2. Academic Validation
  3. Identification of novel triazolopyrimidines as potent α-glucosidase inhibitor through design, synthesis, biological evaluations, and computational analysis

Identification of novel triazolopyrimidines as potent α-glucosidase inhibitor through design, synthesis, biological evaluations, and computational analysis

  • Sci Rep. 2025 Nov 12;15(1):39667. doi: 10.1038/s41598-025-23387-z.
Fariba Peytam 1 2,  Maryam Norouzbahari 3,  Hayrettin Ozan Gulcan 4,  Faezeh Sadat Hosseini 1,  Mahdis Sadeghi Moghadam 2,  Somayeh Mojtabavi 5,  Mohammad Ali Faramarzi 5,  Fahimeh Ghasemi 6,  Mohammadreza Torabi 6,  Seyed Esmaeil Sadat-Ebrahimi 2,  Maliheh Barazandeh Tehrani 2,  Loghman Firoozpour 7 8,  Alireza Foroumadi 9 10
Affiliations

Affiliations

  • 1 Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 3 Faculty of Pharmacy, Final International University, Kyrenia via Mersin 10 Turkey, TRNC, Catalkoy, Turkey.
  • 4 Eastern Mediterranean University, Faculty of Pharmacy, Via Mersin 10 Turkey, TRNC, Famagusta, Turkey.
  • 5 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 6 Department of Bioinformatics and Systems Biology, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
  • 7 Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran. firoozpour@gmail.com.
  • 8 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. firoozpour@gmail.com.
  • 9 Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran. aforoumadi@yahoo.com.
  • 10 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. aforoumadi@yahoo.com.
PMID: 41225142 DOI: 10.1038/s41598-025-23387-z
Abstract

α-Glucosidase inhibitors are widely used in the management of type 2 diabetes mellitus (T2DM) by delaying carbohydrate digestion and reducing postprandial blood glucose levels. However, current drugs suffer from limited efficacy and gastrointestinal side effects, highlighting the need for novel inhibitors with improved potency and selectivity. In this study, a novel series of 5,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidin-6-amines 9a-9t was designed and prepared through an efficient, straightforward synthetic route. Subsequently, they were evaluated for their α-glucosidase inhibitory activity, with compound 9s exhibiting the most potent inhibition (IC50 = 24.32 ± 0.18 µM), outperforming acarbose by over 30-fold. Enzyme kinetics revealed a competitive inhibition mode, and selectivity assays confirmed minimal α-amylase inhibition. Spectroscopic analyses (CD and fluorescence) demonstrated significant conformational changes in α-glucosidase upon ligand binding, suggesting structural stabilization and reduced flexibility. Molecular docking and 200-ns MD simulations confirmed persistent hydrophobic and halogen-bond interactions, particularly with residues Phe303, Arg315, and Gln182. Additionally, a BERT-based deep learning model with SMILES augmentation accurately predicted the biological activity of synthesized compounds, validating our computational pipeline. These findings highlight [1,2,4]triazolo[1,5-a]pyrimidines as promising scaffolds for the development of selective and potent α-glucosidase inhibitors.

Keywords

α-Glucosidase; Antidiabetic; Triazolopyrimidine; [1,2,4]Triazolo[1,5-a]pyrimidine.

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