Development of genistein-O-alkylamines derivatives as multifunctional agents for the treatment of Alzheimer’s disease

• Published in: Bioorganic chemistry 2021-02, Vol.107, p.104602, Article 104602
• Main Authors: Sang, Zhipei, Shi, Jian, Zhou, Yi, Wang, Keren, Zhao, Yiyang, Li, Qingfeng, Qiao, Zhanpin, Wu, Anguo, Tan, Zhenghuai, Liu, Wenmin
• Format: Article
• Language: English
• Subjects: AChE inhibition; Activation of GPX4; Alzheimer’s disease; Antioxidant activity; Autophagy inducer; Aβ aggregation inhibition; Metal chelator; Multi-function agents; Neuroprotectant
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104602

[Display omitted] •7d was a selective AChE inhibitor.•7d was a good antioxidant agent and neuroprotectant.•7d was a selective metal ions chelator.•7d could inhibit self-induced, hAChE-induced and Cu2+-induced Aβ aggregation.•7d could cross BBB in vitro and improved scopolamine-induced memory impairment. The multi-target-directed ligands have been regarded as the promising multifunctional agents for the treatment of Alzheimer’s disease (AD). Based on our previous work, a series of genistein-O-alkylamines derivatives was developed to further explore the structure-activity-relationship. The results showed that compound 7d indicated reversible and highly selective hAChE inhibitory activity with IC50 value of 0.53 μM. Compound 7d also displayed good antioxidant activity (ORAC = 1.1 eq.), promising neuroprotective effect and selective metal chelation property. Moreover, compound 7d significantly inhibited self-induced, hAChE-induced and Cu2+-induced Aβ aggregation with 39.8%, 42.1% and 74.1%, respectively, and disaggregated Cu2+-induced Aβ1-42 aggregation (67.3%). In addition, compound 7d was a potential autophagy inducer and improved the levels of GPX4 protein. Furthermore, compound 7d presented good blood-brain-barrier permeability in vitro. More importantly, compound 7d did not show any acute toxicity at doses of up to 1000 mg/kg and presented good precognitive effect on scopolamine-induced memory impairment. Therefore, compound 7d was a promising multifunctional agent for the development of anti-AD drugs.