Design, synthesis and biological evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease
Design, synthesis and biological evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease
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DOI：
10.1016/j.ejmech.2017.07.055
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发表时间：
2017-10-20
影响因子：
6.7
通讯作者：
Zhang, Tong
中科院分区：
文献类型：
--
作者：
Lan, Jin-Shuai;Ding, Yue;Zhang, Tong
将N-苄基吡啶鎓和香豆素结合在一个分子中，设计并合成了具有胆碱酯酶和单胺氧化酶-B抑制活性的新型杂合物。生物活性筛选结果表明，大部分化合物对ChE和A β（1-42）自聚集均有较强的抑制活性，对MAO-B的抑制作用明显优于对MAO-A的抑制作用。在这些化合物中，化合物7 f是hMAO-B的最有效的抑制剂，并且它也是ChE和hMAO-B的良好和平衡的抑制剂（eeAChE为0.0373 μ M; eqBuChE为2.32 μ M; hMAO-B为1.57 μ M）。分子模拟和动力学研究表明，化合物7 f是一种混合型抑制剂，同时与AChE的CAS和PAS结合，同时也是一种竞争性抑制剂，占据了MAO-B的活性位点。此外，化合物7 f对PC 12神经母细胞瘤细胞无毒性，显示出良好的抑制A β（1-42）自聚集和穿过血脑屏障的能力。总的来说，所有这些结果表明化合物7 f可能是一个有前途的多靶点先导候选物，值得进一步研究。(C)2017年Elsevier Masson SAS。All rights reserved.
Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and A beta (1-42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 mu M for eeAChE; 2.32 mu M for eqBuChE; 1.57 mu M for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit A beta (1-42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit. (C) 2017 Elsevier Masson SAS. All rights reserved.