Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies.

[Display omitted] • 5,6-Dimethoxy-1-indanone-chalcone- O -carbamate 10c was a reversible hu AChE and hu BuChE inhibitor. • 10c also presented significant anti-inflammation effects, inhibition effects on A β 1-42 aggregation, and neuroprotective effect on A β 1-42 -induced PC12 cell injury. • 10c presented good metabolic stability and pharmacokinetic properties. • PET-CT imaging demonstrated that [11C] 10c could quickly penetrate the brain. • 10c could improve scopolamine-induced memory impairment. Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible hu AChE (IC 50 = 0.87 μM) and hu BuChE (IC 50 = 3.3 μM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-α production, and significantly inhibited self-mediated A β 1-42 aggregation (60.6%) and hu AChE-mediated induced A β 1-40 aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on A β 1-42 -induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [11C] 10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations. [ABSTRACT FROM AUTHOR]