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

Authors

Lisa Reichert, Aro Delparente, Ida R Hipfinger, Lukas Reininger, Ana Pinto Castro, Daniel J Hubin, Roger Schibli, Amy E Fraley, Linjing Mu

Published in

ChemMedChem. Volume 21. Issue 14. Pages e70399. Jul 29, 2026.

Abstract

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.

PMID:
42509195
Bibliographic data and abstract were imported from PubMed on 28 Jul 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.