Carbonic anhydrase inhibitors. Regioselective synthesis of novel series 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII

A series of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides 4-6, 9-17 and 21-31 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and cancer-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed K(I)s in the range of 224-4830 nM, whereas toward hCA II, K(I)s = 318-873 nM. Isozyme hCA IX was inhibited with K(I)s = 11.8-93.4 nM, and hCA XII with 23.5 -82.3 nM. Compounds 12-14, 27 and 29-31 have an activity against hCA I (K(I)s = 224-889 nM) which is comparable to the clinically used sulfonamide DCP (K(I)s = 1200 nM). Several of new compounds, including 9, 10, 21, 24, 26-28 and 30 have an activity against hCA IX (K(I)s = 11.8-38.6 nM) which is comparable or more effective than the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND (K(I)s = 24-50 nM). Compounds 9, 10, 13, 21-23, 26 and 27 were also very effective hCA XII inhibitors, with inhibition constants ranged from 23.5 to 47.2 nM comparable or more effective than sulfonamides EZA (K(I)s = 22 nM) or DCP (K(I)s = 50 nM), respectively. (C) 2012 Elsevier Masson SAS. All rights reserved.