Discovery of novel tert-butylhydroquinone derivatives as potential anti-endothelial injury agents: Synthesis, in vitro, and in vivo evaluation.

Tert-butyl hydroquinone (tBHQ) is widely used as a food additive due to its superior protective properties, making it a valuable component in the food, cosmetic, and pharmaceutical industries. This study focused on the discovery of novel tBHQ derivatives as potential vascular endothelial cell (VEC) protective agents by evaluating their potential in mitigating VEC injury, including apoptosis and ferroptosis induced by ox-LDL, HG, or CoCl2 in vitro, as well as endothelial dysfunction in diabetic mice induced by STZ. Notably, compound 3 h demonstrated robust efficacy in protecting VECs against injury induced by these stimuli. Additionally, compound 3 h attenuated vascular fibrosis in diabetic mice. The protective mechanisms of compound 3 h were associated with the stimulation of the Nrf2 signaling pathway, which resulted in the dissociation of Nrf2 from Keap1, Nrf2 nuclear translocation, and an increase in the production of downstream antioxidant enzymes such as HO-1 and GPX4, ultimately preventing damage to HUVECs. The present results suggest that compound 3 h could be a promising lead compound in the treatment of cardiovascular diseases associated with VEC injury.