In Silico Design, Molecular Docking and Synthesis of Novel [1,1-Biphenyl]-4-Carbonitril Schiff Base Derivatives as Cholinesterase Inhibitors

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder expected to affect over 80 million people by 2040. A decline in acetylcholine (ACh), a key neurotransmitter, is linked to cognitive decline in AD. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes break down ACh, making them targets for AD treatment.

Objectives: This study aimed to synthesize Schiff base derivatives and evaluate their ability to inhibit AChE and BChE. Molecular docking was used to explore their binding interactions.

Methods: Three Schiff base derivatives (N1-N3) were synthesized by condensing substituted benzaldehydes with 4-(4'-aminophenyl)benzonitrile. Their cholinesterase inhibitory activity was tested using a modified Ellman’s method, and docking studies were performed using Glide™.

Results: The compounds showed strong inhibition of both AChE and BChE. N1 had the strongest AChE inhibition (IC50 = 1.09 µg/mL), while N3 was most effective against BChE (IC50 = 12.32 µg/mL). Molecular docking confirmed favorable binding through hydrogen bonding and hydrophobic interactions.