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Indazole derivatives as selective inhibitors of butyrylcholinesterase with effective blood-brain-barrier permeability profile

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Abstract

Alzheimer’s disease (AD) is a chronic disease that is multifactorial. Its underlying cause and mechanisms are yet to be fully understood and numerous research are underway to develop more effective drug candidates. This research explores the synthesis of an indazole-containing novel drug targeting AD, particularly by inhibiting cholinesterase activity. Among the 17 indazole derivatives synthesized in this study, compound 4q was demonstrated to have potent and selective butyrylcholinesterase (BChE) inhibitory activity. Molecular docking simulations revealed that the binding of 4q with BChE was through hydrophobic and polar interactions. It was also found to easily permeate through the blood-brain-barrier via an in vitro model and is non-toxic when tested against SH-SY5Y cells.

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Acknowledgements

The authors wish to express their gratitude to the School of Science, Monash University Malaysia and Nanotechnology and Catalysis Research Centre, Universiti Malaya for supporting this work.

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Authors and Affiliations

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

    Asuka Joy Tobuse, Christine Shing Wei Law & Keng Yoon Yeong

  2. Nanotechnology and Catalysis Research Centre, Universiti Malaya, 50603, Kuala Lumpur, Malaysia

    Chun Keng Thy, Jason Jonah James & Chin Fei Chee

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Correspondence to Chin Fei Chee or Keng Yoon Yeong.

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Tobuse, A.J., Law, C.S.W., Thy, C.K. et al. Indazole derivatives as selective inhibitors of butyrylcholinesterase with effective blood-brain-barrier permeability profile. Med Chem Res 33, 298–307 (2024). https://doi.org/10.1007/s00044-023-03179-8

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