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Synthesis of three carbon atom bridged 2,4‐diaminopyrrolo[2,3‐ d ]‐pyrimidines as nonclassical dihydrofolate reductase inhibitors
Author(s) -
Gangjee Aleem,
Ye Zhengqu,
Queener Sherry F.
Publication year - 2005
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570420614
Subject(s) - dihydrofolate reductase , chemistry , malononitrile , pneumocystis carinii , guanidine , carbon atom , stereochemistry , toxoplasma gondii , reductase , enzyme , organic chemistry , ring (chemistry) , catalysis , medicine , family medicine , human immunodeficiency virus (hiv) , antibody , immunology , biology , pneumocystis jirovecii
A series of seven nonclassical three carbon atom bridged 2,4‐diamino‐5‐substituted‐pyrrolo[2,3‐ d ]‐pyrirnidines 1a‐g were synthesized as potential inhibitors of dihydrofolate reductase. Selective oxidation of diols 7a‐g affords α‐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 IC 50 values in the 0.66 μM ‐ 70.1 μM range and some compounds had marginal selectivity for T. gondii dihydrofolate reductase.