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

Aleem Gangjee, Ona Adair, Sherry F. Queener

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2447-2455
Number of pages9
JournalJournal of Medicinal Chemistry
Volume42
Issue number13
DOIs
StatePublished - Jul 1 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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