Divergent strategy for the synthesis of alpha-aryl-substituted fosmidomycin analogues.
Fosmidomycin is the first representative of a new class of antimalarial drugs acting through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway for the synthesis of isoprenoids. This work describes a divergent strategy for the synthesis of a series of alpha-aryl-substituted fosmidomycin analogues, featuring a palladium-catalyzed Stille coupling as the key step. An alpha-(4-cyanophenyl)fosmidomycin analogue emerged as the most potent analogue in the present series. Its antimalarial activity clearly surpasses that of the reference compound fosmidomycin.
Devreux
Vincent
V
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Belgium.
Wiesner
Jochen
J
Jomaa
Hassan
H
Rozenski
Jef
J
Van der Eycken
Johan
J
Van Calenbergh
Serge
S
D000107:Acetylation; D004926:Escherichia coli / Q000737:chemistry; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure
D005578:Fosfomycin; C024640:fosmidomycin