Rational Design, Synthesis, and Evaluation of New Selective Inhibitors of Microbial Class II (Zinc Dependent) Fructose Bis-phosphate Aldolases

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• 作者：Racha Daher ; Mathieu Coinon ; Matthieu Fonvielle ; Petra M. Gest ; Marcelo E. Guerin ; Mary Jackson ; Jurgen Sygusch ; Michel Therisod
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：November 11, 2010
• 年：2010
• 卷：53
• 期：21
• 页码：7836-7842
• 全文大小：883K
• 年卷期：v.53,no.21(November 11, 2010)
• ISSN：1520-4804

文摘

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 10⁵). 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.