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A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer’s disease (AD). The results showed that compound TM - 9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B ( hu AChE, hu BuChE, and hu MAO-B with IC 50 values of 1.2 μM, 3.8 μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM - 9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM - 9 abided by Lipinski’s rule of five. Furthermore, our investigation proved that TM - 9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro . The results suggest that compound TM - 9 , an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

A series of 2-acetyl-5- O -(amino-alkyl)phenol derivatives was designed, synthesized and evaluated as multi-function inhibitors for the treatment of Alzheimer’s disease (AD). The results revealed that compound TM-3 indicated selective AChE inhibitory potency ( ee AChE, IC 50  = 0.69 μM, selective index (SI) = 32.7). Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-3 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. And TM-3 was also a highly selective MAO-B inhibitor (IC 50  = 6.8 μM). Moreover, TM-3 could act as antioxidant (ORAC value was 1.5 eq ) and neuroprotectant, as well as a selective metal chelating agent. More interestingly, compound TM-3 could cross the blood-brain barrier (BBB) in vitro and abided by Lipinski’s rule of five. Therefore, compound TM-3 , a promising multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against AD. [ABSTRACT FROM AUTHOR]

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1 H )-quinoline- O -alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM - 33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC 50 values of 0.56 μM, 2.3 μM, 0.3 μM and 1.4 μM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM - 33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM - 33 could cross the blood-brain barrier (BBB) in vitro , and abided by Lipinski’s rule of five. The results suggest that compound TM - 33 , an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

A series of novel ferulic acid- O -alkylamines derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. In vitro studies displayed that all the synthesized target compounds showed impressive inhibitory activity against butyrylcholinesterase (BuChE), significant inhibition/disaggregation of self-induced β -amyloid (A β ) aggregation and acted as potential antioxidants. Particularly, compound 7f , one of the most potent BuChE inhibitor (IC 50 value of 0.021 μM for equine serum BuChE, 8.63 μM for rat BuChE and 0.07 μM for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC 50 = 2.13 μM for electric eel AChE, 1.8 μM for rat AChE and 3.82 μM for human erythrocytes AChE), and the result of molecular docking provided an explanation for its selective BuChE inhibitory activity. Compound 7f also had noteworthy inhibitory effects on self-induced A β 1-42 aggregation (50.8 ± 0.82%) and was found to disaggregate self-induced A β 1-42 aggregation (38.7 ± 0.65%), which was further elucidated by the transmission electron microscopy. Meanwhile, compound 7f showed the modest antioxidant activity (0.55 eq of Trolox), good protective effect against H 2 O 2 -induced PC12 cell injury, with low toxicity. Moreover, compound 7f could cross the blood-brain barrier (BBB) in vitro . Significantly, compound 7f did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Taken together, the results indicated that compound 7f is a very promising multifunctional agent in the treatment of Alzheimer's disease, particularly the advanced stages of AD. [ABSTRACT FROM AUTHOR]

A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC 50 of 3.2–34.7 μM) and self-induced β -amyloid (A β 1–42 ) aggregation (30.8–39.1%, 25 μM), to act as potential antioxidants (ORAC-FL value of 0.9–1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC 50 = 3.2 μM), and A β 1–42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced A β aggregation. Furthermore, 17d could cross the blood–brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

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]