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Dysregulation of specific CA isoforms, particularly the human variants hCA I, II, IX, and XII, is implicated in multiple pathological conditions, including glaucoma, epilepsy, obesity, and various cancers. Traditionally, sulfonamide\u2010based inhibitors have dominated the therapeutic landscape; however, their limitations, such as off\u2010target side effects, poor selectivity for different isoforms, and allergic reactions, have galvanized interest in alternative scaffolds. This comprehensive review critically examines the burgeoning class of non\u2010sulfonamide inhibitors targeting hCA isoforms, focusing on the chemical diversity, binding mechanisms, and structure\u2013activity relationships of recently developed phenols, carboxylic acids, coumarins, dithiocarbamates, and polyamines. Special attention is given to the advances in X\u2010ray crystallography and computational modeling that have illuminated binding modes distinct from classical sulfonamide interactions. By synthesizing the latest findings, this review aims to guide future efforts in the rational design of selective and efficacious non\u2010sulfonamide CA inhibitors for clinical application.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70090","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T05:54:43Z","timestamp":1758693283000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structural Advances in Non\u2010Sulfonamide Carbonic Anhydrase Inhibitors: Insights Into Design, Bioactivity, and Binding Mechanism"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-7406","authenticated-orcid":false,"given":"Mahmood","family":"Ahmed","sequence":"first","affiliation":[{"name":"Department of Chemistry, Division of Science and Technology University of Education Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5993-043X","authenticated-orcid":false,"given":"Muhammad Zaeem","family":"Mehdi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Division of Science and Technology University of Education Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehwish","family":"Javed","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Division of Science and Technology University of Education Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7343-4083","authenticated-orcid":false,"given":"Mohammed H. AL","family":"Mughram","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy King Khalid University Abha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masooma","family":"Irfan","sequence":"additional","affiliation":[{"name":"Department of Mathematics Saveetha School of Engineering (SIMATS), Thandalam Chennai Tamil Nadu India"},{"name":"Advanced Membrane Technology Research Centre (AMTEC), Faculty of Chemical and Energy Engineering Universiti Teknologi Malaysia Johor Bahru Johor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7721-4325","authenticated-orcid":false,"given":"Ahmad","family":"Saeed","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Division of Science and Technology University of Education Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5868-1213","authenticated-orcid":false,"given":"Ali Abbas","family":"Aslam","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Division of Science and Technology University of Education Lahore Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"15","article-title":"Some Properties of Carbonic Anhydrase, the CO_2 Enzyme Present in Blood","volume":"75","author":"Meldrum N.","year":"1932","journal-title":"Journal of Physiology"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17071150"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00425-020-03553-5"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2016.1203904"},{"issue":"2","key":"e_1_2_10_6_1","article-title":"Therapeutic Potential of Carbonic Anhydrase Inhibitors","volume":"32","author":"Bibi S.","year":"2019","journal-title":"Pakistan Journal of Pharmaceutical Sciences"},{"key":"e_1_2_10_7_1","unstructured":"L.Annunziato N.Zambrano andM.Vitale Characterization of Carbonic Anhydrases in Models of Neuronal Differentiation and in the Nematode Caenorhabditis elegans (2023) 86 http:\/\/www.fedoa.unina.it\/id\/eprint\/9515."},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.14.68"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2022.133672"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm300818k"},{"key":"e_1_2_10_11_1","unstructured":"L.Urba\u0144ski Production and Characterization of \u03b1\u2010and \u03b2\u2010Carbonic Anhydrases From Pathogenic Parasite Trichomonas Vaginalis and Probiotic Bacteria Lactobacillus Rhamnosus GG Vol 696 (Tampere University 2022)."},{"issue":"3","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.3390\/pharmacy7030132","article-title":"Sulfonamide Allergies","volume":"7","author":"Giles A.","year":"2019","journal-title":"Pharmacy: Journal of Pharmacy Education and Practice"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2022.105920"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","unstructured":"R. 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