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

Bioorg Med Chem. 2023 Feb 15:80:117178. doi: 10.1016/j.bmc.2023.117178. Epub 2023 Jan 21.

Abstract

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 μM, AChEIC50 = 6.89 μM, d10: HDACIC50 = 0.45 μM, AChEIC50 = 3.22 μM), and both compounds showed activities on scavenging free radical, metal chelating, and inhibiting Aβ 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.

Keywords: Acetylcholinesterase inhibitor; Alzheimer’s disease; Donepezil moiety; Histone deacetylases inhibitor; Multitarget-directed ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease* / drug therapy
  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Drug Design
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Piperidines / pharmacology
  • Structure-Activity Relationship

Substances

  • Acetylcholinesterase
  • Cholinesterase Inhibitors
  • Histone Deacetylase Inhibitors
  • Piperidines
  • Amyloid beta-Peptides