Design, Synthesis, and Biological Evaluation of 2-((4-Bisarylmethyl-piperazin-1-yl)methyl)benzonitrile Derivatives as HCV Entry Inhibitors

Viral entry inhibitors are absent in hepatitis C virus (HCV) treatment regimens although a dozen direct-acting antiviral (DAA) drugs are available now. Based on a previously identified HCV entry inhibitor L0909, chemical space exploration and structure-activity relationship (SAR) studies led to the discovery of a new derived scaffold 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile. Several new scaffold derivatives exhibited higher in vitro anti-HCV activity at low nanomolar concentrations compared to L0909. A biological study indicated that the high potency of active derivatives 3d, 3h, and 3i was primarily driven by the inhibitory effect on the virus entry stage. Moreover, an SPR experiment confirmed that this class of derivatives might target the HCV El protein. Pharmacokinetic studies indicated that compounds 3d and 3i are orally available and long-lasting in rat plasma after oral administration to rats by a single dose of 15 mg/kg. In conclusion, this work provided a novel 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile chemotype deserving further investigation into its antiviral therapeutic potential.

Automated summary

This study explores the chemical space and structure-activity relationship of a previously identified HCV entry inhibitor, leading to the discovery of a new derived scaffold with higher anti-HCV activity. The active derivatives primarily inhibit the virus entry stage and may target the HCV El protein. Pharmacokinetic studies suggest that these compounds are orally available and long-lasting in rat plasma.