Double ester prodrugs of FR900098 display enhanced in-vitro antimalarial activity

Arch Pharm (Weinheim). 2007 Dec;340(12):667-9. doi: 10.1002/ardp.200700069.

Abstract

Fosmidomycin and FR900098 are inhibitors of the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR; IspC), a key enzyme of the mevalonate-independent isoprenoid biosynthesis pathway. We have determined the in-vitro antimalarial activity of two double ester prodrugs 2, 3 in direct comparison with the unmodified FR900098 1 against intraerythrocytic forms of Plasmodium falciparum. Temporarily masking the polar properties of the phosphonate moiety of the DXR inhibitor FR900098 1 enhanced not only its oral bioavailability but also the intrinsic activity of this series against the parasites.

Publication types

  • Comparative Study

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors
  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Biological Availability
  • Drug Resistance
  • Esters
  • Fosfomycin / analogs & derivatives*
  • Fosfomycin / chemical synthesis
  • Fosfomycin / pharmacokinetics
  • Fosfomycin / pharmacology
  • Mice
  • Multienzyme Complexes / antagonists & inhibitors
  • Oxidoreductases / antagonists & inhibitors
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Esters
  • Multienzyme Complexes
  • Prodrugs
  • Fosfomycin
  • 3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid
  • Oxidoreductases
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases