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 in vivo pharmacokinetics of sulfur donors, as most activity and metabolism tests are conducted in vitro, 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 in vitro and in vivo and evaluated donor efficacy in ischemia-reperfusion models. Results revealed notable in vitro/in vivo metabolic differences, with thioacid-containing donors showing promising therapeutic effects in cerebral ischemia, reducing infarct size, oxidative stress, and neuronal apoptosis.