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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

  • Roshanak Ghobadian
  • Roghaieh Esfandyari
  • Hamid Nadri
  • Alireza Moradi
  • Mohammad Mahdavi
  • Tahmineh Akbarzadeh
  • Hossein Khaleghzadeh-Ahangar
  • Najmeh Edraki
  • Mohammad Sharifzadeh
  • Mohsen AminiEmail author
Original Article

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.

Keywords

Synthesis Carbazole Alzheimer’s disease Butyrylcholinesterase Neuroprotective activity 

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest, financial or otherwise.

Supplementary material

11030_2019_9943_MOESM3_ESM.pdf (11.9 mb)
Supplementary material 1 (PDF 12149 kb)
11030_2019_9943_MOESM2_ESM.pdf (828 kb)
Supplementary material 2 (PDF 828 kb)
11030_2019_9943_MOESM1_ESM.pdf (134 kb)
Supplementary material 3 (PDF 133 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Roshanak Ghobadian
    • 1
  • Roghaieh Esfandyari
    • 1
  • Hamid Nadri
    • 2
  • Alireza Moradi
    • 2
  • Mohammad Mahdavi
    • 3
  • Tahmineh Akbarzadeh
    • 1
    • 4
  • Hossein Khaleghzadeh-Ahangar
    • 5
  • Najmeh Edraki
    • 6
  • Mohammad Sharifzadeh
    • 7
  • Mohsen Amini
    • 1
    Email author
  1. 1.Department of Medicinal Chemistry, Faculty of Pharmacy, and Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS)Tehran University of Medical SciencesTehranIran
  2. 2.Pharmaceutical Science Research Center and Faculty of PharmacyShahid Sadoughi University of Medical SciencesYazdIran
  3. 3.Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran
  4. 4.Persian Medicine and Pharmacy Research CenterTehran University of Medical SciencesTehranIran
  5. 5.Department of Physiology, School of MedicineBabol University of Medical SciencesBabolIran
  6. 6.Medicinal and Natural Products Chemistry Research CenterShiraz University of Medical SciencesShirazIran
  7. 7.Department of Pharmacology and Toxicology, Faculty of PharmacyTehran University of Medical SciencesTehranIran

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