title: Prodrugs of reverse fosmidomycin analogues.
abstract: Fosmidomycin inhibits IspC (Dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However, improvement of the drug's pharmacodynamics and pharmacokinetics is desirable. Here, we show that the conversion of the phosphonate moiety into acyloxymethyl and alkoxycarbonyloxymethyl groups can increase the in vitro activity against asexual blood stages of P. falciparum by more than 1 order of magnitude. We also synthesized double prodrugs by additional esterification of the hydroxamate moiety. Prodrugs with modified hydroxamate moieties are subject to bioactivation in vitro. All prodrugs demonstrated improved antiplasmodial in vitro activity. Selected prodrugs and parent compounds were also tested for their cytotoxicity toward HeLa cells and in vivo in a Plasmodium berghei malaria model as well as in the SCID mouse P. falciparum model.
authors: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität , Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors: Karin
authors: K
authors: Brücher
authors: Tobias
authors: T
authors: Gräwert
authors: Sarah
authors: S
authors: Konzuch
authors: Jana
authors: J
authors: Held
authors: Claudia
authors: C
authors: Lienau
authors: Christoph
authors: C
authors: Behrendt
authors: Boris
authors: B
authors: Illarionov
authors: Louis
authors: L
authors: Maes
authors: Adelbert
authors: A
authors: Bacher
authors: Sergio
authors: S
authors: Wittlin
authors: Benjamin
authors: B
authors: Mordmüller
authors: Markus
authors: M
authors: Fischer
authors: Thomas
authors: T
authors: Kurz
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011355:Prodrugs; D005578:Fosfomycin; C024640:fosmidomycin