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  2. Evaluation of novel 2-(quinoline-2-ylthio)acetamide derivatives linked to diphenyl-imidazole as α-glucosidase inhibitors: Insights from in silico, in vitro, and in vivo studies on their anti-diabetic properties

Evaluation of novel 2-(quinoline-2-ylthio)acetamide derivatives linked to diphenyl-imidazole as α-glucosidase inhibitors: Insights from in silico, in vitro, and in vivo studies on their anti-diabetic properties

  • Eur J Med Chem. 2024 Apr 5:269:116332. doi: 10.1016/j.ejmech.2024.116332.
Minoo Khalili Ghomi 1 Milad Noori 2 Maryam Mirahmad 3 Aida Iraji 4 Ahmad Shahir Sadr 5 Navid Dastyafteh 2 Pooria Asili 3 Mahdi Gholami 6 Shahrzad Javanshir 7 Maryam Lotfi 8 Somayeh Mojtabavi 9 Mohammad Ali Faramarzi 9 Mehdi Asadi 10 Ensieh Nasli-Esfahani 11 Mahdie Palimi 12 Bagher Larijani 3 Mohammad Hadi Meshkatalsadat 13 Mohammad Mahdavi 14
Affiliations

Affiliations

  • 1 Department of Chemistry, Qom University of Technology, Qom, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
  • 2 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, 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 Computer Science Department, Mathematical Sciences Faculty, Shahid Beheshti University, Tehran, Iran; School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran.
  • 6 Toxicology and Diseases Specialty Group, Pharmaceutical Sciences Research Center (PSRC), 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 Pathology, Amir-Alam Hospital, Tehran University of Medical Sciences, Tehran, Iran.
  • 9 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 10 Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Science, Tehran, Iran.
  • 11 Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
  • 12 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 13 Department of Chemistry, Qom University of Technology, Qom, Iran. Electronic address: meshkatalsadat.m@qut.ac.ir.
  • 14 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.
Abstract

The inhibition of the α-glucosidase Enzyme is crucial for targeting type 2 diabetes mellitus (DM). This study introduces a series of synthetic analogs based on thiomethylacetamide-quinoline derivatives linked to diphenyl-imidazole as highly potential α-glucosidase inhibitors. Twenty derivatives were synthesized and screened in vitro against α-glucosidase, revealing IC50 values ranging from 0.18 ± 0.00 to 2.10 ± 0.07 μM, in comparison to the positive control, acarbose. Among these derivatives, compound 10c (IC50 = 0.180 μM) demonstrated the highest potency and revealed a competitive inhibitory mechanism in kinetic studies (Ki = 0.15 μM). Docking and molecular dynamic evaluations elucidated the binding mode of 10c with the active site residues of the α-glucosidase Enzyme. Moreover, in vivo assessments on a rat model of DM affirmed the anti-diabetic efficacy of 10c, evidenced by reduced fasting and overall blood glucose levels. The histopathological evaluation enhanced pancreatic islet architecture and hepatocytes in liver sections. In conclusion, novel 2-(quinoline-2-ylthio)acetamide derivatives as potent α-glucosidase inhibitors were developed. Compound 10c emerged as a promising candidate for diabetes management, warranting further investigation for potential clinical applications and mechanistic insights.

Keywords

2-(quinoline-2-ylthio)acetamide; Diabetes mellitus; In vitro; In vivo; Molecular dynamic; α-glucosidase inhibition.

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