Rational design, synthesis, and evaluation of new selective inhibitors of microbial class II (zinc dependent) fructose bis-phosphate aldolases

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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*


  • Anti-Bacterial Agents
  • Antifungal Agents
  • Antitubercular Agents
  • Fructosediphosphates
  • Hydroxamic Acids
  • Sugar Phosphates
  • sedoheptulose 1,7-bisphosphate
  • Fructose-Bisphosphate Aldolase
  • Zinc
  • fructose-1,6-diphosphate