Antimalarial activity of novel arylene bis(methylketone) compounds

Because of the spread of drug-resistant Plasmodium species, there is an urgent need for novel effective antimalarial agents. A series of arylene bis(methylketone) compounds were screened in vitro against a number of Plasmodium falciparum clones and in vivo against Plasmodium berghei. 2-amino-4-(3,5-diacetylphenyl)amino-1,6-dimethylpyrimidinium chloride (Cytokine Network Inc. [CNI]-H0294) was the most effective of the compounds in vitro, with an IC50 of 1.5-4.0 microM against parasite clones with a wide range of sensitivities to chloroquine and pyrimethamine. Other compounds in the series had in vitro IC50 values of 20-25 microM. In a 4-day test for suppression of P. berghei parasitemia in vivo, 50 mg/kg/day CNI-H0294 significantly decreased parasitemia by >90%. The compound was found to have low toxicity in mice, with an LD50 of 590 +/- 66 mg/kg intraperitoneally, and rapid plasma kinetics. These results show that CNI-H0294 has considerable antimalarial activity and merits further study.