1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.1/17777 |
Resumo: | Leishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on <i>Leishmania</i> parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against <i>L. infantum</i> and <i>L. donovani</i> and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2 <i>Leishmania</i> species, with IC<sub>50</sub> values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on <i>L. infantum</i> amastigotes (IC<sub>50</sub> 13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes. |
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1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of actionLeishmania infantumLeishmania donovaniLeishmaniasis1,2,4-trioxolanes1,2,4,5-tetraoxanesSelectivityMode of actionReactive oxygen speciesLeishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on <i>Leishmania</i> parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against <i>L. infantum</i> and <i>L. donovani</i> and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2 <i>Leishmania</i> species, with IC<sub>50</sub> values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on <i>L. infantum</i> amastigotes (IC<sub>50</sub> 13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes.UID/MULTI/04326/2021; UI0313B/QUI/2020MDPISapientiaMendes, AndreiaArmada, AnaCabral, LíliaAmado, PatríciaCampino, LeneaCristiano, Maria de LurdesCortes, Sofia2022-04-22T13:35:29Z2022-04-032022-04-21T21:04:01Z2022-04-03T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/17777engPharmaceuticals 15 (4): 446 (2022)doi: 10.3390/ph1504044610.3390/ph15040446info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-13T02:07:33Zoai:sapientia.ualg.pt:10400.1/17777Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:07:39.472822Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action |
title |
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action |
spellingShingle |
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action Mendes, Andreia Leishmania infantum Leishmania donovani Leishmaniasis 1,2,4-trioxolanes 1,2,4,5-tetraoxanes Selectivity Mode of action Reactive oxygen species |
title_short |
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action |
title_full |
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action |
title_fullStr |
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action |
title_full_unstemmed |
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action |
title_sort |
1,2,4-Trioxolane and 1,2,4,5-Tetraoxane endoperoxides against old-world Leishmania parasites: in vitro activity and mode of action |
author |
Mendes, Andreia |
author_facet |
Mendes, Andreia Armada, Ana Cabral, Lília Amado, Patrícia Campino, Lenea Cristiano, Maria de Lurdes Cortes, Sofia |
author_role |
author |
author2 |
Armada, Ana Cabral, Lília Amado, Patrícia Campino, Lenea Cristiano, Maria de Lurdes Cortes, Sofia |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
Mendes, Andreia Armada, Ana Cabral, Lília Amado, Patrícia Campino, Lenea Cristiano, Maria de Lurdes Cortes, Sofia |
dc.subject.por.fl_str_mv |
Leishmania infantum Leishmania donovani Leishmaniasis 1,2,4-trioxolanes 1,2,4,5-tetraoxanes Selectivity Mode of action Reactive oxygen species |
topic |
Leishmania infantum Leishmania donovani Leishmaniasis 1,2,4-trioxolanes 1,2,4,5-tetraoxanes Selectivity Mode of action Reactive oxygen species |
description |
Leishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on <i>Leishmania</i> parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against <i>L. infantum</i> and <i>L. donovani</i> and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2 <i>Leishmania</i> species, with IC<sub>50</sub> values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on <i>L. infantum</i> amastigotes (IC<sub>50</sub> 13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-04-22T13:35:29Z 2022-04-03 2022-04-21T21:04:01Z 2022-04-03T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.1/17777 |
url |
http://hdl.handle.net/10400.1/17777 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Pharmaceuticals 15 (4): 446 (2022) doi: 10.3390/ph15040446 10.3390/ph15040446 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
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MDPI |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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