Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro
Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural pr...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320718300496 |
| _version_ | 1818328795876163584 |
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| author | H.M.P. Dilrukshi Herath Hongjian Song Sarah Preston Abdul Jabbar Tao Wang Sean L. McGee Andreas Hofmann Jose Garcia-Bustos Bill C.H. Chang Anson V. Koehler Yuxiu Liu Qiaoqiao Ma Pengxiang Zhang Qiqi Zhao Qingmin Wang Robin B. Gasser |
| author_facet | H.M.P. Dilrukshi Herath Hongjian Song Sarah Preston Abdul Jabbar Tao Wang Sean L. McGee Andreas Hofmann Jose Garcia-Bustos Bill C.H. Chang Anson V. Koehler Yuxiu Liu Qiaoqiao Ma Pengxiang Zhang Qiqi Zhao Qingmin Wang Robin B. Gasser |
| author_sort | H.M.P. Dilrukshi Herath |
| collection | DOAJ |
| description | Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical scaffolds of arylpyrrole or fipronil. The seven most promising compounds, selected based on their anthelmintic activity and/or limited cytotoxicity, are arylpyrroles that reduced the motility of fourth-stage larvae (L4s) with significant potency (IC50 values ranged from 0.04 ± 0.01 μM to 4.25 ± 0.82 μM, and selectivity indices ranged from 10.6 to 412.5). Since the parent structures of the active compounds are uncouplers of oxidative phosphorylation, we tested the effect of selected analogues on oxygen consumption in xL3s using the Seahorse XF24 flux analyser. Larvae treated with the test compounds showed a significant increase in oxygen consumption compared with the untreated control, demonstrating their uncoupling activity. Overall, the results of the present study have identified natural product-derived molecules that are worth considering for chemical optimisation as anthelmintic drug leads. Keywords: Arylpyrrole, Fipronil, Haemonchus contortus, Anthelmintic, Drug discovery |
| first_indexed | 2024-12-13T12:37:51Z |
| format | Article |
| id | doaj.art-7f85d261e2e04397b5b0c85cb1628608 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-12-13T12:37:51Z |
| publishDate | 2018-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-7f85d261e2e04397b5b0c85cb16286082022-12-21T23:45:46ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072018-12-0183379385Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitroH.M.P. Dilrukshi Herath0Hongjian Song1Sarah Preston2Abdul Jabbar3Tao Wang4Sean L. McGee5Andreas Hofmann6Jose Garcia-Bustos7Bill C.H. Chang8Anson V. Koehler9Yuxiu Liu10Qiaoqiao Ma11Pengxiang Zhang12Qiqi Zhao13Qingmin Wang14Robin B. Gasser15Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaState Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, ChinaFaculty of Science and Technology, Federation University, Ballarat, Victoria 3350, AustraliaMelbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaMelbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaMetabolic Research Unit, Metabolic Reprogramming Laboratory, School of Medicine, Faculty of Health, Deakin University, Waurn Ponds, Victoria 3216, AustraliaMelbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia; Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland 4111, AustraliaMelbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaMelbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaMelbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, AustraliaState Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, ChinaState Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, ChinaState Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, ChinaState Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, ChinaState Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China; Corresponding author.Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia; Corresponding author.Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical scaffolds of arylpyrrole or fipronil. The seven most promising compounds, selected based on their anthelmintic activity and/or limited cytotoxicity, are arylpyrroles that reduced the motility of fourth-stage larvae (L4s) with significant potency (IC50 values ranged from 0.04 ± 0.01 μM to 4.25 ± 0.82 μM, and selectivity indices ranged from 10.6 to 412.5). Since the parent structures of the active compounds are uncouplers of oxidative phosphorylation, we tested the effect of selected analogues on oxygen consumption in xL3s using the Seahorse XF24 flux analyser. Larvae treated with the test compounds showed a significant increase in oxygen consumption compared with the untreated control, demonstrating their uncoupling activity. Overall, the results of the present study have identified natural product-derived molecules that are worth considering for chemical optimisation as anthelmintic drug leads. Keywords: Arylpyrrole, Fipronil, Haemonchus contortus, Anthelmintic, Drug discoveryhttp://www.sciencedirect.com/science/article/pii/S2211320718300496 |
| spellingShingle | H.M.P. Dilrukshi Herath Hongjian Song Sarah Preston Abdul Jabbar Tao Wang Sean L. McGee Andreas Hofmann Jose Garcia-Bustos Bill C.H. Chang Anson V. Koehler Yuxiu Liu Qiaoqiao Ma Pengxiang Zhang Qiqi Zhao Qingmin Wang Robin B. Gasser Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro International Journal for Parasitology: Drugs and Drug Resistance |
| title | Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro |
| title_full | Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro |
| title_fullStr | Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro |
| title_full_unstemmed | Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro |
| title_short | Arylpyrrole and fipronil analogues that inhibit the motility and/or development of Haemonchus contortus in vitro |
| title_sort | arylpyrrole and fipronil analogues that inhibit the motility and or development of haemonchus contortus in vitro |
| url | http://www.sciencedirect.com/science/article/pii/S2211320718300496 |
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