{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T21:51:16Z","timestamp":1773179476071,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,3,10]],"date-time":"2019-03-10T00:00:00Z","timestamp":1552176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 \u00b5M concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX\/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar Ki values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies.<\/jats:p>","DOI":"10.3390\/ijms20051208","type":"journal-article","created":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T03:49:31Z","timestamp":1552362571000},"page":"1208","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Novel 8-Substituted Coumarins That Selectively Inhibit Human Carbonic Anhydrase IX and XII"],"prefix":"10.3390","volume":"20","author":[{"given":"Kerem","family":"Buran","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayisdagi Cad., 34755 Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0107-2682","authenticated-orcid":false,"given":"Silvia","family":"Bua","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulio","family":"Poli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"\u00d6nen Bayram","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Kayisdagi Cad., 34755 Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6205-4069","authenticated-orcid":false,"given":"Tiziano","family":"Tuccinardi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu","family":"Supuran","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, University of Florence, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1021\/cr200176r","article-title":"Multiple Binding Modes of Inhibitors to Carbonic Anhydrases: How to Design Specific Drugs Targeting 15 Different Isoforms?","volume":"112","author":"Alterio","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1517\/13543776.2013.780598","article-title":"Diuretics with carbonic anhydrase inhibitory action: A patent and literature review (2005\u20132013)","volume":"23","author":"Carta","year":"2013","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1517\/13543776.2013.794788","article-title":"Antiglaucoma carbonic anhydrase inhibitors: A patent review","volume":"23","author":"Masini","year":"2013","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nrd3554","article-title":"Interfering with pH regulation in tumours as a therapeutic strategy","volume":"10","author":"Neri","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1517\/13543776.2013.798648","article-title":"Anticancer carbonic anhydrase inhibitors: A patent review (2008\u20132013)","volume":"23","author":"Monti","year":"2013","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2017). Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites, 7.","DOI":"10.3390\/metabo7030048"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1517\/13543776.2013.790957","article-title":"Antiobesity carbonic anhydrase inhibitors: A literature and patent review","volume":"23","author":"Scozzafava","year":"2013","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.4155\/fmc.14.68","article-title":"Sulfonamides and their isosters as carbonic anhydrase inhibitors","volume":"6","author":"Carta","year":"2014","journal-title":"Future Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1080\/13543776.2016.1203904","article-title":"Carbonic anhydrase inhibitors: A review on the progress of patent literature (2011\u20132016)","volume":"26","author":"Lomelino","year":"2016","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ejmech.2018.12.049","article-title":"Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment","volume":"164","author":"Krasavin","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1080\/14756366.2018.1532419","article-title":"The carbonic anhydrase IX inhibitor SLC-0111 sensitises cancer cells to conventional chemotherapy","volume":"34","author":"Andreucci","year":"2019","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lomelino, C., Supuran, C., and McKenna, R. (2016). Non-Classical Inhibition of Carbonic Anhydrase. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071150"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1021\/ja809683v","article-title":"Non-Zinc Mediated Inhibition of Carbonic Anhydrases: Coumarins Are a New Class of Suicide Inhibitors","volume":"131","author":"Maresca","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1021\/jm901287j","article-title":"Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins","volume":"53","author":"Maresca","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7255","DOI":"10.1016\/j.bmcl.2010.10.094","article-title":"7,8-Disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar\/subnanomolar range","volume":"20","author":"Maresca","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8271","DOI":"10.1021\/jm200983e","article-title":"Glycosyl Coumarin Carbonic Anhydrase IX and XII Inhibitors Strongly Attenuate the Growth of Primary Breast Tumors","volume":"54","author":"Touisni","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.1158\/0008-5472.CAN-10-4261","article-title":"Targeting Tumor Hypoxia: Suppression of Breast Tumor Growth and Metastasis by Novel Carbonic Anhydrase IX Inhibitors","volume":"71","author":"Lou","year":"2011","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1021\/acs.jmedchem.5b01720","article-title":"Thioxocoumarins Show an Alternative Carbonic Anhydrase Inhibition Mechanism Compared to Coumarins","volume":"59","author":"Ferraroni","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.ejmech.2017.11.061","article-title":"Inhibitory effects and structural insights for a novel series of coumarin-based compounds that selectively target human CA IX and CA XII carbonic anhydrases","volume":"143","author":"Mancuso","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Xiao, Z., Yuan, M., Zhang, S., Wu, J., Qi, S., and Li, Q. (2005). Complete assignments of 1H and 13C-NMR data for ten phenylpiperazine derivatives. Magn. Reson. Chem.","DOI":"10.1002\/mrc.1641"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4671","DOI":"10.1021\/jm400408r","article-title":"Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics","volume":"56","author":"Chen","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1016\/j.bmc.2007.11.045","article-title":"Activity of Mannich bases of 7-hydroxycoumarin against Flaviviridae","volume":"16","author":"Mazzei","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1016\/S0021-9258(18)62326-9","article-title":"The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C","volume":"246","author":"Khalifah","year":"1971","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1021\/ci500209e","article-title":"AutoDock4Zn: An improved AutoDock force field for small-molecule docking to zinc metalloproteins","volume":"54","author":"Forli","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Poli, G., Jha, V., Martinelli, A., Supuran, C., and Tuccinardi, T. (2018). Development of a Fingerprint-Based Scoring Function for the Prediction of the Binding Mode of Carbonic Anhydrase II Inhibitors. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071851"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ejmech.2016.02.032","article-title":"Synthesis and structure activity relationship investigation of triazolo[1,5-a]pyrimidines as CB2 cannabinoid receptor inverse agonists","volume":"113","author":"Baraldi","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tuccinardi, T., Ferrarini, P.L., Manera, C., Ortore, G., Saccomanni, G., and Martinelli, A. (2006). Cannabinoid CB2\/CB1 selectivity. Receptor modeling and automated docking analysis. J. Med. Chem., 49.","DOI":"10.1021\/jm050875u"},{"key":"ref_31","unstructured":"Case, D.A., Berryman, J.T., Betz, R.M., Cerutti, D.S., Darden, T.A., Duke, R.E., Giese, T.J., Gohlke, H., Goetz, A.W., and Homeyer, N. (2019, March 09). The AMBER molecular modeling package. Available online: casegroup.rutgers.edu\/casegr-sh-2.html."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1021\/acs.jnatprod.6b00627","article-title":"Drug Affinity Responsive Target Stability (DARTS) Identifies Laurifolioside as a New Clathrin Heavy Chain Modulator","volume":"79","author":"Franceschelli","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.fitote.2018.09.010","article-title":"New diterpenes from Salvia pseudorosmarinus and their activity as inhibitors of monoacylglycerol lipase (MAGL)","volume":"130","author":"Huallpa","year":"2018","journal-title":"Fitoterapia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/mnfr.200900281","article-title":"Toxicology and risk assessment of coumarin: Focus on human data","volume":"54","author":"Abraham","year":"2010","journal-title":"Mol. Nutr. Food Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/5\/1208\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:37:41Z","timestamp":1760186261000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/5\/1208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,10]]},"references-count":34,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["ijms20051208"],"URL":"https:\/\/doi.org\/10.3390\/ijms20051208","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,10]]}}}