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(2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (Ki = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (Ki &gt; 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (Ki = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions.<\/jats:p>","DOI":"10.3390\/ijms23147685","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T20:52:41Z","timestamp":1657659161000},"page":"7685","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations"],"prefix":"10.3390","volume":"23","author":[{"given":"Giulia","family":"Arrighi","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 Antonio Gonz\u00e1lez (IUBO-AG), Universidad de La Laguna, c\/Astrof\u00edsico Francisco S\u00e1nchez 2, E-38206 La Laguna, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Petrini","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, 50019 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8419-0467","authenticated-orcid":false,"given":"Francisco J.","family":"Hicke","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel X.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"BioLab, Instituto Universitario de Bio-Org\u00e1nica Antonio Gonz\u00e1lez (IUBO-AG), Universidad de La Laguna, c\/Astrof\u00edsico Francisco S\u00e1nchez 2, E-38206 La Laguna, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 Antonio Gonz\u00e1lez (IUBO-AG), Universidad de La Laguna, c\/Astrof\u00edsico Francisco S\u00e1nchez 2, E-38206 La Laguna, Spain"}],"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":"NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, 50019 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8220","DOI":"10.1039\/c3cs60153f","article-title":"Be squared: Expanding the horizon of squaric acid-mediated conjugations","volume":"42","author":"Wurm","year":"2013","journal-title":"Chem. 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