Effects of 3‐Bromo‐4,5‐dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase‐1 Expression

Natural and synthetic electrophilic compounds have been shown to activate the antioxidant protective Nrf2 (nuclear factor erythroid 2‐related factor 2)/heme oxygenase‐1 (HO‐1) axis in cells and tissues. Here, we tested the ability of different isoxazoline‐based electrophiles to up‐regulate Nrf2/HO‐1. The potency of activation is dependent on the leaving group at the 3‐position of the isoxazoline nucleus, and an additional ring on the molecule limits the Nrf2/HO‐1 activating properties. Among the synthetized compounds, we identified 3‐bromo‐5‐phenyl‐4,5‐dihydroisoxazole 1 as the derivative with best activating properties in THP‐1 human monocytic cells. We have confirmed that the target of our compounds is the Cys151 of the BTB domain of Keap1 by using mass spectrometry analyses and X‐ray crystallography. Our findings demonstrate that these compounds affect the Nrf2/HO‐1 axis and highlight a positive activity that can be of relevance from a therapeutic perspective in inflammation and infection.