Optimization of Antifungal 1,5-Diaryl-Pyrazole Acetyl-CoA Synthetase Inhibitors

Jonah P. Propp; Jeffrey C. Ferreira; Parisa Enayati; Kathryn M. Alden; Drashti G. Daraji; Charles L. Lail; Michael E. Heene; Andrew J. Jezewski; Rohan Wakade; Damien Castor; Noelle S. Williams; Timothy J. Hagen; Damian J. Krysan

doi:10.1021/acsomega.5c13157

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Optimization of Antifungal 1,5-Diaryl-Pyrazole Acetyl-CoA Synthetase Inhibitors

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Optimization of Antifungal 1,5-Diaryl-Pyrazole Acetyl-CoA Synthetase Inhibitors

Jonah P. Propp, Jeffrey C. Ferreira, Parisa Enayati, Kathryn M. Alden, Drashti G. Daraji, Charles L. Lail, Michael E. Heene, Andrew J. Jezewski, Rohan Wakade, Damien Castor, …

ACS omega, Vol.11(16), pp.24237-24249

04/28/2026

DOI: 10.1021/acsomega.5c13157

PMCID: PMC13130119

PMID: 42077878

Appears in UI Libraries Support Open Access

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Abstract

Acetyl-CoA Synthetases (ACS) have emerged as a potential drug target for the treatment of diseases ranging from fungal and parasitic infections to cancer and hyperlipidemia. While species-selective ACS inhibitors have been reported, broad-spectrum inhibition of ACS enzymes has only been achieved with nucleoside-derived, bisubstrate analogs such as alkyl esters of adenosine monophosphate (AMP). Previously, we identified the diaryl pyrazole AR-12 as a non-nucleoside inhibitor of S. cerevisiae ACS with broad-spectrum antifungal activity. In this study, we undertook a medicinal-chemistry approach to optimize the AR-12 scaffold with the goals of improving its pharmacology and activity against ACS enzymes from human fungal pathogens such as Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. 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.

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Heterocyclic compounds

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Title: Subtitle: Optimization of Antifungal 1,5-Diaryl-Pyrazole Acetyl-CoA Synthetase Inhibitors
Creators: Jonah P. Propp - University of Iowa
Jeffrey C. Ferreira - Northern Illinois University
Parisa Enayati - Northern Illinois University
Kathryn M. Alden
Drashti G. Daraji - Northern Illinois University
Charles L. Lail - Northern Illinois University
Michael E. Heene - Northern Illinois University
Andrew J. Jezewski - University of Iowa
Rohan Wakade - University of Iowa
Damien Castor - University of Iowa
Noelle S. Williams - Southwestern Medical Center
Timothy J. Hagen - Northern Illinois University
Damian J. Krysan - University of Iowa
Resource Type: Journal article
Publication Details: ACS omega, Vol.11(16), pp.24237-24249
DOI: 10.1021/acsomega.5c13157
PMID: 42077878
PMCID: PMC13130119
NLM abbreviation: ACS Omega
ISSN: 2470-1343
eISSN: 2470-1343
Publisher: American Chemical Society
Grant note: National Institute of Allergy and Infectious Diseases: 5R01AI161973
The authors thank Scott Lowell and Bart Staker for helpful discussions.
Language: English
Electronic publication date: 04/13/2026
Date published: 04/28/2026
Academic Unit: Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9985153392402771

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