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These compounds incorporate an ethylenic spacer between the benzenesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for <jats:italic>in<\/jats:italic>\u2010<jats:italic>vitro<\/jats:italic> cytotoxicity. Most of them act as effective inhibitors of the tumor\u2010linked CA isoforms IX and XII, in nanomolar range. Also, different compounds have shown selectivity in comparable with the standard acetazolamide. Our IBS <jats:bold>5\u2009d<\/jats:bold>, <jats:bold>5\u2009g<\/jats:bold>, and <jats:bold>5\u2009l<\/jats:bold> (with Ki: 10.1, 19.4, 19.8\u2005nM against hCA IX and 47, 45, 20\u2005nM against hCA IX) showed the best inhibitory profile. <jats:italic>In\u2010vitro<\/jats:italic> screening of all derivatives against a full sixty\u2010cell\u2010lined from NCI at a single dose of 10\u2005\u03bcM offered growth inhibition of up to 45\u2009%. Compound\u2005<jats:bold>5\u2009b<\/jats:bold> has been identified with the most potent cytotoxic activity and broad spectrum. Docking studies have also been implemented and were also in accordance with the biological outcomes. Our SAR analysis has interestingly proposed efficient tumor\u2010related hCAs IX\/XII suppression.<\/jats:p>","DOI":"10.1002\/cmdc.202400004","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T03:39:25Z","timestamp":1707968365000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX\/XII Inhibitors"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1091-2885","authenticated-orcid":false,"given":"Ehab S.","family":"Taher","sequence":"first","affiliation":[{"name":"Department of Basic Medical and Dental Sciences Faculty of Dentistry Zarqa University  Zarqa 13110 Jordan"},{"name":"Department of Pharmaceutical Organic Chemistry Faculty of Pharmacy Al-Azhar University  Asyut 71524 Assiut Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4864-2056","authenticated-orcid":false,"given":"Adel A.","family":"Marzouk","sequence":"additional","affiliation":[{"name":"National Center for Natural Products Research School of Pharmacy Mississippi University  Mississippi MS 38677 USA"},{"name":"Department of Pharmaceutical Chemistry Faculty of Pharmacy Al-Azhar University  Asyut 71524 Assiut Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2659-2764","authenticated-orcid":false,"given":"Walaa Hamada","family":"Abd\u2010Allah","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department Collage of Pharmaceutical Science and Drug Manufacturing Misr University for Science and Technology  P.O. 77, 6th of October City Giza Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0669-7481","authenticated-orcid":false,"given":"Simone","family":"Giovannuzzi","sequence":"additional","affiliation":[{"name":"Department of NEUROFARBA Section of Pharmaceutical and Nutraceutical Sciences University of Florence, Polo Scientifico  Via U. 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