Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents

Abstract

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy₃-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H₂O₂-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

Graphical abstract

Summary points

• 19 1-aryldonepezil analogues were prepared by palladium-catalyzed Suzuki cross-coupling.

• The cholinesterase inhibitory activities and neuroprotective effects of these analogues were evaluated.

• 1-(4-tert-butylphenyl)aryldonepezil showed the most potential bioactivity.

• In silico docking experiments demonstrated the possible binding model.

• 1-(4-tert-butylphenyl)aryldonepezil is a promising lead compound for anti-Alzheimer's disease drug development.

Keywords: :

• Alzheimer's disease
• cholinesterase
• donepezil analogues
• neuroprotective activity
• neurotoxicity

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.future-science.com/doi/suppl/10.4155/fmc-2023-0369

Author contributions

L-X Wan conceived the idea, guided the project and wrote the manuscript with feedback from other authors. J Luo and D-M Fang made the initial observations and analyzed the results. J-J Xu and H-J Ren explored the analogues' adaptability. J-B Xu and F Gao performed docking calculations.

Financial disclosure

This research was financially supported by grants from the National Natural Science Foundation of China (82204244), the Natural Science Foundation of Sichuan Province (23NSFSC2370) and the Young Pharmacist Foundation of Sichuan Hospital Association (22031). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Availability of data materials

The datasets used and/or analyzed during the current study are available from the corresponding authors upon reasonable request.

Additional information

Funding

This research was financially supported by grants from the National Natural Science Foundation of China (82204244), the Natural Science Foundation of Sichuan Province (23NSFSC2370) and the Young Pharmacist Foundation of Sichuan Hospital Association (22031). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.