A Druglike Ferrostatin‐1 Analogue as a Ferroptosis Inhibitor and Photoluminescent Indicator

Redox‐based diagnostic and therapeutic applications have long suffered from a shortage of suitable drugs and probes of high specificity. In the context of anti‐ferroptosis research for neurological diseases, the inaccessibility of a blood‐brain barrier permeable (BBB) small molecular ferroptosis inhibitor, and the lack of specific ferroptosis probes seriously impeded a deeper understanding of the mechanism of ferroptosis and the development of clinically applicable drugs. We here report a novel 1,3,4‑thiadiazole‐functionalized drug‐like ferrostatin analogue entitled Ferfluor‐1 with superior anti‐ferroptosis potency, favorable BBB permeability and in vivo activity against stroke and Parkinson’s disease. Moreover, the exclusive pseudo excited‐state intramolecular proton‐transfer (ESIPT) property of Ferfluor‐1 via a long‐distance hydrogen‐bonding network facilitated it as the first sensitive ratiometric photoluminescent probe to detect phospholipid hydroperoxides and a specific indicator for the fluctuation of ferroptosis. These unprecedented advantages not only engendered Ferfluor‐1 as a potential tool for ferroptosis‐related diagnostic and therapeutic applications in the central nervous system, but also paved the way to developing new theragnostic agents for precision redox detection and regulation.