Donepezil-like multifunctional agents: Design, synthesis, molecular modeling and biological evaluation

Area of Science:

• Neuroscience
• Medicinal Chemistry
• Pharmacology

Background:

• Current Alzheimer's disease (AD) treatments offer only symptomatic relief, failing to halt disease progression.
• Developing disease-modifying anti-Alzheimer's drugs (DMAADs) is crucial for effective AD therapy.
• The multifactorial nature of AD necessitates multifunctional therapeutic agents.

Purpose of the Study:

• To design, synthesize, and evaluate novel donepezil-related compounds as potential DMAADs.
• To create multifunctional compounds targeting key enzymatic systems and metal ions implicated in AD.
• To investigate compounds with cholinesterase (ChE) and monoamine oxidase A (MAO-A) inhibition, alongside metal-chelating properties.

Main Methods:

• Synthesis of a new series of donepezil-related compounds.
• Molecular modeling to predict compound interactions.
• In vitro biological evaluation including enzyme inhibition assays (ChEs, MAO-A, MAO-B) and metal ion complexation studies.
• Assessment of antioxidant properties.

Main Results:

• Compound 5f, a novel donepezil-hydroxyquinoline hybrid, demonstrated potent ChEs inhibition.
• Compound 5f exhibited selective MAO-A inhibition over MAO-B.
• 5f displayed strong complexing abilities for zinc and copper ions and moderate antioxidant activity.
• These combined properties suggest a DMAAD profile for compound 5f.

Conclusions:

• Compound 5f represents a promising novel therapeutic candidate for Alzheimer's disease.
• The developed hybrid compound exhibits a multi-target profile addressing key AD pathologies.
• This research paves the way for a new class of DMAADs with potential disease-modifying capabilities.