Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Bioorg Med Chem Lett. 2023 Aug 15;92:129407. doi: 10.1016/j.bmcl.2023.129407. Epub 2023 Jul 10.
The COVID-19 pandemic has caused people immense suffering all over the world. Although the World Health Organization (WHO) has announced the end of the pandemic, the sporadic virus epidemic is still ongoing and may exist permanently. Effective antivirals against SARS-CoV-2 are important to deal with the long-term threat. The main protease (M) is a crucial target for drug development due to its role in the process of virus's replication and transcription. Herein, we report benzodiazepine derivatives as a new class of M inhibitors. Structure-activity relationship (SAR) studies led to the discovery of the most active compound, methyl 10-(2-chloroacetyl)-1-oxo-11-(4-(trifluoromethyl)phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]-diazepine-7-carboxylate (11a), which shows an IC value of 0.180 ± 0.004 μM. The X-ray crystal structure shows that 11a covalently binds to M. Collectively, we have obtained a new small molecule inhibitor targeting M, which can serve as a lead compound for subsequent drug discovery against SARS-CoV-2.
新型冠状病毒肺炎（COVID-19）疫情在全球范围内给人们带来了巨大的痛苦。尽管世界卫生组织（WHO）宣布疫情结束，但散发性病毒疫情仍在持续，且可能会长期存在。针对 SARS-CoV-2 的有效抗病毒药物对于应对长期威胁非常重要。由于其在病毒复制和转录过程中的作用，主要蛋白酶（M）是药物开发的关键靶点。在此，我们报告了苯并二氮杂卓衍生物作为一类新型 M 抑制剂。通过构效关系（SAR）研究，发现了最具活性的化合物甲基 10-(2-氯乙酰基）-1-氧代-11-(4-(三氟甲基）苯基）-2,3,4,5,10,11-六氢-1H-二苯并[b,e][1,4]-二氮杂卓-7-羧酸酯（11a），其 IC 值为 0.180±0.004 μM。X 射线晶体结构表明 11a 与 M 形成共价键。总之，我们获得了一种针对 M 的新型小分子抑制剂，可作为针对 SARS-CoV-2 的后续药物发现的先导化合物。
