Chen Chu-Ran, Ma Ying, Wang Han-Xuan, Liu Xin-Yang, Liu Yan, Meng Qing-Guo, Jin Yong-Sheng
School of Pharmacy, Naval Medical University, Shanghai 200433, China.
School of Pharmacy, Yantai University, Yantai, Shandong Province 264005, China.
Bioorg Med Chem Lett. 2023 Mar 1;83:129188. doi: 10.1016/j.bmcl.2023.129188. Epub 2023 Feb 15.
Chikungunya fever is an acute infectious disease caused by Chikungunya virus (CHIKV) and transmitted by Aedes mosquito. It is characterized by fever, rash and arthralgia with no effective drugs. Lomerizine (Lom) is a new generation calcium antagonist, which is mainly used in the treatment of migraine. Certain antiviral function of Lom was shown by some research. In our study, a series of new derivatives of Lom were designed and synthesized, and their in-vitro anti-CHIKV activity was tested. The results showed that Lom and its derivatives had potent anti-CHIKV activity and low cytotoxicity. Among them, compounds B1 and B7 showed most potent antiviral activity. Besides, structure-activity relationships, in-silico ADMET properties were also analyzed. Molecular docking study was performed to rationalize the SAR and analyze the possible binding modes between B1 and amino acid residues in the active site of nsP3 protein to enhance the understanding of their action as antiviral agents. These finding provides research basis for the design and synthesis of effective anti-CHIKV drugs with Lom as the lead compound.
基孔肯雅热是一种由基孔肯雅病毒（CHIKV）引起、通过伊蚊传播的急性传染病。其特征为发热、皮疹和关节痛，目前尚无有效药物。洛美利嗪（Lom）是一种新一代钙拮抗剂，主要用于治疗偏头痛。一些研究表明Lom具有一定的抗病毒功能。在我们的研究中，设计并合成了一系列Lom的新衍生物，并测试了它们的体外抗CHIKV活性。结果表明，Lom及其衍生物具有较强的抗CHIKV活性且细胞毒性较低。其中，化合物B1和B7表现出最强大的抗病毒活性。此外，还分析了构效关系、计算机辅助药物代谢动力学性质。进行了分子对接研究以合理化构效关系，并分析B1与nsP3蛋白活性位点氨基酸残基之间可能的结合模式，以加深对其作为抗病毒药物作用的理解。这些发现为以Lom为先导化合物设计和合成有效的抗CHIKV药物提供了研究依据。
