Synthesis, Computational Modeling, and Enzymatic Inhibition Screening of Novel Coumarin-Linked Hydrazone Derivatives

International Journal of Chemistry | Vol. 7, No. 2, February 2016 | pp. 9–16

DOI: 10.46882/2016/IJC/000089

Article Type: Original Research Paper

Title: Synthesis, Computational Modeling, and Enzymatic Inhibition Screening of Novel Coumarin-Linked Hydrazone Derivatives

Names of Authors: O. M. Kolawole¹, E. R. Watson²*

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

Abstract: Inhibiting alpha-glucosidase represents a critical therapeutic target for managing postprandial hyperglycemia in type 2 diabetes mellitus. In this work, five novel coumarin-linked hydrazone derivatives were synthesized via the condensation of 3-acetylcoumarin with various substituted benzohydrazides in the presence of catalytic glacial acetic acid. The molecular frameworks of the synthesized targets were verified using elemental analysis, FT-IR, and ¹H-NMR spectroscopy. In vitro alpha-glucosidase enzyme inhibition assays revealed that compound 3c, bearing a p-nitro substituent, possessed the highest inhibitory potency, showing an IC50 value of 12.4 μM, compared to the acarbose clinical standard (IC50 = 38.2 μM). To investigate specific binding configurations, in silico molecular docking simulations were run inside the catalytic domain of alpha-glucosidase using AutoDock Vina software. The computational docking models demonstrated that the coumarin lactone carbonyl forms stable hydrogen bonds with Asp214 and Arg315 residues. The aromatic ring extensions fit well into the hydrophobic pocket, engaging in significant pi-pi stacking interactions with Phe178. These structural contacts stabilize the ligand-protein topology, explaining the sub-micromolar inhibition constants and presenting a potential scaffold for further antidiabetic drug design.

Keywords: Coumarin; Hydrazones; Alpha-glucosidase; Enzyme inhibition; Molecular docking; Antidiabetic drug design

Manuscript Timeline: Received: June 12, 2015; Revised: July 25, 2015; Accepted: August 18, 2015; Published: February 06, 2016.

Citation: Kolawole, O. M., & Watson, E. R. (2016). Synthesis, Computational Modeling, and Enzymatic Inhibition Screening of Novel Coumarin-Linked Hydrazone Derivatives. International Journal of Chemistry, 7(2), 9–16.

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