In vitro activities of 2,4-diaminoquinazoline and 2,4-diaminopteridine derivatives against Plasmodium falciparum.
The activities of 28 6-substituted 2,4-diaminoquinazolines, 2,4-diamino-5,6,7,8-tetrahydroquinazolines, and 2,4-diaminopteridines against Plasmodium falciparum were tested. The 50% inhibitory concentrations (IC(50)s) of six compounds were <50 nM, and the most potent compound was 2,4-diamino-5-chloro-6-[N-(2,5-dimethoxybenzyl)amino]quinazoline (compound 1), with an IC(50) of 9 nM. The activity of compound 1 was potentiated by the dihydropteroate synthase inhibitor dapsone, an indication that these compounds are inhibitors of dihydrofolate reductase. Further studies are warranted to assess the therapeutic potential of this combination in vivo.
Ommeh
Sheila
S
Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Wellcome Trust Research Laboratories, P.O. Box 43640 GPO, 00100 Nairobi, Kenya. anzila@wtnairobi.mimcom.net
Nduati
Eunice
E
Mberu
Eddy
E
Kokwaro
Gilbert
G
Marsh
Kevin
K
Rosowsky
Andre
A
Nzila
Alexis
A
D000818:Animals; D000962:Antimalarials; D003622:Dapsone / Q000494:pharmacology; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011621:Pteridines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
C115021:2,4-diaminopteridine; D000962:Antimalarials; D005493:Folic Acid Antagonists; D011621:Pteridines; D011799:Quinazolines; C013474:2,4-diaminoquinazoline; D003622:Dapsone; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase