title: Double ester prodrugs of FR900098 display enhanced in-vitro antimalarial activity.
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.
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Universitätsklinikum Giessen und Marburg GmbH, Giessen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Wiesner
authors.forename: Regina
authors.initials: R
authors.lastname: Ortmann
authors.forename: Hassan
authors.initials: H
authors.lastname: Jomaa
authors.forename: Martin
authors.initials: M
authors.lastname: Schlitzer
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D004351:Drug Resistance; D004952:Esters; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004952:Esters; D009097:Multienzyme Complexes; D011355:Prodrugs; D005578:Fosfomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases