Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 187, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.111958
Keywords
Alzheimer's disease; Apigenin-rivastigmine hybrids; Multi-function agents; In vivo assay; Transcriptome sequencing; Metabolism in vitro
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Funding
- China Scholarship Council [201808410456]
- International Training of High-level Talents in Henan Province in 2019 [17]
- Key Research Projects of Henan Higher Education Institutions [20A350006]
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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 mu M) and huBChE (IC50 = 16.1 mu M) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated A beta(1-)(42) aggregation, and also inhibited hAChE-mediated induced A beta(1-40) 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 A beta(1)(-)(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. (C) 2019 Elsevier Masson SAS. All rights reserved.
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