Design, synthesis and bioevaluation of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives as potent neuroprotective agents.
Design, synthesis and bioevaluation of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives as potent neuroprotective agents.
复制标题
DOI：
10.1016/j.ejmech.2018.03.052
复制
发表时间：
2018-05
影响因子：
6.7
通讯作者：
Linkui Zhang;Ying Zhao;Jian Wang;D. Yang;Chenwen Zhao;Changli Wang;Chao Ma;M. Cheng
中科院分区：
文献类型：
--
作者：
Linkui Zhang;Ying Zhao;Jian Wang;D. Yang;Chenwen Zhao;Changli Wang;Chao Ma;M. Cheng
设计、合成了多种1,2,3,9-四氢吡咯[2,1-b]喹唑啉-1-羧酸衍生物，并对其体外抗nmda诱导的细胞毒性的神经保护活性进行了评价，结果表明5q具有良好的神经保护活性。选择化合物5q进行进一步研究。我们发现5q能减弱NMDA诱导的Ca2+内流，同时5q能抑制NR2B上调，增加- erk1 /2表达。分子对接结果表明，5q5可以很好地融入到4的结合口袋中，并同时与1的结合口袋中的一些关键残基相互作用。此外，5q表现出可接受的代谢稳定性。这些结果表明，5q是进一步开发新的有效的口服生物可利用的nr2b选择性NMDAR拮抗剂的有希望的先导物。
Diverse of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed, synthesized and evaluated for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, and5qexhibited excellent neuroprotective activity. The compound5qwas selected for further investigation. We found that5qcould attenuate Ca2+influx induced by NMDA, meanwhile,5qcould suppress the NR2B up-regulation and increasep-ERK1/2 expression. The molecular docking results showed that5qmight fit well in the binding pocket of4and interact with some key residues in the binding pocket of1simultaneously. Besides,5qexhibited acceptable metabolic stability. These results suggested that5qwas a promising lead for further development of new potent and orally bioavailable NR2B-selective NMDAR antagonists.