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Development of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives as multifunctional agents for Alzheimer’s disease treatment

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Abstract

Due to the complex pathogenesis of AD, the multitarget-directed ligands (MTDLs) strategy presented the best pharmacological option for AD treatment. Herein, a series of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives (5a–f and 6a–f) was rationally designed and synthesized. Of these derivatives, 5c was a good multifunctional agent (eeAChE IC50 = 7.9 μM, MAO-B IC50 = 9.9 μM, BACE1 IC50 = 8.3 μM) in vitro and displayed a mixed-type AChE inhibition, which could bind to the CAS and PAS of AChE. Compound 5c also exhibited good antioxidant activity (ORAC = 2.5 eq) and neuroprotective effects. Furthermore, compound 5c was a selective metal ions chelator. And it could cross blood–brain barrier in vitro and complied with drug-like properties rule of 5. Therefore, compound 5c was a promising multifunctional agent for the treatment of AD.

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Acknowledgements

This work was supported by funding from the Key Scientific Research Project of Colleges and Universities in Henan Province (NO.20A350006), and the Special Project of Nanyang Normal University (SYKF2020032, 2020QN036, and 2020QN045).

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Author notes

  1. These authors contributed equally: Gaofeng Zhu, Xinfeng Li

Authors and Affiliations

  1. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550004, China

    Gaofeng Zhu, Lei Tang & Zhipei Sang

  2. Henan Key Laboratory of Unconventional Feed Resources Innovative Utilization, College of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou, 450046, China

    Xinfeng Li

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

    Jing Yang, Ying He, Jing Mi & Zhipei Sang

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  1. Gaofeng Zhu
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Correspondence to Lei Tang or Zhipei Sang.

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Zhu, G., Li, X., Yang, J. et al. Development of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives as multifunctional agents for Alzheimer’s disease treatment. Med Chem Res 30, 2016–2029 (2021). https://doi.org/10.1007/s00044-021-02786-7

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