Synthesis of three carbon atom bridged 2,4-diaminopyrrolo[2,3-d]- pyrimidines as nonclassical dihydrofolate reductase inhibitors

Aleem Gangjee, Zhengqu Ye, Sherry F. Queener

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Abstract

A series of seven nonclassical three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-pyrimidines 1a-g were synthesized as potential inhibitors of dihydrofolate reductase. Selective oxidation of diols 7a-g affords oe-hydroxy ketones 8a-g. Subsequent condensation with malononitrile gave the requisite 2-amino-3-cyano-4-substituted furan precursors 9a-g. Cyclocondensation with guanidine in refluxing ethanol in one step affords the three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-pyrimidines 1a-g. Preliminary biological results indicated that these compounds showed moderate inhibitory activities against dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium and rat liver with IC50 values in the 0.66 μM - 70.1 μM range and some compounds had marginal selectivity for T. gondii dihydrofolate reductase.

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ASJC Scopus subject areas

  • Organic Chemistry

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