Synthesis, Computational Modeling, and Enzymatic Inhibition Screening of Novel N-Substituted Maleimide Derivatives

International Journal of Chemistry | Vol. 15, No. 5, May 2024 | pp. 33–40

DOI: 10.46882/2024/IJC/000187

Article Type: Original Research Paper

Title: Synthesis, Computational Modeling, and Enzymatic Inhibition Screening of Novel N-Substituted Maleimide 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 Cambridge, 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 N-substituted maleimide derivatives were synthesized via the condensation of maleic anhydride with various substituted aniline compounds 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 maleimide 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: Maleimide; Chemical synthesis; Alpha-glucosidase; Enzyme inhibition; Molecular docking; Antidiabetic drug design

Manuscript Timeline: Received: September 02, 2022; Revised: October 12, 2022; Accepted: November 05, 2022; Published: May 04, 2024.

Citation: Kolawole, O. M., & Watson, E. R. (2024). Synthesis, Computational Modeling, and Enzymatic Inhibition Screening of Novel N-Substituted Maleimide Derivatives. International Journal of Chemistry, 15(5), 33–40.

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