{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:33:27Z","timestamp":1774917207149,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,28]],"date-time":"2023-05-28T00:00:00Z","timestamp":1685232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Government","award":["PID2020-116460RB-I00"],"award-info":[{"award-number":["PID2020-116460RB-I00"]}]},{"name":"Spanish Government","award":["PID2021-123059OB-I00"],"award-info":[{"award-number":["PID2021-123059OB-I00"]}]},{"name":"Spanish Government","award":["FQM134"],"award-info":[{"award-number":["FQM134"]}]},{"name":"Spanish Government","award":["2017XYBP2R"],"award-info":[{"award-number":["2017XYBP2R"]}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["PID2020-116460RB-I00"],"award-info":[{"award-number":["PID2020-116460RB-I00"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["PID2021-123059OB-I00"],"award-info":[{"award-number":["PID2021-123059OB-I00"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["FQM134"],"award-info":[{"award-number":["FQM134"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["2017XYBP2R"],"award-info":[{"award-number":["2017XYBP2R"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Italian Ministry for University and Research (MIUR)","award":["PID2020-116460RB-I00"],"award-info":[{"award-number":["PID2020-116460RB-I00"]}]},{"name":"Italian Ministry for University and Research (MIUR)","award":["PID2021-123059OB-I00"],"award-info":[{"award-number":["PID2021-123059OB-I00"]}]},{"name":"Italian Ministry for University and Research (MIUR)","award":["FQM134"],"award-info":[{"award-number":["FQM134"]}]},{"name":"Italian Ministry for University and Research (MIUR)","award":["2017XYBP2R"],"award-info":[{"award-number":["2017XYBP2R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The involvement of carbonic anhydrases (CAs) in a myriad of biological events makes the development of new inhibitors of these metalloenzymes a hot topic in current Medicinal Chemistry. In particular, CA IX and XII are membrane-bound enzymes, responsible for tumour survival and chemoresistance. Herein, a bicyclic carbohydrate-based hydrophilic tail (imidazolidine-2-thione) has been appended to a CA-targeting pharmacophore (arylsulfonamide, coumarin) with the aim of studying the influence of the conformational restriction of the tail on the CA inhibition. For this purpose, the coupling of sulfonamido- or coumarin-based isothiocyanates with reducing 2-aminosugars, followed by the sequential acid-promoted intramolecular cyclization of the corresponding thiourea and dehydration reactions, afforded the corresponding bicyclic imidazoline-2-thiones in good overall yield. The effects of the carbohydrate configuration, the position of the sulfonamido motif on the aryl fragment, and the tether length and substitution pattern on the coumarin were analysed in the in vitro inhibition of human CAs. Regarding sulfonamido-based inhibitors, the best template turned out to be a d-galacto-configured carbohydrate residue, meta-substitution on the aryl moiety (9b), with Ki against CA XII within the low nM range (5.1 nM), and remarkable selectivity indexes (1531 for CA I and 181.9 for CA II); this provided an enhanced profile in terms of potency and selectivity compared to more flexible linear thioureas 1\u20134 and the drug acetazolamide (AAZ), used herein as a reference compound. For coumarins, the strongest activities were found for substituents devoid of steric hindrance (Me, Cl), and short linkages; derivatives 24h and 24a were found to be the most potent inhibitors against CA IX and XII, respectively (Ki = 6.8, 10.1 nM), and also endowed with outstanding selectivity (Ki &gt; 100 \u00b5M against CA I, II, as off-target enzymes). Docking simulations were conducted on 9b and 24h to gain more insight into the key inhibitor\u2013enzyme interactions.<\/jats:p>","DOI":"10.3390\/ijms24119401","type":"journal-article","created":{"date-parts":[[2023,5,28]],"date-time":"2023-05-28T15:30:47Z","timestamp":1685287847000},"page":"9401","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors"],"prefix":"10.3390","volume":"24","author":[{"given":"M\u00f3nica","family":"Mart\u00ednez-Montiel","sequence":"first","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Ciudad Universitaria, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72570, PUE, Mexico"},{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9658-532X","authenticated-orcid":false,"given":"Laura L.","family":"Romero-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Ciudad Universitaria, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72570, PUE, Mexico"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0669-7481","authenticated-orcid":false,"given":"Simone","family":"Giovannuzzi","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, 50019 Florence, Italy"}]},{"given":"Paloma","family":"Begines","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, 50019 Florence, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7975-1960","authenticated-orcid":false,"given":"Adri\u00e1n","family":"Puerta","sequence":"additional","affiliation":[{"name":"BioLab, Instituto Universitario de Bio-Org\u00e1nica \u201cAntonio Gonz\u00e1lez\u201d (IUBO-AG), Universidad de La Laguna, c\/Astrof\u00edsico Francisco S\u00e1nchez 2, E-38206 La Laguna, Spain"}]},{"given":"Ana I.","family":"Ahuja-Casar\u00edn","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Ciudad Universitaria, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72570, PUE, Mexico"}]},{"given":"Miguel X.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"BioLab, Instituto Universitario de Bio-Org\u00e1nica \u201cAntonio Gonz\u00e1lez\u201d (IUBO-AG), Universidad de La Laguna, c\/Astrof\u00edsico Francisco S\u00e1nchez 2, E-38206 La Laguna, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1376-9671","authenticated-orcid":false,"given":"Pen\u00e9lope","family":"Merino-Montiel","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Ciudad Universitaria, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72570, PUE, Mexico"}]},{"given":"Sara","family":"Montiel-Smith","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Ciudad Universitaria, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72570, PUE, Mexico"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-702X","authenticated-orcid":false,"given":"Alessio","family":"Nocentini","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, 50019 Florence, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6268-6552","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Padr\u00f3n","sequence":"additional","affiliation":[{"name":"BioLab, Instituto Universitario de Bio-Org\u00e1nica \u201cAntonio Gonz\u00e1lez\u201d (IUBO-AG), Universidad de La Laguna, c\/Astrof\u00edsico Francisco S\u00e1nchez 2, E-38206 La Laguna, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, 50019 Florence, Italy"}]},{"given":"Jos\u00e9 G.","family":"Fern\u00e1ndez-Bola\u00f1os","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain"}]},{"given":"\u00d3scar","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1038\/s41467-020-18425-5","article-title":"Elucidating the role of metal ions in carbonic anhydrase catalysis","volume":"11","author":"Kim","year":"2020","journal-title":"Nat. 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