Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII

• Published in: Bioorganic & medicinal chemistry 2014-03, Vol.22 (6), p.1873-1882
• Main Authors: SitaRam, Celik, Gulsah, Khloya, Poonam, Vullo, Daniela, Supuran, Claudiu T., Sharma, Pawan K.
• Format: Article
• Language: English
• Subjects: Acetazolamide; Benzenesulfonamide; Benzenesulfonamides; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic anhydrase isoforms I, II, IX, XII; Carbonic Anhydrases - metabolism; Dose-Response Relationship, Drug; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Molecular Structure; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Triazoles; Triazoles - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.01.055

Novel heterocyclic compounds containing benzenesulfonamide moiety bearing 1,2,4-triazole scaffold showed excellent carbonic anhydrase hCA IX and hCA XII inhibitory efficiency and also promising selectivity over hCA I and hCA II. Three series of novel heterocyclic compounds (3a–3g, 4a–4g and 5a–5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozymes hCA I and II, compounds of two series (3a–3g and 4a–4g) showed Ki values in the range of 84–868nM and 5.6–390nM, respectively whereas compounds of series 5a–5g were found to be poor inhibitors (Ki values exceeding 10,000nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with Ki values in the range of 2.8–431nM and 1.3–63nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a–5g were comparatively less potent but more selective towards hCA IX and XII.