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

Abstract 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 (BBB) permeable 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 report herein a novel 1,3,4‐thiadiazole‐functionalized druglike 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 makes it the first sensitive ratiometric photoluminescent probe to detect phospholipid hydroperoxides and a specific indicator for the fluctuation of ferroptosis. These unprecedented advantages not only make Ferfluor‐1 a potential tool for ferroptosis‐related diagnostic and therapeutic applications in the central nervous system, but also pave the way to developing new theragnostic agents for precision redox detection and regulation.