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Consequently, the development of M<jats:sup>pro<\/jats:sup> inhibitor is an ideal strategy for combating the virus. In this study, we identified twenty\u2010two dithiocarbamates (<jats:bold>1\u2009a<\/jats:bold>\u2013<jats:bold>h<\/jats:bold>), dithiocarbamate\u2010Cu(II) complexes (<jats:bold>2\u2009a\u2010hCu<\/jats:bold>) and disulfide derivatives (<jats:bold>2\u2009a<\/jats:bold>\u2013<jats:bold>e<\/jats:bold>, <jats:bold>2\u2009i<\/jats:bold>) as potent inhibitors of M<jats:sup>pro<\/jats:sup>, with IC<jats:sub>50<\/jats:sub> value range of 0.09\u20130.72, 0.9\u201324.7, and 15.1\u2013111\u2005\u03bcM, respectively, through FRET screening. The enzyme kinetics, inhibition mode, jump dilution, and DTT assay revealed that <jats:bold>1\u2009g<\/jats:bold> may be a partial reversible inhibitor, while <jats:bold>2\u2009d<\/jats:bold> and <jats:bold>2\u2009f\u2010Cu<\/jats:bold> are the irreversible and dose\u2010 and time\u2010dependent inhibitors, potentially covalently binding to the target. Binding of <jats:bold>2\u2009d<\/jats:bold>, <jats:bold>2\u2009f\u2010Cu<\/jats:bold>, and <jats:bold>1\u2009g<\/jats:bold> to M<jats:sup>pro<\/jats:sup> was found to decrease the stability of the protein. Additionally, DTT assays and thermal shift assays indicated that <jats:bold>2\u2009f\u2010Cu<\/jats:bold> and <jats:bold>2\u2009d<\/jats:bold> are the nonspecific and promiscuous cysteine protease inhibitor. ICP\u2010MS implied that the inhibitory activity of <jats:bold>2\u2009f\u2010Cu<\/jats:bold> may stem from the uptake of Cu(II) by the enzyme. Cytotoxicity assays demonstrated that <jats:bold>2\u2009d<\/jats:bold> and <jats:bold>1\u2009g<\/jats:bold> exhibit low cytotoxicity, whereas <jats:bold>2\u2009f\u2010Cu<\/jats:bold> show certain cytotoxicity in L929 cells. Overall, this work presents two promising scaffolds for the development of M<jats:sup>pro<\/jats:sup> inhibitors to combat COVID\u201019.<\/jats:p>","DOI":"10.1002\/cbdv.202401034","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T12:53:45Z","timestamp":1723035225000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of a Highly Promising Disulfide Derivative Scaffold as Inhibitor of SARS\u2010CoV\u20102 Main Protease"],"prefix":"10.1002","volume":"21","author":[{"given":"Yin\u2010Sui","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials Science Northwest University  Xi'an 710127 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Xiang","sequence":"additional","affiliation":[{"name":"College of Physical Education Yan'an University  Yan'an 716000 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9632-8278","authenticated-orcid":false,"given":"Le","family":"Zhai","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Advanced Ferroelectric Functional Materials Shaanxi Key Laboratory of Phytochemistry College of Chemistry and Chemical Engineering Baoji University of Arts and Sciences  Baoji 721013 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials Science Northwest University  Xi'an 710127 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao\u2010Rong","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials Science Northwest University  Xi'an 710127 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei\u2010Ya","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials Science Northwest University  Xi'an 710127 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials Science Northwest University  Xi'an 710127 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mu\u2010Han","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials Science Northwest University  Xi'an 710127 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao\u2010Long","family":"Liu","sequence":"additional","affiliation":[{"name":"School of medicine Yan'an University  Yan'an 716000 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2560-9659","authenticated-orcid":false,"given":"Ke\u2010Wu","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials Science Northwest University  Xi'an 710127 PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,9,25]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"crossref","unstructured":"C. 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