Objective The availability of new pharmacological models will make possible to select antimalarial molecules With new mechanisms of action, thus delaying resistance. The approach is hinged on fundamental research started in 1980 to investigate the phospholipid metabolism of intraerythrocytic plasmodium that is abundant and indispensable for the production of its membranes. Any drug able to interfere With this metabolism blocks parasitic development. The most effective interference involves blockage of the choline transporter which is a limiting step in de novo synthesis of phosphatidylcholine. The compounds show antimalarial in vitro activity against P. falciparum at 1-10 nM, and in vivo, in the P. berghei or P. chabaudi/mouse System, at doses 20- to 100-times lower than their acute toxicity limit. The bioavailability shows a slow blood clearance and no significant concentration in tissues. The compounds are inexpensive to produce, stable and Water-soluble. The present program aims to develop this pharmacological model as follows: 1) Biochemical studies of the pharmacological target, to find the causes of the hyperfunctioning of the choline carrier after malarial infection , morphological alterations of plasmodium induced by the drugs ;studies of' the criteria to optimize the structure of active compounds leading to lower intrinsic acute toxicity and better oral absorption 2) Synthesis of new molecules among the 3 hyperactive families With structure : activity relationships 3) To specify the antimalarial activity of the compounds in a broad spectrum of resistant strains or isolates in vitro and in vivo, and preclinical evaluation against P. falciparum in monkeys 4) Subcellular localization of radiolabelled lead compounds, and studies on their bioavailability and metabolism 5) determination on the ease by which parasites become resistant to the lead compounds in vitro and in Vivo 6) Research into the possible activities of the compounds against the non-erythrocvtic stage of plasmodium and of other potential activities 7) Toxicological Studies 8) Galenic studies of the lead compounds including ageing, oral absorption and duration of action. Programme(s) FP3-STD 3 - Specific research and technological development programme (EEC) in the field of the life sciences and technologies for developing countries, 1990-1994 Topic(s) Data not available Call for proposal Data not available Funding Scheme CSC - Cost-sharing contracts Coordinator Université de Montpellier 1 Address Place eugène bataillon 34095 Montpellier France See on map EU contribution No data Participants (6) Sort alphabetically Sort by EU Contribution Expand all Collapse all Institut National de la Santé et de la Recherche Médicale (INSERM) France EU contribution € 0,00 Address 369 rue jules guesde 59650 Villeneuve-d'ascq See on map Other funding No data London School of Hygiene and Tropical Medicine United Kingdom EU contribution € 0,00 Address Keppel street WC1E 7HT London See on map Other funding No data Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek Netherlands EU contribution € 0,00 Address 151,lange kleiweg 2280 HV Rijswijk See on map Other funding No data Organisation de Lutte Contre les Endémies en Afrique Centrale Cameroon EU contribution € 0,00 Address 10 Yaoundé See on map Other funding No data UNIVERSIDAD DEL VALLE Colombia EU contribution € 0,00 Address 0344406 Cali See on map Other funding No data Université de Montpellier II (Université des Sciences et Techniques du Languedoc) France EU contribution € 0,00 Address Place eugène bataillon 34095 Montpellier See on map Other funding No data
