2. Academic Validation
  3. Apigenin-rivastigmine hybrids as multi-target-directed liagnds for the treatment of Alzheimer's disease

Apigenin-rivastigmine hybrids as multi-target-directed liagnds for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2020 Feb 1;187:111958. doi: 10.1016/j.ejmech.2019.111958.
Zhipei Sang 1,  Keren Wang 2,  Jian Shi 2,  Xinfeng Cheng 2,  Gaofeng Zhu 3,  Rongrui Wei 4,  Qinge Ma 4,  Lintao Yu 2,  Yiyang Zhao 2,  Zhenghuai Tan 5,  Wenmin Liu 6
Affiliations

Affiliations

  • 1 College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China. Electronic address: [email protected].
  • 2 College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China.
  • 3 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medcial University, Guiyang, 550014, China.
  • 4 State Key Laboratory of Innovative Drugs and High Efficiency Energy Saving and Consumption Reduction Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.
  • 5 Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China. Electronic address: [email protected].
  • 6 College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, 473061, China. Electronic address: [email protected].
PMID: 31865014 DOI: 10.1016/j.ejmech.2019.111958
Abstract

Here we reported novel apigenin-rivastigmine hybrids were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, their activity in vitro results revealed that compound 3d showed significant antioxidant potency (ORAC = 1.3 eq), and it was a reversible huAChE (IC50 = 6.8 μM) and huBChE (IC50 = 16.1 μM) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated Aβ1-42 aggregation, and also inhibited hAChE-mediated induced Aβ1-40 aggregation. Compound 3d exhibited remarkable neuroprotective effect and hepatoprotective activity. In addition, compound 3d presented favourable blood-brain barrier penetration in vitro and drug-like property. Further, the in vivo assay displayed that 3d indicated remarkable dyskinesia recovery rate and response efficiency on AD zebrafish, and exhibited surprising protective effect on Aβ1-40-mediated zebrafish vascular injury. More importantly, 3d did not indicate obvious acute toxicity at dose up to 2000 mg/kg, and could improve scopolamine-induced memory impairment. Subsequently, the regulation of multi-targets for 3d were further confirmed through transcriptome sequencing of brain hippocampi, which also offered novel potential targets and opened a new way to treat Alzheimer's disease. More interestingly, the metabolism of 3din vitro indicated that 4 metabolites in rat liver microsome metabolism, 2 metabolites in human liver microsome metabolism, and 4 metabolites in intestinal flora metabolism, which offered supports for the preclinical study of 3d. Overall, this study exhibited that compound 3d was a promising advanced compound targeted multiple factors associated with AD.

Keywords

Alzheimer’s disease; Apigenin-rivastigmine hybrids; In vivo assay; Metabolism in vitro; Multi-function agents; Transcriptome sequencing.

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