Amberlyst A21 ‐Catalyzed Green Synthesis of Novel Azo‐Fused Benzo[d]Imidazolyl Phenyl Methanones: Molecular Docking, DFT Insights and α‐Glucosidase Inhibitory Activity

Abstract

A green and sustainable synthetic protocol was established for the synthesis of novel azo‐fused benzo[d]imidazolylphenyl methanone derivatives using arylazo salicylaldehydes and 3,4‐diaminobenzophenone in the presence of Amberlyst A21 as a recyclable heterogeneous base catalyst under mild reaction conditions. The developed methodology afforded the desired products in good to excellent yields with operational simplicity and catalyst reusability. Employing ethanol as an eco‐friendly solvent and a recyclable, metal‐free polymer‐supported catalyst reinforces the environmentally benign and sustainable nature of the methodology. Structure elucidation of the synthesized compounds was accomplished using FT‐IR, 1 H NMR, 13 C NMR, and ESI‐MS analyses. In silico molecular docking investigations were conducted against the human lysosomal acid α‐glucosidase enzyme (PDB ID: 5NN8) to explore the binding modes of the synthesized compounds. All the compounds exhibited excellent binding affinities from −9.1 to −10.4 kcal/mol and various biomolecular interactions with the target. Molecular dynamics was performed for the complex 5NN8‐3k at 100 ns. DFT calculations at the B3LYP/6‐311G* (d,p) level were performed to evaluate the electronic properties of compounds 3(a–o). The selected compound 3k was further evaluated through in silico ADMET analysis to predict its pharmacokinetic and toxicity properties. The synthesized compound 3k was further assessed for its antidiabetic potential through an in vitro α‐glucosidase inhibition study, exhibiting significant inhibitory activity with an IC 50 value of 47.487 μg/mL in comparison to the standard acarbose (IC 50  = 29.287 μg/mL). The computational and experimental findings collectively suggest that azo‐fused benzo[d]imidazol‐5‐yl)(phenyl)methanone scaffolds represent promising candidates for further development of potential α‐glucosidase inhibitors through a green and sustainable synthetic approach.