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  • Structure-Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development

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    Author(s)
    Le, Thuy G
    Kundu, Abhijit
    Ghoshal, Atanu
    Nguyen, Nghi H
    Preston, Sarah
    Jiao, Yaqing
    Ruan, Banfeng
    Xue, Lian
    Huang, Fei
    Keiser, Jennifer
    Hofmann, Andreas
    Chang, Bill CH
    Garcia-Bustos, Jose
    Wells, Timothy NC
    Palmer, Michael J
    Jabbar, Abdul
    Gasser, Robin B
    Baell, Jonathan B
    Griffith University Author(s)
    Hofmann, Andreas
    Year published
    2019
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    Abstract
    Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure–activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were ...
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    Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure–activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.
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    Journal Title
    JOURNAL OF MEDICINAL CHEMISTRY
    Volume
    62
    Issue
    2
    DOI
    https://doi.org/10.1021/acs.jmedchem.8b01789
    Copyright Statement
    © 2019 This document is the post-print of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright 2019 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see 10.1021/acs.jmedchem.8b01789
    Subject
    Medicinal and biomolecular chemistry
    Organic chemistry
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/382751
    Collection
    • Journal articles

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