Evaluation of the acetylcholinesterase inhibitory potential of tranilast derivatives using in vitro and in silico approaches

This study was conducted to evaluate the acetylcholinesterase (AChE) inhibitory potential of tranilast derivatives using both in vitro and in silico approaches. Nine tranilast derivatives (5a-i) were screened for AChE inhibitory activity using the Ellman assay, and IC50 values were determined for compounds exhibiting significant activity. Molecular docking studies were performed on AChE (PDB ID: 4EY7) using AutoDock Vina to assess binding affinity and ligand-enzyme interactions. The results showed that four derivatives, namely 5f, 5g, 5h, and 5i, exhibited notable AChE inhibitory activity, with IC50 values of 45.51 ± 5.05, 40.96 ± 2.58, 21.64 ± 1.03, and 44.17 ± 2.45 μM, respectively. Among them, compound 5h bearing a 4,5-dimethoxy substituent demonstrated the most potent activity. Molecular docking analysis revealed binding energies ranging from -9.3 to -11.2 kcal/mol. Notably, compound 5h exhibited the best binding affinity (-11.2 kcal/mol) and formed multiple key interactions with amino acid residues located in both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. The findings indicate that tranilast derivatives, particularly compound 5h, possess promising potential as AChE inhibitors. Electron-donating substituents, especially methoxy groups, appear to enhance interactions with the target enzyme and contribute to improved biological activity.