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Diphenylpiperazine Attached to Different Triazole Acetamide Derivatives As a Potent Α-Glucosidase Inhibitor, New Insight Into the in Silico Study of an Uncompetitive Inhibitor Publisher Pubmed



Ghasemi M ; Sepehri N ; Biglar M ; Mahdavi M ; Irajie C ; Larijani B ; Al Harrasi A ; Iraji A
Authors

Source: Journal of Computer-Aided Molecular Design Published:2026


Abstract

Type 2 diabetes mellitus (T2DM) is considered as one of the major global health challenges, and inhibition of α-glucosidase is an effective strategy for controlling postprandial hyperglycemia. Therefore, this study aimed to design and develop novel α-glucosidase inhibitors. This study synthesized thirteen di-phenyl piperazine-based derivatives attached to different triazole acemamide (8a–m) via a multi-step procedure involving a Cu(I)-catalyzed click reaction and evaluated them as α-glucosidase inhibitors for type 2 diabetes mellitus (T2DM) management. All derivatives were screened as α-glucosidase inhibitors, and compound 8d, bearing 2,4-dimethoxy substitution, exhibited superior potency (IC50 = 37.51 ± 2.83 µM) compared to acarbose (IC50 = 750 µM). Structure-activity relationship analysis revealed that electron-donating and electron-withdrawing substituents enhance inhibitory activity. Kinetic studies confirmed 8d as an uncompetitive inhibitor via reducing both Vmax and Km. A novel docking approach, involving substrate placement in the α-glucosidase active site followed by docking 8d, demonstrated its stabilization of the enzyme–substrate complex through π-π stacking and hydrogen-bonding interactions. Molecular dynamics simulations supported binding stable (RMSD ~ 2 A, RMSF < 0.8 A). In silico ADME and toxicity profiles indicated favorable drug-likeness profiles. Overall, compound 8d emerges as a promising lead for T2DM therapeutics, warranting further optimization and in vivo assessments. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2026.
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