Synthesis and antibacterial activity of mechanism-based inhibitors of KDO8P synthase and DAH7P synthase

Carbohydr Res. 2005 Mar 21;340(4):529-37. doi: 10.1016/j.carres.2004.11.019.

Abstract

KDO8PS (3-deoxy-D-manno-2-octulosonate-8-phosphate synthase) and DAH7PS (3-deoxy-D-arabino-2-heptulosonate-7-phosphate synthase) are attractive targets for the development of new anti-infectious agents. Both enzymes appear to proceed via a common mechanism involving the reaction of phosphoenolpyruvate (PEP) with arabinose 5-phosphate or erythrose-4-phosphate, to produce the corresponding ulosonic acids, KDO8P and DAH7P, respectively. The synthesis of new inhibitors closely related to the supposed tetrahedral intermediate substrates for the enzymes is described. The examination of the antibacterial activity of these derivatives is reported.

MeSH terms

  • 3-Deoxy-7-Phosphoheptulonate Synthase / antagonists & inhibitors*
  • 3-Deoxy-7-Phosphoheptulonate Synthase / metabolism
  • Aldehyde-Lyases / antagonists & inhibitors*
  • Aldehyde-Lyases / metabolism
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology*
  • Catalysis
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Gram-Negative Bacteria / drug effects
  • Mass Spectrometry
  • Molecular Structure
  • Pentosephosphates / metabolism
  • Phosphoenolpyruvate / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Sugar Phosphates / metabolism

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Pentosephosphates
  • Sugar Phosphates
  • arabinose 5-phosphate
  • erythrose 4-phosphate
  • Phosphoenolpyruvate
  • 3-Deoxy-7-Phosphoheptulonate Synthase
  • 2-dehydro-3-deoxyphosphooctonate aldolase
  • Aldehyde-Lyases