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Synthesis and evaluation of chromone-2-carboxamido-alkylamines as potent acetylcholinesterase inhibitors

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Abstract

Alzheimer’s disease (AD) is considered one of the greatest global public burdens. Pathophysiology of AD is proposed to be associated with reduced levels of the neurotransmitter acetylcholine (ACh). Cholinesterase enzymes, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) cleave ACh via hydrolysis. Cholinesterase inhibitors (ChEIs) are the main group of drugs currently used for the treatment of AD. Novel chromone-2-carboxamido-alkylamines (7–18) were designed, synthesized, and evaluated for cholinesterase inhibitory activity. The compounds exhibited potent AChE inhibitory activities at micromolar range (IC50 0.09–9.16 µM) and demonstrated weak BChE inhibitory activities (IC50 12.09–44.56 µM). Compound 14 (IC50 0.09 ± 0.02 µM) was the most potent AChEI in this series; it showed higher activity than the clinical used drug tacrine. Enzyme kinetic study suggested that 14 was an uncompetitive inhibitor. Molecular docking study revealed that 14 was a dual-binding site inhibitor. Compound 14 did not induce any concentration-related cytotoxic effect against SH-SY5Y cells. It also showed neuroprotective effect in the cell line. Chromone-2-carboxamido-alkylamines can be promising lead compounds for development of anti-Alzheimer’s agents.

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Acknowledgements

We would like to thank Prince of Songkla University (Grant No. PHA590412S) and the University of Malaya (UMRG: RP037D-17AFR) for financial support of this study. The authors would like to thank Miss Maria Mullet for providing linguistic proofreading for the manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand

    Paptawan Suwanhom & Luelak Lomlim

  2. Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand

    Teerapat Nualnoi

  3. Institute of Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand

    Pasarat Khongkow

  4. Department of Chemistry, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Vannajan Sanghiran Lee

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  1. Paptawan Suwanhom
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  4. Vannajan Sanghiran Lee
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  5. Luelak Lomlim
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Correspondence to Luelak Lomlim.

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Suwanhom, P., Nualnoi, T., Khongkow, P. et al. Synthesis and evaluation of chromone-2-carboxamido-alkylamines as potent acetylcholinesterase inhibitors. Med Chem Res 29, 564–574 (2020). https://doi.org/10.1007/s00044-020-02508-5

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  • DOI: https://doi.org/10.1007/s00044-020-02508-5

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