Discovery of 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 main protease.
Dou X, Sun Q, Xu G, Liu Y, Zhang C, Wang B, Lu Y, Guo Z, Su L, Huo T, Zhao X, Wang C, Yu Z, Song S, Zhang L, Liu Z, Lai L, Jiao N.
The COVID-19 posed a serious threat to human life and health, and SARS-CoV-2 M<sup>pro</sup> 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 M<sup>pro</sup> developed by in-house library screening and biological evaluation. Similarity search led to the identification of compound F8-S43 with the enzymatic IC<sub>50</sub> 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 M<sup>pro</sup> with IC<sub>50</sub> 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 M<sup>pro</sup>. Besides, F8-B6 showed low cytotoxicity with CC<sub>50</sub> values of more than 100 μM in Vero and MDCK cells. Overall, these novel SARS-CoV-2 M<sup>pro</sup> non-peptidomimetic inhibitors provide a useful starting point for further structural optimization.