Pharmacological Study of Imidazolium and Pyridinium Salts with Antifungal Activity against Chromoblastomycosis Agents

BACKGROUND: Chromoblastomycosis (CBM) is a subcutaneous fungal infection caused by melanized fungi, predominantly in tropical and subtropical climates. CBM-causing fungal strains are becoming resistant to antifungal drugs, leading to prolonged treatments and low cure rates. Therefore, the development of new antifungals to combat this disease is a priority. OBJECTIVES: This study explored imidazolium salts (IS) and a pyridinium salt (PS) as candidate drugs for the treatment of CBM. Their pharmacological properties were investigated as possible therapeutic alternatives to itraconazole (ITZ). METHODS: In silico analyses were performed using Lipinski's rule of five (Ro5). Seventy-eight isolates of CBM-causing fungi were tested following the CLSI M38-A2 protocol to determine minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC). Fourier transform infrared spectroscopy (FTIR) was applied to compare the compound with the lowest MFC against standard antifungals. Cytotoxicity was evaluated using the neutral red (NR) and methyl thiazole tetrazolium (MTT) assays, and genotoxicity was assessed by the alkaline comet assay. In vivo toxicity was tested in Drosophila melanogaster. RESULTS: The in silico analysis indicated probable antifungal activity with low toxicity in humans. The compounds exhibited lower MIC and MFC values than ITZ, with C16PyrCl showing the lowest MFC (0.474 μg/mL). FTIR analysis confirmed distinct alterations in fungal biomass metabolism compared with standard antifungals. Cytotoxicity and genotoxicity assays revealed elevated toxicity of IS toward mammalian cells; however, no toxicity was observed in D. melanogaster. DISCUSSION: The tested compounds showed strong activity against CBM agents, although they also presented cytotoxic and genotoxic effects on animal cells. Metabolic alterations between the chosen PS and existing antifungals were successfully described using FTIR spectroscopy. CONCLUSIONS: The compounds demonstrated potent fungicidal activity against CBM-causing fungi, highlighting their potential as antifungal candidates. Further in vivo studies are required to optimize their safety and therapeutic applicability.