Xin-bei Jiang, Jiali Tan, Yixuan Wang
May 7, 2020
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0
Influential Citations
6
Citations
Quality indicators
Journal
Journal of medicinal chemistry
Abstract
Although the direct-acting antivirals revolutionized the HCV infection treatment in last decade, more efforts are need to reach the elimination of HCV in the absence of vaccine. 4-(Piperazin-1-yl)-2-((p-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using HCV-infected Huh7.5 cells 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 SAR 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 L0909 is long-lasting, oral available and low toxic in vivo. These results endowed L0909 a promising HCV entry inhibitor for single or combinational therapeutic potential.