Miniaturized click chemistry and direct screening facilitate the discovery of triazole piperazine SARS-CoV-2 M<sup>pro</sup> inhibitors with improved metabolic stability
The continuous mutational nature of SARS-CoV-2 and its inter-species' similarities emphasize the urgent need to design and develop more direct-acting antiviral agents against highly infectious variants. Herein, we report on the efficient discovery of potent non-covalent non-peptide-derived M<sup>pro</sup> inhibitors using miniaturized click chemistry and direct screening. Based on the privileged piperazine scaffold, 68 triazole-containing derivatives were assembled and screened. Notably, representative compound C1N46 (IC<sub>50</sub> = 1.87 μM, EC<sub>50</sub> = 6.99 μM, CC<sub>50</sub> > 100 μM) displayed potent inhibition activity against M<sup>pro</sup> and showed promising anti-SARS-CoV-2 properties <i>in vitro</i>. Additionally, C1N46 exhibited improved liver microsome stability compared to lead compound GC-14. Docking studies predicted a multi-site binding mode of the triazole-based compounds. In conclusion, our studies validate the efficacy and feasibility of click chemistry in rapidly discovering antiviral agents.
Authors
- Manyu Gu
- Jun-Yi Li (ORCID: https://orcid.org/0000-0002-2586-9648)
- Károly Tóth (ORCID: https://orcid.org/0000-0001-6624-9683)
- Letian Song
- Xinyong Liu (ORCID: https://orcid.org/0000-0002-7302-2214)
- Mianling Yang
- Shenghua Gao (ORCID: https://orcid.org/0000-0001-9853-3793)
- Ann E. Tollefson (ORCID: https://orcid.org/0000-0001-5010-3241)
- Peng Zhan (ORCID: https://orcid.org/0000-0002-9675-6026)
- Bing Ye (ORCID: https://orcid.org/0000-0002-8080-1224)
Institutions
- Shandong University (CN)
- City University of Hong Kong, Shenzhen Research Institute (CN)
- Saint Louis University (US)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1039/d4md00555d
- Citations
- 6
- Primary Topic
- Click Chemistry and Applications
- Type
- article
- Field-Weighted Citation Impact
- 1.50
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Natural Science Foundation of Shandong Province
- National Outstanding Youth Science Fund Project of National Natural Science Foundation of China
- Basic and Applied Basic Research Foundation of Guangdong Province