| Summary: | A series of novel synthetic substituted benzo[d]oxazole-based derivatives (<b>5a</b>–<b>5v</b>) exerted neuroprotective effects on β-amyloid (Aβ)-induced PC12 cells as a potential approach for the treatment of Alzheimer’s disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aβ<sub>25-35</sub>-induced PC12 cells at 5 μg/mL. We found that compound <b>5c</b> was non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ<sub>25-35</sub>-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound <b>5c</b> promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ<sub>25-35</sub>-induced PC12 cells. In addition, our findings demonstrated that compound <b>5c</b> protected PC12 cells from Aβ<sub>25-35</sub>-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3β/NF-κB signaling pathway. In vivo studies suggest that compound <b>5c</b> shows less toxicity than donepezil in the heart and nervous system of zebrafish.
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