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 E1 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.