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

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.
AuthorsXiaodong Dou, Qi Sun, Guofeng Xu, Yameng Liu, Caifang Zhang, Bingding Wang, Yangbin Lu, Zheng Guo, Lingyu Su, Tongyu Huo, Xinyi Zhao, Chen Wang, Zhongtian Yu, Song Song, Liangren Zhang, Zhenming Liu, Luhua Lai, Ning Jiao
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 238 Pg. 114508 (Aug 05 2022) ISSN: 1768-3254 [Electronic] France
PMID35688005 (Publication Type: Journal Article)
CopyrightCopyright © 2022 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Antiviral Agents
  • Furans
  • Hydrazines
  • Protease Inhibitors
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases
Topics
  • Antiviral Agents (chemistry, pharmacology)
  • Coronavirus 3C Proteases (antagonists & inhibitors, chemistry, metabolism)
  • Drug Discovery (methods)
  • Furans (chemistry, pharmacology)
  • Humans
  • Hydrazines (pharmacology)
  • Molecular Docking Simulation
  • Protease Inhibitors (chemistry, pharmacology)
  • SARS-CoV-2 (drug effects, enzymology)
  • COVID-19 Drug Treatment

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