2‑((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action

Although
the direct-acting antivirals revolutionized the hepatitis
C virus (HCV) infection treatment in the last decade, more efforts
are needed to reach the elimination of HCV in the absence of a vaccine.
4-(Piperazin-1-yl)-2-((p-tolylamino)­methyl)-benzonitrile
(1) is a modest HCV inhibitor identified from an in-house screening
using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical
optimization afforded a new 2-((4-arylpiperazin-1-yl)­methyl)­benzonitrile
scaffold with significantly increased antiviral activity against HCV.
A highly effective HCV inhibitor, 35 (L0909, EC50 = 0.022 μM, SI > 600), was identified
by
the structure–activity relationship study. The biological study
revealed that L0909 could block HCV replication by acting
on the HCV entry stage. The high sensitivity to clinical resistant
HCV mutants and synergistic effect with clinical drugs were observed
for this compound. The further pharmaceutical studies demonstrated
that L0909 is long-lasting, is orally available, and
has low toxicity in vivo. These results show L0909 as
a promising HCV entry inhibitor for single or combinational therapeutic
potential.