Discovery of benzodiazepine derivatives as a new class of covalent inhibitors of SARS-CoV-2 main protease

Falu Wang; Rui Zeng; Jingxin Qiao; Anjie Xia; Yueshan Li; Feng Li; Yunjie Wu; Yuanzhi Liu; Xiu Zhao; Jian Lei; Shengyong Yang

doi:10.1016/j.bmcl.2023.129407

Discovery of benzodiazepine derivatives as a new class of covalent inhibitors of SARS-CoV-2 main protease

Bioorg Med Chem Lett. 2023 Aug 15:92:129407. doi: 10.1016/j.bmcl.2023.129407. Epub 2023 Jul 10.

Authors

Falu Wang¹, Rui Zeng¹, Jingxin Qiao¹, Anjie Xia², Yueshan Li¹, Feng Li¹, Yunjie Wu¹, Yuanzhi Liu¹, Xiu Zhao¹, Jian Lei³, Shengyong Yang⁴

Affiliations

¹ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
² 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.
³ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: leijian@scu.edu.cn.
⁴ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China. Electronic address: yangsy@scu.edu.cn.

PMID: 37437852
DOI: 10.1016/j.bmcl.2023.129407

Abstract

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^pro) 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^pro 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 IC₅₀ value of 0.180 ± 0.004 μM. The X-ray crystal structure shows that 11a covalently binds to M^pro. Collectively, we have obtained a new small molecule inhibitor targeting M^pro, which can serve as a lead compound for subsequent drug discovery against SARS-CoV-2.

Keywords: Benzodiazepine derivatives; Main protease inhibitor; SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anticonvulsants
Antiviral Agents / pharmacology
Benzodiazepines* / pharmacology
COVID-19*
Coronavirus 3C Proteases* / antagonists & inhibitors
Humans
Hypnotics and Sedatives
Molecular Docking Simulation
Pandemics
Protease Inhibitors* / chemistry
Protease Inhibitors* / pharmacology
SARS-CoV-2 / metabolism

Substances

3C-like proteinase, SARS-CoV-2
Anticonvulsants
Antiviral Agents
Benzodiazepines
Hypnotics and Sedatives
Protease Inhibitors
Coronavirus 3C Proteases