Discovery of 5-(4-Hydroxyphenyl)-3-oxo-pentanoic Acid 2-(5-Methoxy-1H-indol-3-yl)-ethyl-amideas a Neuroprotectant for Alzheimer’s Disease by Hybridizationof Curcumin and Melatonin

摘要

In our effort to develop effective neuroprotectants as potential treatments for Alzheimer’s disease (AD), hybrid compounds of curcumin and melatonin, two natural products that have been extensively studied in various AD models, were designed, synthesized, and biologically characterized. A lead hybrid compound (>7) was discovered to show significant neuroprotection with nanomolar potency (EC50 = 27.60 ± 9.4 nM) in MC65 cells, a cellular AD model. Multiple in vitro assay results established that >7 exhibited moderate inhibitory effects on the production of amyloid-β oligomers (AβOs) in MC65 cells, but not on the aggregation of Aβ species. It also exhibited significant antioxidative properties. Further mechanistic studies demonstrated that >7’s antioxidant effects correlate well with its neuroprotective potency for MC65 cells, and these effects might be due to its interference with the interactions of AβOs within the mitochondria of MC65 cells. Furthermore, >7 was confirmed to cross the blood-brain barrier (BBB) and deliver a sufficient amount to brain tissue after oral administration. Collectively, these results strongly support the hybridization approachas an efficient strategy to help identify novel scaffolds with a desiredpharmacology, and strongly encourage further optimization of >7 to develop more potent neuroprotectants for AD.