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.
Berger
B J
BJ
Picower Institute for Medical Research, Manhasset, New York 11030, USA.
Paciorkowski
A
A
Suskin
M
M
Dai
W W
WW
Cerami
A
A
Ulrich
P
P
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D005260:Female; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011739:Pyrimethamine / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*
D000962:Antimalarials; C097286:H 0294; D011743:Pyrimidines; D002738:Chloroquine; D011739:Pyrimethamine