1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii
Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, e...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145641/ https://www.ncbi.nlm.nih.gov/pubmed/33946881 http://dx.doi.org/10.3390/cells10051053 |
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author | Węglińska, Lidia Bekier, Adrian Dzitko, Katarzyna Pacholczyk-Sienicka, Barbara Albrecht, Łukasz Plech, Tomasz Paneth, Piotr Paneth, Agata |
author_facet | Węglińska, Lidia Bekier, Adrian Dzitko, Katarzyna Pacholczyk-Sienicka, Barbara Albrecht, Łukasz Plech, Tomasz Paneth, Piotr Paneth, Agata |
author_sort | Węglińska, Lidia |
collection | PubMed |
description | Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b–12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC(50)) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b–12b, especially 12b with IC(50) of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells. |
format | Online Article Text |
id | pubmed-8145641 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81456412021-05-26 1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii Węglińska, Lidia Bekier, Adrian Dzitko, Katarzyna Pacholczyk-Sienicka, Barbara Albrecht, Łukasz Plech, Tomasz Paneth, Piotr Paneth, Agata Cells Article Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b–12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC(50)) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b–12b, especially 12b with IC(50) of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells. MDPI 2021-04-29 /pmc/articles/PMC8145641/ /pubmed/33946881 http://dx.doi.org/10.3390/cells10051053 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Węglińska, Lidia Bekier, Adrian Dzitko, Katarzyna Pacholczyk-Sienicka, Barbara Albrecht, Łukasz Plech, Tomasz Paneth, Piotr Paneth, Agata 1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii |
title | 1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii |
title_full | 1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii |
title_fullStr | 1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii |
title_full_unstemmed | 1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii |
title_short | 1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii |
title_sort | 1,3,4-thiadiazoles effectively inhibit proliferation of toxoplasma gondii |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145641/ https://www.ncbi.nlm.nih.gov/pubmed/33946881 http://dx.doi.org/10.3390/cells10051053 |
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