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  • Design, Synthesis, and Biological Evaluation of 2-Nitroimidazopyrazin-one/-es with Antitubercular and Antiparasitic Activity

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    Author(s)
    Jarrad, Angie M
    Ang, Chee Wei
    Debnath, Anjan
    Hahn, Hye Jee
    Woods, Kyra
    Tan, Lendl
    Sykes, Melissa L
    Jones, Amy J
    Pelingon, Ruby
    Butler, Mark S
    Avery, Vicky M
    West, Nicholas P
    Karoli, Tomislav
    Blaskovich, Mark AT
    Cooper, Matthew A
    Griffith University Author(s)
    Sykes, Melissa L.
    Avery, Vicky M.
    West, Nic P.
    Year published
    2018
    Metadata
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    Abstract
    Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis, and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that antitubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here, we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazooxazines. Synthetic analogues with a novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed ...
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    Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis, and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that antitubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here, we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazooxazines. Synthetic analogues with a novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed and synthesized, and structure–activity relationships were generated. Selected derivatives had potent antiparasitic and antitubercular activity while maintaining drug-like properties such as low cytotoxicity, good metabolic stability in liver microsomes and high apparent permeability across Caco-2 cells. The kinetic solubility of the new bicyclic derivatives varied and was found to be a key parameter for future optimization. Taken together, these results suggest that promising subclasses of bicyclic nitroimidazoles containing different core architectures have potential for further development.
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    Journal Title
    JOURNAL OF MEDICINAL CHEMISTRY
    Volume
    61
    Issue
    24
    DOI
    https://doi.org/10.1021/acs.jmedchem.8b01578
    Funder(s)
    ARC
    Grant identifier(s)
    LP140100560
    Copyright Statement
    © 2018 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
    Subject
    Medicinal and biomolecular chemistry
    Organic chemistry
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/385735
    Collection
    • Journal articles

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