Résumé
The increasing polypharmacoresistance of malarial parasites to the conventional antimalarial agents makes very acute the need for novel drugs, since, today, none of them can offer protection against malaria in all regions of the world. Drug development efforts generally aim for compounds that work through new, independent mechanisms of action and that are structurally unrelated to existing antimalarial agents. From this perspective, thorough biological and biochemical studies of the parasite could lead to the discovery of a specific target that could be used in the design of original compounds capable of exterminating the parasite without injuring the host.
Phospholipid biosynthesis in Plasmodium is of a crucial importance considering the high degree of membrane biogenesis. Phospholipid metabolism developed by Plasmodium during its intraerythrocytic cycle is essential and constitutes an original pharmacological target. The most promising interference is the blockage of the choline transporter protein, which provides Plasmodium with a precursor for the synthesis of phosphatidylcholine, the major phospholipid of infected erythrocytes.
The two first generations of active lead compounds consisted of quaternary ammonium salts and amidine compounds. The most prominent characteristics of these new molecules are: potent in vitro antimalarial activity against resistant P. falciparum strains and isolates, similar in vitro and in vivo activity against P. vivax, absence of in vitro resistance induction under long term drug pressure, in vivo activity against various murine species and P. falciparum-infected Aotus monkeys even at very high parasitemia and without recrudescence, absence of genotoxicity.
Although tolerance was improved with the second generation of compounds, their intestinal absorption remained low. We thus initiated an original strategy to design neutral prodrugs which require biotransformation once in the seric compartment prior (i.e. after passing through the intestinal barrier) to confer antimalarial activity. These prodrugs showed the same high in vitro antimalarial activity (nM), tolerance (LD(50)ip increased by 100-250 compared to cationic drug) and high relative absorption (improved by 10-15-fold compared to cationic drug). The antimalarial activity of the compounds is very satisfactory, and all these considerations mean that the approach is now quite realistic. Globally, this pharmacological approach is novel and should allow the design of candidates for initiating preclinical studies.