PRESENT DEVELOPMENT CONCERNING ANTIMALARIAL ACTIVITY OF PHOSPHOLIPID-METABOLISM INHIBITORS WITH SPECIAL REFERENCE TO IN-VIVO ACTIVITY

The systematic screening of more than 250 molecules against Plasmodium falciparum in vitro has previously shown that interfering with phosph olipid metabolism is lethal to the malaria parasite. These compounds a ct by impairing choline transport in infected erythrocytes, resulting in phosphatidylcholine de novo biosynthesis inhibition. A thorough stu dy was carried out with the leader compound G25, whose in vitro IC50 i s 0.6 nM. It was very specific to mature parasites (trophozoites) as d etermined in vitro with P. falciparum and in vivo with P. chabaudi-inf ected mice. This specificity corresponds to the most intense phase of phospholipid biosynthesis activity during the parasite cycle, thus cor roborating the mechanism of action. The in vivo antimalarial activity (ED50) against P. chabaudi was 0.03 mg/kg and a similar sensitivity wa s obtained with P. vinckei petteri, when the drug was intraperitoneall y administered in a 4 day suppressive test. In contrast, P. berghei wa s revealed as less sensitive (3- to 20-fold depending on the P. berghe i-strain). This difference in activity could result either from the de gree of synchronism of every strain, their invasion preference for mat ure or immature red blood cells or from an intrinsically lower sensiti vity of the P. berghei strain to G25. Irrespective of the mode of admi nistration, G25 had the same therapeutic index (lethal dose 50 (LD50)/ ED50) but the dose to obtain antimalarial activity after oral treatmen t was 100-fold higher than after intraperitoneal (or subcutaneous) adm inistration. This must be related to the low intestinal absorption of these kind of compounds. G25 succeeded to completely inhibiting parasi temia as high as 11.2% without any decrease in its therapeutic index w hen administered subcutaneously twice a day for at least 8 consecutive days to P. chabaudi-infected mice. Development of the pharmacological model has thus been fully validated with the malaria-infected-rodent model Transition to human preclinical investigations now requires a sy nthesis of molecules which would permit oral absorption.