Design, synthesis and biological evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease

作者：Lan, Jin-Shuai; Ding, Yue; Liu, Yun; Kang, Ping; Hou, Jian-Wei; Zhang, Xin-Yu; Xie, Sai-Sai^*; Zhang, Tong^*

来源：European Journal of Medicinal Chemistry, 2017, 139: 48-59.

DOI：10.1016/j.ejmech.2017.07.055

• Monoamine oxidase inhibitors
• Acetylcholinesterase inhibitors
• Multi-target ligand design
• Alzheimer's disease
• Coumarin derivatives

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.

• 出版日期2017-10-20
• 单位上海中医药大学; 江西中医药大学