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.
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.
Giessmann
Dirk
D
Institute of Pharmacy, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Strasse 17, D-17487 Greifswald.
Heidler
Philipp
P
Haemers
Timothy
T
Van Calenbergh
Serge
S
Reichenberg
Armin
A
Jomaa
Hassan
H
Weidemeyer
Claus
C
Sanderbrand
Silke
S
Wiesner
Jochen
J
Link
Andreas
A
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
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