Design, Synthesis, and Evaluation of Triazolo[1,5-A]Pyridines As Novel and Potent Α‑Glucosidase Inhibitors Publisher Pubmed



Peytam F^{1, 2} ; Foroumadi P³ ; Gulcan HO^{4, 5} ; Norouzbahari M⁶ ; Mojtabavi S⁷ ; Faramarzi MA⁷ ; Ghasemi F⁸ ; Torabi M⁸ ; Bameri B⁹ ; Barazandeh Tehrani M¹ ; Firoozpour L^{1, 2} ; Foroumadi A^{1, 2} Show Affiliations
Source: Scientific Reports Published:2025

Abstract

α-Glucosidase is a key enzyme responsible for controlling the blood glucose, making a pivotal target in the treatment of type 2 diabetes mellitus. Present work introduces1,2,4triazolo[1,5-a]pyridine as a novel, potent scaffold for α-glucosidase inhibition. A diverse scope of targeted compounds was prepared through an efficient, straightforward synthetic protocol. A series of compounds (15a–15v) were synthesized using a simple and efficient protocol, all showing notable inhibitory activity. Among them, compound 15j exhibited the best inhibition potency (IC₅₀ = 6.60 ± 0.09 µM), acting as a competitive and selective α-glucosidase inhibitor with no effect on α-amylase. Moreover, comprehensive computational studies were performed to validate the in vitro results and provide insight into compounds’ binding interactions within the α-glucosidase’s active site. The machine learning model, trained with the Estate fingerprint, achieved an AUC score of 0.65, demonstrating its utility in predicting α-glucosidase inhibition. Random Forest was identified as the most suitable model, and the dataset with the highest R² value was selected for further feature selection and model improvement. Molecular docking studies demonstrated that compound 15j had a strong binding affinity toward α-glucosidase, with a docking score of − 10.04 kcal/mol, and formed several remarkable interactions, particularly three key hydrogen bonds with TYR158, GLN353, and GLU411, contributing to its high inhibitory efficacy. The results of the molecular dynamics simulation demonstrated that the 15j–α-glucosidase complex exhibits high stability and effectively maintains its binding without causing significant structural changes in the enzyme, confirming the stable interaction and selective inhibition of this compound at the enzyme’s active site. © The Author(s) 2025.