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  • Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro

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    Author(s)
    Herath, HMP Dilrukshi
    Song, Hongjian
    Preston, Sarah
    Jabbar, Abdul
    Wang, Tao
    McGee, Sean L
    Hofmann, Andreas
    Garcia-Bustos, Jose
    Chang, Bill CH
    Koehler, Anson V
    Liu, Yuxiu
    Ma, Qiaoqiao
    Zhang, Pengxiang
    Zhao, Qiqi
    Wang, Qingmin
    Gasser, Robin B
    Griffith University Author(s)
    Hofmann, Andreas
    Year published
    2018
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    Abstract
    Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical ...
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    Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical scaffolds of arylpyrrole or fipronil. The seven most promising compounds, selected based on their anthelmintic activity and/or limited cytotoxicity, are arylpyrroles that reduced the motility of fourth-stage larvae (L4s) with significant potency (IC50 values ranged from 0.04 ± 0.01 μM to 4.25 ± 0.82 μM, and selectivity indices ranged from 10.6 to 412.5). Since the parent structures of the active compounds are uncouplers of oxidative phosphorylation, we tested the effect of selected analogues on oxygen consumption in xL3s using the Seahorse XF24 flux analyser. Larvae treated with the test compounds showed a significant increase in oxygen consumption compared with the untreated control, demonstrating their uncoupling activity. Overall, the results of the present study have identified natural product-derived molecules that are worth considering for chemical optimisation as anthelmintic drug leads.
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    Journal Title
    International Journal for Parasitology: Drugs and Drug Resistance
    Volume
    8
    Issue
    3
    DOI
    https://doi.org/10.1016/j.ijpddr.2018.06.002
    Copyright Statement
    © 2018 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported (CC BY-NC-ND 3.0) License (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited. You may not alter, transform, or build upon this work.
    Subject
    Medical microbiology
    Medical microbiology not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/381945
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    • Journal articles

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