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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.

1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodiumfalciparum(PfIspC, PfDxr), believed to be the rate-limiting enzyme of the nonmevalonatepathway of isoprenoid biosynthesis (MEP pathway), is a clinicallyvalidated antimalarial target. The enzyme is efficiently inhibitedby the natural product fosmidomycin. To gain new insights into thestructure activity relationships of reverse fosmidomycin analogs,several reverse analogs of fosmidomycin were synthesized and biologicallyevaluated. The 4-methoxyphenyl substituted derivative 2cshowed potent inhibition of PfIspC as well as of P. falciparumgrowth and was more than one orderof magnitude more active than fosmidomycin. The binding modes of three new derivatives in complexwith PfIspC, reduced nicotinamide adenine dinucleotidephosphate, and Mg2+were determined by X-ray structureanalysis. Notably, PfIspC selectively binds the S-enantiomers of the study compounds. [ABSTRACT FROM AUTHOR]