PLASMODIUM PHOSPHOLIPID-METABOLISM - A TARGET FOR THE DEVELOPMENT OF NOVEL ANTIMALARIAL-DRUGS

A programme for developing new drugs for the treatment of Plasmodium f alciparum malaria is targeted against the essential phospholipid metab olism of the intra-erythrocytic stages of the parasite. Blockage of th e choline transporter that provides the intracellular parasite with ch oline, a precursor required for synthesis of phosphatidylcholine, the major phospholipid of the parasite, seems to hold the most promise. Mo lecules with the ability to interfere with this step, whose structures have been optimised using structure-activity criteria, have been synt hesised. The antimalarial activity of the compounds produced so far, w hich have in-vitro activities in the ng/ml or nanomolar ranges, appear s satisfactory. The present compounds are also active, in vitro, again st parasites resistant to the antimalarial drugs already in clinical u se. In vivo, one of the compounds, G25, successfully cleared high para sitaemias of murine parasites in mice and of P. falciparum in Aotus mo nkeys. There were no recrudescences in the treated monkeys and the the rapeutic index of the drug in monkeys is probably > 50. Targeting of p hospholipid metabolism therefore appears to be a rational and promisin g approach to the development of new antimalarial drugs.