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A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual eeAChE/eqBuChE inhibitor with IC50 values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1β and NO. In addition, compound 3f presented significant neuroprotective effect on Aβ25-35-induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl3-induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid–donepezil–rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that 5a was a reversible and selective eqBChE inhibitor (IC50 = 0.53 μM), and the docking provided the possible mechanism. Compound 5a also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, 5a exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, 5a demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, 5a was a potential multifunctional lead compound against AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • 3c was a good and balanced multifunctional agent. • 3c was a good antioxidant agent and selective metal ions chelator. • 3c presented good neuroprotective effect and hepatoprotective effect. • 3c demonstrated favourable BBB penetration in vitro and drug-like property. In this work, a series of naringenin- O -carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible hu AChE (IC 50 = 9.7 μM) inhibitor. In addition, compound 3c significantly inhibited self-induced A β 1-42 aggregation, and it could activate UPS degradation pathway in HT22 cells and clear the aggregated proteins associated with AD. Moreover, compound 3c was a selective metal chelator, and it significantly inhibited and disaggregated Cu2+-mediated A β 1-42 aggregation. Furthermore, compound 3c displayed remarkable neuroprotective effect and anti-inflammatory property. Interestingly, compound 3c displayed good hepatoprotective effect by its antioxidant activity. More importantly, compound 3c demonstrated favourable blood–brain barrier penetration in vitro and drug-like property. Therefore, compound 3c was a promising multifunctional agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

Accumulation of evidences suggested that excessive amounts of AChE and BuChE in the brain of AD patients at the different stage of AD, which could hydrolyze ACh and accelerated A β aggregation. To develop new "hidden" multifunctional agents through AChE/BuChE would be a promising strategy to treat AD. To this end, firstly, a series of chalcone derivatives with chelating property was designed and synthesized. The in vitro results showed that compound 3f indicated significant selective MAO-B inhibitory activity (IC 50 = 0.67 μM) and remarkable anti-inflammatory property. It also significantly inhibited self-induced A β 1-42 aggregation and showed remarkable neuroprotective effects on A β 25-35 -induced PC12 cell injury. Furthermore, compound 3f was a selective metal chelator and could inhibit Cu2+-induced A β 1-42 aggregation. Based on this, the carbamate fragment was introduced to compound 3f to obtain carbamate derivatives. The biological activity results exhibited that compound 4b showed good BBB permeability, good AChE inhibitory potency (IC 50 = 5.3 μM), moderate BuChE inhibitory potency (IC 50 = 12.4 μM), significant MAO-B inhibitory potency, anti-inflammation potency on LPS-induced BV-2 cells and neuroprotective effects on A β 25-35 -induced PC12 cell injury. Compared with 3f , compound 4b did not show obvious chelation property. Significantly, compound 4b could be activated by AChE/BuChE following inhibition of AChE/BuChE to liberate an active multifunctional chelator 3f , which was consistent with our original intention. More importantly, compounds 3f and 4b presented favorable ADME properties and good stability in artificial gastrointestinal fluid, blood plasma and rat liver microsomes. The in vivo results suggested that compound 4b (0.0195 μg/mL) could significantly improve dyskinesia and reaction capacity of the AlCl 3 -induced zebrafish AD model by increasing the level of ACh. Together our data suggest that compound 4b was a promising "hidden" multifunctional agent by AChE/BuChE, and this strategy deserved further development for the treatment of AD. [Display omitted] • Compound 3f was a promising multifunctional chelator. • Compound 4b was a hidden multifunctional prechelator. • Compound 4b could be activated to compound 3f by AChE/BuChE. • Compounds 3f and 4b presented favorable drug-likeness. • 4b could improve AlCl 3 -induced zebrafish AD model. [ABSTRACT FROM AUTHOR]

[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]

[Display omitted] • 4e was a potent and well-balanced huBuChE and huMAO-B inhibitor. • 4e presented significant antioxidant, anti-inflammatory and neuroprotective effect. • 4e presented good BBB penetration and drug-like property. • 4e improved AlCl 3 -induced zebrafish AD. • 4e improved scopolamine-induced memory impairment. Herein, combining 1,2,3,4-tetrahydroisoquinoline and benzylpiperidine groups into cinnamic acid derivatives, a series of novel cinnamic acid hybrids was rationally designed, synthesized and evaluated by the multi-target-directed ligands (MTDLs) strategy. Hybrid 4e was the most promising one among these hybrids with a reversible hu BuChE inhibitor (IC 50 = 2.5 μM) and good MAO-B inhibition activity (IC 50 = 1.3 μM) and antioxidant potency (ORAC = 0.4 eq). Moreover, compound 4e significantly inhibited self-mediated A β 1-42 aggregation (65.2% inhibition rate). Compound 4e exhibited remarkable anti-inflammatory propery and neuroprotective effect. Furthermore, compound 4e displayed favourable blood–brain barrier penetration via parallel artificial membrane permeation assay (PAMPA). The obtained results also revealed that compound 4e significantly improved dyskinesia recovery rate and response efficiency on AD model zebrafish. Further, 4e did not show obvious acute toxicity at dose up to 1500 mg/kg in vivo and improved scopolamine-induced memory impairment. Importantly, compound 4e showed good stability in both artificial gastric fluid and artificial intestinal fluid. Therefore, compound 4e presented a promising multi-targeted active molecule for treating AD. [ABSTRACT FROM AUTHOR]