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  • A perspective on the discovery of selected compounds with anthelmintic activity against the barber's pole worm—Where to from here?

    Author(s)
    Jiao, Y
    Preston, S
    Hofmann, A
    Taki, A
    Baell, J
    Chang, BCH
    Jabbar, A
    Gasser, RB
    Griffith University Author(s)
    Hofmann, Andreas
    Year published
    2020
    Metadata
    Show full item record
    Abstract
    Parasitic roundworms (nematodes) cause substantial morbidity and mortality in animals worldwide. Anthelmintic treatment is central to controlling these worms, but widespread resistance to most of the commercially available anthelmintics for veterinary and agricultural use is compromising control, such that there is an urgency to discover new and effective drugs. The purpose of this article is to review information on parasitic nematodes, the treatment and control of parasitic nematode infections and aspects of discovering new anthelmintics in the context of anthelmintic resistance problems, and then to discuss some progress ...
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    Parasitic roundworms (nematodes) cause substantial morbidity and mortality in animals worldwide. Anthelmintic treatment is central to controlling these worms, but widespread resistance to most of the commercially available anthelmintics for veterinary and agricultural use is compromising control, such that there is an urgency to discover new and effective drugs. The purpose of this article is to review information on parasitic nematodes, the treatment and control of parasitic nematode infections and aspects of discovering new anthelmintics in the context of anthelmintic resistance problems, and then to discuss some progress that our group has made in identifying selected compounds with activity against nematodes. The focus of our recent work has been on discovering new chemical entities and known drugs with anthelmintic activities against Haemonchus contortus as well as other socioeconomically important parasitic nematodes for subsequent development. Using whole worm-based phenotypic assays, we have been screening compound collections obtained via product-development-partnerships and/or collaborators, and active compounds have been assessed for their potential as anthelmintic candidates. Following the screening of 15,333 chemicals from five distinct compound collections against H. contortus, we have discovered one new chemical entity (designated SN00797439), two human kinase inhibitors (SNS-032 and AG-1295), 14 tetrahydroquinoxaline analogues, one insecticide (tolfenpyrad) and two tolfenpyrad (pyrazole-5-carboxamide) derivatives (a-15 and a-17) with anthelmintic activity in vitro. Some of these 20 ‘hit’ compounds have selectivity against H. contortus in vitro when compared to particular human cell lines. In our opinion, some of these compounds could represent starting points for ‘lead’ development. Accordingly, the next research steps to be pursued include: (i) chemical optimisation of representative chemicals via structure-activity relationship (SAR) evaluations; (ii) assessment of the breadth of spectrum of anthelmintic activity on a range of other parasitic nematodes, such as strongyloids, ascaridoids, enoplids and filarioids; (iii) detailed investigations of the absorption, distribution, metabolism, excretion and toxicity (ADMET) of optimised chemicals with broad nematocidal or nematostatic activity; and (iv) establishment of the modes of action of lead candidates.
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    Book Title
    Advances in Parasitology
    Volume
    108
    DOI
    https://doi.org/10.1016/bs.apar.2019.12.003
    Copyright Statement
    Self-archiving is not yet supported by this publisher. Please refer to the publisher's website or contact the author(s) for more information.
    Subject
    Biological sciences
    Microbiology
    Veterinary sciences
    Medical microbiology
    Anthelmintics
    Drug discovery
    Haemonchus contortus
    Novel chemical entities
    Phenotypic screening
    Publication URI
    http://hdl.handle.net/10072/399986
    Collection
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