Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Donepezil is a widely used Alzheimer's disease (AD) treatment.
• Multi-target-directed ligands (MTDLs) are a key strategy for AD drug design.
• Idebenone is a quinone drug with potential relevance in combination therapy for AD.

Purpose of the Study:

• To design novel 1-based MTDLs targeting both amyloid-beta (Aβ) and oxidative stress pathways relevant to AD.
• To create merged derivatives by replacing the indanone core of donepezil with a 1,4-naphthoquinone moiety.
• To address the physicochemical challenges often associated with large hybrid-based MTDLs.

Main Methods:

• Rational design of novel MTDLs based on donepezil structure.
• Bioisosteric replacement of the indanone core with a 1,4-naphthoquinone.
• Preliminary investigation of multi-target profiles, including enzyme inhibition and antioxidant properties.

Main Results:

• A series of novel merged derivatives were synthesized.
• Compound 9 demonstrated potent and selective butyrylcholinesterase inhibitory activity.
• Compound 9 exhibited significant antioxidant and antiaggregating properties, along with a promising drug-like profile.

Conclusions:

• The designed 1-based MTDLs effectively merge Aβ and oxidative targets.
• Compound 9 represents a promising lead candidate for further Alzheimer's disease therapeutic development.
• The strategy of bioisosteric replacement offers a viable approach to MTDL design for AD.