Synthesis and Macromolecular Docking Evaluation of Nitrile‐Substituted Chalcone Derivatives as Multi‐Target Anti‐Inflammatory Agents

Abstract

This study reports the synthesis, structural characterization, and molecular docking evaluation of two nitrile‐substituted chalcone derivatives ( N1 and N2 ) prepared via Claisen–Schmidt condensation between alkoxy‐substituted benzaldehydes and 4‐acetylbenzonitrile. The synthesized compounds were characterized using FTIR, 1 H‐NMR, 1 3 C‐NMR, and mass spectrometry, confirming the formation of the α,β‐unsaturated carbonyl framework and nitrile functionality. Molecular docking analysis was performed against inflammatory macromolecular targets including cyclooxygenase‐2 (COX‐2), inhibitor of κB kinase β (IKKβ), and nuclear factor kappa B (NF‐κB). Comparative analysis with celecoxib, diclofenac, parthenolide, curcumin, quercetin, and eugenol revealed favorable binding affinities of the synthesized chalcones toward IKKβ and NF‐κB. Among the synthesized derivatives, N2 exhibited the strongest binding affinity toward IKKβ with a docking score of −6.24 kcal/mol. These findings suggest that nitrile‐substituted chalcone derivatives may represent promising scaffolds for multi‐target anti‐inflammatory drug design.