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Synthesis, in vitro and in silico enzymatic inhibition assays, and toxicity evaluations of new 4,5-diphenylimidazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors

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Abstract

α-Glucosidase is responsible for glucose release of oligosaccharides and disaccharides in the intestine and increase postprandial hyperglycemia. Inhibition of this enzyme is a beneficial therapeutic method for glycemic control in diabetes. This study deals with the design and synthesis of 4,5-diphenylimidazole-N-phenylacetamide derivatives 7a–l and the screen of these compounds for their potential for α-glucosidase inhibition. All the synthesized compounds exhibited superior α-glucosidase inhibition (IC50 = 90.0–598.5 µM) as compared to standard inhibitor acarbose (IC50 = 750.0 µM). In contrast, these compounds were inactive against α-amylase. Among the synthesized compounds, compound 7h was the most potent inhibitor of this library and was a competitive inhibitor into α-glucosidase with Ki value = 86.3 μM. Docking study of the most potent compounds was performed to evaluate the binding interactions of these compounds with the active site of enzyme and to determine of binding energies of ligand–enzyme complexes. The results of this in silico study are in complete agreement with the results obtained from in vitro α-glucosidase inhibition assay. Docking study of the most potent compound demonstrated that it interacted with important residues in the active site of α-glucosidase. In vitro cytotoxic activity of the most potent compounds and in silico druglikeness/ADME/toxicity study of these compounds were evaluated.

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Funding

This work was financially supported by Babol University of Medical Sciences (the grant number: 724132438). The ethics code for this study is IR.MUBABOL.HRI.REC.1398.181.

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Authors and Affiliations

  1. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

    Maryam Mohammadi-Khanaposhtani

  2. Department of Medicinal Chemistry, Faculty of Pharmacy, Islamic Azad University, Ayatollah Amoli Branch, Amol, Iran

    Atefeh Nikraftar

  3. School of Chemistry, College of Science, University of Tehran, Tehran, Iran

    Mohammad Sadegh Asgari

  4. Electrical and Computer Engineering Department, Babol Noshirvani University of Technology, Babol, Iran

    Mehdi Emadi

  5. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Somayeh Mojtabavi & Mohammad Ali Faramarzi

  6. Cosmetic Products Research Center, Iranian Food and Drug Administration, MOHE, Tehran, Iran

    Hossein Rastegar

  7. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Bagher Larijani & Mohammad Mahdavi

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  1. Maryam Mohammadi-Khanaposhtani
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  2. Atefeh Nikraftar
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Mohammadi-Khanaposhtani, M., Nikraftar, A., Asgari, M.S. et al. Synthesis, in vitro and in silico enzymatic inhibition assays, and toxicity evaluations of new 4,5-diphenylimidazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors. Med Chem Res 30, 1273–1283 (2021). https://doi.org/10.1007/s00044-021-02734-5

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  • DOI: https://doi.org/10.1007/s00044-021-02734-5

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