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[摘要]：N9-substituted 2,4-diaminoquinazolines were synthesized and evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). Redn. of com. available 2,4-diamino-6-nitroquinazoline with Raney nickel afforded 2,4,6-triaminoquinazoline. Reductive amination of the latter with the appropriate benzaldehydes or naphthaldehydes, followed by N9-alkylation, afforded the target compds. In the 2,5-dimethoxybenzylamino substituted quinazoline analogs, replacement of the N9-CH3 group with the N9-C2H5 group resulted in a 9- and 8-fold increase in potency against pcDHFR and tgDHFR, resp. The N9-C2H5 substituted compd. was highly potent, with IC50 values of 9.9 and 3.7 nM against pcDHFR and tgDHFR, resp. N9-Pr and N9-cyclopropyl Me substitutions did not afford further increases in potency. This study indicates that the N9-Et 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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