Gangjee Aleem, Adair Ona O, Pagley Michelle, Queener Sherry F
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
J Med Chem. 2008 Oct 9;51(19):6195-200. doi: 10.1021/jm800694g. Epub 2008 Sep 5.
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.
合成了N9-取代的2,4-二氨基喹唑啉,并将其作为卡氏肺孢子虫(pc)和刚地弓形虫(tg)二氢叶酸还原酶(DHFR)的抑制剂进行评估。用雷尼镍还原市售的2,4-二氨基-6-硝基喹唑啉14得到2,4,6-三氨基喹唑啉15。15与适当的苯甲醛或萘甲醛进行还原胺化反应,然后进行N9-烷基化反应,得到目标化合物5-13。在2,5-二甲氧基苄基氨基取代的喹唑啉类似物中,用8的N9-C2H5基团取代4的N9-CH3基团,分别使对pcDHFR和tgDHFR的效力提高了9倍和8倍。N9-C2H5取代的化合物8具有高效力,对pcDHFR和tgDHFR的IC50值分别为9.9和3.7 nM。N9-丙基和N9-环丙基甲基取代并没有使效力进一步提高。该研究表明,对于2,4-二氨基喹唑啉,N9-乙基取代对于抑制pcDHFR和tgDHFR的活性是最佳的。选择性不受N9取代的影响。