Studies on the mechanism of antimalarial action of a novel arylene bis(methylketone)

Abstract

2-Amino-4-(3,5-diacetylphenyl)amino-l,6-dimethylpyrimidinium chloride (CNI-H0294) is a novel arylene bis(methylketone) compound that displays antimalarial activity against chloroquine- and pyrimethamine-resistant Plasmodium falciparum clones. The compound has been found to be concentrated into infected erythrocytes, with 80–179 μM accumulated when parasites were cultured in the presence of 1.0 μM CNI-H0294-Uninfected erythrocytes, in contrast, only accumulated 2.5–3.4 μM CNI-H0294 under identical conditions. Using postmitochondrial supernatants from a number of parasite clones, the compound was found to inhibit dihydrofolate reductase (EC 1.5.1.3) activity with an IC₅₀ of 243–483 μM. Thus, while CNI-H0294 is not a powerful inhibitor of plasmodial dihydrofolate reductase, the accumulation of the compound into infected erythrocytes, when correlated to the external ED₅₀ concentration against parasite growth in vitro, reaches concentrations sufficient to inhibit the malarial enzyme.