Novel deoxyxylulosephosphate-reductoisomerase inhibitors: fosmidomycin derivatives with spacious acyl residues.
1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) represents an essential enzyme of the mevalonate-independent pathway of the isoprenoid biosynthesis. Using fosmidomycin as a specific inhibitor of Dxr, this enzyme was previously validated as target for the treatment of malaria and bacterial infections. The replacement of the formyl residue of fosmidomycin by spacious acyl residues yielded inhibitors active in the micromolar range. As predicted by flexible docking, evidence was obtained for the formation of a hydrogen bond between an appropriately placed carbonyl group in the acyl residue and the main-chain NH of Met214 located in the flexible catalytic loop of the enzyme.
Ortmann
Regina
R
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marburg, Germany.
Wiesner
Jochen
J
Silber
Katrin
K
Klebe
Gerhard
G
Jomaa
Hassan
H
Schlitzer
Martin
M
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005578:Fosfomycin / Q000031:analogs & derivatives*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship