Folate antagonists. 7. Antimalarial, antibacterial, and antimetabolite effects of 2,4‐Diamino‐6‐(benzyl and pyridylmethyl)‐5,6,7,8‐tetrahydropyrido[4,3‐d] pyrimidines

2 Various4-diamino-6-(benzyl and pyridyhnethyl)-5,6,7,8-tetrahydropyrido(4,3-d]pyrimidines (IX) have been synthesized for antimalarial and antibacterial evaluation. Alkylation of 4-amino-3-cyano-1,2,5,6-tetrahydropyridine (VI) with the requisite α-chlorotoluene or picolyl chloride in 2-butanone afforded the corresponding 4-amino-3-eyano-1-(benzyl and pyridvlmethyl)-1,2,5,6-tetraliydropyridines (VIII) (16–73%), which were cyclized to the pyrido[4,3-d]pyrimidines (IX) utilizing guanidine carbonate in dimethylformamide. Alternatively, VI was condensed with guanidine carbonate in ethyl cellosolve to give 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine (VII) (52%), which upon treatment with the appropriate α-ehlorotoluene in dimethyllormamide gave other 2,4-diamino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines (IX) (26–27%). Kight compounds were active orally against Plasmodium berghei in mice at doses ranging from 3.9 to 125 mg./kg./day for 6 days (0.6 to 19 times as potent as quinine hydrochloride), while three compounds displayed activity when administered in a single subcutaneous dose of 640 mg./kg. Four substances exhibited in vitro activity against Streptococcus faecalis (MGH-2), normal (UC-76) and drug-resistant (S18713) Staphylococcus aureus, and Streptococcus pyogenes ((1203), with MIC's ranging from > 0.25 to 10 μg./ml. Data on the inhibitory effects of various pyrido[4,3-d]pyrimidines against Streptococcus faecalis R (S. faecium var. durans, ATCC 8043), S. faecalis A (aminopterin, metholrexate-resistant), and Lactobacillus plantarum (ATCC 8014) is summarized.