Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus

Yaqing Jiao, Sarah Preston, Hongjian Song, Abdul Jabbar, Yuxiu Liu, Jonathan Baell, Andreas Hofmann, Dana Hutchinson, Tao Wang, Anson V Koehler, Gillian M. Fisher, Katherine T Andrews, Benoît Laleu, Michael J. Palmer, Jeremy N Burrows, Timothy N.C. Wells, Qingmin Wang, Robin Beat Gasser

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 μM. We studied the effect of these two ‘hit’ compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.

LanguageEnglish
Article number272
JournalParasites and Vectors
Volume10
Issue number1
DOIs
StatePublished - 31 May 2017

Keywords

  • Haemonchus contortus
  • Mitochondrial respiratory chain
  • Phenotypic screening
  • Synthetic pyrazole-5-carboxamide derivatives
  • Tolfenpyrad

Cite this

Jiao, Yaqing ; Preston, Sarah ; Song, Hongjian ; Jabbar, Abdul ; Liu, Yuxiu ; Baell, Jonathan ; Hofmann, Andreas ; Hutchinson, Dana ; Wang, Tao ; Koehler, Anson V ; Fisher, Gillian M. ; Andrews, Katherine T ; Laleu, Benoît ; Palmer, Michael J. ; Burrows, Jeremy N ; Wells, Timothy N.C. ; Wang, Qingmin ; Gasser, Robin Beat. / Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus. In: Parasites and Vectors. 2017 ; Vol. 10, No. 1.
@article{46f2d6e378294fe789769c25abbd899a,
title = "Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus",
abstract = "Background: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 μM. We studied the effect of these two ‘hit’ compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.",
keywords = "Haemonchus contortus, Mitochondrial respiratory chain, Phenotypic screening, Synthetic pyrazole-5-carboxamide derivatives, Tolfenpyrad",
author = "Yaqing Jiao and Sarah Preston and Hongjian Song and Abdul Jabbar and Yuxiu Liu and Jonathan Baell and Andreas Hofmann and Dana Hutchinson and Tao Wang and Koehler, {Anson V} and Fisher, {Gillian M.} and Andrews, {Katherine T} and Beno{\^i}t Laleu and Palmer, {Michael J.} and Burrows, {Jeremy N} and Wells, {Timothy N.C.} and Qingmin Wang and Gasser, {Robin Beat}",
year = "2017",
month = "5",
day = "31",
doi = "10.1186/s13071-017-2191-8",
language = "English",
volume = "10",
journal = "Parasites and Vectors",
issn = "1756-3305",
publisher = "Springer-Verlag London Ltd.",
number = "1",

}

Jiao, Y, Preston, S, Song, H, Jabbar, A, Liu, Y, Baell, J, Hofmann, A, Hutchinson, D, Wang, T, Koehler, AV, Fisher, GM, Andrews, KT, Laleu, B, Palmer, MJ, Burrows, JN, Wells, TNC, Wang, Q & Gasser, RB 2017, 'Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus' Parasites and Vectors, vol. 10, no. 1, 272. DOI: 10.1186/s13071-017-2191-8

Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus. / Jiao, Yaqing; Preston, Sarah; Song, Hongjian; Jabbar, Abdul; Liu, Yuxiu; Baell, Jonathan; Hofmann, Andreas; Hutchinson, Dana; Wang, Tao; Koehler, Anson V; Fisher, Gillian M.; Andrews, Katherine T; Laleu, Benoît; Palmer, Michael J.; Burrows, Jeremy N; Wells, Timothy N.C.; Wang, Qingmin; Gasser, Robin Beat.

In: Parasites and Vectors, Vol. 10, No. 1, 272, 31.05.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus

AU - Jiao,Yaqing

AU - Preston,Sarah

AU - Song,Hongjian

AU - Jabbar,Abdul

AU - Liu,Yuxiu

AU - Baell,Jonathan

AU - Hofmann,Andreas

AU - Hutchinson,Dana

AU - Wang,Tao

AU - Koehler,Anson V

AU - Fisher,Gillian M.

AU - Andrews,Katherine T

AU - Laleu,Benoît

AU - Palmer,Michael J.

AU - Burrows,Jeremy N

AU - Wells,Timothy N.C.

AU - Wang,Qingmin

AU - Gasser,Robin Beat

PY - 2017/5/31

Y1 - 2017/5/31

N2 - Background: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 μM. We studied the effect of these two ‘hit’ compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.

AB - Background: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 μM. We studied the effect of these two ‘hit’ compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus.

KW - Haemonchus contortus

KW - Mitochondrial respiratory chain

KW - Phenotypic screening

KW - Synthetic pyrazole-5-carboxamide derivatives

KW - Tolfenpyrad

UR - http://www.scopus.com/inward/record.url?scp=85019739954&partnerID=8YFLogxK

U2 - 10.1186/s13071-017-2191-8

DO - 10.1186/s13071-017-2191-8

M3 - Article

VL - 10

JO - Parasites and Vectors

T2 - Parasites and Vectors

JF - Parasites and Vectors

SN - 1756-3305

IS - 1

M1 - 272

ER -