Synthesis of 2,4-Diamino-6-[2′-O-(ω -carboxyalkyl)oxydibenz[b,f]azepin-5-yl]-methylpteridines as Potent and Selective Inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium Dihydrofolate Reductase

Andre Rosowsky, Hongning Fu, David C.M. Chan, Sherry F. Queener

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Six previously undescribed N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepines with water-solubilizing O-carboxyalkyloxy or O-carboxybenzyloxy side chains at the 2′-position were synthesized and compared with trimethoprim (TMP) and piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic organisms known to cause significant morbidity and mortality in patients with AIDS and other disorders of the immune system. The ability of the new analogues to inhibit reduction of dihydrofolate to tetrahydrofolate by Pc, Tg, Ma, and rat DHFR was determined, and the selectivity index (SI) was calculated from the ratio IC50(rat DHFR)/IC50(Pc, Tg, or Ma DHFR). The IC50 values of the 2′-O-carboxypropyl analogue (10), with SI values in parentheses, were 1.1 nM (1300) against Pc DHFR, 9.9 nM (120) against Tg DHFR, and 2.0 nM (600) against Ma DHFR. The corresponding values for the 2′-O-(4-carboxybenzyloxy) analogue (12) were 1.0 nM (560), 22 nM (21), and 0.75 nM (630). By comparison, the IC50 and SI values for TMP were Pc, 13 000 nM (14); Tg, 2800 nM (65); and Ma, 300 nM (610). For the prototypical potent but nonselective inhibitors PTX and TMX, respectively, these values were Pc, 13 nM (0.26) and 47 nM (0.17); Tg, 4.3 nM (0.76) and 16 nM (0.50); Ma, 0.61 nM (5.4) and 1.5 nM (5.3). Thus 10 and 12 met the criterion for DHFR inhibitors that combine the high selectivity of TMP with the high potency of PTX and TMX.

Original languageEnglish (US)
Pages (from-to)2475-2485
Number of pages11
JournalJournal of Medicinal Chemistry
Volume47
Issue number10
DOIs
StatePublished - May 6 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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