Allosecurinine Derivative with Two Michael Acceptors Activates Keap1-Nrf2 Pathway

Oxidative stress and neuroinflammation drive neurodegenerative diseases, rendering the Keap1-Nrf2 pathway an attractive therapeutic target. Here, we derivatized securinega alkaloids by introducing a 1,4-conjugated Michael acceptor onto the piperidine ring. Among them, 4,5-dehydro-6-oxoallosecurinine, featuring two Michael acceptors (an α,β-unsaturated lactam and an α,β-γ,δ-unsaturated ester), exhibited the most potent Nrf2 activation. This compound promoted Nrf2 nuclear translocation and induced antioxidant and cytoprotective gene expression in microglial cells. In addition, it significantly reduced nitric oxide production and pro-inflammatory cytokine levels in LPS-stimulated microglia. These findings identify securinega alkaloid derivatives as promising Nrf2 activators and support their further evaluation in neuroinflammatory and neurodegenerative disease models.