2. Academic Validation
  3. Alpha-glucosidase inhibitory and hypoglycemic effects of imidazole-bearing thioquinoline derivatives with different substituents: In silico, in vitro, and in vivo evaluations

Alpha-glucosidase inhibitory and hypoglycemic effects of imidazole-bearing thioquinoline derivatives with different substituents: In silico, in vitro, and in vivo evaluations

  • Bioorg Chem. 2024 Mar:144:107106. doi: 10.1016/j.bioorg.2024.107106.
Anita Azmi 1,  Milad Noori 2,  Minoo Khalili Ghomi 3,  Mohammad Nazari Montazer 3,  Aida Iraji 4,  Navid Dastyafteh 2,  Najmeh Oliyaei 5,  Mona Khoramjouy 1,  Zahra Rezaei 6,  Shahrzad Javanshir 7,  Somayeh Mojtabavi 8,  Mohammad Ali Faramarzi 8,  Mehdi Asadi 9,  Mehrdad Faizi 10,  Mohammad Mahdavi 11
Affiliations

Affiliations

  • 1 Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
  • 2 Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
  • 3 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
  • 4 Research Center for Traditional Medicine and History of Medicine, Department of Persian Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 5 Department of Food Science and Technology, School of Agriculture Shiraz University, Shiraz, Iran.
  • 6 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 7 Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran.
  • 8 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 9 Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Science, Tehran, Iran.
  • 10 Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: m.faizi@sbmu.ac.ir.
  • 11 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: momahdavi@sina.tums.ac.ir.
PMID: 38244380 DOI: 10.1016/j.bioorg.2024.107106
Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of α-glucosidase, an Enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as α-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). 8g as the most potent analog, indicating a competitive inhibition with Ki = 9.66 µM. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against α-glucosidase to determine its mode of action in the Enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an α-glucosidase inhibitor for improving blood sugar control and metabolic health.

Keywords

Diabetic rat; Imidazole; Molecular dynamic simulation; α-Glucosidase.

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