Effects of new 5-amino-1,3,4-thiadiazole-2-sulfonamide derivatives on human carbonic anhydrase isozymes

Pyrazole carboxylic acid amides of 5-amino-1,3,4-thiadiazole-2-sulfonamide 1 (inhibitor 1) were synthesized from 4-benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl chloride and 4-benzoyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-carbonyl chloride compounds. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by the affinity chromatography. The inhibitory effects of inhibitor 1, acetazolamide (AAZ), and of 16 newly synthesized amides (8–11, 12a–f, 13a–c, 14a–b, and 15) on hydratase and esterase activities of these isoenzymes have been studied in vitro. The average IC50 values of the new compounds (8–11, 12a–f, 13a–c, 14a–b, and 15) for hydratase activity ranged from 3.25 to 4.75 μM for hCA-I and from 0.055 to 2.6 μM for hCA-II. The mean IC50 values of the same inhibitors for esterase activity were in the range of 2.7–6.6 μM for hCA-I (with the exception of inhibitor 10, which did not inhibit the esterase activity of hCA-I) and of 0.013–4.2 μM for hCA-II. The Ki values for new compounds (8–11, 12a–f, 13a–c, 14a–b, and 15) were observed well below that of the parent compound inhibitor 1 and were also comparable to that of AAZ under the same experimental conditions. The comparison of newly synthesized amides to inhibitor 1 and to AAZ indicated that the new derivatives preferentially inhibit hCA-II and are more potent inhibitors of hCA-II than the parent inhibitor 1 and AAZ.

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