New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase

Two new series of twenty-eight selenocyanate and diselenide derivatives containing amide moiety were designed, synthesized and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited exc...

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Autores: Etxebeste Mitxeltorena, Mikel, Plano, Daniel, Espuelas Millán, María Socorro, Moreno, Esther, Aydillo Miguel, Carlos, Jiménez Ruiz, Antonio|||0000-0001-8238-3081, García Soriano, Juan Carlos, Sanmartín, Carmen
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad de Alcalá (UAH)
Repositorio:e_Buah Biblioteca Digital Universidad de Alcalá
Idioma:inglés
OAI Identifier:oai:ebuah.uah.es:10017/63306
Acceso en línea:http://hdl.handle.net/10017/63306
https://dx.doi.org/10.1128/AAC.00524-20
Access Level:acceso abierto
Palabra clave:Amides
Diselenide
Selenocyanate
Thiols
Trypanothione reductase
Medicina
Medicine
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spelling New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductaseEtxebeste Mitxeltorena, MikelPlano, DanielEspuelas Millán, María SocorroMoreno, EstherAydillo Miguel, CarlosJiménez Ruiz, Antonio|||0000-0001-8238-3081García Soriano, Juan CarlosSanmartín, CarmenAmidesDiselenideSelenocyanateThiolsTrypanothione reductaseMedicinaMedicineTwo new series of twenty-eight selenocyanate and diselenide derivatives containing amide moiety were designed, synthesized and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited excellent leishmanicidal activity with EC50 values lower than the reference drug miltefosine (EC50 = 2.84 muM). In addition, for six of them the selectivity index ranged from 9 to > 1442, greater than both references used. The most potent and selective compounds were 2h, 2k and 2m that displayed EC50 values of 0.52, 1.19 and 0.50 muM and a high selectivity index (SI) when tested against THP-1 monocytic cells (SI = >1442, > 672 and >1100, respectively). These derivatives showed an efficacy similar to that of the reference drugs but much better SI. They also showed very interesting activity values against infected macrophages. Trypanothione reductase (TryR) activity and intracellular thiol level measurement assays were performed for the three best compounds in an attempt to elucidate their mechanism of action. Even though the new analogues exhibited comparable or better inhibitory activities than reference TryR inhibitors more studies are necessary to confirm this target. To sum up, our findings suggest that the three presented compounds could constitute lead leishmanicidal drug candidates.Ministerio de Ciencia, Innovación y UniversidadesComunidad de Madrid20202020-12-16journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10017/63306https://dx.doi.org/10.1128/AAC.00524-20reponame:e_Buah Biblioteca Digital Universidad de Alcaláinstname:Universidad de Alcalá (UAH)InglésengMinisterio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available PID2019-104070RBC22Comunidad de Madrid http://dx.doi.org/10.13039/100012818 Not available S-2018%2FBAA-4370 PLATESA2-CMopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ebuah.uah.es:10017/633062026-06-18T11:13:07Z
dc.title.none.fl_str_mv New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase
title New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase
spellingShingle New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase
Etxebeste Mitxeltorena, Mikel
Amides
Diselenide
Selenocyanate
Thiols
Trypanothione reductase
Medicina
Medicine
title_short New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase
title_full New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase
title_fullStr New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase
title_full_unstemmed New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase
title_sort New amides containing selenium as potent leishmanicidal agents targeting trypanothione reductase
dc.creator.none.fl_str_mv Etxebeste Mitxeltorena, Mikel
Plano, Daniel
Espuelas Millán, María Socorro
Moreno, Esther
Aydillo Miguel, Carlos
Jiménez Ruiz, Antonio|||0000-0001-8238-3081
García Soriano, Juan Carlos
Sanmartín, Carmen
author Etxebeste Mitxeltorena, Mikel
author_facet Etxebeste Mitxeltorena, Mikel
Plano, Daniel
Espuelas Millán, María Socorro
Moreno, Esther
Aydillo Miguel, Carlos
Jiménez Ruiz, Antonio|||0000-0001-8238-3081
García Soriano, Juan Carlos
Sanmartín, Carmen
author_role author
author2 Plano, Daniel
Espuelas Millán, María Socorro
Moreno, Esther
Aydillo Miguel, Carlos
Jiménez Ruiz, Antonio|||0000-0001-8238-3081
García Soriano, Juan Carlos
Sanmartín, Carmen
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Amides
Diselenide
Selenocyanate
Thiols
Trypanothione reductase
Medicina
Medicine
topic Amides
Diselenide
Selenocyanate
Thiols
Trypanothione reductase
Medicina
Medicine
description Two new series of twenty-eight selenocyanate and diselenide derivatives containing amide moiety were designed, synthesized and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited excellent leishmanicidal activity with EC50 values lower than the reference drug miltefosine (EC50 = 2.84 muM). In addition, for six of them the selectivity index ranged from 9 to > 1442, greater than both references used. The most potent and selective compounds were 2h, 2k and 2m that displayed EC50 values of 0.52, 1.19 and 0.50 muM and a high selectivity index (SI) when tested against THP-1 monocytic cells (SI = >1442, > 672 and >1100, respectively). These derivatives showed an efficacy similar to that of the reference drugs but much better SI. They also showed very interesting activity values against infected macrophages. Trypanothione reductase (TryR) activity and intracellular thiol level measurement assays were performed for the three best compounds in an attempt to elucidate their mechanism of action. Even though the new analogues exhibited comparable or better inhibitory activities than reference TryR inhibitors more studies are necessary to confirm this target. To sum up, our findings suggest that the three presented compounds could constitute lead leishmanicidal drug candidates.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-12-16
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10017/63306
https://dx.doi.org/10.1128/AAC.00524-20
url http://hdl.handle.net/10017/63306
https://dx.doi.org/10.1128/AAC.00524-20
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available PID2019-104070RBC22
Comunidad de Madrid http://dx.doi.org/10.13039/100012818 Not available S-2018%2FBAA-4370 PLATESA2-CM
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:e_Buah Biblioteca Digital Universidad de Alcalá
instname:Universidad de Alcalá (UAH)
instname_str Universidad de Alcalá (UAH)
reponame_str e_Buah Biblioteca Digital Universidad de Alcalá
collection e_Buah Biblioteca Digital Universidad de Alcalá
repository.name.fl_str_mv
repository.mail.fl_str_mv
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