Studies on the mechanism of antimalarial action of a novel arylene bis(methylketone).
2-Amino-4-(3,5-diacetylphenyl)amino-1,6-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 microM accumulated when parasites were cultured in the presence of 1.0 microM CNI-H0294. Uninfected erythrocytes, in contrast, only accumulated 2.5-3.4 microM 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 microM. 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.
Berger
B J
BJ
The Picower Institute for Medical Research, Manhasset, NY 11030, U.S.A. bjberger@bad.dundee.ac.uk
Dai
W W
WW
Cerami
A
A
Ulrich
P
P
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011743:Pyrimidines / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects
D000962:Antimalarials; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; C097286:H 0294; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase