Discovery of Novel Anethole Trithione Derivatives Targeting SQR Pathway to Induce Mitochondrial Uncoupling for Stroke Treatment.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter with therapeutic potential for stroke. Our previous work identified that ADT-OH, an H2S donor with mitochondrial uncoupling activity, protects against stroke by activating the SQR-UCP2-AMPK pathway. Here, we launched a medicinal chemistry campaign based on hit compound ADT-OH to design and synthesize 30 novel derivatives, among which compound 16 displayed more potent mitochondrial uncoupling activity than ADT-OH, effectively reducing the mitochondrial membrane potential at a low concentration of 1 μM. In mouse models of ischemic and hemorrhagic stroke, compound 16 significantly alleviated brain injury and improved functional outcomes. Notably, these therapeutic effects were completely abolished in microglia/macrophage-specific SQR deletion (Cx3cr1Cre: Sqrfl/fl) mice, confirming that the biological function of compound 16 is mediated by a strictly SQR-dependent mechanism. Proteomic analysis further validated these findings. Overall, compound 16 represents a promising lead compound for stroke therapy based on a novel mechanism, warranting further development.