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Alpha-Heteroatom Derivatized Analogues of 3‑(Acetylhydroxyamino)propyl Phosphonic Acid (FR900098) as Antimalarials

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journal contribution
posted on 10.01.2013, 00:00 by Thomas Verbrugghen, Pierre Vandurm, Jenny Pouyez, Louis Maes, Johan Wouters, Serge Van Calenbergh
To explore the hitherto successful derivatization of the α-carbon of fosmidomycin, a series of new α-substituted analogues was prepared. This was done by introduction of a heteroatom (N or O) in α-position to the phosphonate and using the resultant OH and NH2 groups as a handle for appending a variety of substituents by means of several functional groups such as ether, amide, urea, and 1,4-triazole. The synthesized molecules, as a racemic mixture, were assayed for their EcDXR inhibitory potency. Both the α-azido-analogue and the α-hydroxylated analogue proved most promising, and docking experiments were performed. Although several compounds showed high potency when assayed against Plasmodium falciparum K1 in human erythrocytes, a clear correlation between the enzyme inhibition constants and P. falciparum inhibition concentrations could not be found.