Optimization of Antifungal 1,5-Diaryl-Pyrazole Acetyl-CoA Synthetase Inhibitors
. These efforts have led to the improved on-target activity for a set of analogs against multiple fungal enzymes. We identified key substituents that are critical determinants of the ACS inhibition displayed by this diaryl pyrazole class of inhibitors. Modeling and molecular dynamics calculations also indicate that these improved molecules likely bind in the same region of the ACS active site in which the alkyl-AMP esters bind. Finally, the most active diaryl pyrazole has improved mammalian cytotoxicity and pharmacology relative to AR-12. However, additional optimization of this class of ACS inhibitors will be needed to generate a molecule with efficacy in preclinical animal models.
Authors
- Timothy J. Hagen (ORCID: https://orcid.org/0000-0003-1929-9121)
- Andrew J. Jezewski (ORCID: https://orcid.org/0000-0002-2004-1278)
- Parisa Enayati
- Katy M. Alden (ORCID: https://orcid.org/0000-0001-5339-1509)
- Drashti G. Daraji (ORCID: https://orcid.org/0000-0001-6697-4834)
- Noelle S. Williams (ORCID: https://orcid.org/0000-0003-1894-5742)
- Charles L. Lail
- Jeffrey Ferreira
- Michael E. Heene
- Damien Castor
- Jonah P. Propp
- Rohan Wakade
Institutions
- Northern Illinois University (US)
- University of Iowa (US)
- Southwestern Medical Center (US)
- Carver Bible College (US)
- Institute of Molecular Biology and Biophysics (RU)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- ACS Omega
- Published
- 2026-04-14
- DOI
- https://doi.org/10.1021/acsomega.5c13157
- Primary Topic
- Neurological diseases and metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Northern Illinois University
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- Division of Chemistry