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In this regard, carbonic anhydrase (CAIX) and vascular endothelial growth factor receptor (VEGFR\u20102) are emerging as highly effective targets in the battle against cancer. In the present study, two series of 4\u2010thiazolidinones\/2,4\u2010thiazolidinediones carrying 2\u2010methylbenzenesulfonamide derivatives were designed and synthesized as potential dual CAIX\/VEGFR\u20102 inhibitors. All the target compounds were evaluated against CAIX enzyme compared to dorzolamide and acetazolamide, subsequently the most potent CAIX inhibitors (<jats:bold>3a<\/jats:bold>, <jats:bold>3b<\/jats:bold>, <jats:bold>3o<\/jats:bold>, <jats:bold>6d<\/jats:bold>, <jats:bold>6g<\/jats:bold>, and <jats:bold>6i<\/jats:bold>) were selected to evaluate their inhibitory activity against VEGFR\u20102 using sorafenib as a reference drug. These compounds were also evaluated against MCF\u20107 breast cancer cells and the murine fibroblast 3T3 cell line. According to the results, <jats:bold>3b<\/jats:bold> (CAIX IC<jats:sub>50<\/jats:sub>\u2009=\u20090.035\u2009\u00b5M, VEGFR\u20102 IC<jats:sub>50<\/jats:sub>\u2009=\u20090.093\u2009\u00b5M) and <jats:bold>6i<\/jats:bold> (CAIX IC<jats:sub>50<\/jats:sub>\u2009=\u20090.041\u2009\u00b5M, VEGFR\u20102 IC<jats:sub>50<\/jats:sub>\u2009=\u20090.048\u2009\u00b5M) emerged the most potent compounds against CAIX and VEGFR\u20102. Furthermore, docking studies of selected compounds were performed with the CAIX and the tyrosine kinase domain of VEGFR\u20102 to comprehend the ligand\u2010binding interactions. Physicochemical predictions were examined using in silico techniques. In conclusion, these scaffolds present promising leads and furnish promising chemical backbones for the design of potent dual CAIX and VEGFR\u20102 inhibitors.b<\/jats:p>","DOI":"10.1002\/ddr.70030","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T13:06:04Z","timestamp":1733922364000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Design and Discovery of New Dual Carbonic Anhydrase IX and VEGFR\u20102 Inhibitors Based on the Benzenesulfonamide\u2010Bearing 4\u2010Thiazolidinones\/2,4\u2010Thiazolidinediones Scaffold"],"prefix":"10.1002","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1586-5448","authenticated-orcid":false,"given":"Merve","family":"Zengin","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Hacettepe University Ankara 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