Synthesis and study of new enantiopur antimalarial compounds – SEAPAL

Malaria, caused by protozoa of the genus Plasmodium, is transmitted to humans through bites from female Anopheles mosquitoes. Among the five species of the kind, Plasmodium falciparum is the most pathogenic one and is responsible for most of the fatalities. This specie is present in tropical zones of Africa, Latin America and Asia, and is dominant in Africa. According to the World Health Organization (WHO), more than 100 tropical and sub-tropical countries are endemic for malaria and as many as 3.3 billion people are exposed to malarial infections. Approximately, 1.24 million people die of malaria every year.In addition to people living in endemic area, the long-term travellers such as the military are affected by malaria as well.The extremely fast development of resistance phenomena to antimalarial drugs, even with the most recent ones, urges the development of new molecules.Although new families of molecules with antimalarial activity are under development, the fact that no innovating solution was marketed during these last ten years can be deplored.
For several years now, the “thera” team of the “Laboratoire des Glucides” works on the synthesis and the evaluation of anti-malarial molecules: (i) hemisynthesis of acid ursolic derivatives, (ii) synthesis of news 4-aminoquinolinols, (iii) development of routine tests to understand the molecular mechanisms of the synthesized anti-malarial molecules. Recently, we have patented the synthesis to prepare enantiopure4-aminoquinolinols with excellent antimalarial activities, which iseasily transposable to an industrial scale.
This project will be carried out through an already existing collaboration between the “Laboratoire des Glucides” (CNRS FRE 3517, UPJV, Amiens), the “Institut de MédecineTropicale du Service de Santé des Armées” (UMR-MD3, Marseilles) and the“Laboratoire de Pharmacochimie de Bordeaux” (FRE 3396-CNRS), to which will be added an industrial partner, sanofi-aventis R&D.
The realization of this project will require an important work in asymmetrical organic synthesis for the preparation of new library of compounds whose design will take into account the first structure-activity relashionship established recently. Always in the goal to reach most quickly and effectively possible these various families of molecules, two principal chemical ways (dihydroxylation of Sharpless, asymmetric hydroamination) will be studied. It should be noted that the asymmetric hydroamination that we wish to apply is an original reaction still little studied. The physicochemical properties (log P, log D, pKa) and the antiplasmodial activity of the various compounds will be given as soon as available in order to establish structure-activity relationships to optimize the design of these novel antimalarial compounds (molecular modelling support).
By using the same strategies of synthesis, the most active compounds will be coupled to a chemosensitizer to limit the emergence of resistance phenomena. Pharmacokinetic properties of each compound will be realized by our industrial partner. Molecular mechanism of the most active molecules will be studied, as well as their cytotoxicity and genotoxicity to support the emergence of new candidate drugs.

Project details

Drug-based Strategies

Dec 2012 — Dec 2015

$315,877

France