Novel Resorcinol-Based 2-Amino-4H-chromene-3-carbonitrile Derivatives as α-Glucosidase Inhibitors: Synthesis, In Vitro Evaluation, and Molecular Dynamics Simulation Studies

Abstract

A novel series of resorcinol-based 2-amino-4H-chromene-3-carbonitrile derivatives was synthesized and assessed against yeast α-glucosidase enzyme. All synthesized compounds showed significant inhibitory activities toward the enzyme with IC₅₀ values ranging from 44.0 ± 1.2 to 551.5 ± 1.6 µM in comparison with acarbose, as a standard agent (IC₅₀ = 750.0 µM). Among them, 2-amino-4-(4-((4-bromobenzyl)oxy)-3-methoxyphenyl)-7-hydroxy-4H-chromene-3-carbonitrile (6e) indicated the most potent inhibitory activity. The kinetic study indicated that the compound 6e acts as a competitive α-glucosidase inhibitor. Afterward, molecular docking and molecular dynamics (MD) simulations of the R- and S-enantiomers of compound 6e against a homology-modeled enzyme confirmed significant interactions with the catalytic residues. Additionally, in silico ADMET predictions showed that resorcinol-based 2-amino-4H-chromene-3-carbonitrile derivatives possess acceptable pharmacokinetic properties and therapeutic potential for the future treatment of type 2 diabetes mellitus (T2DM).