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Novel Pyrido[2,3-D]Pyrimidine Linked to Benzyloxy-Phenyl and Benzyl-Triazole Hybrids As Alpha-Glucosidase Inhibitors: Synthesis, in Vitro Evaluation, and in Silico Studies Publisher



S Alizadeh SIMIN ; Sa Ebadi Seyed AHMAD ; S Esmaeili SOHEILA ; F Ghamari FATEMEH ; Ma Faramarzi Mohammad ALI ; S Mojtabavi SOMAYEH ; M Mahdavic MOHAMMAD ; Z Najafi ZAHRA
Authors

Source: Journal of Molecular Structure Published:2025


Abstract

In this research, a new series of pyrido[2,3-d]pyrimidine linked to benzyloxy-phenyl and benzyl-triazole hybrids was synthesized and evaluated for their inhibitory activities against the alpha-glucosidase enzyme. The target compounds exhibited IC50 values ranging from 72.6 to 465.7 μM, in comparison to acarbose (750 μM). Among them, 7-amino-5-(3-methoxy-4-((1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1,3-dimethyl- 2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d]pyrimidine-6-carbonitrile (compound 11e) demonstrated the most potent inhibition against alpha-glucosidase enzyme with an IC50 value of 72.6 μM. Kinetic studies revealed that compound 11e inhibits the enzyme in a competitive manner. Molecular docking and dynamics simulations (MD) were performed to investigate the binding interactions of compound 11e with critical amino acids inside the active site of alpha-glucosidase. MD also confirmed the stability of the system and enzymes. These findings provide valuable insight into the development of novel alpha-glucosidase inhibitors based on pyrido[2,3-d]pyrimidine scaffold for treating type 2 diabetes. © 2025 Elsevier B.V., All rights reserved.
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