Parallel inhibition of amino acid efflux and growth of erythrocytic Plasmodium falciparum by mefloquine and non-piperidine analogs: Implication for the mechanism of antimalarial action

[Display omitted] Despite the troubling psychiatric side-effects it causes in some patients, mefloquine (MQ) has been used for malaria prophylaxis and therapy, due to its activity against all Plasmodium species, its ease of dosing, and its relative safety in children and pregnant women. Yet at prese...

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Published in:Bioorganic & medicinal chemistry letters 2016-10, Vol.26 (19), p.4846-4850
Main Authors: Ghavami, Maryam, Dapper, Christie H., Dalal, Seema, Holzschneider, Kristina, Klemba, Michael, Carlier, Paul R.
Format: Article
Language:English
Subjects:
Animals
Antimalarials - pharmacology
Endocytosis
Growth inhibition
Inhibitory Concentration 50
Malaria
Mefloquine
Mefloquine - pharmacology
Plasmodium falciparum
Plasmodium falciparum - drug effects
Plasmodium falciparum - growth & development
Plasmodium falciparum - metabolism
Quinoline methanol
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Summary:[Display omitted] Despite the troubling psychiatric side-effects it causes in some patients, mefloquine (MQ) has been used for malaria prophylaxis and therapy, due to its activity against all Plasmodium species, its ease of dosing, and its relative safety in children and pregnant women. Yet at present there is no consensus on the mechanism of antimalarial action of MQ. Two leading hypotheses for the mechanism of MQ are inhibition of heme crystallization and inhibition of host cell hemoglobin endocytosis. In this report we show that MQ is a potent and rapid inhibitor of amino acid efflux from intact parasitized erythrocytes, which is a measure of the in vivo rate of host hemoglobin endocytosis and catabolism. To further explore the mechanism of action of MQ, we have compared the effects of MQ and 18 non-piperidine analogs on amino acid efflux and parasite growth. Among these closely related compounds, an excellent correlation over nearly 4 log units is seen for 50% inhibition concentration (IC50) values for parasite growth and leucine efflux. These data and other observations are consistent with the hypothesis that the antimalarial action of these compounds derives from inhibition of hemoglobin endocytosis.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.08.005