Identification of Pyrazolidine‐3‐One Derivatives as a Novel Structural Scaffold for ATP Synthase Inhibitors

In a recent study, the oxadiazin‐5‐one‐based compound CJ1‐34 was identified as a partial ATP synthase inhibitor, which was found to bind the F 1 region of the ATP synthase. These findings were used as a starting point for the design and synthesis of smaller heterocycles, such as pyrazolidine‐3‐ones and pyrazol‐3‐ones, as novel structural scaffolds for potential ATP synthase inhibitors. Among the newly synthesized compounds, pyrazolidin‐3‐one derivatives 9a and 10a outperformed the lead compound CJ1‐34 in vitro by inhibiting ATP hydrolytic activity and decreasing ATP levels in HT‐22 cells. Subsequent dose‐dependent studies identified compound 9a as the most promising ATP synthase inhibitor. Molecular docking revealed similar binding modes for all compounds in the F1‐binding site and the calculated docking scores aligned with the measured IC 50 values of the tested compounds. This study identified pyrazolidine‐3‐ones as promising structural scaffolds for ATP synthase inhibition, opening avenues for further biomedical applications in central nervous system diseases such as Alzheimer's and Parkinson's.