title: In vitro activities of 2,4-diaminoquinazoline and 2,4-diaminopteridine derivatives against Plasmodium falciparum.
abstract: 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.
authors.affiliation: 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
authors.forename: Sheila
authors.initials: S
authors.lastname: Ommeh
authors.forename: Eunice
authors.initials: E
authors.lastname: Nduati
authors.forename: Eddy
authors.initials: E
authors.lastname: Mberu
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kokwaro
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Andre
authors.initials: A
authors.lastname: Rosowsky
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
mesh_terms: 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*
chemical_list: 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