Reverse fosmidomycin derivatives against the antimalarial drug target IspC (Dxr)

J Med Chem. 2011 Oct 13;54(19):6796-802. doi: 10.1021/jm200694q. Epub 2011 Sep 13.

Abstract

Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot experiments have demonstrated in vivo potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Aldose-Ketose Isomerases / chemistry
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Crystallography, X-Ray
  • Erythrocytes / drug effects
  • Erythrocytes / parasitology
  • Fosfomycin / analogs & derivatives*
  • Fosfomycin / chemical synthesis
  • Fosfomycin / chemistry
  • Fosfomycin / pharmacology
  • Humans
  • Malaria / drug therapy
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / chemistry
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry
  • Parasitic Sensitivity Tests
  • Plasmodium berghei
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Multienzyme Complexes
  • Fosfomycin
  • fosmidomycin
  • Oxidoreductases
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases

Associated data

  • PDB/3R0I