论文题目：2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as OrallyAvailable Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action

作者：Xinbei Jiang, Jiali Tan, YixuanWang, Jinhua Chen, Jianrui Li, Zhi Jiang, Yanni Quan, Jie Jin, Yuhuan Li, ShanCen, Yanping Li*, Zonggen Peng*, ZhuorongLi*

期刊名称：J Med Chem

IF：6.205

年份：2020

卷期页：63(11):5972-5989

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.