Synthesis and biological evaluation of cyclopropyl analogues of fosmidomycin as potent Plasmodium falciparum growth inhibitors.
A series of fosmidomycin analogues featuring restricted conformational mobility has been synthesized and evaluated as inhibitors of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase and as growth inhibitors of P. falciparum. The enantiomerically pure trans-cyclopropyl N-acetyl analogue 3b showed comparable inhibitory activity as fosmidomycin toward E. coli DOXP reductoisomerase and proved equally active when tested in vitro for P. falciparum growth inhibition. Conversely, the alpha-phenyl cis-cyclopropyl analogue 4 showed virtually no inhibition of the enzyme.
Devreux
Vincent
V
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium.
Wiesner
Jochen
J
Goeman
Jan L
JL
Van der Eycken
Johan
J
Jomaa
Hassan
H
Van Calenbergh
Serge
S
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors; D000818:Animals; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009097:Multienzyme Complexes; D005578:Fosfomycin; C024640:fosmidomycin; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases