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In this study, twenty-one novel sulfonylurea derivatives containing phenyl-5-vinyl and pyrimidinyl-4-aryl moieties were designed and synthesized, among which, nine compounds exhibited inhibitory potencies against Gram-positive bacterial strains: MRSA (Chaoyang clinical isolates), S. aureus ATCC6538, vancomycin-resistant Enterococci-309 (VRE-309), and Bacillus subtilis ATCC 6633. Especially, 9i and 9q demonstrated inhibitory activities against the four bacterial strains with minimum inhibitory concentrations (MICs) of 0.78\u20131.56 \u03bcg\/mL, and quite a few of other MRSA clinical strains with MICs of 0.78 \u03bcg\/mL, superior to those of the positive controls vancomycin (MIC of 1 \u03bcg\/mL) and methicillin (MIC of &gt;200 \u03bcg\/mL). This is the very first time that sulfonylurea derivatives have been identified as promising inhibitors against different MRSA clinical isolates. In addition, all the MIC values of the synthesized compounds against Candida albicans were greater than 100 \u03bcg\/mL. Since the reported anti-Candida activities of sulfonylureas were due to acetohydroxyacid synthase (AHAS) inhibition, the molecular target against MRSA for the target sulfonylureas was thought to be a different mode of action. Density functional theory (DFT) calculations were finally performed to understand the structure\u2013activity relationships, based on which, significant differences were observed between their HOMO maps for compounds with strong antibacterial activities and weak anti-MRSA effects. The present results hence provide valuable guidance for the discovery of novel agents to treat bacterial infections, especially against MRSA.<\/jats:p>","DOI":"10.3390\/antibiotics12020323","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T03:34:30Z","timestamp":1675654470000},"page":"323","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel Sulfonylurea Derivatives as Potential Antimicrobial Agents: Chemical Synthesis, Biological Evaluation, and Computational Study"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8929-8074","authenticated-orcid":false,"given":"Fan-Fei","family":"Meng","sequence":"first","affiliation":[{"name":"State-Key Laboratory of Research Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4754-1245","authenticated-orcid":false,"given":"Ming-Hao","family":"Shang","sequence":"additional","affiliation":[{"name":"State-Key Laboratory of Research Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"State-Key Laboratory of Research Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Wu","family":"Yu","sequence":"additional","affiliation":[{"name":"State-Key Laboratory of Research Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Lian","family":"Liu","sequence":"additional","affiliation":[{"name":"Scientific Research Training Center for Chinese Astronauts, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng-Ming","family":"Li","sequence":"additional","affiliation":[{"name":"State-Key Laboratory of Research Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1029-7904","authenticated-orcid":false,"given":"Zhong-Wen","family":"Wang","sequence":"additional","affiliation":[{"name":"State-Key Laboratory of Research Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7577-1502","authenticated-orcid":false,"given":"Jian-Guo","family":"Wang","sequence":"additional","affiliation":[{"name":"State-Key Laboratory of Research Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8108-815X","authenticated-orcid":false,"given":"Huan-Qin","family":"Dai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.mib.2020.02.005","article-title":"Staphylococcus aureus bloodstream infections: Pathogenesis and regulatory mechanisms","volume":"53","author":"Kwiecinski","year":"2020","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e00020-18","DOI":"10.1128\/CMR.00020-18","article-title":"Methicillin-resistant staphylococcus aureus: Molecular characterization, evolution, and epidemiology","volume":"31","author":"Lakhundi","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1126\/science.321.5887.356","article-title":"The bacteria fight back","volume":"321","author":"Taubes","year":"2008","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9791","DOI":"10.1021\/jacs.7b04881","article-title":"Peptidoglycan cross-linking preferences of Staphylococcus aureus penicillin binding proteins have implications for treating MRSA Infections","volume":"139","author":"Srisuknimit","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"476","DOI":"10.4103\/0255-0857.195364","article-title":"Molecular characterisation of Panton-Valentine leucocidin-producing methicillin-resistant Staphylococcus aureus clones isolated from the main hospitals in Taif, KSA","volume":"34","author":"Eed","year":"2016","journal-title":"Indian J. Med. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.annemergmed.2004.10.011","article-title":"High prevalence of methicillin-resistant Staphylococcus aureus in emergency department skin and soft tissue infections","volume":"45","author":"Frazee","year":"2005","journal-title":"Ann. Emer. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112686","DOI":"10.1016\/j.ejmech.2020.112686","article-title":"1,2,3-Triazole-containing hybrids with potential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)","volume":"206","author":"Xu","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S191","DOI":"10.1086\/519470","article-title":"Limitations of vancomycin in the management of resistant staphylococcal infections","volume":"45","author":"Kollef","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1128\/CMR.00042-09","article-title":"Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: Resistance mechanisms, laboratory detection, and clinical implications","volume":"23","author":"Howden","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1093\/cid\/cir935","article-title":"The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: A systematic review and meta-analysis","volume":"54","author":"Lodise","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0140-6736(88)91037-9","article-title":"Vancomycin-resistant enterococci","volume":"1","author":"Uttley","year":"1988","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1007\/s10096-021-04219-0","article-title":"Characterization of an osteomyelitis case caused by dalbavancin, ceftaroline, and vancomycin non-susceptible methicillin-resistant Staphylococcus aureus","volume":"40","author":"Dahdouh","year":"2021","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_13","first-page":"269","article-title":"Vancomycin Resistance in Staphylococcus aureus","volume":"90","author":"Mcguinness","year":"2017","journal-title":"Yale J. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jare.2019.10.005","article-title":"Vancomycin resistant Staphylococcus aureus infections: A review of case updating and clinical features","volume":"21","author":"Cong","year":"2019","journal-title":"J. Adv. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8753","DOI":"10.1016\/S0021-9258(17)47217-6","article-title":"The sulfonylurea herbicide sulfometuron methyl is an extremely potent and selective inhibitor of acetolactate synthase in Salmonella typhimurium","volume":"259","author":"LaRossa","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_16","first-page":"438","article-title":"New oral hypoglycemic agent: K 4024 or glipizide. Clinical trial","volume":"63","author":"Angeli","year":"1972","journal-title":"Clin. Ter."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1128\/jb.49.2.193-197.1945","article-title":"Sulfamethazine: In vitro Action on enteric pathogens as compared with sulfadiazine and sulfamerazine","volume":"49","author":"Schweinburg","year":"1945","journal-title":"J. Bacteriol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.ejmech.2018.11.005","article-title":"Chemical preparation, biological evaluation and 3D-QSAR of ethoxysulfuron derivatives as novel antifungal agents targeting acetohydroxyacid synthase","volume":"162","author":"Wu","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1021\/jm301501k","article-title":"Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase","volume":"56","author":"Lee","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E9649","DOI":"10.1073\/pnas.1809422115","article-title":"Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections","volume":"115","author":"Garcia","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ejmech.2012.01.011","article-title":"Synthesis and evaluation of novel monosubstituted sulfonylurea derivatives as antituberculosis agents","volume":"50","author":"Pan","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8356","DOI":"10.1039\/C6OB01555G","article-title":"Design, synthesis and SAR study of novel sulfonylureas containing an alkenyl moiety","volume":"14","author":"Wei","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"132756","DOI":"10.1016\/j.molstruc.2022.132756","article-title":"Design, synthesis and biological evaluation of 5\u2013substituted sulfonylureas as novel antifungal agents targeting acetohydroxyacid synthase","volume":"1260","author":"Meng","year":"2022","journal-title":"J. Mol. Struct."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1021\/bi00174a038","article-title":"N5-Carboxyaminoimidazole ribonucleotide: Evidence for a new intermediate and two new enzymatic activities in the de novo purine biosynthetic pathway of Escherichia coli","volume":"33","author":"Mueller","year":"1994","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1016\/j.bmc.2015.02.016","article-title":"Identification of Bacillus anthracis PurE inhibitors with antimicrobial activity","volume":"23","author":"Kim","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.ejmech.2015.06.047","article-title":"Synthesis and evaluation of isatin-\u03b2-thiosemicarbazones as novel agents against antibiotic-resistant Gram-positive bacterial species","volume":"101","author":"Zhang","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7324","DOI":"10.1021\/acs.jafc.0c01042","article-title":"Synthesis and pesticidal activities of new quinoxalines","volume":"68","author":"Liu","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.ejmech.2019.02.002","article-title":"Chemical synthesis, crystal structure, versatile evaluation of their biological activities and molecular simulations of novel pyrithiobac derivatives","volume":"167","author":"Wu","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8415","DOI":"10.1021\/acs.jafc.1c02081","article-title":"Discovery of ortho-alkoxy substituted novel sulfonylurea compounds that display strong herbicidal activity against monocotyledon grasses","volume":"69","author":"Wang","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/cbdd.14114","article-title":"Chemical synthesis, biological activities, and molecular simulations of novel sulfonylurea compounds bearing ortho-alkoxy substitutions","volume":"100","author":"Shang","year":"2022","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1002\/jcc.20464","article-title":"Development of a general quantum-chemical descriptor for steric effects: Density functional theory based QSAR study of herbicidal sulfonylurea analogues","volume":"27","author":"Xi","year":"2006","journal-title":"J. Comput. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1039\/C9CC08582C","article-title":"Stereoselective synthesis of trifluoromethyl-substituted 2H-furan-amines from enaminones","volume":"56","author":"Liang","year":"2020","journal-title":"Chem. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13834","DOI":"10.1021\/acs.joc.8b02153","article-title":"Synthesis of 5-aryl-3(2 H)-furanones using intramolecular cyclization of sulfonium salts","volume":"83","author":"Inagaki","year":"2018","journal-title":"J. Org. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1016\/j.bmc.2011.02.036","article-title":"The synthesis and evaluation of indolylureas as PKC\u03b1 inhibitors","volume":"19","author":"Djung","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_35","unstructured":"Mallesham, B., Subramanya, H., and Natarajan, M. (2014). Trisubstituted Heterocyclic Derivatives as ROR\u03b3 Modulators. International Patent Application No. PCT\/IB2014\/058957; PCT Patent WO 2014125426A1."},{"key":"ref_36","unstructured":"Jacob, B., Allen, F.L., Robert, G., Saul, J.F., Liu, Y., Kern, M.A., George, P.D., Kurt, W.K., and Zhao, S.H. (1999). Aryl Pyrimidine Derivatives. (5952331A), U.S. Patent."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7661","DOI":"10.1021\/acs.jafc.7b03029","article-title":"Research on controllable degradation of novel sulfonylurea herbicides in acidic and alkaline soils","volume":"65","author":"Zhou","year":"2017","journal-title":"J. Agric. Food. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.bmcl.2012.11.103","article-title":"Synthesis and evaluation of novel sulfenamides as novel anti Methicillin-resistant Staphylococcus aureus agents","volume":"23","author":"Shang","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4606","DOI":"10.1073\/pnas.0609370104","article-title":"High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections","volume":"104","author":"Zhang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","unstructured":"Clinical and Laboratory Standards Institute (CLSI) (2008). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Clinical and Laboratory Standards Institute. [3rd ed.]. Approved standard M27-A3."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"64","author":"Sheldrick","year":"2008","journal-title":"Acta Crystallogr. Sect. A"},{"key":"ref_42","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (2009). Gaussian09, Gaussian, Inc."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/2\/323\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:23:39Z","timestamp":1760120619000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/2\/323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["antibiotics12020323"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics12020323","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,3]]}}}