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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Synthesis and Antifungal Activity of Derivatives of 2- and 3-Benzofurancarboxylic Acids

Elżbieta Hejchman, Kinga Ostrowska, Dorota Maciejewska, Jerzy Kossakowski and William E. Courchesne
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 380-388; DOI: https://doi.org/10.1124/jpet.112.196980
Elżbieta Hejchman
Department of Organic Chemistry, Faculty of Pharmacy (E.H., K.O., D.M), and Department of Medical Chemistry (J.K.), Medical University of Warsaw, Warsaw, Poland; and Department of Microbiology and Immunology, School of Medicine, University of Nevada, Reno, Nevada (W.E.C.)
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Kinga Ostrowska
Department of Organic Chemistry, Faculty of Pharmacy (E.H., K.O., D.M), and Department of Medical Chemistry (J.K.), Medical University of Warsaw, Warsaw, Poland; and Department of Microbiology and Immunology, School of Medicine, University of Nevada, Reno, Nevada (W.E.C.)
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Dorota Maciejewska
Department of Organic Chemistry, Faculty of Pharmacy (E.H., K.O., D.M), and Department of Medical Chemistry (J.K.), Medical University of Warsaw, Warsaw, Poland; and Department of Microbiology and Immunology, School of Medicine, University of Nevada, Reno, Nevada (W.E.C.)
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Jerzy Kossakowski
Department of Organic Chemistry, Faculty of Pharmacy (E.H., K.O., D.M), and Department of Medical Chemistry (J.K.), Medical University of Warsaw, Warsaw, Poland; and Department of Microbiology and Immunology, School of Medicine, University of Nevada, Reno, Nevada (W.E.C.)
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William E. Courchesne
Department of Organic Chemistry, Faculty of Pharmacy (E.H., K.O., D.M), and Department of Medical Chemistry (J.K.), Medical University of Warsaw, Warsaw, Poland; and Department of Microbiology and Immunology, School of Medicine, University of Nevada, Reno, Nevada (W.E.C.)
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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 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).

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.196980.

  • ABBREVIATIONS:

    IFI
    invasive fungal infection
    [Ca2+]cyt
    cytoplasmic calcium concentration
    DMSO
    dimethyl sulfoxide
    RLU
    relative light unit
    1a
    7-acetyl-6-methoxy-3-methyl-2-benzofurancarboxylic acid
    2a
    methyl 7-acetyl-6-methoxy-3-methyl-2-benzofurancarboxylate
    2b
    methyl 7-acetyl-6-hydroxy-3-methyl-2-benzofurancarboxylate
    2c
    methyl 6-hydroxy-7-(p-methoxycinnamoyl)-3-methyl-2- benzofurancarboxylate
    2d
    methyl 5-bromo-7-hydroxy-6-methoxy-2-benzofurancarboxylate
    2e
    methyl 4,5-dibromo-7-hydroxy-6-methoxy-2-benzofurancarboxylate
    3b
    methyl 7-acetyl-6-(O-ethyl-2′-diethylamino)-3-methyl-2-benzofurancarboxylate
    3c
    methyl 6-(O-ethyl-2′-diethylamino)-7-(p-methoxycinnamoyl)- 3-methyl-2-benzofurancarboxylate
    3d
    methyl 5-bromo-7-(O-ethyl-2′-diethylamino)-6-methoxy-2-benzofurancarboxylate
    3f
    methyl 7-acetyl-6-(O-ethyl-2′-diethylamino)-5-methoxy-3-methyl-2-benzofurancarboxylate
    3g
    methyl 6-acetyl-5-(O-ethyl-2′-diethylamino)-2-methyl-3- benzofurancarboxylate
    4
    methyl 7-acetyl-5-bromo-6-hydroxy-3-bromomethyl-2-benzofurancarboxylate
    RO-09-4609
    ethyl 3-methyl-4-[3-(pyridin-3-ylmethylamino)propoxy]-1-benzofuran-2-carboxylate.

  • Received May 29, 2012.
  • Accepted August 13, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Synthesis and Antifungal Activity of Benzofuran Derivatives

Elżbieta Hejchman, Kinga Ostrowska, Dorota Maciejewska, Jerzy Kossakowski and William E. Courchesne
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 380-388; DOI: https://doi.org/10.1124/jpet.112.196980

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Synthesis and Antifungal Activity of Benzofuran Derivatives

Elżbieta Hejchman, Kinga Ostrowska, Dorota Maciejewska, Jerzy Kossakowski and William E. Courchesne
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 380-388; DOI: https://doi.org/10.1124/jpet.112.196980
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