{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T15:45:26Z","timestamp":1764603926338,"version":"3.41.2"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,11,13]],"date-time":"2022-11-13T00:00:00Z","timestamp":1668297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007787","name":"National Research Centre","doi-asserted-by":"publisher","award":["12010113"],"award-info":[{"award-number":["12010113"]}],"id":[{"id":"10.13039\/100007787","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Novel benzenesulfonamide derivatives linked to diverse functionalized thiouracils through a flexible <jats:italic>N<\/jats:italic>\u2010ethyl acetamide linker were designed and synthesized as carbonic anhydrase (CA) inhibitors. The synthesized candidates demonstrated a potent inhibitory activity against four different CA isoforms in the nanomolar range. Compound <jats:bold>10d<\/jats:bold> showed more than twofold higher potency than the reference AAZ against CA II with <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> of 5.65 and 12\u2009nM, respectively. Moreover, compounds <jats:bold>10d<\/jats:bold> and <jats:bold>20<\/jats:bold> revealed potent activity against CA IX with <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> of 18.1 and 14.2\u2009nM, respectively. In addition, <jats:bold>10c<\/jats:bold>, <jats:bold>10d<\/jats:bold>, <jats:bold>11b<\/jats:bold>, <jats:bold>11c<\/jats:bold>, and <jats:bold>20<\/jats:bold> demonstrated high potency against the CA XII isozyme with a <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> range of 4.18\u20134.8\u2009nM. Most of the synthesized derivatives displayed preferential selectivity toward\u00a0the CA IX and CA XII isoforms over CA I and CA II. Compounds <jats:bold>11a<\/jats:bold> and <jats:bold>20<\/jats:bold> exhibited favorable selectivity toward CA IX over CA II with a selectivity index (SI) of 14.36 and 16.62, respectively, and toward CA XII over CA II with SI of 71.01 and 51.19, respectively. Molecular docking simulations showed that the synthesized conjugates adopted comparable binding modes in the CA I, CA II, CA IX, and CA XII isoforms, involving the deep fitting of the sulfonamide moiety in the base of the CA active site via chelation of the Zn<jats:sup>2+<\/jats:sup> ion and H\u2010bond interaction with the key amino acids Thr199 and\/or Thr200. Moreover, the <jats:italic>N<\/jats:italic>\u2010ethyl acetamide flexible linker enables the substituted thiouracils and fused thiouracil tail to achieve multiple interactions with the surrounding hydrophobic and hydrophilic regions.<\/jats:p>","DOI":"10.1002\/ardp.202200434","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:00:46Z","timestamp":1668391246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel benzenesulfonamide\u2010thiouracil conjugates with a flexible <i>N<\/i>\u2010ethyl acetamide linker as selective CA IX and CA XII inhibitors"],"prefix":"10.1002","volume":"356","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7610-8312","authenticated-orcid":false,"given":"Heba T.","family":"Abdel\u2010Mohsen","sequence":"first","affiliation":[{"name":"Department of Chemistry of Natural and Microbial Products, Pharmaceutical and Drug Industries Research Institute National Research Centre Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed M.","family":"El Kerdawy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Cairo University Cairo Egypt"},{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy Newgiza University (NGU) Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Petreni","sequence":"additional","affiliation":[{"name":"Department NEUROFARBA\u2014Pharmaceutical and Nutraceutical Section, Universit\u00e0 degli Studi di Firenze University of Firenze Firenze 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":"Department NEUROFARBA\u2014Pharmaceutical and Nutraceutical Section, Universit\u00e0 degli Studi di Firenze University of Firenze Firenze Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo8020025"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1967.47.4.595"},{"volume-title":"Carbonic Anhydrases Biochemistry and Pharmacology of an Evergreen Pharmaceutical Target","year":"2019","author":"Supuran C. 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