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

Aleem Gangjee, Xin Lin, Sherry Queener

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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
Pages (from-to)507-512
Number of pages6
JournalJournal of Heterocyclic Chemistry
Volume40
Issue number3
StatePublished - May 2003

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Pyrimidines
Tetrahydrofolate Dehydrogenase
Trimethoprim
Folic Acid
Benzaldehydes
Folic Acid Antagonists
Guanidine
Enzymes
Lithium
Hydrogenation
Copper
Condensation
Acids
phosphoryl chloride
ethyl cyanoacetate

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

7-Methyl trimethoprim analogues as inhibitors of the folate metabolizing enzymes. / Gangjee, Aleem; Lin, Xin; Queener, Sherry.

In: Journal of Heterocyclic Chemistry, Vol. 40, No. 3, 05.2003, p. 507-512.

Research output: Contribution to journalArticle

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