N9-Substituted 24-Diaminoquinazolines: Synthesis and Biological Evaluation of Lipophilic Inhibitors of Pneumocystis carinii and Toxoplasma gondii Dihydrofolate Reductase

摘要

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.