Synthesis of alpha-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors.
In view of the promising antimalarial activity of fosmidomycin or its N-acetyl homologue FR900098, the objective of this work was to investigate the influence of aromatic substituents in the alpha-position of the phosphonate moiety. The envisaged analogues were prepared using a linear route involving a 3-aryl-3-phosphoryl propanal intermediate. The activities of all compounds were evaluated on Eschericia coli 1-deoxy-d-xylulose 5-phosphate reductoisomerase and against two Plasmodium falciparum strains. Compared with fosmidomycin, several analogues displayed enhanced activity towards the P. falciparum strains. Compound 1e with a 3,4-dichlorophenyl substitution in the alpha-position of fosmidomycin emerged as the most potent analogue of this series. It is approximately three times more potent in inhibiting the growth of P. falciparum than FR900098, the most potent representative of this class reported so far.
Haemers
Timothy
T
Laboratory for Medicinal Chemistry (FFW), Ghent University, Harelbekestraat 72, 9000 Gent, Belgium.
Wiesner
Jochen
J
Van Poecke
Sara
S
Goeman
Jan
J
Henschker
Dajana
D
Beck
Edwald
E
Jomaa
Hassan
H
Van Calenbergh
Serge
S
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
D000962:Antimalarials; D005578:Fosfomycin; C024640:fosmidomycin