Discovery of highly potent SARS-CoV-2 Mpro inhibitors based on benzoisothiazolone scaffold

Weixiong Chen; Bo Feng; Sheng Han; Peipei Wang; Wuhong Chen; Yi Zang; Jia Li; Youhong Hu

doi:10.1016/j.bmcl.2022.128526

Discovery of highly potent SARS-CoV-2 M^pro inhibitors based on benzoisothiazolone scaffold

Bioorg Med Chem Lett. 2022 Feb 15:58:128526. doi: 10.1016/j.bmcl.2022.128526. Epub 2022 Jan 5.

Authors

Weixiong Chen¹, Bo Feng², Sheng Han³, Peipei Wang³, Wuhong Chen³, Yi Zang⁴, Jia Li⁵, Youhong Hu⁶

Affiliations

¹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenyang 110016, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: yzang@simm.ac.cn.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenyang 110016, China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei Jimo, Qingdao 266237, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: jli@simm.ac.cn.
⁶ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: yhhu@simm.ac.cn.

Abstract

The COVID-19 pandemic has drastically impacted global economies and public health. Although vaccine development has been successful, it was not sufficient against more infectious mutant strains including the Delta variant indicating a need for alternative treatment strategies such as small molecular compound development. In this work, a series of SARS-CoV-2 main protease (M^pro) inhibitors were designed and tested based on the active compound from high-throughput diverse compound library screens. The most efficacious compound (16b-3) displayed potent SARS-CoV-2 M^pro inhibition with an IC₅₀ value of 116 nM and selectivity against SARS-CoV-2 M^pro when compared to PL^pro and RdRp. This new class of compounds could be used as potential leads for further optimization in anti COVID-19 drug discovery.

Keywords: Benzoisothiazolone; COVID-19; Main protease inhibitors; SARS-CoV-2.

Publication types

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

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
COVID-19 Drug Treatment
Coronavirus 3C Proteases / antagonists & inhibitors*
Coronavirus 3C Proteases / metabolism
Drug Discovery*
Humans
Microbial Sensitivity Tests
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
SARS-CoV-2 / drug effects*
SARS-CoV-2 / enzymology
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Antiviral Agents
Protease Inhibitors
Thiazoles
3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases