Fosmidomycin antimalarial

Fosmidomycin, initially discovered as a product of Strepto-myces lavendulae with antibacterial and herbicide activity, was recently shovm to act via the inhibition of IspC protein that catalyzes the first committed step in the nonmevalonate pathway of isoprenoid biosynthesis that is absent in humans (43 90, Fig. 11). Based on these findings, the compound is now under clinical evaluation as an antimalarial drug (78). 

The enzyme 2-C-methyl-D-erythritol-4-phosphate synthetase appears to catalyse a Bilik reaction (Figure 6.10) the substrate l-deoxyxylulose-5-phosphate is converted to the title compound via an intermediate aldehyde, whose carbonyl derives from C3 of the substrate. The first step is thus a Bilik reaction and the aldehyde is subsequently reduced by the enzyme using NADPH as reductant, The X-ray crystal structure of the Escherichia coli enzyme in complex with the promising antimalarial Fosmidomycin (a hydroxamic acid) reveals a bound Mn " coordinated to oxygens equivalent to the substrate carbonyl and 03. The stereochemistry and regiochemistry follow the normal Bilik course, although the crystallographers favour an alkyl shift rather than a reverse aldol-aldol mechanism. The intermediate aldehyde has been shown to be a catalytically competent intermediate. 

Kurz T, Schlueter K, Kaula U, Bergmann B, Walter RD, Geffken D (2006) Synthesis and antimalarial activity of chain substituted pivaloyloxymethyl ester analogues of fosmidomycin and FR900098. Bioorg Med Chem 14 5121-5135... 

Schluter K, Walter RD, Bergmann B, Kurz T (2006) Aryhnethyl substituted derivatives of fosmidomycin synthesis and antimalarial activity. Eur J Med Chem 41 1385-1397... 

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