Synthesis, Molecular Docking, and In Vitro Evaluation of Novel Isatin Derivatives as Potential Acetylcholinesterase Inhibitors

International Journal of Chemistry | Vol. 5, No. 6, June 2014 | pp. 41–48

DOI: 10.46882/2014/IJC/000069

Article Type: Original Research Paper

Title: Synthesis, Molecular Docking, and In Vitro Evaluation of Novel Isatin Derivatives as Potential Acetylcholinesterase Inhibitors

Names of Authors: O. M. Kolawole¹, E. J. Cook²*

Authors’ Affiliations:
¹Department of Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria.
²Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.

Abstract: Inhibiting acetylcholinesterase (AChE) represents a vital clinical strategy for managing Alzheimer's disease by maintaining systemic acetylcholine neurotransmitter levels. In this work, five novel N-substituted isatin derivatives were synthesized via nucleophilic substitution reactions of isatin with various benzyl bromides in the presence of potassium carbonate. The molecular structures of the synthesized targets were verified using elemental analysis, FT-IR, and ¹H-NMR spectroscopy. In vitro AChE enzyme inhibition assays revealed that compound 5b, bearing a p-fluorobenzyl substituent, possessed the highest inhibitory potency, showing an IC50 value of 8.4 μM compared to the donepezil clinical standard (IC50 = 2.1 μM). To investigate specific binding modes, in silico molecular docking simulations were run inside the catalytic active site of human AChE using AutoDock Vina software. The computational docking models demonstrated that the isatin core forms stable hydrogen bonds with Gly121 and Ser203 residues. The aromatic ring extensions fit well into the peripheral anionic site, engaging in significant edge-to-face pi-pi stacking interactions with Trp286. These structural contacts stabilize the ligand-protein topology, explaining the sub-micromolar inhibition constants and presenting a potential scaffold for further antidementia drug design.

Keywords: Isatin derivatives; Chemical synthesis; Acetylcholinesterase; Enzyme inhibition; Molecular docking; Alzheimer's disease

Manuscript Timeline: Received: June 12, 2013; Revised: July 25, 2013; Accepted: August 18, 2013; Published: June 03, 2014.

Citation: Kolawole, O. M., & Cook., E. J. (2014). Synthesis, Molecular Docking, and In Vitro Evaluation of Novel Isatin Derivatives as Potential Acetylcholinesterase Inhibitors. International Journal of Chemistry, 5(6), 41–48.

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