Antimalarial activity of novel arylene bis(methylketone) compounds.

Abstract

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.

• Authors: B J Berger, A Paciorkowski, M Suskin, W W Dai, A Cerami, P Ulrich
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 174 Issue 3 Pg. 659-62 (Sep 1996) ISSN: 0022-1899 [Print] United States
• PMID: 8769633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimalarials
• H 0294
• Pyrimidines
• Chloroquine
• Pyrimethamine

Topics

• Animals
• Antimalarials (pharmacology)
• Chloroquine (pharmacology)
• Female
• Malaria (drug therapy)
• Mice
• Mice, Inbred Strains
• Molecular Structure
• Plasmodium berghei (drug effects)
• Plasmodium falciparum (drug effects)
• Pyrimethamine (pharmacology)
• Pyrimidines (pharmacology)