7-Methyl trimethoprim analogues as inhibitors of the folate metabolizing enzymes

Aleem Gangjee, Xin Lin, Sherry F. Queener

Research output: Contribution to journalArticle

4 Scopus citations


A series of 5-(1-phenylethyl)pyrimidines 2-10 (Table I) were designed and synthesized as potent and selective inhibitors of Pneumocystis carinii (P. carinii), Toxoplasma gondii (T. gondii) and Mycobacterium avium (M. avium) dihydrofolate reductases (DHFR). The structure of 2-10 incorporates a 7-methyl group to increase the potency of monocyclic trimethoprim (TMP). The target compounds were synthesized by an acid catalyzed condensation of ethyl cyanoacetate and appropriately substituted benzaldehydes followed by a Michael addition using methyl copper-lithium. The resulting adduct was cyclocondensed with guanidine to afford 2,6-diamino-4-hydroxy-5-(1-phenylethyl)pyrimidines 2-7. Both amino moieties of 2-4 were protected with pivaloyl groups and their 4-hydroxy group chlorinated with phosphorus oxychloride. The resulting intermediates were subjected to hydrogenation and deprotection to afford 8-10. Compound 7 was a good inhibitor of DHFR, however the other compounds were poor inhibitors of P. carinii, T. gondii and M. avium DHFR.

Original languageEnglish (US)
Pages (from-to)507-512
Number of pages6
JournalJournal of Heterocyclic Chemistry
Issue number3
StatePublished - Jan 1 2003

ASJC Scopus subject areas

  • Organic Chemistry

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