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 F₁ 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 IC₅₀ 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.