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    SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents
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    • Krupanandan Haranahalli
      Krupanandan Haranahalli
      Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794-3400, United States
      Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, United States
      More by Krupanandan Haranahalli
    • Cristina Lazzarini
      Cristina Lazzarini
      Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794-5222, United States
      Veterans Administration Medical Center, Northport, New York 11768, United States
      More by Cristina Lazzarini
    • Yi Sun
      Yi Sun
      Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, United States
      More by Yi Sun
    • Julia Zambito
      Julia Zambito
      Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, United States
      More by Julia Zambito
    • Senuri Pathiranage
      Senuri Pathiranage
      Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, United States
      More by Senuri Pathiranage
    • J. Brian McCarthy
      J. Brian McCarthy
      MicroRid Technologies Inc., 86 Deer Park Road, Dix Hills, New York 11746, United States
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    • John Mallamo
      John Mallamo
      MicroRid Technologies Inc., 86 Deer Park Road, Dix Hills, New York 11746, United States
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    • Maurizio Del Poeta
      Maurizio Del Poeta
      Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794-3400, United States
      Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794-5222, United States
      Veterans Administration Medical Center, Northport, New York 11768, United States
      Division of Infectious Diseases, School of Medicine, Stony Brook University, New York 11794-8434, United States
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    • Iwao Ojima*
      Iwao Ojima
      Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794-3400, United States
      Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, United States
      *Phone: 631-632-1339. Fax: 631-632-7942. E-mail: [email protected]
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      Orcidhttp://orcid.org/0000-0002-3628-1161
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2019, 62, 17, 8249–8273
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    https://doi.org/10.1021/acs.jmedchem.9b01004
    Published August 1, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    Recently, the fungal sphingolipid glucosylceramide (GlcCer) synthesis has emerged as a highly promising new target for drug discovery of next-generation antifungal agents, and we found two aromatic acylhydrazones as effective inhibitors of GlcCer synthesis based on HTP screening. In the present work, we have designed libraries of new aromatic acylhydrazones, evaluated their antifungal activities (MIC80 and time-kill profile) against C. neoformans, and performed an extensive SAR study, which led to the identification of five promising lead compounds, exhibiting excellent fungicidal activities with very large selectivity index. Moreover, two compounds demonstrated broad spectrum antifungal activity against six other clinically relevant fungal strains. These five lead compounds were examined for their synergism/cooperativity with five clinical drugs against seven fungal strains, and very encouraging results were obtained; e.g., the combination of all five lead compounds with voriconazole exhibited either synergistic or additive effect to all seven fungal strains.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b01004.

    • 1H and 13C NMR spectra of new compounds (PDF)

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2019, 62, 17, 8249–8273
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.9b01004
    Published August 1, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

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