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. Epub 2022 Jun 3.


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.

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • COVID-19 Drug Treatment*
  • Coronavirus 3C Proteases* / antagonists & inhibitors
  • Coronavirus 3C Proteases* / chemistry
  • Coronavirus 3C Proteases* / metabolism
  • Drug Discovery / methods
  • Furans* / chemistry
  • Furans* / pharmacology
  • Humans
  • Hydrazines / pharmacology
  • Molecular Docking Simulation
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / enzymology


  • Antiviral Agents
  • Furans
  • Hydrazines
  • Protease Inhibitors
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases