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 previously reported disubstituted phenyl analogues. N10-Methylation generally resulted in a marginal increase in potency against both pcDHFR and tgDHFR. Compounds 5, 7, and 9 were evaluated and shown to inhibit the growth of T. gondii cells in culture at nanomolar concentrations. Compounds 6-8, 9, 11, and 16 were selected by the National Cancer Institute for evaluation in an in vitro preclinical antitumor screening program. All six compounds showed GI50 values in the 10(-7)-10(-9) M range in more than 20 cell lines.
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
A
A
Gangjee
O
O
Adair
S F
SF
Queener
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D011010:Pneumocystis / Q000201:enzymology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D014122:Toxoplasma / Q000187:drug effects / Q000201:enzymology*; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase