Liu_2021_Eur.J.Med.Chem_227_113973

On the basis of our previous work, a novel series of (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives were synthesized and evaluated as multifunctional ligands for the treatment of Alzheimer's disease (AD). Biological evaluations indicated that the derivatives can be used as anti-AD drugs that have multifunctional properties, inhibit the activity of butyrylcholinesterase (BuChE), inhibit neuroinflammation, have neuroprotective properties, and inhibit the self-aggregation of Abeta. Compound f9 showed good potency in BuChE inhibition (IC(50): 1.28 +/- 0.18 microM), anti-neuroinflammatory potency (NO, IL-1beta, TNF-alpha; IC(50): 0.67 +/- 0.14, 1.61 +/- 0.21, 4.15 +/- 0.44 microM, respectively), and inhibited of Abeta self-aggregation (51.91 +/- 3.90%). Preliminary anti-inflammatory mechanism studies indicated that the representative compound f9 blocked the activation of the NF-kappaB signaling pathway. Moreover, f9 exhibited 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect, and an inhibitory effect on the production of intracellular reactive oxygen species (ROS). In the bi-directional transport assay, f9 displayed proper blood-brain barrier (BBB) permeability. In addition, the title compound improved memory and cognitive functions in a mouse model induced by scopolamine. Hence, the compound f9 can be considered as a promising lead compound for further investigation in the treatment of AD.