Development of novel salicylic acid-donepezil-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2231661. doi: 10.1080/14756366.2023.2231661.


Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid-donepezil-rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that 5a was a reversible and selective eqBChE inhibitor (IC50 = 0.53 μM), and the docking provided the possible mechanism. Compound 5a also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, 5a exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, 5a demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, 5a was a potential multifunctional lead compound against AD.

Keywords: Alzheimer’s disease; drug-likeness; multi-functional agent; salicylic acid–donepezil–rivastigmine hybrids; scopolamine-induced AD model.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Aged
  • Alzheimer Disease* / drug therapy
  • Cholinesterase Inhibitors / pharmacology
  • Donepezil
  • Humans
  • Neuroprotective Agents* / pharmacology
  • Neuroprotective Agents* / therapeutic use
  • Rivastigmine / pharmacology
  • Rivastigmine / therapeutic use
  • Structure-Activity Relationship


  • Donepezil
  • Rivastigmine
  • Cholinesterase Inhibitors
  • Neuroprotective Agents
  • Acetylcholinesterase

Grants and funding

This work was financially supported by the Science and Technology Project of Henan Province (No. 2121023111000); The Special Project of Nanyang Normal University (2020ZX015 and 2021CX002); The Fundamental Research Funds for Hainan University (KYQD(ZR)23002).