Journal article
Second generation repurposing of phenothiazine antipsychotic drugs as antifungal lead molecules via optimization of phenoxazine derivatives
European journal of medicinal chemistry, Vol.302(Pt 3), 118373
01/2026
DOI: 10.1016/j.ejmech.2025.118373
PMCID: PMC12674827
PMID: 41297389
Abstract
With millions of cases reported annually, fungal infections represent a growing public health concern. The effectiveness of current treatment options is hindered by the availability of only three antifungal drug classes, rising resistance, and suboptimal efficacy against certain pathogens. One promising strategy to overcome these challenges is to enhance the antifungal activity of existing drugs while maintaining favorable pharmacokinetic profiles. Herein, we describe the repurposing and optimization of a series of phenoxazine analogs of the antipsychotic drugs fluphenazine and trifluoperazine as antifungals. Optimization and the structure activity relationship studies identified novel phenoxazine derivatives as potent antifungal agents against Cryptococcus neoformans and Candida albicans (MIC 1-4 μg/mL and 2-8 μg/mL, respectively, 4-16 fold more potent than fluphenazine and trifluoperazine). In addition, the POZ analogs displayed reduced affinities towards serotonin and dopamine receptors compared to trifluoperazine. However, potent and moderately selective POZ analog 61 failed to demonstrate efficacy in a mouse model of cryptococcosis, demonstrating the need for further optimization.
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•Fungal infections are an increasingly challenging global health concern•Cryptococcosis is a CNS-invasive fungal infection leading to >600,000 deaths annually•Antipsychotic phenothiazine drugs are leads for antifungal drug discovery•Developed the first SAR study of 41 novel phenoxazine analogs of phenothiazines•Improved antifungal potency and reduced neuroreceptor affinity
Details
- Title: Subtitle
- Second generation repurposing of phenothiazine antipsychotic drugs as antifungal lead molecules via optimization of phenoxazine derivatives
- Creators
- Soumitra Guin - Saint Louis UniversityKathryn M. Alden - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA USAEmily Harshbarger - Saint Louis UniversityLaurie C. Ristow - University of IowaAndrew J. Jezewski - University of IowaDamian J. Krysan - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA USAMarvin J. Meyers - Saint Louis University
- Resource Type
- Journal article
- Publication Details
- European journal of medicinal chemistry, Vol.302(Pt 3), 118373
- DOI
- 10.1016/j.ejmech.2025.118373
- PMID
- 41297389
- PMCID
- PMC12674827
- NLM abbreviation
- Eur J Med Chem
- ISSN
- 0223-5234
- eISSN
- 1768-3254
- Publisher
- Elsevier Masson SAS
- Grant note
- National Institutes of Health (NIH): R21 AI164578
This manuscript is the result of funding in part by the National Institutes of Health (NIH) grant R21 AI164578. It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make this manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH. The views expressed are those of the authors and do not necessarily represent the official views of the National Institutes of Health.
- Language
- English
- Electronic publication date
- 11/21/2025
- Date published
- 01/2026
- Academic Unit
- Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9985035032102771
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