1,5-Diarylidene-4-Piperidones as Promising Antifungal Candidates Against Cryptococcus neoformans

Background/Objectives: The present study investigates the antifungal potential of 1,5-diarylidene-4-piperidones. Methods: These compounds were synthesized via Claisen–Schmidt condensation, and their antifungal efficacy was tested against Cryptococcus neoformans, a yeast recently qualified as a critical priority pathogen by the World Health Organization, through determination of their minimum inhibitory concentration (MIC). We designed and synthesized a series of piperidones to explore structure–activity relationships. Results: Systematic modification of the substituent pattern revealed that tetrabutoxy groups exhibited potent activity (MIC of 7.8 µM), surpassing standard antifungals like fluconazole. The selectivity index (SI) values confirmed their safety profile across various human cells. Docking analysis demonstrated that these compounds target sterol 14-demethylase, suggesting potential inhibition of ergosterol synthesis as a mechanism of action. Interestingly, the compounds also demonstrated broad-spectrum activity against other pathogenic yeasts and fungi, including Candida and Aspergillus species, and against fluconazole-resistant strains. Conclusions: These findings underscore the potential of 1,5-diarylidene-4-piperidones as promising antifungal candidates with a favorable safety profile.