The prevalence of Zika virus (ZIKV) has become widespread in recent years. ZIKV infection is associated with severe congenital CNS malformations in both newborns and adults. However, neither vaccines nor therapeutics are available to control ZIKV infection until now. We started by hit screening our in-house small molecule library, then designed, synthesized, and evaluated a new class of 1, 4-bibenzylsubstituted piperazine derivatives for their cytopathic effect (CPE) protection effect in a ZIKV-infected Vero E6 cellular assay. A preliminary structure-activity relationship study identified five novel 4-amino-2-(4-benzylpiperazin-1-yl)methylbenzonitrile analogs with obvious CPE reduction effects against ZIKV at micromolar concentrations. Moreover, compound 3p exerted a significant antiviral effect on both Zika RNA replication and virus protein expression in a dose-dependent manner at low micromolar concentrations. This study demonstrated the potential of a novel 4-amino-2-(4-benzylpiperazin-1-yl)methylbenzonitrile scaffold for the development of anti-ZIKV candidates.

中文翻译：

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设计，合成和评估新型的Zika抑制剂4-氨基-2-（4-苄基哌嗪-1-基）甲基苄腈化合物。

近年来，寨卡病毒（ZIKV）的流行已变得广泛。ZIKV感染与新生儿和成年人中严重的先天性中枢神经系统畸形有关。但是，到目前为止，尚无疫苗和治疗剂可用于控制ZIKV感染。我们从筛选内部小分子库开始，然后设计，合成并评估了新的1类，4-联苄基取代的哌嗪衍生物在ZIKV感染的Vero E6细胞分析中的细胞病变效应（CPE）保护作用。初步的结构活性关系研究确定了五个新颖的4-氨基-2-（4-苄基哌嗪-1-基）甲基苄腈类似物，在微摩尔浓度下，它们对ZIKV具有明显的CPE还原作用。而且，在低微摩尔浓度下，化合物3p以剂量依赖的方式对Zika RNA复制和病毒蛋白表达均具有显着的抗病毒作用。这项研究证明了新型4-氨基-2-（4-苄基哌嗪-1-基）甲基苄腈支架在开发抗ZIKV候选药物方面的潜力。