Antimalarial versus cytotoxic properties of dual drugs derived from 4-aminoquinolines and Mannich bases: interaction with DNA.

The synthesis and biological evaluation of new organic and organometallic dual drugs designed as potential antimalarial agents are reported. A series of 4-aminoquinoline-based Mannich bases with variations in the aliphatic amino side chain were prepared via a three-steps synthesis. These compounds were also tested against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falciparum and assayed for their ability to inhibit the formation of beta-hematin in vitro using a colorimetric beta-hematin inhibition assay.

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.

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.

Probing the role of the covalent linkage of ferrocene into a chloroquine template.

A new therapeutic approach to malaria led to the discovery of ferroquine (FQ, SR97276). To assess the importance of the linkage of the ferrocenyl group to a 4-aminoquinoline scaffold, two series of 4-aminoquinolines, structurally related to FQ, were synthesized. Evaluation of antimalarial activity, physicochemical parameters, and the beta-hematin inhibition property indicate that the ferrocene moiety has to be covalently flanked by a 4-aminoquinoline and an alkylamine.

Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities.

Three ferroquine (FQ) derivatives, closely mimicking the antimalarial drug hydroxychloroquine (HCQ), have been prepared. Whereas these organometallic compounds provide the expected reduced cytotoxic effects compared to FQ, they inhibit in vitro growth of Plasmodium falciparum far better than chloroquine (CQ). Moreover, this new class of bioorganometallic compounds exert antiviral effects with some selectivity toward SARS-CoV infection.