Synthesis and bioactivity of β-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase

J Med Chem. 2015 Apr 9;58(7):2988-3001. doi: 10.1021/jm5014264. Epub 2015 Mar 31.


Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of 2. While direct addition of a β-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Aldose-Ketose Isomerases / chemistry*
  • Aldose-Ketose Isomerases / genetics
  • Aldose-Ketose Isomerases / metabolism
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects
  • Fosfomycin / analogs & derivatives*
  • Fosfomycin / chemistry
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Targeted Therapy
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology
  • Plasmodium falciparum / drug effects
  • Protein Conformation
  • Structure-Activity Relationship


  • Antimalarials
  • Enzyme Inhibitors
  • Fosfomycin
  • fosmidomycin
  • 3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases

Associated data

  • PDB/4Y67
  • PDB/4Y6P
  • PDB/4Y6R
  • PDB/4Y6S