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Design, synthesis and evaluation of salicylic acid-donepezil hybrids as functional agents for the treatment of Alzheimer’s disease

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Abstract

In this work, a series of salicylic acid derivatives was designed through the multi-target-directed ligand strategy (MTDLs). The synthesized compounds were evaluated as multifunctional agents. The in vitro biological activity results revealed that compound 3a was a selective eqBuChE inhibitor (IC50 = 0.29 μM), compound 3k was a selective eeAChE inhibitor (IC50 = 0.77 μM), and compound 3p was a selective eqBuChE inhibitor (IC50 = 0.82 μM). Compounds 3a, 3k and 3p also showed good antioxidant activity and anti-inflammatory property. Furthermore, compounds 3a, 3k and 3p were selective metal chelators. Moreover, compounds 3a, 3k and 3p showed significant neuroprotective effects on H2O2-/Aβ25-35-induced PC12 cells injury. More importantly, compounds 3a, 3k and 3p possessed favorable ADME properties. Taken together, compounds 3a, 3k and 3p were promising multifunctional agents, deserving further investigations.

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Acknowledgements

This work was financially supported by the Science and Technology Project of Henan Province (NO.2121023111000); The Special Project of Nanyang Normal University (2020STP006, SYKF2020032, 2020ZX015, 2020QN036, 2020QN045 and 2021CX002) and the Technical System Project of Traditional Chinese medicinal Industry in Henan Province (HARS-22-11-Z2)

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The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

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  1. These authors contributed equally: Ying He, Zhili Rao, Zhengwei Liu

Authors and Affiliations

  1. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China

    Ying He, Zhengwei Liu, Jing Mi, Jing Yang, Yi Zhou, Wenmin Liu & Zhipei Sang

  2. Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China

    Zhili Rao & Nan Zeng

  3. School of Pharmacy, Army Medical University, ChongQing, 400000, ChongQing, China

    Zhili Rao

  4. Nanyang Academy of Agricultural Sciences, Nanyang, 473061, China

    Zhigang Yin & Peiyu Chen

  5. State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China

    Nan Zeng

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He, Y., Rao, Z., Liu, Z. et al. Design, synthesis and evaluation of salicylic acid-donepezil hybrids as functional agents for the treatment of Alzheimer’s disease. Med Chem Res 32, 355–368 (2023). https://doi.org/10.1007/s00044-022-03010-w

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