Carbonic anhydrase inhibitors. Synthesis, molecular structures, and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with novel 3-pyridinesulfonamide derivatives

A series of novel 3-pyridinesulfonamide derivatives (2–5, 9–11 and 13–15) 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 CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed KIs in the range of 0.089–251 μM, whereas toward hCA II, KIs = 50.5–487 nM. Isozyme hCA IX was inhibited with KIs in the range of 5.2–18.3 nM, while hCA XII with KIs = 6.0–16.4 nM, and hCA XIV with KIs = 76.4–152.0 nM. All of the new compounds 2–5, 9–11 and 13–15 showed excellent hCA IX inhibitory efficacy, with KIs = 5.2–18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (KIs = 24–50 nM).

Graphical abstractA series of novel 3-pyridinesulfonamide derivatives have been synthesized and investigated as inhibitors of carbonic anhydrase isozymes hCA I, II, IX, XII and XIV. Cancer-associated isozyme hCA IX was inhibited with KIs in the range of 5.2–18.3 nM, while hCA XII with KIs = 6.0–16.4 nM.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of novel 3-pyridinesulfonamide derivatives have been synthesized. ► These compounds were tested as inhibitors of five human CA isozymes. ► We found excellent hCA IX and XII inhibitory efficacy and selectivity. ► They were more effective than the clinically used sulfonamides, e.g. AAZ or MZA.