Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Drug Discovery

Background:

• Alzheimer's disease (AD) is a leading cause of neurodegeneration, necessitating novel therapeutic strategies.
• Multifunctional agents offer a promising approach by targeting multiple AD pathological pathways simultaneously.

Purpose of the Study:

• To synthesize and evaluate novel nitroxoline-based analogs as potential multifunctional agents for Alzheimer's disease.
• To investigate the ability of these compounds to inhibit amyloid beta aggregation, butyrylcholinesterase, and complex copper ions.

Main Methods:

• Design and synthesis of nitroxoline-based analogs merging 8-hydroxyquinoline and butyrylcholinesterase inhibitor scaffolds.
• Biological evaluation including inhibition of amyloid beta (Aβ1-42) aggregation and butyrylcholinesterase (BChE) activity.
• Assessment of copper(II) complexation properties and determination of the crystal structure of BChE in complex with compound 8g.

Main Results:

• Compound 8g demonstrated significant inhibition of Aβ1-42 self-induced aggregation.
• Compound 8g potently inhibited butyrylcholinesterase with an IC50 of 215 nM.
• Compound 8g selectively complexed Cu(2+) ions, indicating its multifunctional capabilities.

Conclusions:

• Compound 8g emerges as a promising multifunctional agent for Alzheimer's disease therapy.
• The 8-hydroxyquinoline scaffold is valuable for developing multi-target directed ligands.
• Structural insights from the BChE-8g complex can guide future optimization of AD therapeutics.