US EPA

7458287 

Journal Article 

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

Sang, Z; Wang, K; Shi, J; Cheng, X; Zhu, G; Wei, R; Ma, Q; Yu, L; Zhao, Y; Tan, Z; Liu, W 

2020 

Yes 

European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254 

Elsevier Masson SAS 

187 

English 

10.1016/j.ejmech.2019.111958 

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 3d in 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. © 2019 Elsevier Masson SAS 

Alzheimer's disease; Apigenin-rivastigmine hybrids; In vivo assay; Metabolism in vitro; Multi-function agents; Transcriptome sequencing; 2 [4 [(diethylcarbamoyl)oxy]phenyl] 5 hydroxy 4 oxo 4h chromen 7 yl dimethylcarbamate; 2 [4 [(dimethylcarbamoyl)oxy]phenyl] 4 oxo 4h chromene 5,7 diyl bis(dimethylcarbamate); 2 [4 [(dimethylcarbamoyl)oxy]phenyl] 5 hydroxy 4 oxo 4h chromen 7 yl dimethylcarbamate; 2 [4 [(diphenylcarbamoyl)oxy]phenyl] 5 hydroxy 4 oxo 4h chromen 7 yl dimethylcarbamate; 2 [4 [[ethyl(methyl)carbamoyl]oxy]phenyl] 4 oxo 4h chromene 5,7 diyl bis[ethyl(methyl)carbamate]; 2 [4 [[ethyl(methyl)carbamoyl]oxy]phenyl] 5 hydroxy 4 oxo 4h chromen 7 yl ethyl(methyl(carbamate; 2 [4 [[ethyl(methyl)carbamoyl]oxy]phenyl] 5 hydroxy 4 oxo 4h chromen 7 yl ethyl(methyl)carbamate; 2 [4 [[methoxy(methyl)carbamoyl]oxy]phenyl] 4 oxo 4h chromene 5,7 diyl bis[methoxy(methyl)carbamate]; 5 hydroxy 2 [4 [(morpholine 4 carbonyl)oxy]phenyl] 4 oxo 4h chromen 7 yl morpholine 4 carboxylate; 5 hydroxy 2 [5 [[methoxy(methyl)carbamoyl]oxy]phenyl] 4 oxo 4h chromen 7 yl methoxy(methyl)carbamate; 5 hydroxy 4 oxo 2 [4 [(morpholine 1 carbonyl)oxy]phenyl] 4h chromen 7 yl morpholine 1 carboxylate; 5 hydroxy 4 oxo 2 [4 [(pyrrolidine 1 carbonyl)oxy]phenyl] 4h chromen 7 yl pyrrolidine 1 carboxylate; acetylcholinesterase; aluminum; amyloid beta protein[1-40]; amyloid beta protein[1-42]; antioxidant; apigenin; apigenin derivative; chelating agent; cholinesterase; cuprous ion; curcumin; donepezil; ferrous ion; liver protective agent; neuroprotective agent; rivastigmine; transcriptome; unclassified drug; zinc ion; acetylcholinesterase; amyloid beta protein; apigenin; cholinesterase; cholinesterase inhibitor; ligand; neuroprotective agent; rivastigmine; acute toxicity; Alzheimer disease; animal cell; animal experiment; animal model; antioxidant activity; Article; bacterial metabolism; blood brain barrier; blood vessel injury; chelation; cholinesterase inhibition; controlled study; drug dose comparison; drug efficacy; drug mechanism; drug megadose; drug potency; drug solubility; drug synthesis; drug targeting; dyskinesia; human; human cell; IC50; in vitro study; in vivo study; intestine flora; liver microsome metabolism; liver protection; liver toxicity; molecular docking; mouse; nephrotoxicity; neuroprotection; neurotoxicity; nonhuman; optimal drug dose; oxygen radical absorbance capacity; PC12 cell line (pheochromocytoma); preclinical study; protein aggregation; rat; regulatory mechanism; scopolamine-induced cognitive defect; transcriptomics; zebra fish; Alzheimer disease; animal; chemical structure; chemistry; dose response; liver microsome; metabolism; structure activity relation; synthesis; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apigenin; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Ligands; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; Rats; Rivastigmine; Structure-Activity Relationship; Zebrafish