title: Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity.
abstract: 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.
authors.affiliation: Department für Pharmazie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, D-81377, München, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Ortmann
authors.forename: Jochen
authors.initials: J
authors.lastname: Wiesner
authors.forename: Armin
authors.initials: A
authors.lastname: Reichenberg
authors.forename: Dajana
authors.initials: D
authors.lastname: Henschker
authors.forename: Ewald
authors.initials: E
authors.lastname: Beck
authors.forename: Hassan
authors.initials: H
authors.lastname: Jomaa
authors.forename: Martin
authors.initials: M
authors.lastname: Schlitzer
mesh_terms: 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*
chemical_list: 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