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 IC 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 F 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.