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

  • Bioorg Med Chem Lett. 2022 Feb 15;58:128526. doi: 10.1016/j.bmcl.2022.128526.
Weixiong Chen  1 ,  Bo Feng  2 ,  Sheng Han  3 ,  Peipei Wang  3 ,  Wuhong Chen  3 ,  Yi Zang  4 ,  Jia Li  5 ,  Youhong Hu  6
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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 34998903 DOI: 10.1016/j.bmcl.2022.128526
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 (Mpro) 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 Mpro inhibition with an IC50 value of 116 nM and selectivity against SARS-CoV-2 Mpro when compared to PLpro 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.
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