Antimalarial activities of ferroquine conjugates with either glutathione reductase inhibitors or glutathione depletors via a hydrolyzable amide linker.
Based on the prodrug concept as well as the combination of two different classes of antimalarial agents, we designed and synthesized two series of ferrocenic antimalarial dual molecules consisting of a ferroquine analogue conjugated with a glutathione reductase inhibitor (or a glutathione depletor) through a cleavable amide bond in order to target two essential pathways in the malarial parasites. The results showed no enhancement of the antimalarial activity of the dual molecules but evidenced a unique mode of action of ferroquine and ferrocenyl analogues distinct of those of chloroquine and nonferrocenic 4-aminoquinoline analogues.
Université de Lille 1, Unité de Catalyse et Chimie du Solide-UMR CNRS 8181, ENSCL, Bâtiment C7, B.P. 90108, 59652 Villeneuve d'Ascq Cedex, France. natchavain@yahoo.fr
Natascha
N
Chavain
Elisabeth
E
Davioud-Charvet
Xavier
X
Trivelli
Linda
L
Mbeki
Matthias
M
Rottmann
Reto
R
Brun
Christophe
C
Biot
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005296:Ferrous Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006427:Hemin / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010963:Plasmodium falciparum / Q000254:growth & development; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization
D000634:Aminoquinolines; D000962:Antimalarials; D004791:Enzyme Inhibitors; D005296:Ferrous Compounds; D011355:Prodrugs; D006427:Hemin