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Design, synthesis, in vivo and in vitro studies of 1,2,3,4-tetrahydro-9H-carbazole derivatives, highly selective and potent butyrylcholinesterase inhibitors

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Abstract

Inhibition of butyrylcholinesterase (BChE) might be a useful therapeutic target for Alzheimer’s disease (AD). A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit (> 100 µM), they were selective potent BChE inhibitors. 1-(2-(6-fluoro-1,2,3,4-tetrahydro-9H-carbazole-9-yl)ethyl)piperidin-1-ium chloride (15 g) had the most potent anti-BChE activity (IC50 value = 0.11 μM), the highest BChE selectivity and mixed-type inhibition. Pharmacokinetic properties were accordant to Lipinski rule and compound 15g demonstrated neuroprotective and inhibition of β-secretase (BACE1) activities. Furthermore, in vivo study of compound 15g in Morris water maze task has confirmed memory improvement in scopolamine-induced impairment. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

Graphical abstract

A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit, they were selective potent BChE inhibitors. Compound 15g had the most potent anti-BChE activity. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

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Acknowledgements

The authors thank the equipment supports from Department of Medicinal Chemistry, Shahid Sadoughi University of Medical Sciences, Yazd, Iran, and Department of Cellular Biotechnology at Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran. This work was supported by Grants (9211302001) from the Research Council of Tehran University of Medical Sciences.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Faculty of Pharmacy, and Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

    Roshanak Ghobadian, Roghaieh Esfandyari, Tahmineh Akbarzadeh & Mohsen Amini

  2. Pharmaceutical Science Research Center and Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, 8915173143, Iran

    Hamid Nadri & Alireza Moradi

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

    Mohammad Mahdavi

  4. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Tahmineh Akbarzadeh

  5. Department of Physiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran

    Hossein Khaleghzadeh-Ahangar

  6. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Najmeh Edraki

  7. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Sharifzadeh

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  1. Roshanak Ghobadian
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Correspondence to Mohsen Amini.

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Ghobadian, R., Esfandyari, R., Nadri, H. et al. Design, synthesis, in vivo and in vitro studies of 1,2,3,4-tetrahydro-9H-carbazole derivatives, highly selective and potent butyrylcholinesterase inhibitors. Mol Divers 24, 211–223 (2020). https://doi.org/10.1007/s11030-019-09943-6

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