Structure–activity relationships of 4-N-substituted ferroquine analogues: Timeto re-evaluate the mechanism of action of ferroquine

Journal of Organometallic Chemistry (Impact Factor: 2.17). 03/2009; 694(6):845. DOI: 10.1016/j.jorganchem.2008.09.033


A series of five new alkyl 4-N-substituted analogues of ferroquine (FQ, SR97193) were designed, synthesized,
and characterized. The antimalarial activity of the compounds was measured against twelve strains
of Plasmodium falciparum. The compounds were more active than chloroquine (CQ) against all the CQresistant
clones. For a better understanding of their mechanism of action, their physicochemical properties
(lipophilicity and basicity) and their action on the inhibition of b-hematin formation were evaluated.
The importance of the intramolecular hydrogen bond in neutral FQ in the antimalarial activity was
probed, compared to the methyl analogue 1.
Results of additional physicochemical measurements suggested new insights into the mechanism of
action of FQ in sharp contrast with CQ. We complement here our understanding on the mechanism of
action of FQ with the process of catalysis-mediated hemozoin formation at the interface between vacuolar
content and membrane lipids.

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    • "In order to assess the synergy of AVA with QN, 25 μl of AVA per well and 200 μl of the suspension of synchronous parasitized red blood cells (final parasitaemia, 0.5%; final haematocrit, 1.5%) per well were plated in 96-well plates containing the QN concentrations. The in vitro isotopic micro-test used had been previously described [34]. "
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    • "The enhanced lipophilicity of 1 (P o/w 5 5.0) and 2, compared with 3 (P o/w 5 4.4), could also play a role. Recent studies suggest that the activity of ferroquine results, at least in part, from its superior lipophilicity compared with chloroquine, and possibly from its localization in the lipidic sites of heme crystallization [Biot et al., 2009]. "
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    ABSTRACT: Ferroquine (FQ or SR97193) is a novel antimalarial drug candidate, currently in development at Sanofi-Aventis. In contrast to conventional drugs, FQ is the first organometallic drug: a ferrocenyl group covalently flanked by a 4-aminoquinoline and a basic alkylamine. FQ is able to overcome the CQ resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. After fifteen years of effort, it is now possible to propose a multifactorial mechanism of action of FQ by its capacity to target lipids, to inhibit the formation of hemozoin and to generate reactive oxygen species.
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