Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine
A safer treatment for toxoplasmosis would be achieved by improving the selectivity profile of novel chemotherapeutics compared to the standard therapy pyrimethamine (PYR) and sulfadiazine (SDZ). We previously reported on the identification of the compounds with imidazole-thiosemicarbazide scaffold a...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2112576 |
| _version_ | 1828111430600097792 |
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| author | Lidia Węglińska Adrian Bekier Nazar Trotsko Barbara Kaproń Tomasz Plech Katarzyna Dzitko Agata Paneth |
| author_facet | Lidia Węglińska Adrian Bekier Nazar Trotsko Barbara Kaproń Tomasz Plech Katarzyna Dzitko Agata Paneth |
| author_sort | Lidia Węglińska |
| collection | DOAJ |
| description | A safer treatment for toxoplasmosis would be achieved by improving the selectivity profile of novel chemotherapeutics compared to the standard therapy pyrimethamine (PYR) and sulfadiazine (SDZ). We previously reported on the identification of the compounds with imidazole-thiosemicarbazide scaffold as potent and selective anti-Toxoplasma gondii (T. gondii) agents. In our current research, we report on the optimisation of this chemical scaffold leading to the discovery cyclic analogue 20 b with s-triazole core structure. This compound displayed prominent CC30 to IC50 selectivity index (SI) of 70.72, making it 160-fold more selective than SDZ, 11-fold more selective than PYR, and 4-fold more selective than trimethoprim (TRI). Additionally, this compound possesses prerequisite drug-like anti-Toxoplasma properties to advance into preclinical development; it showed ability to cross the BBB, did not induce genotoxic and haemolytic changes in human cells, and as well as it was characterised by low cellular toxicity. |
| first_indexed | 2024-04-11T11:34:41Z |
| format | Article |
| id | doaj.art-79d58e45c8734949b193085685825372 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-11T11:34:41Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-79d58e45c8734949b1930856858253722022-12-22T04:26:00ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013712621263410.1080/14756366.2022.2112576Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazineLidia Węglińska0Adrian Bekier1Nazar Trotsko2Barbara Kaproń3Tomasz Plech4Katarzyna Dzitko5Agata Paneth6Department of Organic Chemistry, Medical University of Lublin, Lublin, PolandDepartment of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandDepartment of Organic Chemistry, Medical University of Lublin, Lublin, PolandDepartment of Clinical Genetics, Medical University of Lublin, Lublin, PolandDepartment of Pharmacology, Medical University of Lublin, Lublin, PolandDepartment of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandDepartment of Organic Chemistry, Medical University of Lublin, Lublin, PolandA safer treatment for toxoplasmosis would be achieved by improving the selectivity profile of novel chemotherapeutics compared to the standard therapy pyrimethamine (PYR) and sulfadiazine (SDZ). We previously reported on the identification of the compounds with imidazole-thiosemicarbazide scaffold as potent and selective anti-Toxoplasma gondii (T. gondii) agents. In our current research, we report on the optimisation of this chemical scaffold leading to the discovery cyclic analogue 20 b with s-triazole core structure. This compound displayed prominent CC30 to IC50 selectivity index (SI) of 70.72, making it 160-fold more selective than SDZ, 11-fold more selective than PYR, and 4-fold more selective than trimethoprim (TRI). Additionally, this compound possesses prerequisite drug-like anti-Toxoplasma properties to advance into preclinical development; it showed ability to cross the BBB, did not induce genotoxic and haemolytic changes in human cells, and as well as it was characterised by low cellular toxicity.https://www.tandfonline.com/doi/10.1080/14756366.2022.2112576s-triazoleanti-Toxoplasma gondii activityselectivity index |
| spellingShingle | Lidia Węglińska Adrian Bekier Nazar Trotsko Barbara Kaproń Tomasz Plech Katarzyna Dzitko Agata Paneth Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine Journal of Enzyme Inhibition and Medicinal Chemistry s-triazole anti-Toxoplasma gondii activity selectivity index |
| title | Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine |
| title_full | Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine |
| title_fullStr | Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine |
| title_full_unstemmed | Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine |
| title_short | Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine |
| title_sort | inhibition of toxoplasma gondii by 1 2 4 triazole based compounds marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine |
| topic | s-triazole anti-Toxoplasma gondii activity selectivity index |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2112576 |
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