Kasimoğullari Rahmi, Bülbül Metin, Günhan Hatice, Güleryüz Hülya
Department of Chemistry, Dumlupinar University, Art and Science Faculty, Kutahya, Turkey.
Bioorg Med Chem. 2009 May 1;17(9):3295-301. doi: 10.1016/j.bmc.2009.03.048. Epub 2009 Mar 28.
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 IC(50) 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 microM for hCA-I and from 0.055 to 2.6 microM for hCA-II. The mean IC(50) values of the same inhibitors for esterase activity were in the range of 2.7-6.6 microM 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 microM for hCA-II. The K(i) 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.
5-氨基-1,3,4-噻二唑-2-磺酰胺1（抑制剂1）的吡唑羧酸酰胺是由4-苯甲酰基-1-(4-硝基苯基)-5-苯基-1H-吡唑-3-羰基氯和4-苯甲酰基-1-(3-硝基苯基)-5-苯基-1H-吡唑-3-羰基氯化合物合成的。人碳酸酐酶同工酶（hCA-I和hCA-II）通过亲和色谱法从红细胞中纯化得到。在体外研究了抑制剂1、乙酰唑胺（AAZ）以及16种新合成的酰胺（8-11、12a-f、13a-c、14a-b和15）对这些同工酶的水合酶和酯酶活性的抑制作用。新化合物（8-11、12a-f、13a-c、14a-b和15）对hCA-I水合酶活性的平均IC(50)值范围为3.25至4.75微摩尔，对hCA-II为0.055至2.6微摩尔。相同抑制剂对hCA-I酯酶活性的平均IC(50)值范围为2.7-6.6微摩尔（抑制剂10除外，其不抑制hCA-I的酯酶活性），对hCA-II为0.013-4.2微摩尔。新化合物（8-11、12a-f、13a-c、14a-b和15）的K(i)值在相同实验条件下远低于母体化合物抑制剂1，且与AAZ相当。将新合成的酰胺与抑制剂1和AAZ进行比较表明，新衍生物优先抑制hCA-II，并且是比母体抑制剂1和AAZ更有效的hCA-II抑制剂。
