title: Towards new antimalarial drugs: synthesis of non-hydrolyzable phosphate mimics as feed for a predictive QSAR study on 1-deoxy-D-xylulose-5-phosphate reductoisomerase inhibitors.
abstract: The conversion of 1-deoxy-D-xylulose-5-phosphate (DOXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP) is effectively blocked by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) inhibitors such as the natural antibiotic fosmidomycin. Prediction of binding affinities for closely related Dxr ligands as well as estimation of the affinities of structurally more distinct inhibitors within this class of non-hydrolyzable phosphate mimics relies on the synthesis of fosmidomycin derivatives with a broad range of target affinity. Maintaining the phosphonic acid moiety, linear modifications of the lead structure were carried out in an effort to expand the SAR of this physicochemically challenging class of compounds. Synthetic access to a set of phosphonic acids with inhibitory activity (IC(50)) in the range from 1 to >30 microM vs. E. coli Dxr and 0.4 to 20 microM against P. falciparum Dxr is reported.
authors.affiliation: Institute of Pharmacy, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Strasse 17, D-17487 Greifswald.
authors.forename: Dirk
authors.initials: D
authors.lastname: Giessmann
authors.forename: Philipp
authors.initials: P
authors.lastname: Heidler
authors.forename: Timothy
authors.initials: T
authors.lastname: Haemers
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
authors.forename: Armin
authors.initials: A
authors.lastname: Reichenberg
authors.forename: Hassan
authors.initials: H
authors.lastname: Jomaa
authors.forename: Claus
authors.initials: C
authors.lastname: Weidemeyer
authors.forename: Silke
authors.initials: S
authors.lastname: Sanderbrand
authors.forename: Jochen
authors.initials: J
authors.lastname: Wiesner
authors.forename: Andreas
authors.initials: A
authors.lastname: Link
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D005578:Fosfomycin / Q000031:analogs & derivatives / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000201:enzymology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D063065:Organophosphonates; D005578:Fosfomycin; C024640:fosmidomycin; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases