Antifungal Activity of a Library of Aminothioxanthones

Abstract

Fungal infections are one of the main causes of mortality and morbidity worldwide and taking into account the increasing incidence of strains resistant to classical antifungal drugs, the development of new agents has become an urgent clinical need. Considering that thioxanthones are bioisosteres of xanthones with known anti-infective actions, their scaffolds were selected for this study. A small library of synthesized aminothioxanthones (1–10) was evaluated for in vitro antifungal activity against Candida albicans, Aspergillus fumigatus, and Trichophyton rubrum; for the active compounds, the spectrum was further extended to other clinically relevant pathogenic fungi. The results showed that only compounds 1, 8, and 9 exhibited inhibitory and broad-spectrum antifungal effects. Given the greater antifungal potential presented, compound 1 was the subject of further investigations to study its anti-virulence activity and in an attempt to elucidate its mechanism of action; compound 1 seems to act predominantly on the cellular membrane of C. albicans ATCC 10231, altering its structural integrity, without binding to ergosterol, while inhibiting two important virulence factors—dimorphic transition and biofilm formation—frequently associated with C. albicans pathogenicity and resistance. In conclusion, the present work proved the usefulness of thioxanthones in antifungal therapy as new models for antifungal agents.

Keywords

• aminotioxanthones
• antifungal activity
• structure-activity relationship
• virulence factors
• mechanism of action