Semi-Synthetic H ₂ S Releasing Compounds with Antioxidant and Vasorelaxant Properties

Hypertension represents a severe cardiovascular pathology linked to the increase in reactive oxygen species that impair blood vessel function. Herein, we report on the synthesis of hybrid compounds designed to release H₂S and incorporate natural or semisynthetic scaffolds capable of activating the Nrf2 pathway. The molecular hybrids enable a multitarget approach concurrently inducing vasorelaxation upon H₂S release and mitigating oxidative stress through Nrf2-dependent antioxidant responses via the upregulation of cytoprotective proteins, including HO-1. The itaconate derivative <b>8b</b> displayed an optimal H₂S release in both amperometric and cellular assays. In human aortic smooth muscle cells, compound <b>8b</b> counteracted ROS production and cytotoxicity in H₂O₂-injured cells and led to the activation of potassium channels with consequent cell hyperpolarization and vasorelaxation, which was also observed in isolated rat aortic rings. Overall, our findings indicate that simultaneous Nrf2 activation and H₂S release hold significant potential as a new therapeutic strategy for the treatment of hypertension.