Alkoxycarbonyloxyethyl ester prodrugs of FR900098 with improved in vivo antimalarial activity.

Abstract

FR900098 represents a derivative of the new antimalarial drug fosmidomycin with enhanced activity. The mechanism of action is the inhibition of the 1-desoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Prodrugs with increased oral activity in mice infected with the rodent malaria parasite Plasmodium vinckei were obtained by masking the phosphonate moiety of FR900098 as alkoxycarbonyloxyethyl esters.

• Authors: Regina Ortmann, Jochen Wiesner, Armin Reichenberg, Dajana Henschker, Ewald Beck, Hassan Jomaa, Martin Schlitzer
• Journal: Archiv der Pharmazie (Arch Pharm (Weinheim)) Vol. 338 Issue 7 Pg. 305-14 (Jul 2005) ISSN: 0365-6233 [Print] Germany
• PMID: 15996004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Administration, Oral
• Aldose-Ketose Isomerases (antagonists & inhibitors, metabolism)
• Animals
• Antimalarials (chemical synthesis, pharmacokinetics, therapeutic use)
• Biological Availability
• Dose-Response Relationship, Drug
• Fosfomycin (analogs & derivatives, blood, chemical synthesis, pharmacokinetics, therapeutic use)
• Malaria (parasitology, prevention & control)
• Mice
• Mice, Inbred BALB C
• Multienzyme Complexes (antagonists & inhibitors, metabolism)
• Oxidoreductases (antagonists & inhibitors, metabolism)
• Plasmodium (drug effects)
• Prodrugs (chemical synthesis, pharmacokinetics, therapeutic use)
• Quantitative Structure-Activity Relationship