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While flexible compounds can increase target affinity, they often result in non\u2010specific interactions and reduced selectivity. In contrast, rigid compounds may recognize their target more precisely and have lower off\u2010target effects. In this study, we incorporated a 1,1\u2010dioxido\u20101,4\u2010thiazine ring into fluorinated benzenesulfonamide derivatives with bulky\n                    <jats:italic>meta<\/jats:italic>\n                    \u2010substituents to enhance selectivity for human carbonic anhydrase IX (CAIX), an important cancer\u2010associated target. Due to the structural similarities of CAIX with other carbonic anhydrase isozymes, selective inhibition remains a significant challenge. A series of 3,4\u2010substituted trifluorobenzenesulfonamides containing oxidized thiazine rings were synthesized using a novel synthetic pathway. Although the potency against CAIX was modestly reduced compared to more flexible analogs, selectivity increased significantly, with lead compounds\n                    <jats:bold>7\u2009d<\/jats:bold>\n                    and\n                    <jats:bold>7\u2009e<\/jats:bold>\n                    exhibiting over 1000\u2010fold selectivity for CAIX over most other isozymes. X\u2010ray crystallography revealed the structural basis for this selectivity, confirming the advantageous positioning of rigidified compounds within some CA isozyme active sites. These findings highlight the potential of molecular rigidity in the design of highly selective inhibitors for therapeutic applications.\n                  <\/jats:p>","DOI":"10.1002\/chem.202404409","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T03:25:02Z","timestamp":1738725902000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design of Rigid Compounds to Enhance Selectivity for Carbonic Anhydrase IX"],"prefix":"10.1002","volume":"31","author":[{"given":"Aivaras","family":"Va\u0161kevi\u010dius","sequence":"first","affiliation":[{"name":"Department of Biothermodynamics and Drug Design Institute of Biotechnology Life Sciences Center Vilnius University, Saul\u0117tekio 7  Vilnius LT-10257 Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel\u0117","family":"Trumpickait\u0117","sequence":"additional","affiliation":[{"name":"Department of 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