Structure-guided design and photochemical synthesis of new carbamo(dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CL pro .

Autor: Yin DH; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China., Xin J; The People's Hospital of Feicheng, Feicheng 271600, China., Chen S; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Li SS; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China., Li ZY; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China., Meng JX; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China., Lin YC; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China., Yin BQ; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China., Zhao C; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China., Li J; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., Gao H; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China. Electronic address: hanggao@tyut.edu.cn., Tian J; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China., Gao WC; College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China. Electronic address: gaowenchao@tyut.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Nov 15; Vol. 114, pp. 117940. Date of Electronic Publication: 2024 Oct 11.
DOI: 10.1016/j.bmc.2024.117940
Abstrakt: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CL pro of SARS-CoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CL pro ; however, its structure lacks bonding site with active pockets of 3CL pro and its highly symmetric structure doesn't match well with the irregular cavity of the active center, limiting its therapeutic applications. To enhance their affinity for the 3CL pro target, in this study, two kinds of disulfiram derivatives, designed based on the reevaluation and optimization of disulfiram, have been synthesized through photoredox chemistry, and the novel carbamo(dithioperoxo)thioates 4g-m were found to display 5-17 folds potency against SARS-CoV-2 3CL pro compared to the parent disulfiram, with resulting half-maximal inhibitory concentration (IC 50 ) values ranging from 0.14-0.47 μM. Carbamo(dithioperoxo)thioates 4i containing a 4-hydroxy piperidine and a 4-trifluoromethyl phenyl ring, was identified as the most potent inhibitor to both 3CL pro (IC 50  = 0.14 μM) and PL pro (IC 50  = 0.04 μM). Furthermore, molecular dynamics simulations, binding free energy analysis and mass analysis were performed and provided insights on the stability, conformational behavior, and interactions of 4g with 3CL pro . The green synthetic methodology, the privileged carbamo(dithioperoxo)thioate scaffold, and the molecular mechanisms presented might serve as a useful system for the further discovery of highly potent inhibitors targeting SARS-CoV-2 3CL pro .
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: