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
  • 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: [email protected].
  • 4. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: [email protected].
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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