Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socioeconomic impact on epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain-Barré syndrome. To develop potentially prophylactic antiviral drugs for combating these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivatives for SAR analysis. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 μM and displayed EC50 values of 1.52 μM and 1.91 μM against DENV and ZIKV infections of human neuronal BE(2)C cells, respectively. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.

中文翻译：

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苯磺酰胺衍生物作为钙/钙调蛋白依赖性蛋白激酶抑制剂和抗登革热和寨卡病毒感染的抗病毒剂。

蚊媒黄病毒的出现和复苏是一项重要的公共卫生挑战。登革热病毒（DENV）感染的增加对流行国家产生了重大的社会经济影响。最近爆​​发的寨卡病毒（ZIKV）引起了国际社会的突发公共卫生事件，因为ZIKV感染与先天性缺陷和吉兰-巴雷综合征有关。为了开发潜在的预防性抗病毒药物来对抗这些急性感染性疾病，我们已针对宿主钙/钙调蛋白依赖性激酶II（CaMKII）进行了抑制。通过使用CaMKII结构指导的抑制剂设计，我们生成了四族苯磺酰胺（BSA）衍生物用于SAR分析。在这些物质中，N-（4-环庚基-4-氧代丁基）-4-甲氧基-N-苯基苯磺酰胺（9）具有领先的CaMKII抑制剂和抗病毒剂性能。BSA 9抑制CaMKII活性，其IC50值为0.79μM，对人神经元BE（2）C细胞的DENV和ZIKV感染显示的EC50值为1.52μM和1.91μM。值得注意的是，在小鼠攻击模型中，9显着降低了病毒血症水平并增加了动物存活时间。