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  • Optimization of Novel 1-Methyl-1H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm

    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
    Jabbar, Abdul
    Wells, Timothy NC
    Palmer, Michael J
    Gasser, Robin B
    Baell, Jonathan B
    Griffith University Author(s)
    Hofmann, Andreas
    Year published
    2018
    Metadata
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    Abstract
    A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure–activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting ...
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    A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure–activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM.
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    Journal Title
    JOURNAL OF MEDICINAL CHEMISTRY
    Volume
    61
    Issue
    23
    DOI
    https://doi.org/10.1021/acs.jmedchem.8b01544
    Subject
    Medicinal and biomolecular chemistry
    Organic chemistry
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/382752
    Collection
    • Journal articles

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