Investigation of the redox behavior of ferroquine, a new antimalarial.
Ferroquine (FQ or SR97193) is a unique ferrocene antimalarial drug candidate which just entered phase IIb clinical trials in autumn 2007. FQ is able to overcome the chloroquine (CQ) resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. However, as for other therapeutic agents such as chloroquine (CQ) and artemisin, its mechanism of action remains partially unknown. Most investigations have so far focused on comparing the activity of FQ to that of CQ in order to understand how the ferrocene core contributes to a stronger antiplasmodial activity. Studies have already shown that the ferrocene altered the shape, volume, lipophilicity, basicity and also electronic profile of the parent molecule and, hence, its pharmacodynamic behavior. However, few investigations have been undertaken to probe the real contribution of redox properties of the ferrocene (iron(II))/ferricinium (iron(III)) system in FQ as reported in this article. In our experimental and theoretical approach, we considered the redox profile of the ferrocene core of FQ in the specific conditions (acidic and oxidizing) of the parasitic digestive vacuole as a possible discriminating property from CQ in the antimalarial activity.
Universite des Sciences et Technologies de Lille, Unite de Catalyse et Chimie du Solide-UMR CNRS 8181, Ecole Nationale Superieure de Chimie de Lille, Batiment C7, B.P. 90108, 59652 Villeneuve d'Ascq cedex, France.
Natascha
N
Chavain
Hervé
H
Vezin
Daniel
D
Dive
Nadia
N
Touati
Jean-François
JF
Paul
Eric
E
Buisine
Christophe
C
Biot
D000634:Aminoquinolines / Q000737:chemistry*; D000962:Antimalarials / Q000737:chemistry*; D003198:Computer Simulation; D004355:Drug Stability; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000737:chemistry*; D006861:Hydrogen Peroxide / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D013058:Mass Spectrometry; D000075163:Metallocenes; D015394:Molecular Structure; D010084:Oxidation-Reduction; D019097:Spin Trapping
D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D000075163:Metallocenes; C479230:ferroquine; D006861:Hydrogen Peroxide