title: Binding modes of reverse fosmidomycin analogs toward the antimalarial target IspC.
abstract: 1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodium falciparum (PfIspC, PfDxr), believed to be the rate-limiting enzyme of the nonmevalonate pathway of isoprenoid biosynthesis (MEP pathway), is a clinically validated antimalarial target. The enzyme is efficiently inhibited by the natural product fosmidomycin. To gain new insights into the structure activity relationships of reverse fosmidomycin analogs, several reverse analogs of fosmidomycin were synthesized and biologically evaluated. The 4-methoxyphenyl substituted derivative 2c showed potent inhibition of PfIspC as well as of P. falciparum growth and was more than one order of magnitude more active than fosmidomycin. The binding modes of three new derivatives in complex with PfIspC, reduced nicotinamide adenine dinucleotide phosphate, and Mg(2+) were determined by X-ray structure analysis. Notably, PfIspC selectively binds the S-enantiomers of the study compounds.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität , Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Konzuch
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Umeda
authors.forename: Jana
authors.initials: J
authors.lastname: Held
authors.forename: Saskia
authors.initials: S
authors.lastname: Hähn
authors.forename: Karin
authors.initials: K
authors.lastname: Brücher
authors.forename: Claudia
authors.initials: C
authors.lastname: Lienau
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Behrendt
authors.forename: Tobias
authors.initials: T
authors.lastname: Gräwert
authors.forename: Adelbert
authors.initials: A
authors.lastname: Bacher
authors.forename: Boris
authors.initials: B
authors.lastname: Illarionov
authors.forename: Markus
authors.initials: M
authors.lastname: Fischer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
authors.forename: Nobutada
authors.initials: N
authors.lastname: Tanaka
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurz
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain; D003460:Crystallization; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009249:NADP / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D005578:Fosfomycin; D009249:NADP; C024640:fosmidomycin; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases