A Bifunctional Sulfide Donor Approach for Ischemic Stroke: Leveraging Butylphthalide as a Carrier for Sulfide Prodrug

The physiological and pharmacological benefits of hydrogen sulfide (H₂S) are well established, and various H₂S and persulfide donors have been developed. However, few studies have examined the <i>in vivo</i> pharmacokinetics of sulfur donors, as most activity and metabolism tests are conducted <i>in vitro</i>, limiting insights into their clinical applications. This study utilized butylphthalide (NBP), an approved drug for ischemic stroke, by integrating H₂S and persulfide moieties directly into NBP's carbonyl groups. We systematically compared drug metabolism <i>in vitro</i> and <i>in vivo</i> and evaluated donor efficacy in ischemia-reperfusion models. Results revealed notable <i>in vitro</i>/<i>in vivo</i> metabolic differences, with thioacid-containing donors showing promising therapeutic effects in cerebral ischemia, reducing infarct size, oxidative stress, and neuronal apoptosis.