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 KIs in the range of 224–4830 nM, whereas toward hCA II, KIs = 318–873 nM. Isozyme hCA IX was inhibited with KIs = 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 (KIs = 224–889 nM) which is comparable to the clinically used sulfonamide DCP (KIs = 1200 nM). Several of new compounds, including 9, 10, 21, 24, 26–28 and 30 have an activity against hCA IX (KIs = 11.8–38.6 nM) which is comparable or more effective than the clinically used sulfonamides AAZ, MZA, EZA, DCP and IND (KIs = 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 (KIs = 22 nM) or DCP (KIs = 50 nM), respectively.

Graphical abstractA series of novel 1-substituted 1,4-dihydro-4-oxo-3-pyridinesulfonamide derivatives have been synthesized and investigated as inhibitors of 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 slideHighlights► A series of 1,4-dihydro-4-oxo-3-pyridinesulfonamides have been synthesized. ► These compounds were tested as inhibitors of four human CA isozymes. ► We found substantial hCA IX and XII inhibitory efficacy. ► They were more effective than the clinically used sulfonamides, e.g.AAZ or EZA.