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Novel tacrine-based acetylcholinesterase inhibitors as potential agents for the treatment of Alzheimer’s disease: Quinolotacrine hybrids

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Abstract

A new series of quinolotacrine hybrids including cyclopenta- and cyclohexa-quinolotacrine derivatives were designed, synthesized, and assessed as anti-cholinesterase (ChE) agents. The designed derivatives indicated higher inhibitory effect on the acetylcholinesterase (AChE) with IC50 values of 0.285–100 µM compared to butyrylcholinesterase (BChE) with IC50 values of > 100 µM. Of these compounds, cyclohexa-quinolotacrine hybrids displayed a little better anti-AChE activity than cyclopenta-quinolotacrine hybrids. Compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6m) including 3-hydroxyphenyl and cyclohexane ring moieties exhibited the best AChE inhibitory activity with IC50 value of 0.285 µM. The kinetic and molecular docking studies indicated that compound 6m occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE as a mixed inhibitor. Using neuroprotective assay against H2O2-induced cell death in PC12 cells, the compound 6h illustrated significant protection among the assessed compounds. In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these quinolotacrine hybrids can be very encouraging AChE inhibitors to treat Alzheimer’s disease.

Graphic abstract

A novel series of quinolotacrine hybrids were designed, synthesized, and evaluated against AChE and BChE enzymes as potential agents for the treatment of AD. The hybrids showed good to significant inhibitory activity against AChE (0.285–100 μM) compared to butyrylcholinesterase (BChE) with IC50 values of > 100 μM. Among them, compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c′] diquinolin-6-one (6 m) bearing 3-hydroxyphenyl moiety and cyclohexane ring exhibited the highest anti-AChE activity with IC50 value of 0.285 μM. The kinetic and molecular docking studies illustrated that compound 6 m is a mixed inhibitor and binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.

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Acknowledgements

This work was supported by Research Council of Hamadan University of Medical Sciences with project No. 9709065238.

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Authors and Affiliations

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

    Mehrdad Sadafi Kohnehshahri, Gholamabbas Chehardoli, Masoomeh Bahiraei & Zahra Najafi

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

    Tahmineh Akbarzadeh & Arezoo Rastegari

  3. Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

    Akram Ranjbar

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  1. Mehrdad Sadafi Kohnehshahri
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Sadafi Kohnehshahri, M., Chehardoli, G., Bahiraei, M. et al. Novel tacrine-based acetylcholinesterase inhibitors as potential agents for the treatment of Alzheimer’s disease: Quinolotacrine hybrids. Mol Divers 26, 489–503 (2022). https://doi.org/10.1007/s11030-021-10307-2

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