ECBB, ICMMO, Univ Paris-Sud, UMR 8182, F-91405 Orsay, France.
J Med Chem. 2010 Nov 11;53(21):7836-42. doi: 10.1021/jm1009814.
We report the synthesis and biochemical evaluation of several selective inhibitors of class II (zinc dependent) fructose bis-phosphate aldolases (Fba). The products were designed as transition-state analogues of the catalyzed reaction, structurally related to the substrate fructose bis-phosphate (or sedoheptulose bis-phosphate) and based on an N-substituted hydroxamic acid, as a chelator of the zinc ion present in active site. The compounds synthesized were tested on class II Fbas from various pathogenic microorganisms and, by comparison, on a mammalian class I Fba. The best inhibitor shows K(i) against class II Fbas from various pathogens in the nM range, with very high selectivity (up to 10(5)). Structural analyses of inhibitors in complex with aldolases rationalize and corroborate the enzymatic kinetics results. These inhibitors represent lead compounds for the preparation of new synthetic antibiotics, notably for tuberculosis prophylaxis.
我们报告了几种选择性抑制 II 类（锌依赖性）果糖双磷酸醛缩酶（Fba）的合成和生化评估。这些产物被设计为催化反应的过渡态类似物，与底物果糖双磷酸（或 sedoheptulose 双磷酸）结构相关，并基于 N-取代羟肟酸，作为活性部位中锌离子的螯合剂。合成的化合物在来自各种致病微生物的 II 类 Fbas 上进行了测试，并与哺乳动物的 I 类 Fba 进行了比较。最佳抑制剂对来自各种病原体的 II 类 Fbas 的 K(i) 在纳摩尔范围内，具有非常高的选择性（高达 10(5)）。抑制剂与醛缩酶复合物的结构分析合理化并证实了酶动力学结果。这些抑制剂代表了制备新型合成抗生素的先导化合物，特别是用于结核病预防。
