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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...

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Autores principales: Węglińska, Lidia, Bekier, Adrian, Dzitko, Katarzyna, Pacholczyk-Sienicka, Barbara, Albrecht, Łukasz, Plech, Tomasz, Paneth, Piotr, Paneth, Agata
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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