Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection

Recently,
we reported that chlorcyclizine (CCZ, Rac-2), an over-the-counter
antihistamine piperazine drug, possesses in vitro and in vivo activity against hepatitis
C virus. Here, we describe structure–activity relationship
(SAR) efforts that resulted in the optimization of novel chlorcyclizine
derivatives as anti-HCV agents. Several compounds exhibited EC50 values below 10 nM against HCV infection, cytotoxicity selectivity
indices above 2000, and showed improved in vivo pharmacokinetic
properties. The optimized molecules can serve as lead preclinical
candidates for the treatment of hepatitis C virus infection and as
probes to study hepatitis C virus pathogenesis and host–virus
interaction.