Carbonic anhydrase inhibitors. Regioselective synthesis of novel 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 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamide (2–16) 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 ubiquitous CA I and II, and cancer-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed inhibition constants in the range of 1.09–12.1 μM, against hCA II in the range of 50.5–172 nM, against hCA IX in the range of 5.2–118 nM, and against hCA XII in the range of 8.7–381 nM, respectively. Compounds 2, 3, 5–9, 11, 13 and 14 showed excellent hCA IX inhibitory efficacy, with KIs = 5.2–11.0 nM, being much more effective as compared to the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND (KIs = 24–50 nM). Compounds 2, 3, 5–9, 11 and 13 were also very effective hCA XII inhibitors (KIs = 8.7–45.2 nM) which are comparable or more effective than those clinically used EZA and DCP (KIs = 22 and 50 nM), respectively.

Graphical abstractA novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamides have been synthesized and investigated as inhibitors of carbonic anhydrase isozymes hCA I, II, IX and XII. Some of them showed excellent hCA IX and XII inhibitory efficacy. Figure optionsDownload full-size imageDownload as PowerPoint slide