A thiocoumarin based self-reporting sulfide prodrug strategy with a favorable safety profile.

H2S as the third gasotransmitter is an important endogenous bioregulator that shows various therapeutic potentials. Herein, we present a novel thiocoumarin-based self-reporting sulfide prodrug strategy that utilizes esterase-mediated hydrolysis of thionoesters to release H2S and provide real-time fluorescence monitoring. Our key discovery is that thionoesters can be hydrolyzed by esterases to release H2S under physiological conditions, providing ample opportunities to design prodrugs based on ester-containing molecules. Thiocoumarin derivatives bearing a unique lactone structure offer advantages that simplify prodrug construction by substituting oxygen with sulfur in coumarin backbone and allow in-situ monitoring of H2S release through thiocoumarin-coumarin transformation. Our prodrug candidates are demonstrated with favorable H2S release kinetics and showed combined therapeutic effects of H2S and coumarin, making them promising for treating cerebral infarction. Fluorescent monitoring in mouse confirmed sustained H2S release and revealed the organ distribution, further validating the self-reporting system. Additionally, this approach that ensures therapeutic efficacy and reduces the hepatorenal toxicity of coumarin derivatives constitutes a facile prodrug strategy to overcome the toxicity of drug candidates.