Abstract：
The COVID-19 pandemic highlights the urgent need to develop effective small-molecule antivirals. Thirty-three novel biaryl amide derivatives were synthesized and evaluated for anti-coronaviral activity. Some significant SARs were uncovered and the intensive structure modifications led to the most active compounds 8b and 8h. The broad-spectrum anti-coronaviral effects of 8h were validated at RNA and protein levels. 8h inhibits coronavirus replication at multiple stages, from virus entry to virus dsRNA synthesis. The mechanism of action showed that 8h may simultaneously act on 3CLpro and TMPRSS2 to display anti-coronaviral effects. 8h combined with RdRp inhibitor showed synergistic inhibitory activity against coronavirus. This study confirmed that biaryl amide derivatives may be a new class of potential therapeutic agents against coronavirus with multiple target effect, worthy of further investigation.
摘要：
COVID-19大流行凸显了开发有效小分子抗病毒药物的迫切需要。合成了33种新型联芳基酰胺衍生物，并评估了其抗冠状病毒活性。一些显著的SAR被发现,并且强烈的结构修饰导致最具活性的化合物8b和8h。在RNA和蛋白质水平上验证了8h的广谱抗冠状病毒作用。8h在多个阶段抑制冠状病毒复制，从病毒进入到病毒dsRNA合成。作用机制显示8h可同时作用于3CLpro和TMPRSS2发挥抗冠状病毒作用。8h联合RdRp抑制剂对冠状病毒具有协同抑制活性。这项研究证实，联芳基酰胺衍生物可能是一类具有多靶点效应的新型冠状病毒潜在治疗剂，值得进一步调查。
