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

Abstract

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.

Graphical Abstract

Keywords:

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

Acknowledgements

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).

Disclosure statement

The authors declare no competing financial interest.

Additional information

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).