Gao Shenghua, Song Letian, Sylvester Katharina, Mercorelli Beatrice, Loregian Arianna, Toth Karoly, Weiße Renato H, Useini Abibe, Sträter Norbert, Yang Mianling, Ye Bing, Tollefson Ann E, Müller Christa E, Liu Xinyong, Zhan Peng
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, China.
Shenzhen Research Institute of Shandong University, A301 Virtual University Park in South District of Shenzhen, Shenzhen, Guangdong 518057, PR China.
J Med Chem. 2023 Dec 14;66(23):16426-16440. doi: 10.1021/acs.jmedchem.3c01876. Epub 2023 Nov 22.
The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (M) inhibitors with prominent antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal demonstrated high enzyme-inhibitory potency (IC = 0.19 μM) and exhibited excellent antiviral activity (EC = 0.40 μM), reaching the same level as Nirmatrelvir (EC = 0.38 μM). Additionally, displayed potent antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic M inhibitor with promising antiviral activity and a favorable pharmacokinetic profile.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的持续传播使得有必要开发额外的强效抗病毒药物，以对抗当前具有高度传染性的变体以及未来出现的冠状病毒。在此，我们展示了具有显著抗病毒活性和改善药代动力学性质的强效非肽类主蛋白酶（M）抑制剂的发现。设计并合成了三个系列的1,2,4-三取代哌嗪衍生物，其中最优的化合物表现出高酶抑制效力（IC = 0.19 μM），并展现出优异的抗病毒活性（EC = 0.40 μM），达到了与奈玛特韦（EC = 0.38 μM）相同的水平。此外，该化合物对多种SARS-CoV-2变体以及人冠状病毒OC43（HCoV-OC43）和人冠状病毒229E（HCoV-229E）均表现出强效抗病毒活性，表明其具有潜在的广谱抗冠状病毒活性。值得注意的是，与先导化合物相比，该化合物的药代动力学性质有所增强。此外，共晶体和分子对接阐明了其作用机制。总之，我们发现了一种新型非肽类M抑制剂，具有有前景的抗病毒活性和良好的药代动力学特征。
