Alkoxycarbonyloxyethyl ester prodrugs of FR900098 with improved in vivo antimalarial activity.
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.
Department für Pharmazie, Ludwig-Maximilians-Universität, München, Germany.
Regina
R
Ortmann
Jochen
J
Wiesner
Armin
A
Reichenberg
Dajana
D
Henschker
Ewald
E
Beck
Hassan
H
Jomaa
Martin
M
Schlitzer
D000284:Administration, Oral; D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D008288:Malaria / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010961:Plasmodium / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D021281:Quantitative Structure-Activity Relationship
D000962:Antimalarials; D009097:Multienzyme Complexes; D011355:Prodrugs; D005578:Fosfomycin; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases