Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents: synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl] pyrido[2,3-d]pyrimidines.

Thirteen 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl]pyrido[2,3-d]pyrimidines 5−17 were synthesized as potential Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR) inhibitors and as antitumor agents. Compounds 5−17 were designed to investigate the structure−activity relationship of monomethoxy and monohalide substitution in the phenyl ring and N10-methylation of the C9−N10 bridge. The synthetic route to compounds 5−12 involved the reductive amination of a common intermediate, 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile (18), with the appropriate anilines. N10-Methylation was achieved by reductive methylation. In contrast to previous reports of trimethoprim, the removal of methoxy and chloro groups from the phenyl ring in the 2,4-diamino-5-methyl-6-[(substituted anilino)methyl]pyrido[2,3-d]pyrimidine series generally did not decrease DHFR inhibitory activity. The monosubstituted phenyl analogues 5−12 were as potent against pcDHFR and tgDHFR as the...