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.