PT  - JOURNAL ARTICLE
AU  - Elizbieta Hejchman
AU  - Kinga Ostrowska
AU  - Dorota Maciejewska
AU  - Jerzy Kossakowski
AU  - William Courchesne
TI  - Synthesis and antifungal activity of derivatives of 2- and 3-benzofurancarboxylic acids
AID  - 10.1124/jpet.112.196980
DP  - 2012 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.112.196980
4099  - http://jpet.aspetjournals.org/content/early/2012/08/14/jpet.112.196980.short
4100  - http://jpet.aspetjournals.org/content/early/2012/08/14/jpet.112.196980.full
AB  - 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).