Abstract：
By inducing steric activation of the 10CH bond with a 12-acyl group to form a key imine oxime intermediate, 20 novel (10S)-10,12-disubstituted aloperine derivatives were successfully synthesized and assessed for their antiviral efficacy against HCoV-OC43. Of them, compound 3i exhibited the moderate activities against HCoV-OC43, as well as against the SARS-CoV-2 variant EG.5.1 with the comparable EC50 values of 4.7 and 4.1 μM. A mechanism study revealed that it inhibited the protease activity of host TMPRSS2 by binding to an allosteric site, rather than the known catalytic center, different from that of camostat. Also, the combination of compound 3i and molnupiravir, as an RdRp inhibitor, showed an additive antiviral effect against HCoV-OC43. The results provide a new binding mode and lead compound for targeting TMPRSS2, with an advantage in combating broad-spectrum coronavirus.
摘要：
通过诱导具有12-酰基的10CH键的空间激活以形成关键的亚胺肟中间体，成功合成了20种新的（10S）-10,12-二取代的aloperine衍生物，并评估了它们对HCoV-OC43的抗病毒功效。其中,化合物3i对HCoV-OC43以及SARS-CoV-2变体EG.5.1表现出中等活性，相当的EC50值为4.7和4.1μM。一项机制研究表明，它通过与变构位点结合来抑制宿主TMPRSS2的蛋白酶活性，而不是已知的催化中心，与camostat不同。此外，化合物3i和莫那普拉韦的组合，作为RdRp抑制剂，显示出对HCoV-OC43的加性抗病毒作用。该结果为靶向TMPRSS2提供了一种新的结合模式和先导化合物，在对抗广谱冠状病毒方面具有优势。
