Eric Buisine

The antimalarial ferroquine: role of the metal and intramolecular hydrogen bond in activity and resistance.

Inhibition of hemozoin biocrystallization is considered the main mechanism of action of 4-aminoquinoline antimalarials including chloroquine (CQ) but cannot fully explain the activity of ferroquine (FQ) which has been related to redox properties and intramolecular hydrogen bonding. Analogues of FQ, methylferroquine (Me-FQ), ruthenoquine (RQ), and methylruthenoquine (Me-RQ), were prepared. Combination of physicochemical and molecular modeling methods showed that FQ and RQ favor intramolecular hydrogen bonding between the 4-aminoquinoline NH group and the terminal amino group in the absence of water, suggesting that this structure may enhance its passage through the membrane. This was further supported by the use of Me-FQ and Me-RQ where the intramolecular hydrogen bond cannot be formed. Docking studies suggest that FQ can interact specifically with the {0,0,1} and {1,0,0} faces of hemozoin, blocking crystal growth. With respect to the structure-activity relationship, the antimalarial activity on 15 different P. falciparum strains showed that the activity of FQ and RQ were correlated with each other but not with CQ, confirming lack of cross resistance. Conversely, Me-FQ and Me-RQ showed significant cross-resistance with CQ. Mutations or copy number of pfcrt, pfmrp, pfmdr1, pfmdr2, or pfnhe-1 did not exhibit significant correlations with the IC(50) of FQ or RQ. We next showed that FQ and Me-FQ were able to generate hydroxyl radicals, whereas RQ and me-RQ did not. Ultrastructural studies revealed that FQ and Me-FQ but not RQ or Me-RQ break down the parasite digestive vacuole membrane, which could be related to the ability of the former to generate hydroxyl radicals.

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.

2-Amino diphenylsulfides as inhibitors of trypanothione reductase: modification of the side chain

A molecular modeling study meant to detect pharmacophore-like patterns in the active site of trypanothione reductase (TR) offered hints about the opportunity of synthesizing and testing diphenylsulfide derivatives with prolonged or branched polyamino side chains as putative TR inhibitors. The inhibition results within the synthesized series confirmed the main working hypothesis inspired by the molecular modeling study. The different compounds were tested in vitro on the enzyme and on Trypanosoma cruzi and Trypanosoma brucei trypomastigotes as well as in vivo in infected mice.

Design and synthesis of new leads for PKC bisubstrate inhibitors.

Abstract In order to obtain selective protein kinase C (PKC) inhibitors competitive toward ATP, an efficient synthetic process of a series of monoindolylmaleimide derivatives was achieved. As expected from the PKC/PKA homology, the PKC selectivity was promoted by addition of amine chains on the maleimide ring. The most active derivative could be used as starting molecule for the preparation of specific PKC isotype inhibitors according to the bisubstrate concept.