A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity
Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including <i>Haemonchus contortus</i>, are particularly important. The excessive use of anthelmintic compounds to treat infections...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/2/257 |
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| author | Harrison T. Shanley Aya C. Taki Joseph J. Byrne Abdul Jabbar Tim N. C. Wells Kirandeep Samby Peter R. Boag Nghi Nguyen Brad E. Sleebs Robin B. Gasser |
| author_facet | Harrison T. Shanley Aya C. Taki Joseph J. Byrne Abdul Jabbar Tim N. C. Wells Kirandeep Samby Peter R. Boag Nghi Nguyen Brad E. Sleebs Robin B. Gasser |
| author_sort | Harrison T. Shanley |
| collection | DOAJ |
| description | Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including <i>Haemonchus contortus</i>, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread resistance to these compounds in nematodes, such that there is a need for new anthelmintics with distinctive mechanisms of action. With a focus on discovering new anthelmintic entities, we screened 400 chemically diverse compounds within the ‘<i>Pandemic Response Box</i>’ (from Medicines for Malaria Venture, MMV) for activity against <i>H. contortus</i> and its free-living relative, <i>Caenorhabditis elegans</i>—a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of <i>H. contortus</i> and <i>C. elegans</i>. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of <i>H. contortus</i> larvae (IC<sub>50</sub> = 3.4 ± 1.1 μM) and young adults of <i>C. elegans</i> (IC<sub>50</sub> = 7.1 ± 4.6 μM), and the development of <i>H. contortus</i> larvae (IC<sub>50</sub> = 2.2 ± 0.7 μM). The favourable characteristics of MMV1581032, such as suitable physicochemical properties and an efficient, cost-effective pathway to analogue synthesis, indicates a promising candidate for further evaluation as a nematocide. Future work will focus on a structure-activity relationship investigation of this chemical scaffold, a toxicity assessment of potent analogues and a mechanism/mode of action investigation. |
| first_indexed | 2024-03-09T21:15:28Z |
| format | Article |
| id | doaj.art-f387b558c3dd43088d72f1557f097ddd |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T21:15:28Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-f387b558c3dd43088d72f1557f097ddd2023-11-23T21:35:33ZengMDPI AGPharmaceuticals1424-82472022-02-0115225710.3390/ph15020257A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic ActivityHarrison T. Shanley0Aya C. Taki1Joseph J. Byrne2Abdul Jabbar3Tim N. C. Wells4Kirandeep Samby5Peter R. Boag6Nghi Nguyen7Brad E. Sleebs8Robin B. Gasser9Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3010, AustraliaDepartment of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3010, AustraliaDepartment of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3010, AustraliaDepartment of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3010, AustraliaMedicines for Malaria Venture (MMV), 1215 Geneva, SwitzerlandMedicines for Malaria Venture (MMV), 1215 Geneva, SwitzerlandMonash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, AustraliaChemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, AustraliaChemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, AustraliaDepartment of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3010, AustraliaParasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including <i>Haemonchus contortus</i>, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread resistance to these compounds in nematodes, such that there is a need for new anthelmintics with distinctive mechanisms of action. With a focus on discovering new anthelmintic entities, we screened 400 chemically diverse compounds within the ‘<i>Pandemic Response Box</i>’ (from Medicines for Malaria Venture, MMV) for activity against <i>H. contortus</i> and its free-living relative, <i>Caenorhabditis elegans</i>—a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of <i>H. contortus</i> and <i>C. elegans</i>. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of <i>H. contortus</i> larvae (IC<sub>50</sub> = 3.4 ± 1.1 μM) and young adults of <i>C. elegans</i> (IC<sub>50</sub> = 7.1 ± 4.6 μM), and the development of <i>H. contortus</i> larvae (IC<sub>50</sub> = 2.2 ± 0.7 μM). The favourable characteristics of MMV1581032, such as suitable physicochemical properties and an efficient, cost-effective pathway to analogue synthesis, indicates a promising candidate for further evaluation as a nematocide. Future work will focus on a structure-activity relationship investigation of this chemical scaffold, a toxicity assessment of potent analogues and a mechanism/mode of action investigation.https://www.mdpi.com/1424-8247/15/2/257<i>Haemonchus contortus</i>parasitic nematode<i>Caenorhabditis elegans</i>anthelminticssmall molecules<i>Pandemic Response Box</i> |
| spellingShingle | Harrison T. Shanley Aya C. Taki Joseph J. Byrne Abdul Jabbar Tim N. C. Wells Kirandeep Samby Peter R. Boag Nghi Nguyen Brad E. Sleebs Robin B. Gasser A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity Pharmaceuticals <i>Haemonchus contortus</i> parasitic nematode <i>Caenorhabditis elegans</i> anthelmintics small molecules <i>Pandemic Response Box</i> |
| title | A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity |
| title_full | A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity |
| title_fullStr | A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity |
| title_full_unstemmed | A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity |
| title_short | A High-Throughput Phenotypic Screen of the ‘Pandemic Response Box’ Identifies a Quinoline Derivative with Significant Anthelmintic Activity |
| title_sort | high throughput phenotypic screen of the pandemic response box identifies a quinoline derivative with significant anthelmintic activity |
| topic | <i>Haemonchus contortus</i> parasitic nematode <i>Caenorhabditis elegans</i> anthelmintics small molecules <i>Pandemic Response Box</i> |
| url | https://www.mdpi.com/1424-8247/15/2/257 |
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