Folate antagonists. 18. Synthesis and antimalarial effects of N6-(arylmethyl)-N6-methyl-2,4,6-pteridinetriamines and related N6,N6-disubstituted 2,4,6-pteridinetriamines.
N6-(Arylmethyl)-N6-methyl-2,4,6-pteridinetriamines (1-15) and related N6-substituted 2,4,6-pteridinetriamines (16-20) were obtained by the condensation of 6-chloro-2,4-pteridinediamine with N-methylarylmethanamine and other selected secondary amines. The requisite N-methylarylmethanamines (21-32) were prepared by the hydrogenation over Pt/C of the corresponding arylcarboxaldehyde in the presence of methanamine. Several of the N6-(arylmethyl)-N6-methyl-2,4,6-pteridinetriamines exhibited exceptional suppressive antimalarial activity against a drug-sensitive line of Plasmodium berghei in mice. N6-Methyl-N6-(1-naphthalenylmethyl)-2,4,6-pteridinetriamine (9), the most active of these compounds, was also shown to be curative at 3.16 mg/kg in a single oral dose against P. cynomolgi in the rhesus monkey. This compound was also shown to be effective against a chloroquine-resistant line of P. berghei in the mouse but showed cross-resistance to a pyrimethamine-resistant strain. Most of the 2,4,6-pteridinetriamines showed strong antibacterial action against Streptococcus faecalis and Staphylococcus aureus.
D000818:Animals; D000890:Anti-Infective Agents; D000962:Antimalarials / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000138:chemical synthesis*; D008253:Macaca mulatta; D051379:Mice; D008826:Microbial Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D011621:Pteridines / Q000138:chemical synthesis* / Q000494:pharmacology
D000890:Anti-Infective Agents; D000962:Antimalarials; D005493:Folic Acid Antagonists; D011621:Pteridines