Discovery of 1,3,4‐oxadiazin‐5‐one Derivative CJ1‐34 as a Partial ATP Synthase Inhibitor for CNS Applications

ATP synthase dysregulation has been implicated in many diseases, including cancer and neurodegenerative diseases. Whilst ATP synthase‐targeting compounds have been reported, most are large or polar compounds and lack appropriate properties for a CNS drug. We designed, synthesised, and evaluated a novel series of ATP synthase targeting compounds, resulting in a 1,3,4‐oxadiazin‐5‐one scaffold with improved physiochemical properties. In vitro evaluation of our library led to the discovery of CJ1 34 as a partial ATP synthase inhibitor with a determined IC50 of 394 nM in isolated bovine mitochondria. Molecular docking experiments demonstrated that calculated docking scores aligned with the observed in vitro pharmacology and supports the F1 region of the ATP synthase as the potential binding site. Overall, this provides the foundation to further investigate CJ1‐34 as a potential CNS drug for diseases where mitochondria are implicated, including Alzheimer’s and Parkinson’s disease.