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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Brücher K,Gräwert T,Konzuch S,Held J,Lienau C,Behrendt C,Illarionov B,Maes L,Bacher A,Wittlin S,Mordmüller B,Fischer M,Kurz Tdoi
10.1021/jm5019719subject
Has Abstractpub_date
2015-02-26 00:00:00pages
2025-35issue
4eissn
0022-2623issn
1520-4804journal_volume
58pub_type
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