2. Academic Validation
  3. Identification of Ebselen derivatives as novel SARS-CoV-2 main protease inhibitors: Design, synthesis, biological evaluation, and structure-activity relationships exploration

Identification of Ebselen derivatives as novel SARS-CoV-2 main protease inhibitors: Design, synthesis, biological evaluation, and structure-activity relationships exploration

  • Bioorg Med Chem. 2023 Dec 15:96:117531. doi: 10.1016/j.bmc.2023.117531.
Heng Zhang 1,  Jing Li 1,  Karoly Toth 2,  Ann E Tollefson 2,  Lanlan Jing 1,  Shenghua Gao 1,  Xinyong Liu 3,  Peng Zhan 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China.
  • 2 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States; Saint Louis University Institute for Drug and Biotherapeutic Innovation, St. Louis, Missouri 63104, United States.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: [email protected].
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Ji'nan, Shandong, PR China. Electronic address: [email protected].
PMID: 37972434 DOI: 10.1016/j.bmc.2023.117531
Abstract

The main protease (Mpro) represents one of the most effective and attractive targets for designing anti-SARS-CoV-2 drugs. In this study, we designed and synthesized a novel series of Ebselen derivatives by incorporating privileged fragments from different pockets of the Mpro active site. Among these compounds, 11 compounds showed submicromolar activity in the FRET-based SARS-CoV-2 Mpro inhibition assay, with IC50 values ranging from 233 nM to 550 nM. Notably, compound 3a displayed submicromolar Mpro activity (IC50 = 364 nM) and low micromolar Antiviral activity (EC50 = 8.01 µM), comparable to that of Ebselen (IC50 = 339 nM, EC50 = 3.78 µM). Time-dependent inhibition assay confirmed that these compounds acted as covalent inhibitors. Taken together, our optimization campaigns thoroughly explored the structural diversity of Ebselen and verified the impact of specific modifications on potency against Mpro.

Keywords

Bioactivity evaluation; Drug design; Ebselen; Main protease; SARS-CoV-2.

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