含哌嗪生物等排体的磺胺类化合物对人碳酸酐酶 I、II、IV 和 IX 的强效抑制作用。
Sulfonamides incorporating piperazine bioisosteres as potent human carbonic anhydrase I, II, IV and IX inhibitors.
机构信息
University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
University of Florence, Department of Chemistry, via della Lastruccia, 50019 Sesto Fiorentino, Italy.
出版信息
Bioorg Chem. 2019 Oct;91:103130. doi: 10.1016/j.bioorg.2019.103130. Epub 2019 Jul 20.
Starting from the molecular simplification of (R) 4-(3,4-dibenzylpiperazine-1-carbonyl)benzenesulfonamide 9a, a compound endowed with selectivity for human Carbonic Anhydrase (hCA) IV, a series of piperazines and 4-aminopiperidines carrying a 4-sulfamoylbenzamide moiety as Zn-binding group have been designed and tested on human isoforms hCA I, II, IV and IX, using a stopped flow CO hydrase assay. The aim of the work was to derive structure-activity relationships useful for designing isoform selective compounds. These structural modifications changed the selectivity profile of the analogues from hCA IV to hCA I and II, and improved potency. Several of the new compounds showed subnanomolar activity on hCA II. X-ray crystallography of ligand-hCAII complexes was used to compare the binding modes of the new piperazines and the previously synthesized 2-benzyl-piperazine analogues, explaining the inhibition profiles.
从（R）4-（3,4-二苄基哌嗪-1-羰基）苯磺酰胺 9a 的分子简化开始，设计了一系列哌嗪和 4-氨基哌啶，它们带有作为 Zn 结合基团的 4-磺酰胺基苯甲酰胺部分，对人碳酸酐酶（hCA）IV 具有选择性，并使用停流 CO 水解酶测定法对人同工酶 hCA I、II、IV 和 IX 进行了测试。这项工作的目的是得出有用的构效关系，用于设计同工酶选择性化合物。这些结构修饰改变了类似物对 hCA IV 的选择性概况，使其对 hCA I 和 II 的选择性增强，并提高了效力。一些新化合物对 hCA II 的活性达到亚纳摩尔水平。配体-hCAII 复合物的 X 射线晶体学用于比较新哌嗪和以前合成的 2-苄基-哌嗪类似物的结合模式，解释了抑制谱。
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