Carbonic anhydrase inhibitors: Synthesis and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with 4-substituted 3-pyridinesulfonamides

A series of novel 4-substituted-3-pyridinesulfonamides (2–27 and 31–33) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic, ubiquitous isozymes CA I and II, and transmembrane isozymes CA IX, XII (cancer-associated) and XIV. Against the human isozymes hCA I, the new compounds showed inhibition constants in the range of 0.078–11.7 μM, against hCA II in the range of 9.9–140 nM, against hCA IX in the range of 4.6–313 nM, against hCA XII in the range of 3.4–21.6 nM, and against hCA XIV in the range of 50.9–160 nM, respectively. Compounds 4, 6, 7, 9, 11–14, 19, 20, 22–24, 26, 27, 31 and 32 showed excellent hCA IX inhibitory efficacy, with inhibition constants of 4.6–12.0 nM, being much more effective as compared to the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND. 4-[N′-(6-Chloro-7-cyano-1,1-dioxo-1,4,2-benzodithiazin-3-yl)hydrazino]-3-pyridinesulfonamide (31) is the prominent of the compounds due to its remarkable inhibitory activity toward hCA I (KIs = 0.078 μM), hCA IX (KIs = 7.2 nM) and hCA XII (KIs = 3.4 nM).

Graphical abstractA series of novel 4-substituted-3-pyridinesulfonamides have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA) that is, isozymes hCA I, II, IX, XII and XIV. Figure optionsDownload full-size imageDownload as PowerPoint slide