Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China.
National Institutes for Food and Drug Control, Beijing, 100050, China.
Eur J Med Chem. 2022 Apr 15;234:114209. doi: 10.1016/j.ejmech.2022.114209. Epub 2022 Mar 5.
Thirty-two clofazimine derivatives, of which twenty-two were new, were synthesized and evaluated for their antiviral effects against both rabies virus and pseudo-typed SARS-CoV-2, taking clofazimine (1) as the lead. Among them, compound 15f bearing 4-methoxy-2-pyridyl at the N5-position showed superior or comparable antiviral activities to lead 1, with the EC values of 1.45 μM and 14.6 μM and the SI values of 223 and 6.1, respectively. Compound 15f inhibited rabies and SARS-CoV-2 by targeting G or S protein to block membrane fusion, as well as binding to L protein or nsp13 to inhibit intracellular biosynthesis respectively, and thus synergistically exerted a broad-spectrum antiviral effect. The results provided useful scientific data for the development of clofazimine derivatives into a new class of broad-spectrum antiviral candidates.
合成了 32 个氯法齐明衍生物，其中 22 个为新化合物，评估了它们对狂犬病病毒和假型 SARS-CoV-2 的抗病毒作用，以氯法齐明（1）为先导化合物。其中，N5 位带有 4-甲氧基-2-吡啶基的化合物 15f 表现出优于或与先导化合物 1 相当的抗病毒活性，其 EC 值分别为 1.45 μM 和 14.6 μM，SI 值分别为 223 和 6.1。化合物 15f 通过靶向 G 或 S 蛋白来阻止膜融合，以及分别与 L 蛋白或 nsp13 结合来抑制细胞内生物合成，从而抑制狂犬病和 SARS-CoV-2，从而发挥出广谱的抗病毒作用。这些结果为将氯法齐明衍生物开发成一类新的广谱抗病毒候选药物提供了有用的科学数据。
Zotero 插件
