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

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Journal of Medicinal Chemistry

OSTI ID:1041707

Daher, R; Coincon, M; Fonvielle, M; Gest, P; Guerin, M; Jackson, M; Sygusch, J; Therisod, M

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 Ki 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.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1041707
• Report Number(s): BNL--97385-2012-JA
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 21 Vol. 53; ISSN JMCMAR; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ALDOLASES
ANTIBIOTICS
DESIGN
EVALUATION
FRUCTOSE
HYDROXAMIC ACIDS
KINETICS
LEAD COMPOUNDS
MICROORGANISMS
PATHOGENS
PREVENTIVE MEDICINE
SUBSTRATES
SYNTHESIS
TUBERCULOSIS
ZINC
ZINC IONS