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Synthesis of novel carboxamide- and carbohydrazide-benzimidazoles as selective butyrylcholinesterase inhibitors

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Abstract

Selectively inhibiting butyrylcholinesterase (BChE) is hypothesized to help in the management of Alzheimer’s disease (AD). Several studies have determined a correlation between the increased activity of BChE and the onset of AD. An advantage of BChE over acetylcholinesterase inhibition is that absence of BChE activity does not lead to obvious physiological disturbance. However, currently no BChE inhibitors are available commercially as potential therapeutics for AD. In our continuous effort to find potent BChE inhibitors for Alzheimer’s disease, a total of 22 novel benzimidazoles with diversified substitutions were synthesized and evaluated for their anticholinesterase activities in this study. Among the synthesized compounds, 2j and 3f were found to exhibit potent and selective BChE inhibition with IC50 values of 1.13 and 1.46 μM, respectively. Molecular docking studies were carried out to rationalize the observed inhibitory activities. The compounds were predicted to have high penetration across the blood–brain barrier. Moreover, cell proliferative studies were also performed to evaluate the toxicity profile of the interested compounds.

Graphical abstract

Compound 3f was found to be a potent and selective butyrylcholinesterase inhibitor with an IC50 value of 1.46 µM.

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Availability of data and materials

Compound characterization data including NMR and mass spectra for all compounds, detailed cholinesterase inhibition and compound cytotoxic information are available in Supplementary Data.

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Acknowledgements

The authors would like to thank School of Science, Monash University Malaysia, for supporting this work. This work was funded through Monash University Malaysia Early Career Researcher Seed Fund (ECRG-2019-10-SCI).

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Authors and Affiliations

  1. School of Science, Monash University Malaysia Campus, Jalan Lagoon Selatan, 47500, Bandar Sunway, Selangor, Malaysia

    Fathima Manaal Farouk, Luyi Ooi, Christine Shing Wei Law & Keng Yoon Yeong

  2. Faculty of Pharmacy, Pharmaceutical Chemistry Department, Ankara University, 06100, Tandogan, Ankara, Turkey

    Ozum Ozturk & Esin Aki-Yalcin

  3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suleyman Demirel University, 32200, Isparta, Turkey

    Muhammed Tilahun Muhammed

Authors
  1. Ozum Ozturk
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  2. Fathima Manaal Farouk
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  3. Luyi Ooi
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  6. Esin Aki-Yalcin
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  7. Keng Yoon Yeong
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Contributions

Keng Yoon Yeong and Esin-Aki Yalcin conceptualized the project. Material preparation and data collection were performed by Ozum Ozturk, Fathima Manaal Farouk, Luyi Ooi, Christine Shing Wei Law and Muhammed Tilahun Muhammed. Data analyses were performed by all authors. All authors read and approved the manuscript.

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Correspondence to Esin Aki-Yalcin or Keng Yoon Yeong.

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Ozturk, O., Farouk, F.M., Ooi, L. et al. Synthesis of novel carboxamide- and carbohydrazide-benzimidazoles as selective butyrylcholinesterase inhibitors. Mol Divers 26, 2863–2876 (2022). https://doi.org/10.1007/s11030-022-10476-8

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