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  • Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro

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    Author(s)
    Jiao, Yaqing
    Preston, Sarah
    Garcia-Bustos, Jose F
    Baell, Jonathan B
    Ventura, Sabatino
    Le, Thuy
    McNamara, Nicole
    Nguyen, Nghi
    Botteon, Antony
    Skinner, Cameron
    Danne, Jill
    Ellis, Sarah
    Koehler, Anson
    Wang, Tao
    Chang, Bill CH
    Hofmann, Andreas
    Jabbar, Abdul
    Gasser, Robin B
    Griffith University Author(s)
    Hofmann, Andreas
    Year published
    2019
    Metadata
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    Abstract
    In the present study, the anthelmintic activity of a human tyrosine kinase inhibitor, AG-1295, and 14 related tetrahydroquinoxaline analogues against Haemonchus contortus was explored. These compounds were screened against parasitic larvae - exsheathed third-stage (xL3) and fourth-stage (L4) - using a whole-organism screening assay. All compounds were shown to have inhibitory effects on larval motility, development and growth, and induced evisceration through the excretory pore in xL3s. The estimated IC 50 values ranged from 3.5 to 52.0 μM for inhibition of larval motility or development. Cytotoxicity IC 50 against human ...
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    In the present study, the anthelmintic activity of a human tyrosine kinase inhibitor, AG-1295, and 14 related tetrahydroquinoxaline analogues against Haemonchus contortus was explored. These compounds were screened against parasitic larvae - exsheathed third-stage (xL3) and fourth-stage (L4) - using a whole-organism screening assay. All compounds were shown to have inhibitory effects on larval motility, development and growth, and induced evisceration through the excretory pore in xL3s. The estimated IC 50 values ranged from 3.5 to 52.0 μM for inhibition of larval motility or development. Cytotoxicity IC 50 against human MCF10A cells was generally higher than 50 μM. Microscopic studies revealed that this eviscerated (Evi) phenotype occurs rapidly (<20 min) and relates to a protrusion of internal tissues and organs (evisceration) through the excretory pore in xL3s; severe pathological damage in L4s as well as a suppression of larval growth in both stages were also observed. Using a relatively low concentration (12.5 μM) of compound m10, it was established that the inhibitor has to be present for a relatively short time (between 30 h and 42 h) during in vitro development from xL3 to L4, to induce the Evi phenotype. Increasing external osmotic pressure prevented evisceration and moulting, and xL3s remained unaffected by the test compound. These results point to a mode of action involving a dysregulation of morphogenetic processes during a critical time-frame, in agreement with the expected behaviour of a tyrosine kinase inhibitor, and suggest potential for development of this compound class as nematocidal drugs.
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    Journal Title
    International Journal for Parasitology: Drugs and Drug Resistance
    Volume
    9
    DOI
    https://doi.org/10.1016/j.ijpddr.2018.12.007
    Copyright Statement
    © 2019 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Subject
    Medical Microbiology
    Science & Technology
    Life Sciences & Biomedicine
    Parasitology
    Pharmacology & Pharmacy
    Quinoxalines
    Publication URI
    http://hdl.handle.net/10072/386793
    Collection
    • Journal articles

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