Twenty-two compounds in this series were found to inhibit HCV with EC50 values ranging between 0.64 to 63 ?M with compound 22 being the most active of this series. In protease assays, 22 had a comparable inhibition profile for the common mutant HCV GT1b D168A and the wild type enzyme.