α-Substituted β-oxa isosteres of fosmidomycin: synthesis and biological evaluation.
Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. α-Aryl-substituted β-oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of  Plasmodium falciparum  and for their in vitro antiplasmodial activity against chloroquine-sensitive and resistant strains of  P. falciparum . The most active derivative inhibits IspC protein of  P. falciparum  (PfIspC) with an IC(50) value of 12 nM and shows potent in vitro antiplasmodial activity. In addition, lipophilic ester prodrugs demonstrated improved  P. falciparum  growth inhibition in vitro.
Institut für Pharmazeutische und Medizinische Chemie, Heinrich Heine Universität, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Karin
K
Brücher
Boris
B
Illarionov
Jana
J
Held
Serena
S
Tschan
Andrea
A
Kunfermann
Miriam K
MK
Pein
Adelbert
A
Bacher
Tobias
T
Gräwert
Louis
L
Maes
Benjamin
B
Mordmüller
Markus
M
Fischer
Thomas
T
Kurz
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors / Q000737:chemistry; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism; D011487:Protein Conformation
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011355:Prodrugs; D005578:Fosfomycin; C024640:fosmidomycin; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases