Discovery of 7-O-1, 2, 3-triazole hesperetin derivatives as multi-target-directed ligands against Alzheimer's disease

The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC50 = 3.08 +/- 0.29 mu M) and exhibited good anti-neuroinflammatory activity (IC50 = 2.91 +/- 0.47 mu M) against NO production through remarkably blocking the NF-kappa B signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 mu M concentration. Furthermore, possessing significant self-mediated A beta 1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood-brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.

Automated summary

The study evaluated a series of hesperetin derivatives for their multi-target-directed activities. Among them, compound a8 showed strong inhibition of cholinesterase, anti-neuroinflammatory activity, and neuroprotective effects. The results suggest that a8 has the potential to be developed as a multi-target-directed ligand for anti-Alzheimer's disease agents.