One-step synthesis of novel 2,4-diaminopyrimidine antifolates from bridged alicyclic ketones and cyanoguanidine

Andre Rosowsky, Andrew T. Papoulis, Sherry F. Queener

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

A convenient one-step reaction with cyanoguanidine was used to convert alicyclic ketones to previously undescribed 2,4-diamino-5,6,7,8- tetrahydroquinazolines with a one-, two-, or three-carbon bridge in the carbocyclic ring. Although the yields of the desired products were modest, the principal advantage of this one-step process was that it provided easy access to a variety of novel bridged heterocyclic ring systems whose synthesis from sterically hindered ketones by other methods would have required multiple steps with an even lower overall yield. The products were tested as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and rat liver with a view to examining the effect of a space-filling bridge on binding. The most potent and selective compound in the group was 4,6-diamino-3,5-diazatricyclo[7.2.1.02.7]dodeca-2,4,6- triene (13), whose potency and selectivity approached those of trimethoprim, a drug commonly used to treat P. carinii and T. gondii infection. 3,5- Diamino-4,6-diazatricyclo[6.2.1.02.7]undeca-2,4,6-triene (14), the analog of 13 with a one-carbon rather than a two-carbon bridge showed similar potency and selectivity against the T. gondii enzyme, but was a weak and nonselective inhibitor of P carinii dihydrofolate reductase. The other compounds tested were likewise weak and nonselective.

Original languageEnglish (US)
Pages (from-to)723-728
Number of pages6
JournalJournal of Heterocyclic Chemistry
Volume36
Issue number3
DOIs
StatePublished - Jan 1 1999

    Fingerprint

ASJC Scopus subject areas

  • Organic Chemistry

Cite this