4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I, II, IX and XII

• Published in: Bioorganic & medicinal chemistry 2014-12, Vol.22 (24), p.6945-6952
• Main Authors: SitaRam, Ceruso, Mariangela, Khloya, Poonam, Supuran, Claudiu T., Sharma, Pawan K.
• Format: Article
• Language: English
• Subjects: 6-Aminosulfonylbenzothiazole; Acetazolamide; Antigens, Neoplasm - chemistry; Antigens, Neoplasm - metabolism; Benzothiazoles - chemistry; Carbonic Anhydrase I - antagonists & inhibitors; Carbonic Anhydrase I - metabolism; Carbonic Anhydrase II - antagonists & inhibitors; Carbonic Anhydrase II - metabolism; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - metabolism; Carbonic anhydrase isoforms I, II, IX, XII; Carbonic Anhydrase IX; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - metabolism; Humans; Protein Binding; Pyrazoles; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.10.018

Novel heterocyclic compounds bearing 6-aminosulfonylbenzothiazole moiety at position 1 of 4-functionalized pyrazole ring showed moderate to excellent carbonic anhydrase hCA I, II, IX and hCA XII inhibitory efficiency. [Display omitted] •Library of novel hCA I, II, IX and XII inhibitors was synthesized.•Sulfonamide possessing benzothiazole is incorporated on pyrazole scaffold.•Compounds were screened against hCA isoforms I, II, IX and XII.•Tested compounds showed moderate to excellent affinity for CA isozymes. A series of 24 novel heterocyclic compounds—functionalized at position 4 with aldehyde (5a–5f), carboxylic acid (6a–6f), nitrile (7a–7f) and oxime (8a–8f) functional groups—bearing 6-aminosulfonybenzothiazole moiety at position 1 of pyrazole has been synthesized and investigated for the inhibition of four isoforms 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 isozyme hCA I, compounds 6a–6f showed medium-weak inhibitory potential with Ki values in the range of 157–690nM with 6a showing better potential than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed excellent to moderate inhibition with Ki values of compounds 5a, 5d, 5f, 6a–6f, 8d and 8f lower than 12nM (Ki of AZA). Against hCA IX, all the compounds showed moderate inhibition with the exception of 6e which showed nearly 9 fold a better profile compared to AZA, whereas against hCA XII, four compounds 6e, 7a, 7b and 7d showed Ki in the same order as that of AZA. Carboxylic acid 6e was found to be an excellent inhibitor of both hCA IX and XII, with Ki values of 2.8nM and 5.5nM, respectively.