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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 M^pro 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^pro 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 M^pro 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 M^pro. 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 M^pro non-peptidomimetic inhibitors provide a useful starting point for further structural optimization.

SUBMITTER: Dou X

PROVIDER: S-EPMC9162962 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Dou Xiaodong X Sun Qi Q Xu Guofeng G Liu Yameng Y Zhang Caifang C Wang Bingding B Lu Yangbin Y Guo Zheng Z Su Lingyu L Huo Tongyu T Zhao Xinyi X Wang Chen C Yu Zhongtian Z Song Song S Zhang Liangren L Liu Zhenming Z Lai Luhua L Jiao Ning N

European journal of medicinal chemistry 20220603

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 struc ...[more]

PMID: 35688005

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Project description:Background: Due to the constant mutation of virus and the lack of specific therapeutic drugs, the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still poses a huge threat to the health of people, especially those with underlying diseases. Therefore, drug discovery against the SARS-CoV-2 remains of great significance. Methods: With the main protease of virus as the inhibitor target, 9,614 genistein derivatives were virtually screened by LeDock and AutoDock Vina, and the top 20 compounds with highest normalized scores were obtained. Molecular dynamics simulations were carried out for studying interactions between these 20 compounds and the target protein. The drug-like properties, activity, and ADMET of these compounds were also evaluated by DruLiTo software or online server. Results: Twenty compounds, including compound 11, were screened by normalized molecular docking, which could bind to the target through multiple non-bonding interactions. Molecular dynamics simulation results showed that compounds 2, 4, 5, 11, 13, 14, 17, and 18 had the best binding force with the target protein of SARS-CoV-2, and the absolute values of binding free energies all exceeded 50 kJ/mol. The drug-likeness properties indicated that a variety of compounds including compound 11 were worthy of further study. The results of bioactivity score prediction found that compounds 11 and 12 had high inhibitory activities against protease, which indicated that these two compounds had the potential to be further developed as COVID-19 inhibitors. Finally, compound 11 showed excellent predictive ADMET properties including high absorption and low toxicity. Conclusion: These in silico work results show that the preferred compound 11 (ZINC000111282222), which exhibited strong binding to SARS-CoV-2 main protease, acceptable drug-like properties, protease inhibitory activity and ADMET properties, has great promise for further research as a potential therapeutic agent against COVID-19.

Dataset Information

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

Publications

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

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