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Antimalarials are at the origin of PALUMED

PALUMED takes roots from the research group led by Dr Bernard Meunier at the Laboratoire de Chimie de Coordination of the CNRS in Toulouse. This team is specialized in studies related to the oxidation mechanisms in chemistry and biochemistry.

In 1996, Bernard Meunier and Anne Robert became interested into the mechanism of action of artemisinin derivatives. This class of antimalarial molecules contain an endoperoxide function that is homolytically cleaved by free heme that results from the digestion of hemoglobin by the parasite. That reductive activation of the endoperoxide bridge by the Fe(II) heme gives an alkoxyl radical that generata C4-alkyl radical which is able to alkylate free heme in vitro and in vivo (in infected mice). This work led to several publications in international journals (Journal of the American Chemical Society in 1997, Accounts of Chemical Research in 2002 and the Proceedings of the National Academy sciences of the USA in 2005).

Remember: the extract of leaves of Artemisia annua have been used for centuries in traditional Chinese medicine to treat malaria. The therapeutic activity is related to the endoperoxide function. Artemisinin is the paradigm for the preparation of trioxane-containing antimalarial agents.

TRIOXAQUINES® : new antimalarial drugs

These hybrid (or chimeric) molecules have the free heme as main target within infected red bood cells. These molecules combine two active pharmacophores: a trioxane motif designed to be a potential alkylating agent for the heme and/or proteins of the Plasmodium parasite, and an aminoquinoline moiety which has been selected to facilitate a good accumulation in the parasite and for the interaction with free heme.

Such bimodal molecules combine the penetrative capacity of the 4-aminoquinoline moiety toward infected erythrocytes, with the alkylating properties of the trioxane residue, both pharmacophores being lethal for the parasite. These molecules are highly active both on chloroquine-sensitive and chloroquine-resistant strains.

A covalent link allows a synergistic effect between the two active fragments of these hybrid molecules. In addition, this linkage synchronizes the bio-availability of the two active moieties, thus avoiding problems due to different pharmacokinetics that are frequently encountered for simple drug combinations.

This "twin-barreled gun" (or “double-edge sword”) strategy should avoid the emergence of resistant strains. Essentially the approach is poly-chemotherapy with a single molecule: such a concept has hot been previously developed for the treatment of malaria (B. Meunier, Acc. Chem. Res., 2008).

Trioxaquines®: from patents to drug-candidate

The synthesis of several trioxaquines and the first results on their biological activities against chloroquine-resistant strains of P. falciparum have been at the origin of the French patent application filed by CNRS in April 2000 (inventors: Odile Dechy-Cabaret, Françoise Benoit-Vical, Anne Robert and Bernard Meunier, US patent number 6,949,569 B2, sept.27, 2005). All these first-generation trioxaquines are more active than chloroquine on both sensitive- and resistant-strains of Plasmodium falciparum.

The efficacy of trioxaquines is far above the activity of both separate quinoline-amine and trioxane-ketone fragments, indicating a real synergistic effect of both entities within these hybrid molecules. Second-generation trioxaquines are also highly active on chloroquino-resistant strains of parasites (O. Dechy-Cabaret et al., ChemBioChem, 2004; F. Benoit-Vival et al., Antimicrob. Agents Chemother., 2007).

A third generation (with a simplified trioxane) are also curative by oral route at 25-30 mg/kg/day (4-day treatment) on mice infected by chloroquino-resistant strains (Patent application by PALUMED/Sanofi-aventis/CNRS, November 2003 and June 2006). More than 100 trioxaquines have been prpepared and evaluated in vitro between 2003 and 2006. 77 of them have been evaluated in vivo on mice and finally 6 have been selected for a multi-parametric evaluation to choose one drug-candidate, PA1103 (F. Coslédan et al., PNAS, 2008, accepted for publication).

Since January 2007, the trioxaquine PA1103 (SAR116242) has been selected for pre-clinical development with Sanofi-Aventis. Due to restructuration of Sanofi, the development of PA1103 has been stopped in 2010

Trioxaquines : active molecules against schistosomiases (= bilharzioses)

Trioxaquines are also active at low concentrations against schistosomes that are responsible for schistosomiases (French patent application, December 2007). The activity of these trioxaquines is complementary to that of praziquantel (the only active drug currently used in endemic zones) and will make possible a biotherapy for this tropical disease that concerns 200 to 300 million persons per year and causes more than 300,000 deaths/year (WHO source). This research is performed in collaboration with the team of Jérôme Boissier of the Laboratory of Tropical Biology and Ecology of the University of Perpignan and with Anne Robert of the Laboratory of Coordination Chemistry of CNRS in Toulouse. This program is financially supported by the ANR (“Agence Nationale de la Recherche”) for the period 2009-2010.