Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity.
FR900098 represents an improved derivative of the new antimalarial drug fosmidomycin and acts through inhibition of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Prodrugs with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield acyloxyalkyl esters. The most successful compound demonstrated 2-fold increased activity in mice infected with the rodent malaria parasite Plasmodium vinckei.
Ortmann
Regina
R
Department für Pharmazie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, D-81377, München, Germany.
Wiesner
Jochen
J
Reichenberg
Armin
A
Henschker
Dajana
D
Beck
Ewald
E
Jomaa
Hassan
H
Schlitzer
Martin
M
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007202:Indicators and Reagents; D008246:Lysophospholipids / Q000378:metabolism; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
D000962:Antimalarials; D007202:Indicators and Reagents; D008246:Lysophospholipids; D011355:Prodrugs; C120117:dioxazaphosphocane-H; D005578:Fosfomycin; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D008798:Mevalonic Acid