Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides

A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these deriv...

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Autores: Díaz, Marta, Lucio, Hector de, Moreno, Esther, Espuelas, Socorro, Aydillo, Carlos, Jiménez Ruiz, Antonio, Toro, Miguel Ángel, Gutiérrez, Killian Jesús, Martínez Merino, Víctor, Cornejo Ibergallartu, Alfonso
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Universidad Pública de Navarra
Repositorio:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
OAI Identifier:oai:academica-e.unavarra.es:2454/36162
Acceso en línea:https://hdl.handle.net/2454/36162
Access Level:acceso abierto
Palabra clave:Selenium
Selenourea
Thiourea
Trypanothione reductase
Urea
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spelling Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenidesDíaz, MartaLucio, Hector deMoreno, EstherEspuelas, SocorroAydillo, CarlosJiménez Ruiz, AntonioToro, Miguel ÁngelGutiérrez, Killian JesúsMartínez Merino, VíctorCornejo Ibergallartu, AlfonsoSeleniumSelenoureaThioureaTrypanothione reductaseUreaA novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84 mu M). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95 mu M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leish-manicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.The authors thank the Foundation for Applied Medical Investigation (FIMA), University of Navarra. They also acknowledge the Ministerio de Educación y Ciencia, Spain (grant SAF2015-64629-C2), and Comunidad de Madrid (BIPEDD-2-CM ref. S-2010/BMD-2457) for financial support. They also thank the Caixa Foundation, Roviralta, and Ubesol for supporting this research. This work, including the efforts of M.D., was funded by Foundation for Applied Medical Investigation (ISTUN-API-2011/02). This work, including the efforts of A.J.-R., was funded by Ministerio de Educacion y Ciencia, Spain (grant SAF2015-64629-C2), and Comunidad de Madrid (BIPEDD-2-CM ref. S-2010/BMD-2457).American Society for MicrobiologyCienciasZientziak2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2454/36162reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglésinfo:eu-repo/grantAgreement/MINECO//SAF2015-64629-C2-1-R© 2019 American Society for Microbiologyinfo:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/361622026-06-17T12:41:47Z
dc.title.none.fl_str_mv Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
title Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
spellingShingle Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
Díaz, Marta
Selenium
Selenourea
Thiourea
Trypanothione reductase
Urea
title_short Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
title_full Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
title_fullStr Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
title_full_unstemmed Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
title_sort Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
dc.creator.none.fl_str_mv Díaz, Marta
Lucio, Hector de
Moreno, Esther
Espuelas, Socorro
Aydillo, Carlos
Jiménez Ruiz, Antonio
Toro, Miguel Ángel
Gutiérrez, Killian Jesús
Martínez Merino, Víctor
Cornejo Ibergallartu, Alfonso
author Díaz, Marta
author_facet Díaz, Marta
Lucio, Hector de
Moreno, Esther
Espuelas, Socorro
Aydillo, Carlos
Jiménez Ruiz, Antonio
Toro, Miguel Ángel
Gutiérrez, Killian Jesús
Martínez Merino, Víctor
Cornejo Ibergallartu, Alfonso
author_role author
author2 Lucio, Hector de
Moreno, Esther
Espuelas, Socorro
Aydillo, Carlos
Jiménez Ruiz, Antonio
Toro, Miguel Ángel
Gutiérrez, Killian Jesús
Martínez Merino, Víctor
Cornejo Ibergallartu, Alfonso
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ciencias
Zientziak
dc.subject.none.fl_str_mv Selenium
Selenourea
Thiourea
Trypanothione reductase
Urea
topic Selenium
Selenourea
Thiourea
Trypanothione reductase
Urea
description A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84 mu M). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95 mu M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leish-manicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2454/36162
url https://hdl.handle.net/2454/36162
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MINECO//SAF2015-64629-C2-1-R
dc.rights.none.fl_str_mv © 2019 American Society for Microbiology
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © 2019 American Society for Microbiology
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
dc.source.none.fl_str_mv reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
instname:Universidad Pública de Navarra
instname_str Universidad Pública de Navarra
reponame_str Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
collection Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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