ANTIMALARIAL ACTIVITY OF 77 PHOSPHOLIPID POLAR HEAD ANALOGS - CLOSE CORRELATION BETWEEN INHIBITION OF PHOSPHOLIPID-METABOLISM AND IN-VITRO PLASMODIUM-FALCIPARUM GROWTH

Seventy-seven potential analogs of phospholipid polar heads, choline a nd ethanolamine, were evaluated in vitro as inhibitors of Plasmodium f alciparum growth. Their IC50 ranged from 10(-3) to 10(-7) mol/L. Ten c ompounds showed similar antimalarial activity when tested against thre e different parasite strains (2 chloroquine-sensitive strains and 1 ch loroquine-resistant strain). Compounds showing marked antimalarial act ivity were assayed for their effects on phospholipid metabolism. The m ost active compounds (IC50 of 1 to 0.03 mu mol/L) were inhibitors of d e novo phosphatidylcholine (PC) biosynthesis from choline. For a serie s of 50 compounds, there was a close correlation between impairment of phospholipid biosynthesis and inhibition of in vitro malaria parasite growth. High choline concentrations caused a marked specific shift in the curves for PC biosynthesis inhibition. Concentrations inhibiting 50% PC metabolism from choline were in close agreement with the Ki of these compounds for the choline transporter in Plasmodium knowlesi-inf ected erythrocytes. By contrast, measurement of the effects of 12 of t hese compounds on rapidly dividing lymphoblastoid cells showed a total absence of correlation between parasite growth inhibition and human l ymphoblastoid cell growth inhibition. Specific antimalarial effects of choline or ethanolamine analogs are thus likely mediated by their alt eration of phospholipid metabolism. This indicates that de novo PC bio synthesis from choline is a very realistic target for new malaria chem otherapy, even against pharmacoresistant strains. (C) 1998 by The Amer ican Society of Hematology.