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

• Published in: Biochemical pharmacology 1997-09, Vol.54 (6), p.739-742
• Main Authors: Berger, Bradley J, Dai, Wei Wei, Cerami, Anthony, Ulrich, Peter
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - pharmacology; Antiparasitic agents; arylene bis(methylketone)s; Biological and medical sciences; dihydrofolate reductase; drug accumulation; Enzyme Inhibitors - pharmacology; Erythrocytes - drug effects; Erythrocytes - parasitology; Folic Acid Antagonists - pharmacology; malaria; Medical sciences; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Pyrimidines - pharmacology; Tetrahydrofolate Dehydrogenase - drug effects
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00255-4

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 IC 50 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 ED 50 concentration against parasite growth in vitro, reaches concentrations sufficient to inhibit the malarial enzyme.