Design and Synthesis of a NTR-Sensitive Fluorescent H2S Donor as a Potential Therapeutic Agent for Myocardial Ischemia–Reperfusion Injury

Myocardial ischemia is a key feature of myocardial ischemia-reperfusion injury (MIRI), which upregulates nitroreductase (NTR) expression. Targeting this mechanism, the design of NTR-responsive prodrugs has emerged as an innovative strategy for MIRI treatment. Herein, we synthesized HSD-NTR-B, a novel NTR-responsive hydrogen sulfide donor. In the presence of NTR and NADH, the nitro group of HSD-NTR-B is reduced to amino groups, triggering decarboxylation reactions to release carbonyl sulfide (COS). COS is rapidly converted to H₂S by carbonic anhydrase (CA) in biological fluids. The H₂S release can be quantitatively monitored via self-reported fluorescence signaling. In a rat model of MIRI, HSD-NTR-B significantly improved cardiac structure and function recovery. Mechanistically, its effects stem from inhibiting cardiomyocyte apoptosis and reducing local inflammation. H₂S donors modulate macrophage polarization by reducing M1 and increasing M2 macrophages, emerging therapeutic targets for MIRI. This NTR-sensitive H₂S donor shows promise for treating MIRI and other ischemic conditions.