Zhang_2021_Eur.J.Med.Chem_213_113154

In this study, a series of multifunctional hybrids against Alzheimer's disease were designed and obtained by conjugating the pharmacophores of xanthone and alkylbenzylamine through the alkyl linker. Biological activity results demonstrated that compound 4j was the most potent and balanced dual ChEs inhibitor with IC(50) values 0.85 microM and 0.59 microM for eeAChE and eqBuChE, respectively. Kinetic analysis and docking study indicated that compound 4j was a mixed-type inhibitor for both AChE and BuChE. Additionally, it exhibited good abilities to penetrate BBB, scavenge free radicals (4.6 trolox equivalent) and selectively chelate with Cu(2+) and Al(3+) at a 1:1.4 ligand/metal molar ratio. Importantly, after assessments of cytotoxic and acute toxicity, we found compound 4j could improve memory function of scopolamine-induced amnesia mice. Hence, the compound 4j can be considered as a promising lead compound for further investigation in the treatment of AD.