STUDIES ON THE MECHANISM OF ANTIMALARIAL ACTION OF A NOVEL ARYLENE BIS(METHYLKETONE)

(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium chloride (CNI-H0294 ) is a novel arylene bis(methylketone) compound that displays antimala rial activity against chloroquine-and pyrimethamine-resistant Plasmodi um falciparum clones. The compound has been found to be concentrated i nto infected erythrocytes, with 80-179 mu M accumulated when parasites were cultured in the presence of 1.0 mu M CNI-H0294. Uninfected eryth rocytes, in contrast,only accumulated 2.5-3.4 mu M CNI-H0294 under ide ntical conditions. Using postmitochondrial supernatants from a number oi parasite clones, the compound was found to inhibit dihydrofolate re ductase (EC 1.5.1.3) activity with an IC50 of 243-483 mu M. Thus, whil e CNI-H0294 is not a powerful inhibitor of plasmodial dihydrofolate re ductase, the accumulation of the compound into infected erythrocytes, when correlated to the external ED50 concentration against parasite gr owth in vitro, reaches concentrations sufficient to inhibit the malari al enzyme. (C) 1997 Elsevier Science Inc.