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J Med Chem. 2008 Oct 9;51(19):6195-200. doi: 10.1021/jm800694g. Epub 2008 Sep 5.

N9-substituted 2,4-diaminoquinazolines: synthesis and biological evaluation of lipophilic inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase.

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1
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu

Erratum in

  • J Med Chem. 2009 Aug 13;52(15):4979.

Abstract

N9-substituted 2,4-diaminoquinazolines were synthesized and evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). Reduction of commercially available 2,4-diamino-6-nitroquinazoline 14 with Raney nickel afforded 2,4,6-triaminoquinazoline 15. Reductive amination of 15 with the appropriate benzaldehydes or naphthaldehydes, followed by N9-alkylation, afforded the target compounds 5- 13. In the 2,5-dimethoxybenzylamino substituted quinazoline analogues, replacement of the N9-CH 3 group of 4 with the N9-C2H5 group of 8 resulted in a 9- and 8-fold increase in potency against pcDHFR and tgDHFR, respectively. The N9-C2H5 substituted compound 8 was highly potent, with IC50 values of 9.9 and 3.7 nM against pcDHFR and tgDHFR, respectively. N9-propyl and N9-cyclopropyl methyl substitutions did not afford further increases in potency. This study indicates that the N9-ethyl substitution is optimum for inhibitory activity against pcDHFR and tgDHFR for the 2,4-diaminoquinazolines. Selectivity was unaffected by N9 substitution.

PMID:
18771252
PMCID:
PMC3885247
DOI:
10.1021/jm800694g
[Indexed for MEDLINE]
Free PMC Article

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