{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T23:23:14Z","timestamp":1782948194559,"version":"3.54.5"},"reference-count":38,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T00:00:00Z","timestamp":1589500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>A series of 1,2,3-triazole-linked triazino[5,6-b]indole-benzene sulfonamide hybrids (6a\u20136o) was synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against the human (h) isoforms hCA I, II, XIII (cytosolic isoforms), and hCA IX (transmembrane tumor-associated isoform). The results revealed that the compounds 6a\u20136o exhibited Ki values in the low to medium nanomolar range against hCA II and hCA IX (Kis ranging from 7.7 nM to 41.3 nM) and higher Ki values against hCA I and hCA XIII. Compound 6i showed potent inhibition of hCA II (Ki = 7.7nM), being more effective compared to the standard inhibitor acetazolamide (AAZ) (Ki = 12.1 nM). Compounds 6b and 6d showed moderate activity against hCA XIII (Ki = 69.8 and 65.8 nM). Hence, compound 6i could be consider as potential lead candidate for the design of potent and selective hCA II inhibitors.<\/jats:p>","DOI":"10.3390\/metabo10050200","type":"journal-article","created":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T10:53:59Z","timestamp":1589540039000},"page":"200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Design, Synthesis, and Biological Evaluation of 1,2,3-Triazole-linked triazino[5,6-b]indole-benzene sulfonamide Conjugates as Potent Carbonic Anhydrase I, II, IX, and XIII Inhibitors"],"prefix":"10.3390","volume":"10","author":[{"given":"Krishna Kartheek","family":"Chinchilli","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1470-7192","authenticated-orcid":false,"given":"Andrea","family":"Angeli","sequence":"additional","affiliation":[{"name":"Neurofarba Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Universit\u00e0 degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavitra S.","family":"Thacker","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laxman Naik","family":"Korra","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmita","family":"Biswas","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0158-5683","authenticated-orcid":false,"given":"Mohammed","family":"Arifuddin","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India"},{"name":"Department of Chemistry, Anwarul Uloom College, 11-3-918, New Malleypally, Hyderabad 500001, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, Universit\u00e0 degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,15]]},"reference":[{"key":"ref_1","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_2","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_3","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1042\/BCJ20160115","article-title":"Structure and function of carbonic anhydrases","volume":"473","author":"Supuran","year":"2016","journal-title":"Biochem. J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Supuran, C.T. (2018). Carbonic anhydrases and metabolism. Metabolites, 8.","DOI":"10.3390\/metabo8020025"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1038\/s41396-019-0426-8","article-title":"A new wide spread sub class of carbonic anhydrase in marine phytoplankton","volume":"13","author":"Jensen","year":"2019","journal-title":"ISME J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.1038\/onc.2012.550","article-title":"Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche","volume":"32","author":"Lock","year":"2013","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9101","DOI":"10.1016\/j.bmc.2008.09.028","article-title":"In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II","volume":"16","author":"Bayram","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9673","DOI":"10.1021\/jm501497m","article-title":"A Class of 4-Sulfamoylphenyl-\u03c9-aminoalkyl Ethers with Effective Carbonic Anhydrase Inhibitory Action and Antiglaucoma Effects","volume":"57","author":"Bozdag","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1016\/j.bmc.2014.06.016","article-title":"Furazan and furoxan sulfonamides are strong \u03b1-carbonic anhydrase inhibitors and potential anti-glaucoma agents","volume":"22","author":"Chegaev","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.ejmech.2013.10.071","article-title":"Structure-based screening for the discovery of new carbonic anhydrase XII inhibitors, Eur","volume":"71","author":"Ferro","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1002\/cmdc.201500596","article-title":"In Vivo Evaluation of Selective Carbonic Anhydrase Inhibitors as Potential Anticonvulsant Agents","volume":"11","author":"Bruno","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1021\/jm0108202","article-title":"Carbonic anhydrase inhibitors: A general approach for the preparation of water-soluble sulfonamides incorporating polyamino-polycarboxylate tails and of their metal complexes possessing long-lasting, Topical intraocular pressure-lowering properties","volume":"45","author":"Scozzafava","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1021\/jm301625s","article-title":"Sulfocoumarins (1,2-Benzoxathiine-2,2-dioxides): A Class of Potent and Isoform-Selective Inhibitors of Tumor-Associated Carbonic Anhydrases","volume":"56","author":"Tars","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_14","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 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_15","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1016\/j.bmc.2010.01.076","article-title":"Carbonic anhydrase inhibitors, Inhibition of mammalian isoforms I-XIV with a series of natural product polyphenols and phenolic acids","volume":"18","author":"Innocenti","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"453543","DOI":"10.1155\/2015\/453543","article-title":"Probing the surface of human carbonicanhydrase for clues towards the design of isoform specific inhibitors","volume":"2015","author":"Pinard","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1016\/j.bmc.2012.08.019","article-title":"Insights towards sulfonamide drug specificity in alpha-carbonic anhydrases","volume":"21","author":"Aggarwal","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1016\/j.bmc.2005.02.017","article-title":"1,2,4-Triazino-[5,6b]indole derivatives: Effects of trifluoromethyl group on in-vitro antimalarial activity","volume":"13","author":"Kgokong","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.bioorg.2014.12.001","article-title":"Triazinoindole analogs as potent inhibitors of \u03b1-glucosidase: Synthesis, biological evaluation and molecular docking studies","volume":"58","author":"Rahim","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4661","DOI":"10.1016\/j.bmcl.2010.05.100","article-title":"Synthesis, antidepressant evaluation and QSAR studies of novel 2-(5H-[1,2,4]triazino[5,6b]indol3-ylthio)-N-(substituted phenyl)acetamides","volume":"20","author":"Shelke","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0223-5234(91)90027-K","article-title":"New 5H-1,2,4-triazino[5,6b]indole and aminoindole derivatives. Synthesis and studies as inhibitors of blood platelet aggregation, anti-hypertensive agents and thromboxane synthetase inhibitors","volume":"26","author":"Monge","year":"1991","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/S2221-1691(13)60012-X","article-title":"Effect of newly synthesized 1,2,4-triazino[5,6b]indole-3-thione derivatives on olfactory bulbectomy induced depression in rats","volume":"2","author":"Aswar","year":"2012","journal-title":"Asian. J. Trop. Biomed."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1007\/BF02464248","article-title":"Thiourea and thiosemicarbazide derivatives: Structure, transformations, and pharmacological activity. Part III. Antihypoxic and anti-inflammatory activity of 1,2,4-triazino[5,6b]indole derivatives","volume":"31","author":"Tomchin","year":"1997","journal-title":"Pharma. Chem. J."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Demir-Yazici, K., Bua, S., and Supuran, C.T. (2019). Indole-Based Hydrazones Containing A Sulfonamide Moiety as Selective Inhibitors of Tumor-Associated Human Carbonic Anhydrase Isoforms IX and XII. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092354"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ejmech.2018.05.034","article-title":"Synthesis, characterization and biological evaluation of tertiary sulfonamide derivatives of pyridyl-indole based heteroaryl chalcone as potential carbonic anhydrase IX inhibitors and anticancer agents","volume":"155","author":"Peerzada","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.bioorg.2018.09.007","article-title":"Tumor-associated carbonic anhydrase isoform IX and XII inhibitory properties of certain isatin-bearing sulfonamides endowed with in-vitro antitumor activity towards colon cancer","volume":"81","author":"Eldehna","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3674","DOI":"10.1016\/j.bmc.2015.04.011","article-title":"C.T. New pyrazolo[4,3e][1.2.4]triazino sulfonamides as carbonic anhydrase inhibitors","volume":"23","author":"Mojzych","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.compbiolchem.2017.09.006","article-title":"QSAR study of pyrazolo[4,3e][1,2,4]triazino sulfonamide against tumor-associated human carbonic anhydrase isoforms IX and XII","volume":"71","author":"Matysiak","year":"2017","journal-title":"Comp. Boil. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10692","DOI":"10.1021\/acs.jmedchem.6b01389","article-title":"Benzene sulfonamides incorporating flexible Triazole Moieties Are Highly Effective Carbonic anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational and Intraocular Pressure Lowering Investigations","volume":"59","author":"Nocentini","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1021\/acsinfecdis.8b00074","article-title":"Potent 1,2,4-Triazino[5,6b]indole-3-thioether inhibitors of Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis","volume":"4","author":"Huy","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3635","DOI":"10.1021\/acschemneuro.9b00226","article-title":"Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents","volume":"10","author":"Patel","year":"2019","journal-title":"ACS. Chem. Neurosci."},{"key":"ref_32","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. Stopflowkinetic studies on the native human isoenzymes B and C","volume":"246","author":"Khalifah","year":"1971","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/0223-5234(96)89555-9","article-title":"Carbonic anhydrase activators. Part 14. Synthesis of mono- and bis- pyridinium salt derivatives of 2-amino-5-(2-aminoethyl)- and 2-amino-5-(3-aminopropyl)-1,3,4-thiadiazole, and their interaction with isozyme II","volume":"31","author":"Supuran","year":"1996","journal-title":"Eur. J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1111\/j.1747-0285.2010.00965.x","article-title":"Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of phenolic acids Chem","volume":"75","author":"Supuran","year":"2010","journal-title":"Biol. Drug Des."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1039\/c2cc16395k","article-title":"Dithiocarbamates: A new class of carbonic anhydrase inhibitors. Crystallographic and kinetic investigations","volume":"48","author":"Carta","year":"2012","journal-title":"Chem Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1021\/jm501573b","article-title":"Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxybromophenol derivatives incorporating cyclopropane moieties","volume":"58","author":"Topal","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jinorgbio.2011.11.017","article-title":"(In)organic anions as carbonic anhydrase inhibitors","volume":"111","author":"Supuran","year":"2012","journal-title":"J. Inorg. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5050","DOI":"10.1016\/j.bmcl.2010.07.038","article-title":"Carbonic anhydrase inhibitors. Antioxidant polyphenols effectively inhibit mammalian isoforms I\u2013XV","volume":"20","author":"Innocenti","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/10\/5\/200\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:29:15Z","timestamp":1760174955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/10\/5\/200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,15]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["metabo10050200"],"URL":"https:\/\/doi.org\/10.3390\/metabo10050200","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,15]]}}}