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

• Published in: Journal of medicinal chemistry 2013-01, Vol.56 (1), p.376-380
• Main Authors: Verbrugghen, Thomas, Vandurm, Pierre, Pouyez, Jenny, Maes, Louis, Wouters, Johan, Van Calenbergh, Serge
• Format: Article
• Language: English
• Subjects: Aldose-Ketose Isomerases - antagonists & inhibitors; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Erythrocytes - drug effects; Erythrocytes - parasitology; Fosfomycin - analogs & derivatives; Fosfomycin - chemical synthesis; Fosfomycin - chemistry; Fosfomycin - pharmacology; Humans; In Vitro Techniques; Molecular Docking Simulation; Parasitic Sensitivity Tests; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301577q

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.