Coordination chemistry based approach to lipophilic inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase

J Med Chem. 2009 Nov 12;52(21):6539-42. doi: 10.1021/jm9012592.

Abstract

1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate pathway found in most bacteria is a validated anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is active against Gram-negative bacteria. A coordination chemistry and structure based approach was used to discover a novel, lipophilic DXR inhibitor with an IC(50) of 1.4 microM. It exhibited a broad spectrum of activity against Gram-negative and -positive bacteria with minimal inhibition concentrations of 20-100 microM (or 3.7-19 microg/mL).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Aldose-Ketose Isomerases / chemistry*
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Cell Line
  • Cell Membrane Permeability
  • Chelating Agents / chemical synthesis*
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology
  • Drug Resistance, Bacterial
  • Fosfomycin / analogs & derivatives
  • Fosfomycin / chemistry
  • Fosfomycin / pharmacology
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Humans
  • Magnesium / chemistry*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / chemistry*
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry*
  • Pyridones / chemical synthesis*
  • Pyridones / chemistry
  • Pyridones / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Chelating Agents
  • Multienzyme Complexes
  • Pyridones
  • Fosfomycin
  • fosmidomycin
  • Oxidoreductases
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases
  • Magnesium