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...
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doaj-23c9a23e634d4f5fa18d8f7b336a309d2020-11-24T21:04:43ZengBMCParasites & Vectors1756-33052017-05-011011710.1186/s13071-017-2191-8Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortusYaqing Jiao0Sarah Preston1Hongjian Song2Abdul Jabbar3Yuxiu Liu4Jonathan Baell5Andreas Hofmann6Dana Hutchinson7Tao Wang8Anson V. Koehler9Gillian M. Fisher10Katherine T. Andrews11Benoît Laleu12Michael J. Palmer13Jeremy N. Burrows14Timothy N. C. Wells15Qingmin Wang16Robin B. Gasser17Faculty of Veterinary and Agricultural Sciences, The University of MelbourneFaculty of Veterinary and Agricultural Sciences, The University of MelbourneState Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai UniversityFaculty of Veterinary and Agricultural Sciences, The University of MelbourneState Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai UniversityMedicinal Chemistry, Monash University Institute of Pharmaceutical Sciences (MIPS), Monash UniversityGriffith Institute for Drug Discovery, Griffith UniversityDrug Discovery Biology, Monash University Institute of Pharmaceutical Sciences (MIPS), Monash UniversityFaculty of Veterinary and Agricultural Sciences, The University of MelbourneFaculty of Veterinary and Agricultural Sciences, The University of MelbourneGriffith Institute for Drug Discovery, Griffith UniversityGriffith Institute for Drug Discovery, Griffith UniversityMedicines for Malaria Venture (MMV)Medicines for Malaria Venture (MMV)Medicines for Malaria Venture (MMV)Medicines for Malaria Venture (MMV)State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai UniversityFaculty of Veterinary and Agricultural Sciences, The University of MelbourneAbstract 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.http://link.springer.com/article/10.1186/s13071-017-2191-8Haemonchus contortusPhenotypic screeningTolfenpyradSynthetic pyrazole-5-carboxamide derivativesMitochondrial respiratory chain |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 B. Gasser |
spellingShingle |
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 B. Gasser Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus Parasites & Vectors Haemonchus contortus Phenotypic screening Tolfenpyrad Synthetic pyrazole-5-carboxamide derivatives Mitochondrial respiratory chain |
author_facet |
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 B. Gasser |
author_sort |
Yaqing Jiao |
title |
Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus |
title_short |
Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus |
title_full |
Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus |
title_fullStr |
Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus |
title_full_unstemmed |
Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus |
title_sort |
assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against haemonchus contortus |
publisher |
BMC |
series |
Parasites & Vectors |
issn |
1756-3305 |
publishDate |
2017-05-01 |
description |
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. |
topic |
Haemonchus contortus Phenotypic screening Tolfenpyrad Synthetic pyrazole-5-carboxamide derivatives Mitochondrial respiratory chain |
url |
http://link.springer.com/article/10.1186/s13071-017-2191-8 |
work_keys_str_mv |
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