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Antimalarial Activity of 77 Phospholipid Polar Head Analogs: Close
Correlation Between Inhibition of Phospholipid Metabolism and In
Vitro Plasmodium Falciparum Growth
Marie L. Ancelin,
Michèle Calas,
Jacques Bompart,
Gérard Cordina,
Dominique Martin,
Mohammed Ben Bari,
Taïb Jei,
Pierre Druilhe, and
Henri J. Vial
From CNRS UMR 5539, Department of Biologie-Santé, Montpellier,
France; the Laboratoire des Aminoacides, Peptides et protéines,
CNRS UMR, 5810, Montpellier, France; the Laboratoire de Chimie
Organique Pharmaceutique, Faculté de Pharmacie, Montpellier,
France; the Département de Chimie, Faculté des Sciences Ben
M'Sik, Casablanca, Morocco; and the Laboratoire de Parasitologie
Bio-Médicale, Institut Pasteur, Paris, France.
Seventy-seven potential analogs of phospholipid polar heads, choline
and ethanolamine, were evaluated in vitro as inhibitors of
Plasmodium falciparum growth. Their IC50 ranged
from 10 3 to 107 mol/L. Ten compounds
showed similar antimalarial activity when tested against three
different parasite strains (2 chloroquine-sensitive strains and 1 chloroquine-resistant strain). Compounds showing marked antimalarial
activity were assayed for their effects on phospholipid metabolism. The
most active compounds (IC50 of 1 to 0.03 µmol/L) were
inhibitors of de novo phosphatidylcholine (PC) biosynthesis from
choline. For a series 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-infected erythrocytes. By contrast,
measurement of the effects of 12 of these compounds on rapidly dividing
lymphoblastoid cells showed a total absence of correlation between
parasite growth inhibition and human lymphoblastoid cell growth
inhibition. Specific antimalarial effects of choline or ethanolamine
analogs are thus likely mediated by their alteration of phospholipid
metabolism. This indicates that de novo PC biosynthesis from choline is
a very realistic target for new malaria chemotherapy, even against pharmacoresistant strains.
Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1426-1437
© 1998 by The American Society of Hematology.
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