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Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro

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...

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Autores principales: 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 V., Wang, Tao, Chang, Bill C.H., Hofmann, Andreas, Jabbar, Abdul, Gasser, Robin B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357688/
https://www.ncbi.nlm.nih.gov/pubmed/30690282
http://dx.doi.org/10.1016/j.ijpddr.2018.12.007
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author 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 V.
Wang, Tao
Chang, Bill C.H.
Hofmann, Andreas
Jabbar, Abdul
Gasser, Robin B.
author_facet 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 V.
Wang, Tao
Chang, Bill C.H.
Hofmann, Andreas
Jabbar, Abdul
Gasser, Robin B.
author_sort Jiao, Yaqing
collection PubMed
description 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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spelling pubmed-63576882019-02-07 Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro 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 V. Wang, Tao Chang, Bill C.H. Hofmann, Andreas Jabbar, Abdul Gasser, Robin B. Int J Parasitol Drugs Drug Resist Article 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. Elsevier 2018-12-30 /pmc/articles/PMC6357688/ /pubmed/30690282 http://dx.doi.org/10.1016/j.ijpddr.2018.12.007 Text en © 2019 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
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 V.
Wang, Tao
Chang, Bill C.H.
Hofmann, Andreas
Jabbar, Abdul
Gasser, Robin B.
Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro
title Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro
title_full Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro
title_fullStr Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro
title_full_unstemmed Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro
title_short Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro
title_sort tetrahydroquinoxalines induce a lethal evisceration phenotype in haemonchus contortus in vitro
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357688/
https://www.ncbi.nlm.nih.gov/pubmed/30690282
http://dx.doi.org/10.1016/j.ijpddr.2018.12.007
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