Abstract
We found that amiodarone has potent antifungal activity against a broad range of fungi potentially defining a new class of antimycotics. Investigations into its molecular mechanisms showed amiodarone mobilized intracellular Ca2+, which is thought to be an important antifungal characteristic of its fungicidal activity. Amiodarone is a synthetic drug based on the benzofuran ring system, which is contained in numerous compounds both synthetic and isolated from natural sources with antifungal activity. In order to define the structural components responsible for antifungal activity, we synthesized a series of benzofuran derivatives not yet described previously in publications and tested them for inhibition of growth of two pathogenic fungi Cryptococcus neoformans and Aspergillus fumigatus in order to find new compounds with antifungal activity. We found several derivatives that inhibited fungal growth, two of which had significant antifungal activity. Surprisingly, we found that calcium fluxes in cells treated with these derivatives did not correlate directly with their antifungal effects, however the derivatives did augment the amiodarone-elicited calcium flux into the cytoplasm. We conclude that antifungal activity of these new compounds include activities in addition to changes in the cytoplasmic calcium concentration. Analyses of these benzofuran derivatives suggest that certain structural features are important for antifungal activity. Antifungal activity drastically increased on converting methyl 7-acetyl-6-hydroxy-3-methyl-2-benzofurancarboxylate (2b) into its dibromo derivative - methyl 7-acetyl-5-bromo-6-hydroxy-3-bromomethyl-2- benzofurancarboxylate(4).
- Received May 29, 2012.
- Revision received August 10, 2012.
- Accepted August 13, 2012.
- The American Society for Pharmacology and Experimental Therapeutics