2. Academic Validation
  3. Discovery of 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 main protease

Discovery of 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 main protease

  • Eur J Med Chem. 2022 Aug 5;238:114508. doi: 10.1016/j.ejmech.2022.114508.
Xiaodong Dou 1,  Qi Sun 2,  Guofeng Xu 1,  Yameng Liu 1,  Caifang Zhang 1,  Bingding Wang 1,  Yangbin Lu 2,  Zheng Guo 2,  Lingyu Su 1,  Tongyu Huo 1,  Xinyi Zhao 1,  Chen Wang 1,  Zhongtian Yu 2,  Song Song 1,  Liangren Zhang 1,  Zhenming Liu 1,  Luhua Lai 3,  Ning Jiao 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 2 BNLMS, Peking-Tsinghua Center for Life Sciences at College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
  • 3 BNLMS, Peking-Tsinghua Center for Life Sciences at College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China. Electronic address: lhlai@pku.edu.cn.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: jiaoning@pku.edu.cn.
PMID: 35688005 DOI: 10.1016/j.ejmech.2022.114508
Abstract

The COVID-19 posed a serious threat to human life and health, and SARS-CoV-2 Mpro has been considered as an attractive drug target for the treatment of COVID-19. Herein, we report 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 Mpro developed by in-house library screening and biological evaluation. Similarity search led to the identification of compound F8-S43 with the enzymatic IC50 value of 10.76 μM. Further structure-based drug design and synthetic optimization uncovered compounds F8-B6 and F8-B22 as novel non-peptidomimetic inhibitors of Mpro with IC50 values of 1.57 μM and 1.55 μM, respectively. Moreover, enzymatic kinetic assay and mass spectrometry demonstrated that F8-B6 was a reversible covalent inhibitor of Mpro. Besides, F8-B6 showed low cytotoxicity with CC50 values of more than 100 μM in Vero and MDCK cells. Overall, these novel SARS-CoV-2 Mpro non-peptidomimetic inhibitors provide a useful starting point for further structural optimization.

Keywords

2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives; Main protease; Non-peptidomimetic inhibitors; SARS-CoV-2.

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