Chen_2014_Chem.Biol.Interact_223C_45

Four oxoisoaporphine-lipoic acid hybrids were designed, synthesized, and investigated in this study. To develop the hybrids, the oxoisoaporphine fragment was used for its inhibition of cholinesterases and beta-amyloid (Abeta) aggregation, while the unit of lipoic acid was used for its radical-capturing and neuroprotective effects. The hybrids exhibited moderate inhibitory effects on the activity of acetylcholinesterase (AChE), with IC50 values in the micromolar range and low toxicity in SH-SY5Y cells. Moreover, the learning and memory abilities, climbing capability, and average life expectancy of the Abeta42 transgenic Drosophila were all significantly improved by the hybrids. They also enhanced the intracephalic antioxidant activity, the metabolism, and the activity cholinesterase in the flies. More strikingly, Abeta42 aggregation in the hybrids-treated Drosophila was attenuated with effective neuroprotection. Our results indicate the potential of using these oxoisoaporphine-lipoic acid hybrids in AD treatments.