Molecular Pharmacology, Vol 18, 320-325, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Antimalarial Activity of Selected Aromatic Chelators

¹ Laboratory of Parasitology, The Rockefeller University, New York, New York 10021

Disulfiram and its physiological reduction product diethyldithiocarbamate have been shown to inhibit the growth of the human malaria parasite Plasmodium falciparum in vitro. It has been suggested that activity of these agents against malaria depends on at least two factors: (1) inhibition of metalloprotein oxidases and (2) chelation by agents with favorable lipid/water partition coefficients (lipophilic) and favorable binding constants. The aromatic chelators 8-hydroxyqumoline and 2-mercaptopyridine-N-oxide possess these characteristics and also exhibit active antimalarial effects in vitro at concentrations to 6.89 x 10^-10 and 7.86 x 10^-10 M, respectively, the lowest level tested. On the other hand, either the introduction of a methyl group in the number 2 position of 8-hydroxyquinoline or the movement of the hydroxyl group to the 5 position impairs the chelating ability of this compound and, correspondingly, reduces toxicity to the parasite. Approximately 6.28 x 10^-6 M 2-methyl-8-hydroxyquinoline and 6.89 x 10^-5 M 5-hydroxyquinoline were required to achieve the same inhibition as 6.89 x 10^-9 M 8-hydroxyquinoline. This suggests that formation of the ligand-metal complex by these chelating agents is associated with their antimalarial activity. In addition, 8-hydroxyquinoline at a level as low as 6.89 x 10^-6 M inhibited parasite glycolysis with no statistically significant effect on the glycolysis of normal red cells. This is similar to effects of disulfiram reported previously.

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ACKNOWLEDGMENTS The authors wish to thank Dr. Ernest Bueding for suggestions made during the preparation of the manuscript and Dr. Joel Cohen for statistical interpretation of the data. We would also like to acknowledge Dr. William Trager for his support.