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

• Published in: Journal of medicinal chemistry 2010-11, Vol.53 (21), p.7836-7842
• Main Authors: Daher, Racha, Coinçon, Mathieu, Fonvielle, Matthieu, Gest, Petra M, Guerin, Marcelo E, Jackson, Mary, Sygusch, Jurgen, Therisod, Michel
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Crystallography, X-Ray; Drug Design; Fructose-Bisphosphate Aldolase - antagonists & inhibitors; Fructosediphosphates - chemistry; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Inhibitory Concentration 50; Kinetics; Microbial Sensitivity Tests; Models, Molecular; Rabbits; Structure-Activity Relationship; Sugar Phosphates - chemistry; Zinc - physiology
• ISSN: 0022-2623; 1520-4804
• 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 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.