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New acridine-9-carboxamide linked to 1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: design, synthesis, in vitro, and in silico biological evaluations

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Abstract

α-Glucosidase plays a major role in degradation of carbohydrates to glucose. Therefore, inhibition of this enzyme can be useful in the treatment of carbohydrate-related diseases such as diabetes, cancer, and viral infections. In this study, a new series of acridine-9-carboxamide linked to 1,2,3-triazole-N-phenylacetamide derivatives 5a–m were designed, synthesized, and evaluated as potent α-glucosidase inhibitors. All the synthesized compounds showed excellent to good inhibitory activity against α-glucosidase with IC50 values of 80.3 ± 0.9–564.3 ± 7.2 µM in comparison with standard drug acarbose (IC50 value = 750.0 ± 10.5 μM). Among the synthesized compounds, the most active compound was 3-bromo derivative 5h with inhibitory activity around 9.3 times more than acarbose. this compound was selected for farther biological evaluations. Kinetic study of compound 5h revealed that it is a competitive inhibitor against α-glucosidase. Docking study of compound 5h and its regioisomer 5i with 4-bromo substituent were also carried out in the active site of α-glucosidase to gain an insight into the interaction modes of the synthesized compounds and rationalized structure–activity relationship between these two compounds. Compound 5h was also evaluated against α-amylase and no activity was observed in comparison with acarbose. Furthermore, in vitro cytotoxic assay of compound 5h against human normal and cancer cell lines HDF and MCF-7, respectively, revealed that this compound is a noncytotoxic agent. In silico pharmacokinetic and toxicity assays of compound 5h was performed and obtained results were compared with acarbose.

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Authors and Affiliations

  1. Nano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran, 1439955991, Iran

    Nima Sepehri

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

    Nafise Asemanipoor, Mahmood Biglar, Bagher Larijani & Mohammad Mahdavi

  3. School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran

    Seyed Ali Mousavianfard & Mehdi Adib

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

    Seyedhamid Hoseini & Mohammad Ali Faramarzi

  5. CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran

    Haleh Hamedifar

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

    Maryam Mohammadi-Khanaposhtani

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  1. Nima Sepehri
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  2. Nafise Asemanipoor
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  3. Seyed Ali Mousavianfard
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  4. Seyedhamid Hoseini
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  7. Mahmood Biglar
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Correspondence to Maryam Mohammadi-Khanaposhtani or Mohammad Mahdavi.

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Sepehri, N., Asemanipoor, N., Mousavianfard, S.A. et al. New acridine-9-carboxamide linked to 1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: design, synthesis, in vitro, and in silico biological evaluations. Med Chem Res 29, 1836–1845 (2020). https://doi.org/10.1007/s00044-020-02603-7

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  • DOI: https://doi.org/10.1007/s00044-020-02603-7

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