Discovery of novel diphenylbutene derivative ferroptosis inhibitors as neuroprotective agents

• Published in: European journal of medicinal chemistry 2022-03, Vol.231, p.114151-114151, Article 114151
• Main Authors: Fang, Yuying, Tan, Qingyun, Zhou, Huihao, Gu, Qiong, Xu, Jun
• Format: Article
• Language: English
• Subjects: Animals; Cell Death; Diphenylbutene; Ferroptosis; Ferroptosis inhibitor; FSP1; Hippocampus; Mice; Neurons; Neuroprotective; Neuroprotective Agents - pharmacology; Rats; Structural modification
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114151

Ferroptosis is a regulated and iron-dependent cell death. Ferroptosis inhibitors are promising for treating many neurological diseases. Herein, with phenotypic assays, we discovered a new diphenylbutene derivative ferroptosis inhibitor, DPT. Based on this hit, we synthesized fourteen new diphenylbutene derivatives, evaluated their ferroptosis inhibitory activities in HT22 mouse hippocampal neuronal cells, and found that three compounds exhibited improved inhibitory activities compared with DPT. Among these active compounds, compound 3f displayed the most potent anti-ferroptosis activity (EC50 = 1.7 μM). Further studies demonstrated that 3f is a specific ferroptosis inhibitor. And we revealed that different from the classic ferroptosis inhibitors, 3f blocked ferroptosis by increasing FSP1 protein level. Moreover, 3f can penetrate blood-brain barrier (BBB). In a rat model of ischemic stroke, 3f effectively mitigated cerebral ischemic injury. Therefore, we are confirmed that 3f, as a novel ferroptosis inhibitor with a new scaffold, is promising for further development as an agent against neurological diseases. [Display omitted] •A new scaffold for ferroptosis inhibitors was discovered through phenotypic screening.•Fourteen diphenylbutene derivatives were designed and synthesized for anti-ferroptosis.•Compound 3f is a specific ferroptosis inhibitor, which blocked ferroptosis by elevating FSP protein level.•Compound 3f effectively alleviated ischemic reperfusion injury in vivo.•The scaffold and mechanism of action of 3f are distinct from the known ferroptosis inhibitors.