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

Abstract

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.

Ruthenium‐Catalyzed Modular Synthesis of Cyclic Tertiary Amines from Lactams

“…The respective amine functionality is present in many active principal drugs,agrochemicals,and numerous specialty chemicals.P articularly,t ertiary cyclic amines are promising lead structures towards the synthesis of novel anticonvulsants, kinase inhibitors,and antiviral compounds. [1][2][3][4] Novel access to these important molecules could in principle be established by the utilization of versatile amides or lactam starting materials.L actams can be synthesized from easily accessible amino acids and the most prominent example, e-caprolactam, the precursor to Nylon 6, is aw idely used synthetic polymer with an annual production of approximately 4.5 billion kilograms. [5] Moreover, recent biobased synthetic pathways were developed, thus enabling the possibility to produce these compounds by new benign routes.…”

Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle

“…These elevations are unlikely due to the effect of the compound because similar random elevations were noted in mice treated with vehicle only ( Figure 4C). 16 Moreover, there was not an obvious correlation between the ALT levels and the liver concentration of compound 7ii. Overall, the representative analogue 7ii exhibited high liver distribution and long half-life without obvious hepatotoxicity, indicated by ALT level in the mouse model.…”

Ruthenium‐Catalyzed Modular Synthesis of Cyclic Tertiary Amines from Lactams

“…The respective amine functionality is present in many active principal drugs, agrochemicals, and numerous specialty chemicals. Particularly, tertiary cyclic amines are promising lead structures towards the synthesis of novel anticonvulsants, kinase inhibitors, and antiviral compounds …”