Design and synthesis of new piperidone grafted acetylcholinesterase inhibitors

作者：Basiri Alireza; Xiao Michelle; McCarthy Alec; Dutta Debashis; Byrareddy Siddappa N; Conda Sheridan Martin^*

来源：Bioorganic & Medicinal Chemistry Letters, 2017, 27(2): 228-231.

DOI：10.1016/j.bmcl.2016.11.065

• N-Benzylpiperidines
• Thiazolopyrimidinium
• AChE activity
• Molecular modeling
• pi-pi-Stacking interactions
• SH-SY5Y cell
• Cytotoxicity

Alzheimer's disease (AD) is a neurodegenerative disorder affecting 35 million people worldwide. A common strategy to improve the well-being of AD patients consists on the inhibition of acetylcholinesterase with the concomitant increase of the neurotransmitter acetylcholine at cholinergic synapses. Two series of unreported N-benzylpiperidines 5(a-h) and thiazolopyrimidines 9(a-q) molecules were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activities. Among the newly synthesized compounds, 5h, 9h, 9j, and 9p displayed higher AChE enzyme inhibitory activities than the standard drug, galantamine, with IC50 values of 0.83, 0.98, and 0.73 mu M, respectively. Cytotoxicity studies of 5h, 9h, 9j, 9n and 9p on human neuroblastoma cells SH-SY5Y, showed no toxicity up to 40 mu M concentration. Molecular docking simulations of the active compounds 5h and 9p disclosed the crucial role of pi-pi-stacking in their binding interaction to the active site AChE enzyme. The presented compounds have potential as AChE inhibitors and potential AD drugs.

• 出版日期2017-1-15