Design, synthesis, and biological evaluation of novel N-Benzyl piperidine derivatives as potent HDAC/AChE inhibitors for Alzheimer's disease

The multitarget-directed ligands approach represents a potential strategy to provide effective treatments for Alzheimer's disease (AD) given its multifactorial pathology. Herein, a series of N-benzyl piperidine derivatives were designed, synthesized, and biologically characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Among the compounds tested, d5 and d10 exhibited dual enzyme inhibitions (d5: HDACIC50 = 0.17 mu M, AChEIC50 = 6.89 mu M, d10: HDACIC50 = 0.45 mu M, AChEIC50 = 3.22 mu M), and both compounds showed activities on scavenging free radical, metal chelating, and inhibiting A beta aggregations. More importantly, both compounds exhibited promising neuroprotective activities in PC-12 cells and good AChE selectivity. Collectively, the multifunctional profiles of compound d5 and d10 encourage further optimization and exploration to develop more potent analogues as potential treatments for AD.

Automated summary

The multitarget-directed ligands approach is a potential strategy for treating Alzheimer's disease, due to its multifactorial pathology. In this study, a series of N-benzyl piperidine derivatives were designed, synthesized, and characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Compound d5 and d10 exhibited dual enzyme inhibitions, scavenging free radicals, chelating metal, and inhibiting A beta aggregations. Additionally, they showed promising neuroprotective activities and good AChE selectivity in PC-12 cells. These findings encourage further optimization and exploration for developing more potent analogues as potential treatments for Alzheimer's disease.