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

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 hu AChE (IC 50 = 6.8 μM) and hu BChE (IC 50 = 16.1 μM) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated A β 1-42 aggregation, and also inhibited h AChE-mediated induced A β 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 β 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. Image 1 • Novel apigenin-rivastigmine hybrids was rationally designed. • 3d was a promising multi-function agent. • 3d could improve AlCl 3 -induced zebrafish AD. • 3d could protect A β 1-40 -mediated zebrafish vascular injury. • 3d could improve scopolamine-induced memory impairment. [ABSTRACT FROM AUTHOR]