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  3. 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: [email protected].
  • 14 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected].
PMID: 38508120 DOI: 10.1016/j.ejmech.2024.116332
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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