Synthesis of 2, 4-diaminopyrido[2, 3-d]pyrimidines and 2, 4-diamino-quinazolines with bulky dibenz[b, f]azepine and dibenzo[a, d]-cycloheptene substituents at the 6-position as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium

Andre Rosowsky, Hongning Fu, Sherry F. Queener

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The synthesis of four previously undescribed 2, 4-diaminopyrido[2, 3-d]pyrimidines (3, 4) and 2, 4-diaminoquinazolines (5, 6) with a bulky tricyclic aromatic group at the 6-position is described. Condensation of dibenz[b, f]azepine with 2, 4-diamino-6-bromomethylpyrido[2, 3-d]pyrimidine (8) and 2, 4-diamino-6-bromomethylquinazoline (17) in the presence of sodium hydride afforded N-[(2, 4-diaminopyrido[2, 3-d]-pyrimidin-6-yl)methyl]dibenz[b, f]azepine (3) and N-[(2, 4-diaminoquinazolin-6-yl)methyl]dibenz[b, f]-azepine (4), respectively. Condensation of 5-chlorodibenzo[a, d]cycloheptene (19) and 5-chloro-10, 11-dihydrodibenzo[a, d]cycloheptene (20) with 2, 4, 6-triaminoquinazoline (13) afforded 5-[(2, 4-diamino-quinazolin-6-yl)amino]-5H-dibenzo[a, d]cycloheptene (5) and the corresponding 10, 11-dihydro derivative (6), respectively. The bromides 8 and 17, as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three-step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3-6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liven Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC50 values in the 0.03-0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was <10-fold, whereas the recently reported lead compound in this series, N-[(2, 4-diaminopteridin-6-yl)methyl]dibenz[b, f]azepine (1) has >100-fold selectivity for the T. gondii and M. avium enzyme and 21-fold selectivity for the P. carinii enzyme.

Original languageEnglish (US)
Pages (from-to)921-926
Number of pages6
JournalJournal of Heterocyclic Chemistry
Issue number4
StatePublished - Jan 1 2000


ASJC Scopus subject areas

  • Organic Chemistry

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