Antifungal activities and toxicity studies of water-soluble non-steroidal analgesic salts.

BACKGROUND: The emergence of antifungal resistance among Candida albicans strains poses a growing clinical challenge, underscoring the urgent need for alternative therapeutic strategies. Drug repositioning of non-steroidal anti-inflammatory drugs (NSAIDs) has attracted attention due to their reported antimicrobial properties and well-established safety profiles. OBJECTIVES: This study aimed to synthesize and characterize water-soluble sodium salts of ibuprofen (IBU-Na), ketoprofen (KET-Na), and indomethacin (IM-Na), and to evaluate their antifungal activity and toxicity profiles, individually and in combination with fluconazole (FLU), against C. albicans strains. METHODS: NSAID sodium salts were synthesized and characterized, and their antifungal activity, synergistic interactions with FLU, and toxicity profiles were evaluated against FLU-susceptible and -resistant C. albicans strains. RESULTS: IBU-Na and KET-Na exhibited inhibitory and fungicidal activities against both FLU-susceptible and -resistant C. albicans strains, whereas IM-Na was inactive. Combination assays revealed strong synergistic interactions with FLU (FICI = 0.008-0.009), resulting in marked reductions in fungal viability. Neither hemolytic activity nor genotoxic effects were detected at the tested concentrations. CONCLUSIONS: Water-soluble NSAID salts, particularly IBU-Na, demonstrate potent synergistic antifungal activity with FLU and favorable safety profiles, supporting their potential as candidates for antifungal drug repurposing. These findings emphasize the importance of reassessing sodium salt derivatives rather than assuming equivalence with their acidic precursors.