Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation

Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases a common factor many them. We describe synthesis library derivatives 4-arylmethylen-2-pyrrolin-5-one framework by sequential application three-component reaction primary amines, ?-dicarbonyl compounds, ?-haloketones Knoevenagel condensation. These compounds can be viewed as cyclic amides caffeic ferulic acids, are also structurally related bisavenanthramide family natural antioxidants. Most members showed low cytotoxicity good activity inductors Nrf2, transcription that acts master regulator antioxidant response associated with activation element (ARE). Nrf2-dependent protein expression was proved significant increase in levels HMOX1 NQO1 proteins. Some exerted neuroprotective properties oxidative situations, such rotenone/oligomycin-induced toxicity, against hyperphosphorylation induced phosphatase inhibitor okadaic acid. Compound 3i, which considered candidate for further hit-to-lead development due its well-balanced multitarget profile, characterized proving ability reduce phosphorylated Tau levels.