Synthesis and antifungal activity of derivatives of 2- and 3-benzofurancarboxylic acids.
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 that are both synthetic and isolated from natural sources with antifungal activity. To define the structural components responsible for antifungal activity, we synthesized a series of benzofuran derivatives and tested them for the inhibition of growth of two pathogenic fungi, Cryptococcus neoformans and Aspergillus fumigatus, to find new compounds with antifungal activity. We found several derivatives that inhibited fungal growth, two of which had significant antifungal activity. We were surprised to find 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 includes changes in 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).
Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.
Elzbieta
E
Hejchman
Kinga
K
Ostrowska
Dorota
D
Maciejewska
Jerzy
J
Kossakowski
William E
WE
Courchesne
D000331:Aequorin; D000638:Amiodarone / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000254:growth & development; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004357:Drug Synergism; D005658:Fungi / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D020014:K562 Cells; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001572:Benzofurans; D007202:Indicators and Reagents; D000331:Aequorin; D000638:Amiodarone; D002118:Calcium