1. Apigenin-rivastigmine hybrids as multi-target-directed liagnds for the treatment of Alzheimer's disease.
- Author
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Sang Z, Wang K, Shi J, Cheng X, Zhu G, Wei R, Ma Q, Yu L, Zhao Y, Tan Z, and Liu W
- Subjects
- Acetylcholinesterase metabolism, Alzheimer Disease metabolism, Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides metabolism, Animals, Apigenin chemistry, Apigenin metabolism, Butyrylcholinesterase metabolism, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors chemistry, Dose-Response Relationship, Drug, Humans, Ligands, Microsomes, Liver chemistry, Microsomes, Liver metabolism, Molecular Docking Simulation, Molecular Structure, Neuroprotective Agents chemical synthesis, Neuroprotective Agents chemistry, Rats, Rivastigmine chemistry, Rivastigmine metabolism, Structure-Activity Relationship, Zebrafish, Alzheimer Disease drug therapy, Apigenin pharmacology, Cholinesterase Inhibitors pharmacology, Neuroprotective Agents pharmacology, Rivastigmine pharmacology
- 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 (IC
50 = 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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2020
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