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Fosmidomycin represents a new antimalarial drug, acting by inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. This work describes the synthesis of a series of α-aryl substituted fosmidomycin analogues exhibiting improved antimalarial activity. A linear synthetic route, involving a 3-aryl-3-phosphoryl propanal intermediate, proved practical to prepare these derivatives. A phospha-Michael addition to cyclopent-2-enone gave access to conformationally restricted analogues.-3 -

To expand the structure-activity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in β-position of the phosphonate moiety of these leads by an oxygen atom. β-oxa-FR900098 (11) proved equally active as the parent compound.When applied to 4-[hydroxyl(methyl)amino]-4-oxobutyl phosphonic acid, featuring a hydroxamate instead of the retrohydroxamate moiety, a β-oxa modification yielded a derivative (13) with superior activity against a 3D7 P. falciparum strain than fosmidomycin, while a γ-oxa modification resulted in less active derivatives.A bis(pivaloyloxymethyl)ester of phosphonate 13 proved twice as active in inhibiting cultured parasites than a similar prodrug of FR900098.

The conversion of 1-deoxy-D-xylulose-5-phosphate (DOXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP) is effectively blocked by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitors such as the natural antibiotic fosmidomycin. Prediction of binding affinities for closely related Dxr ligands as well as estimation of the affinities of structurally more distinct inhibitors within this class of non-hydrolyzable phosphate mimics relies on the synthesis of fosmidomycin derivatives with a broad range of target affinity. Maintaining the phosphonic acid moiety, linear modifications of the lead structure were carried out in an effort to expand the SAR of this physicochemically challenging class of compounds. Synthetic access to a set of phosphonic acids with inhibitory activity (IC(50)) in the range from 1 to >30 microM vs. E. coli Dxr and 0.4 to 20 microM against P. falciparum Dxr is reported.