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1H-benzimidazole derivatives as butyrylcholinesterase inhibitors: synthesis and molecular modeling studies

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Abstract

A series of N-{2-[2-(1H-benzimidazole-2-yl)phenoxy]ethyl} substituted amine derivatives were synthesized and tested for their cholinesterase inhibitor activity. Acetylcholinesterase and butyrylcholinesterase inhibitor activities were evaluated in vitro by using Ellman’s method. According to the activity results, all of the compounds displayed moderate acetylcholinesterase inhibitory activity and most of the compounds displayed remarkable butyrylcholinesterase inhibitory activity. Compound 3d was the most active compound in the series and also a selective butyrylcholinesterase inhibitor. Molecular docking studies and molecular dynamic simulations were also carried out.

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Abbreviations

AD:

Alzheimer’s disease

ACh:

acetylcholine

AChE:

acetylcholinesterase

AChEI:

acetylcholinesterase inhibitor

ATC:

acetylthiocholine iodide

BTC:

butyrylthiocholine iodide

BuChE:

butyrylcholinesterase

BuChEI:

butyrylcholinesterase inhibitor

CAS:

catalytic active site

ChE:

cholinesterase

ChEI:

cholinesterase inhibitor

DMF:

dimethyl formamide

DMSO:

dimethylsulfoxide

DTNB:

5,5-dithiobis(2-nitrobenzoic acid)

HMBC:

Heteronuclear Multiple Bond Correlation

HSQC:

Heteronuclear Single Quantum Correlation

MD:

molecular dynamics

RMSD:

root main square deviation

TLC:

thin-layer chromatography

VMD:

visual molecular dynamics

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Acknowledgments

This study was partially supported by TUBITAK (Turkish Scientific and Technical Research Council) (Project number: 213S027). We appreciate the support of Professor Dr. Wolfgang Sippl for molecular modeling studies. We also thank the Medicinal Chemistry Department of Martin Luther University Institute of Pharmacy and also Pharmaceutical Sciences Research Centre (FABAL) of Ege University Faculty of Pharmacy for equipmental support.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, Bornova, 35100, Izmir, Turkey

    Gunes Coban, Ayse Hande Tarikogullari, Sülünay Parlar, Görkem Sarıkaya, Vildan Alptüzün, Ayşe Selcen Alpan, Hasan Semih Güneş & Erçin Erciyas

  2. Department of Pharmaceutical Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Halle/Saale, 06120, Germany

    Luca Carlino

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  1. Gunes Coban
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  2. Luca Carlino
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  3. Ayse Hande Tarikogullari
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  4. Sülünay Parlar
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Correspondence to Ayşe Selcen Alpan.

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Coban, G., Carlino, L., Tarikogullari, A.H. et al. 1H-benzimidazole derivatives as butyrylcholinesterase inhibitors: synthesis and molecular modeling studies. Med Chem Res 25, 2005–2014 (2016). https://doi.org/10.1007/s00044-016-1648-1

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