2. Academic Validation
  3. Design, synthesis, and antidiabetic evaluation of triazolopyrimidine thioacetamides as potent and selective α-glucosidase inhibitors

Design, synthesis, and antidiabetic evaluation of triazolopyrimidine thioacetamides as potent and selective α-glucosidase inhibitors

  • Bioorg Chem. 2026 Mar:170:109482. doi: 10.1016/j.bioorg.2026.109482.
Fariba Peytam 1,  Maryam Norouzbahari 2,  Bahareh Bayati 3,  Hayrettin Ozan Gülcan 4,  Vahid Sheibani 5,  Maliheh Barazandeh Tehrani 6,  Somayeh Mojtabavi 7,  Mohammad Ali Faramarzi 7,  Fahimeh Ghasemi 8,  Mohammadreza Torabi 8,  Meghdad Payab 9,  Fatemeh Safari 10,  Loghman Firoozpour 11,  Alireza Foroumadi 12
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
  • 2 Faculty of Pharmacy, Final International University, Catalkoy, Kyrenia via Mersin, 10, TRNC, Turkey.
  • 3 Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
  • 4 Eastern Mediterranean University, Faculty of Pharmacy, Famagusta, TRNC, via Mersin, 10, Turkey.
  • 5 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
  • 6 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 7 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 8 Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • 9 Faculty of Chemistry, University of Mazandaran, Babolsar, Iran.
  • 10 Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
  • 11 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected].
  • 12 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected].
PMID: 41518938 DOI: 10.1016/j.bioorg.2026.109482
Abstract

Diabetes mellitus is a global health challenge characterized by chronic hyperglycemia. α-Glucosidase inhibitors, like acarbose, are pivotal in managing postprandial blood glucose levels but are often associated with gastrointestinal side effects. This study aimed to rationally design and synthesize a library of 2-((6-amino-5,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)thio)-N-arylacetamide derivatives (15a-15ae) as potent and selective α-glucosidase inhibitors. All 31 target compounds exhibited inhibitory activity (IC50 ranging from 7.09 μM to 245.57 μM) under assay conditions where the reference drug, acarbose, exhibited an IC50 value of 750.67 μM. The most potent compound, 15o (IC50 = 7.09 ± 0.2 μM), demonstrated approximately 106-fold higher potency than acarbose under the identical assay conditions. Kinetic analysis indicated that 15o acted as a competitive inhibitor (Kᵢ = 6.9 μM). Moreover, this compound did not show α-amylase inhibitory activity and cytotoxicity at concentration of 100 μM, showing preliminary indications of favorable safety and selectivity. Spectroscopic studies (CD, fluorescence) and computational analyses (model performance and augmentation, docking, and MD simulations) confirmed the strong binding affinity and stabilization of compound 15o within the enzyme's active site. In vivo evaluation in a diabetic rat model demonstrated that 15o (30 mg/kg BW) significantly reduced fasting blood glucose, improved glucose tolerance in OGTT, reduced HbA1c levels to near-normal ranges, and restored hepatic and pancreatic histology, with effects better than those observed with acarbose in this model. Compound 15o also exhibited acceptable acute toxicity profiles. These findings introduced compound 15o as a promising lead candidate for further structural development of anti-diabetic agents.

Keywords

Diabetes mellitus; In vivo efficacy; Triazolo[1,5-a]pyrimidine; Triazolopyrimidine; Α-Glucosidase inhibitor.

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