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Antifungal and Antiparasitic Activities of Metallocene-Containing Fluconazole Derivatives
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    Antifungal and Antiparasitic Activities of Metallocene-Containing Fluconazole Derivatives
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    • Yan Lin
      Yan Lin
      Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France
      More by Yan Lin
    • Gonzalo Scalese
      Gonzalo Scalese
      Área Química Inorgánica, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay
    • Christina A. Bulman
      Christina A. Bulman
      Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States
    • Robin Vinck
      Robin Vinck
      Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France
      More by Robin Vinck
    • Olivier Blacque
      Olivier Blacque
      Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
    • Margot Paulino
      Margot Paulino
      Área Bioinformática, Departamento DETEMA, Facultad de Química, Universidad de la República, 11600 Montevideo, Uruguay
    • Andres Ballesteros-Casallas
      Andres Ballesteros-Casallas
      Área Bioinformática, Departamento DETEMA, Facultad de Química, Universidad de la República, 11600 Montevideo, Uruguay
    • Leticia Pérez Díaz
      Leticia Pérez Díaz
      Sección Genómica Funcional, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay
    • Gustavo Salinas
      Gustavo Salinas
      Worm Biology Lab, Institut Pasteur de Montevideo, 11400 Montevideo, Uruguay
      Departamento de Biociencias, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay
    • Makedonka Mitreva*
      Makedonka Mitreva
      Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63108, United States
      *Email: [email protected]
    • Tobias Weil*
      Tobias Weil
      Research and Innovation Centre, Fondazione Edmund Mach, Via E. Mach 1, 38010 San Michele all’Adige, Italy
      *Email: [email protected]
      More by Tobias Weil
    • Kevin Cariou*
      Kevin Cariou
      Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France
      *Email: [email protected]
      More by Kevin Cariou
    • Judy A. Sakanari*
      Judy A. Sakanari
      Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States
      *Email: [email protected]
    • Dinorah Gambino*
      Dinorah Gambino
      Área Química Inorgánica, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay
      *Email: [email protected]
    • Gilles Gasser*
      Gilles Gasser
      Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France
      *Email: [email protected]
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    ACS Infectious Diseases

    Cite this: ACS Infect. Dis. 2024, 10, 3, 938–950
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    https://doi.org/10.1021/acsinfecdis.3c00577
    Published February 8, 2024
    Copyright © 2024 American Chemical Society

    Abstract

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    The search for new anti-infectives based on metal complexes is gaining momentum. Among the different options taken by researchers, the one involving the use of organometallic complexes is probably the most successful one with a compound, namely, ferroquine, already in clinical trials against malaria. In this study, we describe the preparation and in-depth characterization of 10 new (organometallic) derivatives of the approved antifungal drug fluconazole. Our rationale is that the sterol 14α-demethylase is an enzyme part of the ergosterol biosynthesis route in Trypanosoma and is similar to the one in pathogenic fungi. To demonstrate our postulate, docking experiments to assess the binding of our compounds with the enzyme were also performed. Our compounds were then tested on a range of fungal strains and parasitic organisms, including the protozoan parasite Trypanosoma cruzi (T. cruzi) responsible for Chagas disease, an endemic disease in Latin America that ranks among some of the most prevalent parasitic diseases worldwide. Of high interest, the two most potent compounds of the study on T. cruzi that contain a ferrocene or cobaltocenium were found to be harmless for an invertebrate animal model, namely, Caenorhabditis elegans (C. elegans), without affecting motility, viability, or development.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.3c00577.

    • Synthetic pathways (Schemes S1–S8), procedures and characterization of the compounds, selected crystal data and structural refinement parameters (Tables S1–S5), NMR (Figures S1–S73) spectra, copies of the IR (Figures S74–S84), and stability studies (Figures S85–S95), computational studies (Figures S96–S99), the results of docking analysis (Table S7), animate version of the best-docked conformation for the A2 molecule (Figure S100), and cytotoxicity studies on healthy cell HEK293 (Figure S101) (PDF)

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    This article is cited by 2 publications.

    1. Sara Abdolmaleki, Alireza Aliabadi, Samad Khaksar. Bridging the gap between theory and treatment: Transition metal complexes as successful candidates in medicine. Coordination Chemistry Reviews 2025, 531 , 216477. https://doi.org/10.1016/j.ccr.2025.216477
    2. Tiansheng Wang, Didier Astruc. Electron-reservoir applications of ferrocenes and other late transition-metal sandwich complexes: Flow batteries, sensing, catalysis, and biomedicine. Coordination Chemistry Reviews 2025, 524 , 216300. https://doi.org/10.1016/j.ccr.2024.216300

    ACS Infectious Diseases

    Cite this: ACS Infect. Dis. 2024, 10, 3, 938–950
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsinfecdis.3c00577
    Published February 8, 2024
    Copyright © 2024 American Chemical Society

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