title: Synthesis of beta- and gamma-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates.
abstract: 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 beta-position of the phosphonate moiety of these leads by an oxygen atom. beta-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 beta-oxa modification yielded a derivative (13) with superior activity against the Plasmodium falciparum 3D7 strain than fosmidomycin, while a gamma-oxa modification resulted in less active derivatives. A bis(pivaloyloxymethyl)ester of phosphonate 13 proved twice as active in inhibiting cultured parasites as a similar prodrug of FR900098.
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Ghent University, Harelbekestraat 72, 9000 Gent, Belgium.
authors.forename: Timothy
authors.initials: T
authors.lastname: Haemers
authors.forename: Jochen
authors.initials: J
authors.lastname: Wiesner
authors.forename: Dirk
authors.initials: D
authors.lastname: Giessmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Verbrugghen
authors.forename: Ulrik
authors.initials: U
authors.lastname: Hillaert
authors.forename: Regina
authors.initials: R
authors.lastname: Ortmann
authors.forename: Hassan
authors.initials: H
authors.lastname: Jomaa
authors.forename: Andreas
authors.initials: A
authors.lastname: Link
authors.forename: Martin
authors.initials: M
authors.lastname: Schlitzer
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D005578:Fosfomycin; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid