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Abstract：
A novel library of human carbonic anhydrase (hCA) inhibitors based on the 2-sulfanilamido[1,2,4]triazolo[1,5-a]pyrimidine skeleton modified at its 7-position was prepared by an efficient convergent procedure. These derivatives were evaluated in vitro for their inhibition properties against a representative panel of hCA isoforms (hCA I, II, IV, IX, and XII). The target tumour-associated isoforms hCA IX and XII were potently inhibited with KIs in the low nanomolar range of 5-96 nM and 4-72 nM, respectively. Compounds 1d, 1j, 1v, and 1x were the most potent hCA IX inhibitors with KIs of 5.1, 8.6, 4.7, and 5.1 nM, respectively. Along with derivatives 1d and 1j, compounds 1r and 1ab potently inhibited hCA XII isoform with KIs in a single-digit nanomolar range of 8.8, 5.4, 4.3, and 9.0 nM, respectively. Compounds 1e, 1m, and 1p exhibited the best selectivity against hCA IX and hCA XII isoforms over off-target hCA II, with selectivity indexes ranging from 5 to 14.
摘要：
通过有效的会聚程序制备了基于在其7位修饰的2-磺胺酰氨基[1,2,4]三唑并[1,5-a]嘧啶骨架的新型人类碳酸酐酶（hCA）抑制剂库。在体外评估了这些衍生物对一组代表性的hCA同种型（hCAI，II,IV,IX,和XII）。目标肿瘤相关同工型hCAIX和XII在5-96nM和4-72nM的低纳摩尔范围内被KIs有效抑制。分别。化合物1d,1j,1v,和1x是最有效的hCAIX抑制剂，其KIs为5.1、8.6、4.7和5.1nM，分别。随着导数1d和1j，化合物1r和1ab在8.8、5.4、4.3和9.0nM的个位数纳摩尔范围内，用KIs有效抑制hCAXII同工型，分别。化合物1e,1m,与脱靶hCAII相比，1p对hCAIX和hCAXII亚型表现出最佳选择性，选择性指数范围从5到14。
