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

Recently, we reported that chlorcyclizine (CCZ, <b>Rac-2</b>), an over-the-counter antihistamine piperazine drug, possesses <i>in vitro</i> and <i>in vivo</i> 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 <i>in vivo</i> 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

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

Recently, we reported that chlorcyclizine (CCZ, <b>Rac-2</b>), an over-the-counter antihistamine piperazine drug, possesses <i>in vitro</i> and <i>in vivo</i> 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 <i>in vivo</i> 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