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Novel indolotacrine hybrids as acetylcholinesterase inhibitors: design, synthesis, biological evaluation, and molecular docking studies

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Abstract

A new class of indolotacrine hybrids including cyclopenta- and cyclohexa-indolotacrine derivatives was designed, synthesized, and assessed as acetylcholinesterase inhibitors (AChEIs). Some of the designed derivatives indicated a good inhibitory effect against acetylcholinesterase (AChE). Among them, cyclopenta-indolotacrine hybrids showed a slightly better anti-AChE activity than cyclohexa-indolotacrine hybrids. Compound 5-amino-4-(4-chlorophenyl)-2-(1H-indol-3-yl)-4,6,7,8-tetrahydrocyclopenta[b]pyrano[3,2-e]pyridine-3-carbonitrile (8g) including 4-chlorophenyl and cyclopentane ring showed the best AChE inhibitory activity with IC50 value of 0.4 µM. The kinetic study indicated that compound 8g acted as a competitive inhibitor. Based on molecular docking results, it occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE. Using a neuroprotective assay against H2O2-induced cell death in PC12 neurons, only compound 8b with 4-methoxyphenyl moiety and cyclopentane ring illustrated significant protection (P < 0.0001) at a concentration of 100 μM compared to quercetin at a concentration of 10 μM (P < 0.0001). In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these indolotacrine hybrids can be a very encouraging AChE inhibitor to treat Alzheimer’s disease.

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Acknowledgements

This work was supported by Vice chancellor for Research and Technology of Hamadan University of Medical Sciences with project No. 9605103032.

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Authors and Affiliations

  1. Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran

    Saeed Babaee & Mohammad Ali Zolfigol

  2. Department of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

    Gholamabbas Chehardoli

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

    Mohammad Ali Faramarzi & Somayeh Mojtabavi

  4. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Tahmineh Akbarzadeh & Roshanak Hariri

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

    Tahmineh Akbarzadeh & Arezoo Rastegari

  6. Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran

    Farshad Homayouni Moghadam

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

    Mohammad Mahdavi

  8. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

    Zahra Najafi

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  1. Saeed Babaee
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Correspondence to Zahra Najafi.

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Zahra Najafi et al. declare that there are no conflicts of interest.

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Babaee, S., Zolfigol, M.A., Chehardoli, G. et al. Novel indolotacrine hybrids as acetylcholinesterase inhibitors: design, synthesis, biological evaluation, and molecular docking studies. J IRAN CHEM SOC 20, 1049–1060 (2023). https://doi.org/10.1007/s13738-022-02726-1

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