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Chalcones constitute another important scaffold in medicinal chemistry and numerous chalcone derivatives have been reported to exhibit diverse biological activities, including anticancer and enzyme inhibitory effects. Several chalcone-based compounds have also been investigated as carbonic anhydrase inhibitors. Sulfonamides are a classical class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors with diverse therapeutic relevance, being employed as diuretics, anticonvulsants, topical antiglaucoma agents and in the management of obesity and cancer. Herein, we designed and synthesized a novel series of indolylchalcone\u2013benzenesulfonamide hybrids (\n                    <jats:bold>15a<\/jats:bold>\n                    \u2212\n                    <jats:bold>m<\/jats:bold>\n                    and\n                    <jats:bold>16a<\/jats:bold>\n                    \u2212\n                    <jats:bold>d<\/jats:bold>\n                    ) and evaluated their inhibitory activities against a panel of four human carbonic anhydrases (hCA isoforms I, II, IX and XII). Interestingly, most of the tested compounds inhibited the tumor-associated hCA IX and XII isoforms with single- to double-digit nanomolar inhibition constants (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    s). In particular, compound\n                    <jats:bold>15h<\/jats:bold>\n                    ((\n                    <jats:italic>E<\/jats:italic>\n                    )-4-(3-(5-cyano-1\n                    <jats:italic>H<\/jats:italic>\n                    -indol-3-yl)acryloyl)benzenesulfonamide) showed potent inhibition of hCA IX (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    = 8.9 nM) with marked selectivity over hCA I, II, and XII (SI\u2009=\u200961.9, 7.2, and 5.7, respectively), whereas compound\n                    <jats:bold>15j<\/jats:bold>\n                    ((\n                    <jats:italic>E<\/jats:italic>\n                    )-4-(3-(6-bromo-1\n                    <jats:italic>H<\/jats:italic>\n                    -indol-3-yl)acryloyl)benzenesulfonamide) exhibited strong inhibition of hCA XII (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    = 4.9 nM) with pronounced selectivity over hCA I, II, and IX (SI\u2009=\u2009628.4, 12.8, and 11.9, respectively), compared with the reference inhibitor acetazolamide (AAZ). Structure\u2013activity relationship analysis revealed that electron withdrawing groups, particularly cyano and bromo substituents on the indole scaffold, conferred enhanced selectivity toward tumor-associated carbonic anhydrase isoforms. Molecular docking demonstrated that both compounds adopted the canonical sulfonamide-binding mode, coordinating with Zn\u00b2\u207a and engaging in stable hydrogen-bond interactions with key active-site residues. Complementary molecular dynamics simulations confirmed the persistence of these interactions, as reflected by lower RMSD values and the maintenance of critical contacts throughout the simulation period. In addition, in silico ADME prediction using the SwissADME server suggested that compound\n                    <jats:bold>15j<\/jats:bold>\n                    possesses a more favorable balance of lipophilicity and polarity, indicating improved membrane permeability and oral absorption potential compared to\n                    <jats:bold>15h<\/jats:bold>\n                    and acetazolamide (AAZ), whereas\n                    <jats:bold>15h<\/jats:bold>\n                    exhibited relatively higher polarity that may limit permeability despite comparable lipophilicity. Accordingly, these findings suggest that the novel indolylchalcone-benzenesulfonamide hybrids\n                    <jats:bold>15h<\/jats:bold>\n                    and\n                    <jats:bold>15j<\/jats:bold>\n                    represent promising leads for the development of potent and selective inhibitors of tumor-associated carbonic anhydrases.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-49231-6","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T10:57:56Z","timestamp":1783508276000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of indolylchalcone benzenesulfonamides as selective inhibitors of tumor-associated carbonic anhydrase IX and XII"],"prefix":"10.1038","volume":"16","author":[{"given":"Joohan","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karol","family":"Biernacki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Giovannuzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossam","family":"Nada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubham","family":"C Rivonker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changseong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Elkamhawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyeong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"issue":"2","key":"49231_CR1","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/nrd2467","volume":"7","author":"CT Supuran","year":"2008","unstructured":"Supuran, C. 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