Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis
Giardia duodenalis is the causative agent of the neglected diarrhoeal disease giardiasis. While often self-limiting, giardiasis is ubiquitous and impacts hundreds of millions of people annually. It is also a common gastro-intestinal disease of domestic pets, wildlife, and livestock animals. However,...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320723000295 |
| _version_ | 1827591179637620736 |
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| author | Christopher JS. Hart Andrew G. Riches Snigdha Tiash Rebecca Abraham Keely Fayd’Herbe Ellis Joch Bilal Zulfiqar Melissa L. Sykes Vicky M. Avery Jan Šlapeta Sam Abraham John H. Ryan Tina S. Skinner-Adams |
| author_facet | Christopher JS. Hart Andrew G. Riches Snigdha Tiash Rebecca Abraham Keely Fayd’Herbe Ellis Joch Bilal Zulfiqar Melissa L. Sykes Vicky M. Avery Jan Šlapeta Sam Abraham John H. Ryan Tina S. Skinner-Adams |
| author_sort | Christopher JS. Hart |
| collection | DOAJ |
| description | Giardia duodenalis is the causative agent of the neglected diarrhoeal disease giardiasis. While often self-limiting, giardiasis is ubiquitous and impacts hundreds of millions of people annually. It is also a common gastro-intestinal disease of domestic pets, wildlife, and livestock animals. However, despite this impact, there is no vaccine for Giardia currently available. In addition, treatment relies on chemotherapies that are associated with increasing failure rates. To identify new treatment options for giardiasis we recently screened the Compounds Australia Scaffold Library for new chemotypes with selective anti-Giardia activity, identifying three compounds with sub-μM activity and promising selectivity. Here we extended these studies by examining the anti-Giardia activity of series CL9569 compounds. This compound series was of interest given the promising activity (IC50 1.2 μM) and selectivity demonstrated by representative compound, SN00798525 (1). Data from this work has identified an additional three thieno [3,2-b]pyrrole 5-carboxamides with anti-Giardia activity, including 2 which displayed potent cytocidal (IC50 ≤ 10 nM) and selective activity against multiple Giardia strains, including representatives from both human-infecting assemblages and metronidazole resistant parasites. Preclinical studies in mice also demonstrated that 2 is well-tolerated, does not impact the normal gut microbiota and can reduce Giardia parasite burden in these animals. |
| first_indexed | 2024-03-09T01:28:10Z |
| format | Article |
| id | doaj.art-3fa7736589924458957c5c2cc3f0b335 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-03-09T01:28:10Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-3fa7736589924458957c5c2cc3f0b3352023-12-10T06:14:47ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072023-12-01235462Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalisChristopher JS. Hart0Andrew G. Riches1Snigdha Tiash2Rebecca Abraham3Keely Fayd’Herbe4Ellis Joch5Bilal Zulfiqar6Melissa L. Sykes7Vicky M. Avery8Jan Šlapeta9Sam Abraham10John H. Ryan11Tina S. Skinner-Adams12Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia; School of Environment and Sciences, Griffith University, Nathan, Queensland, AustraliaCommonwealth Scientific and Industrial Research Organization, Biomedical Manufacturing, Clayton, Victoria, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, AustraliaHarry Butler Institute, Murdoch University, Western Australia, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia; School of Environment and Sciences, Griffith University, Nathan, Queensland, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia; School of Environment and Sciences, Griffith University, Nathan, Queensland, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia; Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, Queensland, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia; Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, Queensland, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia; School of Environment and Sciences, Griffith University, Nathan, Queensland, Australia; Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, Queensland, AustraliaSydney School of Veterinary Science, Faculty of Science, University of Sydney, New South Wales, AustraliaHarry Butler Institute, Murdoch University, Western Australia, AustraliaCommonwealth Scientific and Industrial Research Organization, Biomedical Manufacturing, Clayton, Victoria, AustraliaGriffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia; School of Environment and Sciences, Griffith University, Nathan, Queensland, Australia; Corresponding author. Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.Giardia duodenalis is the causative agent of the neglected diarrhoeal disease giardiasis. While often self-limiting, giardiasis is ubiquitous and impacts hundreds of millions of people annually. It is also a common gastro-intestinal disease of domestic pets, wildlife, and livestock animals. However, despite this impact, there is no vaccine for Giardia currently available. In addition, treatment relies on chemotherapies that are associated with increasing failure rates. To identify new treatment options for giardiasis we recently screened the Compounds Australia Scaffold Library for new chemotypes with selective anti-Giardia activity, identifying three compounds with sub-μM activity and promising selectivity. Here we extended these studies by examining the anti-Giardia activity of series CL9569 compounds. This compound series was of interest given the promising activity (IC50 1.2 μM) and selectivity demonstrated by representative compound, SN00798525 (1). Data from this work has identified an additional three thieno [3,2-b]pyrrole 5-carboxamides with anti-Giardia activity, including 2 which displayed potent cytocidal (IC50 ≤ 10 nM) and selective activity against multiple Giardia strains, including representatives from both human-infecting assemblages and metronidazole resistant parasites. Preclinical studies in mice also demonstrated that 2 is well-tolerated, does not impact the normal gut microbiota and can reduce Giardia parasite burden in these animals.http://www.sciencedirect.com/science/article/pii/S2211320723000295Giardia duodenalisDrug discoveryThieno[3,2-b]pyrrole 5-carboxamides |
| spellingShingle | Christopher JS. Hart Andrew G. Riches Snigdha Tiash Rebecca Abraham Keely Fayd’Herbe Ellis Joch Bilal Zulfiqar Melissa L. Sykes Vicky M. Avery Jan Šlapeta Sam Abraham John H. Ryan Tina S. Skinner-Adams Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis International Journal for Parasitology: Drugs and Drug Resistance Giardia duodenalis Drug discovery Thieno[3,2-b]pyrrole 5-carboxamides |
| title | Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis |
| title_full | Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis |
| title_fullStr | Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis |
| title_full_unstemmed | Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis |
| title_short | Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis |
| title_sort | thieno 3 2 b pyrrole 5 carboxamides as potent and selective inhibitors of giardia duodenalis |
| topic | Giardia duodenalis Drug discovery Thieno[3,2-b]pyrrole 5-carboxamides |
| url | http://www.sciencedirect.com/science/article/pii/S2211320723000295 |
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