N9-substituted 2,4-diaminoquinazolines

Synthesis and biological evaluation of lipophilic inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase

Aleem Gangjee, Ona O. Adair, Michelle Pagley, Sherry Queener

Research output: Contribution to journalArticle

33 Citations (Scopus)

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-CH3 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.

Original languageEnglish
Pages (from-to)6195-6200
Number of pages6
JournalJournal of Medicinal Chemistry
Volume51
Issue number19
DOIs
StatePublished - Oct 9 2008

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Pneumocystis carinii
Tetrahydrofolate Dehydrogenase
Toxoplasma
Benzaldehydes
Quinazolines
Amination
Alkylation
Nickel
Inhibitory Concentration 50
2,4-diaminoquinazoline

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

N9-substituted 2,4-diaminoquinazolines : Synthesis and biological evaluation of lipophilic inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. / Gangjee, Aleem; Adair, Ona O.; Pagley, Michelle; Queener, Sherry.

In: Journal of Medicinal Chemistry, Vol. 51, No. 19, 09.10.2008, p. 6195-6200.

Research output: Contribution to journalArticle

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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-CH3 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.",
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T2 - Synthesis and biological evaluation of lipophilic inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase

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