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A wide series of compounds were synthesized and then assessed for their CA inhibitory activity using a CO<jats:sub>2<\/jats:sub> hydrase stopped\u2010flow assay. Generally, these inhibitors demonstrated micromolar activity against the evaluated hCAs. Specifically, some derivatives bearing a ureido\u2010linker exhibited the highest inhibitory potency, showing inhibition constants (<jats:italic>K<\/jats:italic><jats:sub>I<\/jats:sub>s) in the low\u2010micromolar range against hCAs IV, XI, and XII. Moreover, two of them were detected as submicromolar inhibitors of isoform IV (<jats:italic>K<\/jats:italic><jats:sub>I<\/jats:sub>s: 0.8\u20130.96\u2009\u00b5M). Molecular modeling was carried out to investigate the binding mode of the most selective and potent compounds and reinforce the experimental results. The latter suggests that hydrazide compounds act as zinc binders, being bidentate ligands, and can be developed as an alternative to classic CA inhibitors.<\/jats:p>","DOI":"10.1002\/ardp.202400963","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T05:13:10Z","timestamp":1743570790000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploration of Aromatic Hydrazides as Inhibitors of Human Carbonic Anhydrases"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2510-5237","authenticated-orcid":false,"given":"German Benito","family":"Menendez","sequence":"first","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section University of Florence Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0669-7481","authenticated-orcid":false,"given":"Simone","family":"Giovannuzzi","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section University of Florence Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5520-740X","authenticated-orcid":false,"given":"Alessandro","family":"Bonardi","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section University of Florence Florence Italy"},{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics &amp; QSAR University of Florence Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-702X","authenticated-orcid":false,"given":"Alessio","family":"Nocentini","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section University of Florence Florence Italy"},{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics &amp; QSAR University of Florence Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9137-2509","authenticated-orcid":false,"given":"Paola","family":"Gratteri","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section University of Florence Florence Italy"},{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics &amp; QSAR University of Florence Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section University of Florence Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,4]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2467"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr200176r"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/9780470508169","volume-title":"Drug Design of Zinc\u2010Enzyme Inhibitors: Functional, Structural, and Disease Applications","author":"Supuran C. 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