title: Alpha-heteroatom derivatized analogues of 3-(acetylhydroxyamino)propyl phosphonic acid (FR900098) as antimalarials.
abstract: 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.
authors.affiliation: Laboratory for Medicinal Chemistry-FFW, UGent, Harelbekestraat 72, B-9000 Gent, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Verbrugghen
authors.forename: Pierre
authors.initials: P
authors.lastname: Vandurm
authors.forename: Jenny
authors.initials: J
authors.lastname: Pouyez
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D062105:Molecular Docking Simulation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D005578:Fosfomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases