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Design, synthesis, and evaluation of 2,2’-bipyridyl derivatives as bifunctional agents against Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is a complex multifactorial neurodegenerative disease. Metal ion dyshomeostasis and Aβ aggregation have been proposed to contribute to AD progression. Metal ions can bind to Aβ and promote Aβ aggregation, and ultimately lead to neuronal death. Bifunctional (metal chelation and Aβ interaction) compounds are showing promise against AD. In this work, eleven new 3,3’-diamino-2,2’-bipyridine derivatives 4a-4k were synthesized, and evaluated as bifunctional agents for AD treatment. In vitro Aβ aggregation inhibition assay confirmed that most of the synthesized compounds exhibited significant self-induced Aβ1−42 aggregation inhibition. Among them, compound 4d displayed the best inhibitory potency of self-induced Aβ1−42 aggregation with IC50 value of 9.4 µM, and it could selectively chelate with Cu2+ and exhibited 66.2% inhibition of Cu2+-induced Aβ1−42 aggregation. Meanwhile, compound 4d showed strong neuroprotective activity against Aβ1−42 and Cu2+-treated Aβ1−42 induced cell damage. Moreover, compound 4d in high dose significantly reversed Aβ-induced memory impairment in mice.

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Acknowledgements

The authors thank the research funds of the Doctoral Program of Guangdong Medical University (B2017011), the National Natural Science Foundation of China (21502025), and the research funds of the Students’ Innovative Program of Guangdong Province (202110571029, 202110571048) for financial support of this study.

Funding

This study was supported by the Students' Innovative Program of Guangdong Province (Grant Nos. 202110571029, 202110571048); National Natural Science Foundation of China (Grant No. 21502025), The Doctoral Program of Guangdong Medical University (Grant No. B2017011).

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  1. School of Pharmacy, Guangdong Medical University, Dongguan, 523808, Guangdong, China

    Ren-Xian Tan, Wei-Hao Li, Jia-Min Pang, Si-Min Zhong, Xin-Yi Huang, Jun-Ze Deng, Lu-Yi Zhou & Xiao-Qin Wang

  2. School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China

    Jia-Qiang Wu

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Contributions

X-QW conceptualized the project and prepared the manuscript. R-XT performed the synthesis experiments, collected data and analyzed the data; W-HL, J-MP and S-MZ performed the synthesis experiments; J-ZD, X-YH and L-YZ performed the biological studies. J-QW performed the structure identification. All authors have read and approved the final manuscript.

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Correspondence to Xiao-Qin Wang.

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Tan, RX., Li, WH., Pang, JM. et al. Design, synthesis, and evaluation of 2,2’-bipyridyl derivatives as bifunctional agents against Alzheimer’s disease. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10651-5

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