Abstract
A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a–5v) 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 Aβ25-35-induced PC12 cells at 5 μg/mL. We found that compound 5c was non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ25-35-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aβ25-35-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 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.
Highlights
Benzo[d]oxazoles are important scaffolds in heterocyclic compounds, which are extensively found in diverse pharmacologically active substances and natural compounds
Final product synthesis was performed in parallel using water-soluble EDCI and HOBt corresponding of phosphorus oxychloride, and substituted benzoic to activate aniline the carboxylic acid and treated with thethiosemicarbazide requisite amine in the presence of DMAP
Compound 5c and donepezil decreased the expression of Bcl-2-associated X protein (Bax) and increased the expression of B-cell lymphoma 2 (Bcl-2) (p < 0.001, Figure 5)
Summary
Benzo[d]oxazoles are important scaffolds in heterocyclic compounds, which are extensively found in diverse pharmacologically active substances and natural compounds. Behjat Pouramiri et al reported that a series of novel benzo[d]oxazole derivatives have been synthesized as potential inhibitors of acetylcholinesterases (AChE). Some of these compounds were most effective against AChE [6]. Some studies predict that by 2030 approximately 65.7 million people worldwide will suffer from AD. Aβ could induce neuronal apoptosis by regulating glycogen synthase kinase (GSK-3β) signaling. Aβ could induce neuronal apoptosis by regulating glycogen synthase kinase (GSK-3β) signaling pathways [15]. GSK-3β, an important kinase, is a critical element involved in the regulation of pathways [15]. GSK-3β, an important kinase, is a critical element involved in the regulation of amyloidogenic processing of Aβ. PC12 cell examined this protection through Akt, GSK-3β and NF-κB signaling pathways
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