Prodrugs of reverse fosmidomycin analogues

Brücher, Karin and Gräwert, Tobias and Konzuch, Sarah and Held, Jana and Lienau, Claudia and Behrendt, Christoph and Illarionov, Boris and Maes, Louis and Bacher, Adelbert and Wittlin, Sergio and Mordmüller, Benjamin and Fischer, Markus and Kurz, Thomas. (2015) Prodrugs of reverse fosmidomycin analogues. Journal of medicinal chemistry, 58 (4). pp. 2025-2035.

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Official URL: http://edoc.unibas.ch/dok/A6357895

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Oct 2017 06:13
Deposited On:10 Apr 2015 09:14

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