Synthesis, Molecular Docking, and In Vitro Enzymatic Evaluation of Novel Indole-Linked Chalcone Derivatives

International Journal of Chemistry | Vol. 8, No. 10, October 2017 | pp. 73–80

DOI: 10.46882/2017/IJC/000109

Article Type: Original Research Paper

Title: Synthesis, Molecular Docking, and In Vitro Enzymatic Evaluation of Novel Indole-Linked Chalcone Derivatives

Names of Authors: O. M. Kolawole¹, E. C. J. Smith²*

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

Abstract: Inhibiting acetylcholinesterase (AChE) represents a vital clinical strategy for managing Alzheimer's disease by maintaining systemic acetylcholine neurotransmitter levels in brain tissue. In this work, five novel indole-linked chalcone derivatives were synthesized via Claisen-Schmidt condensation of indole-3-carboxaldehyde with various substituted acetophenones in the presence of potassium hydroxide catalysts. 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 3d, bearing a p-chlorosubstituent, possessed the highest inhibitory potency, showing an IC50 value of 7.8 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 chalcone carbonyl forms stable hydrogen bonds with Gly121 and Ser203 residues. The indole 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 low inhibition constants and presenting a potential scaffold for further antidementia drug design.

Keywords: Indole; Chalcones; Acetylcholinesterase; Enzyme inhibition; Molecular docking; Alzheimer's disease

Manuscript Timeline: Received: September 10, 2016; Revised: October 22, 2016; Accepted: November 15, 2016; Published: October 05, 2017.

Citation: Kolawole, O. M., & Smith, E. C. J. (2017). Synthesis, Molecular Docking, and In Vitro Enzymatic Evaluation of Novel Indole-Linked Chalcone Derivatives. International Journal of Chemistry, 8(10), 73–80.

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