Abstract

DESIGN AND IN SILICO STUDY OF CHROMONE –DONEPEZIL HYBRIDS AS MUTI-TARGET AGENTS FOR INFLAMMATORY, ALZHEIMER DISEASE

Rooban S.*, Vignesh S., Gandhi P., Bakkiyaraj K., Rajalingam D.

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive impairment, β-amyloid accumulation, oxidative stress, and neuronal degeneration. The present study focused on the design and in silico evaluation of novel Chromone–Donepezil hybrid compounds as potential multi-target-directed ligands (MTDLs) for the treatment of Alzheimer’s disease. Ten hybrid compounds (CDH1–CDH10) were designed using a molecular hybridization approach by combining the antioxidant and neuroprotective properties of chromone with the acetylcholinesterase (AChE) inhibitory activity of donepezil. Molecular docking studies were performed against five important Alzheimer’s disease-related targets: AChE (4EY7), BuChE (4BDS), BACE1 (2WJO), GSK-3β (1Q5K), and MAOB (2V5Z). The docking results demonstrated favorable binding interactions with multiple targets. Among the designed compounds, CDH6, CDH7, and CDH9 showed the most promising overall docking profiles. CDH9 showed the highest affinity against AChE, while CDH7 showed strong binding toward BuChE and BACE1. CDH6 demonstrated strong interactions with GSK-3β and MAO-B. ADME and drug-likeness analysis indicated high gastrointestinal absorption, acceptable pharmacokinetic properties, and compliance with Lipinski’s Rule of Five. These findings suggest that Chromone–Donepezil hybrids, particularly CDH6, CDH7, and CDH9, may serve as promising lead compounds for further development of multi-target anti-Alzheimer’s agents. Further in vitro and in vivo studies are required to validate their therapeutic potential.

Keywords: Alzheimer’s disease, Chromone, Donepezil, Molecular hybridization, Multi-target-directed ligands, Molecular docking, AChE, BuChE, BACE1, GSK-3β, MAO-B, ADMET, Drug-likeness, In silico drug design.