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All compounds were evaluated for their inhibitory potency and selectivity toward human cancer\u2010associated carbonic anhydrase isoforms IX and XII, as well as the off\u2010target isoforms I and II. Compounds\n                    <jats:bold>4a<\/jats:bold>\n                    ,\n                    <jats:bold>4g<\/jats:bold>\n                    ,\n                    <jats:bold>4j<\/jats:bold>\n                    , and\n                    <jats:bold>4k<\/jats:bold>\n                    selectively inhibited cancer\u2010associated isoforms IX and XII, with no activity against the off\u2010target isozymes I and II. Among them, compound\n                    <jats:bold>4k<\/jats:bold>\n                    was the most potent and isozyme\u2010selective inhibitor, with\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    0.31\u2009\u00b5M for\n                    <jats:italic>h<\/jats:italic>\n                    CA IX and 0.24\u2009\u00b5M for\n                    <jats:italic>h<\/jats:italic>\n                    CA XII. To estimate drug\u2010likeness, in silico ADMET predictions were performed, indicating that all compounds possess physicochemical and pharmacokinetic properties within the acceptable ranges. Molecular docking studies on the\n                    <jats:italic>h<\/jats:italic>\n                    CA IX isoform highlighted an optimal orientation within the binding pocket, with the chromene moiety positioned toward the zinc ion. In cellular assays\n                    <jats:bold>4a<\/jats:bold>\n                    ,\n                    <jats:bold>4g<\/jats:bold>\n                    ,\n                    <jats:bold>4j<\/jats:bold>\n                    , and\n                    <jats:bold>4k<\/jats:bold>\n                    selectively inhibited metabolic activity in HepG2 cells expressing\n                    <jats:italic>h<\/jats:italic>\n                    CA IX in normal conditions, whereas no activity was observed in Caco\u20102 cells lacking\n                    <jats:italic>h<\/jats:italic>\n                    CA IX expression.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70224","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T15:43:07Z","timestamp":1773675787000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chromones as Nonclassical Inhibitors of Carbonic Anhydrase IX and XII Isoforms: Probing Chromone\u2010Based Derivatives"],"prefix":"10.1002","volume":"359","author":[{"given":"Lisa","family":"Sequeira","sequence":"first","affiliation":[{"name":"MedInUP, Department of Biomedicine, Faculty of Medicine University of Porto Porto Portugal"}]},{"given":"Simona","family":"Distinto","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari Monserrato Italy"}]},{"given":"Carlos","family":"Fernandes","sequence":"additional","affiliation":[{"name":"MedInUP, Department of Biomedicine, Faculty of Medicine University of Porto Porto Portugal"}]},{"given":"Erica","family":"Sanna","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari Monserrato Italy"}]},{"given":"Rita","family":"Meleddu","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari Monserrato Italy"}]},{"given":"Marco","family":"Gaspari","sequence":"additional","affiliation":[{"name":"Research Centre for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, \u201cMagna Gr\u00e6cia\u201d University of Catanzaro Catanzaro Italy"}]},{"given":"Filippo","family":"Cottiglia","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari Monserrato Italy"}]},{"given":"Alessia","family":"Onali","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari Monserrato Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1470-7192","authenticated-orcid":false,"given":"Andrea","family":"Angeli","sequence":"additional","affiliation":[{"name":"Department NEUROFARBA, Section of Pharmaceutical Sciences University of Florence Florence Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1050-2402","authenticated-orcid":false,"given":"Fernanda","family":"Borges","sequence":"additional","affiliation":[{"name":"MedInUP, Department of Biomedicine, Faculty of Medicine University of Porto Porto Portugal"},{"name":"Department of Chemistry and Biochemistry, Faculty of Sciences University of Porto Porto Portugal"}]},{"given":"Eugenio","family":"Uriarte","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry, Faculty of Pharmacy University of Santiago de Compostela Santiago de Compostela Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0437-358X","authenticated-orcid":false,"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, \u201cMagna Gr\u00e6cia\u201d University of Catanzaro Catanzaro Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"Department NEUROFARBA, Section of Pharmaceutical Sciences University of Florence Florence Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2175-2802","authenticated-orcid":false,"given":"Elias","family":"Maccioni","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences University of Cagliari Monserrato Italy"}]}],"member":"311","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2014.03.047"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01720"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr400265z"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.13951"},{"key":"e_1_2_8_6_1","first-page":"341","article-title":"Synthesis of Chromones and Pyrazolines as Antimicrobial & Antifungal Agents","volume":"19","author":"Ghotekar D. 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