Benzenesulfonamide Derivatives as Calcium/Calmodulin-Dependent Protein Kinase Inhibitors and Antiviral Agents against Dengue and Zika Virus Infections

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.

新发与复燃的蚊媒黄病毒（flaviviruses）是公共卫生领域的重大挑战。登革病毒（DENV）感染的患病率持续升高，已对疫情流行国家造成显著的社会经济影响。近期暴发的寨卡病毒（ZIKV）疫情引发了国际公共卫生紧急事件，原因在于ZIKV感染与先天性缺陷及吉兰-巴雷综合征（Guillain–Barré syndrome）密切相关。
为开发可用于对抗这类急性传染病的预防性抗病毒药物，我们以宿主钙/钙调蛋白依赖性蛋白激酶II（CaMKII）作为抑制靶点。通过基于CaMKII结构的抑制剂设计策略，我们合成了四类苯磺酰胺（BSA）衍生物用于构效关系（Structure-Activity Relationship，SAR）分析。在上述化合物中，N-(4-环庚基-4-氧代丁基)-4-甲氧基-N-苯基苯磺酰胺（9）展现出作为先导CaMKII抑制剂与抗病毒制剂的优异性能。BSA 9对CaMKII活性的半数抑制浓度（IC50）为0.79 μM，针对人神经BE(2)C细胞的登革病毒与寨卡病毒感染的半数有效浓度（EC50）分别为1.52 μM与1.91 μM。值得注意的是，化合物9可显著降低小鼠攻毒模型中的病毒血症水平，并延长动物存活时间。