Present development concerning antimalarial activity of phospholipid metabolism inhibitors with special reference to in vivo activity

Abstract

The systematic screening of more than 250 molecules against Plasmodium falciparum in vitro has previously shown that interfering with phospholipid metabolism is lethal to the malaria parasite. These compounds act by impairing choline transport in infected erythrocytes, resulting in phosphatidylcholine de novo biosynthesis inhibition. A thorough study was carried out with the leader compound G25, whose in vitro IC50 is 0.6 nM. It was very specific to mature parasites (trophozoïtes) as determined in vitro with P. falciparum and in vivo with P. chabaudi -infected mice. This specificity corresponds to the most intense phase of phospholipid biosynthesis activity during the parasite cycle, thus corroborating the mechanism of action. The in vivo antimalarial activity (ED50) against P. chabaudi was 0.03 mg/kg, and a similar sensitivity was obtained with P. vinckei petteri, when the drug was intraperitoneally administered in a 4 day suppressive test. In contrast, P. berghei was revealed as less sensitive (3- to 20-fold, depending on the P. berghei-strain). This difference in activity could result either from the degree of synchronism of every strain, their invasion preference for mature or immature red blood cells or from an intrinsically lower sensitivity of the P. berghei strain to G25. Irrespective of the mode of administration, G25 had the same therapeutic index (lethal dose 50 (LD50)/ED50) but the dose to obtain antimalarial activity after oral treatment was 100-fold higher than after intraperitoneal (or subcutaneous) administration. This must be related to the low intestinal absorption of these kind of compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo anti-malarial effect of the ß-amino alcohol 1t on Plasmodium berghei

“…In vivo anti-malarial activity of the compound 1t was determined against the rodent malaria P. berghei ANKA strain according to a 4-day suppressive test (Ancelin et al 1994). The experiment was performed independently twice: first with ten NMRI mice and secondly with 14 Balb/c mice.…”

“…The compound 1t was tested in mice infected with P. berghei ANKA according to a version of a 4-day suppressive test (Ancelin et al 1994). Compounds were administered i.p.…”

Crystal Structure of the Apo and the ADP-Bound Form of Choline Kinase from Plasmodium falciparum

“…One of the most striking consequences of the blood-stage parasitization is the dramatic increase of the phospholipid content, especially phosphatidylcholine (PC) and phosphatidylethanolamine (PE), inside the infected erythrocyte, which can reach up to five times its physiological level; this is a necessary requirement for the parasite membrane biosynthesis and, therefore, for its growth and replication [2,[10][11][12][13][14].…”

“…Moreover, P. falciparum plasma membrane is mainly composed by PC and PE, which represent 40-50% and 35-40% of the total phospholipid content, respectively [15]. Hence, targeting the parasite lipid metabolism for pharmacological action constitutes an effective way of dealing with the spreading of the disease and with conventional therapy-resistant strains [2,[10][11][12][13].…”