Design, Synthesis, and Biological Evaluation of Novel Vinyl Selenone Derivatives as Potent Nrf2 Activators for Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is an inflammatory skin disease characterized by barrier dysfunction, immune dysregulation, and elevated oxidative stress. Since oxidative stress and inflammation are central to AD pathogenesis, activation of the Keap1-Nrf2 pathway, a regulator of antioxidant and cytoprotective defenses, has emerged as a promising therapeutic strategy for AD. We previously developed vinyl sulfone and sulfoximine compounds as potent Nrf2 activators with antioxidant and anti-inflammatory properties. In this study, we introduced a vinyl selenone core as an isosteric replacement to enhance Nrf2 activation potency. Among the synthesized compounds, 5w exhibited excellent potency (EC50 = 4.9 nM), inducing Nrf2-dependent antioxidant enzymes and suppressing cytokine-driven inflammation in HaCaT keratinocytes. In Raw264.7 macrophages, 5w attenuated inflammatory, nitrosative, and oxidative stress responses. Therapeutic efficacy was validated in a DNCB-induced AD mouse model, where 5w alleviated local inflammation and AD-like symptoms. Collectively, these findings highlight 5w as a novel therapeutic agent for inflammatory skin diseases such as AD.