Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides
| dc.contributor.author | Díaz, Marta | |
| dc.contributor.author | Lucio, Hector de | |
| dc.contributor.author | Moreno, Esther | |
| dc.contributor.author | Espuelas, Socorro | |
| dc.contributor.author | Aydillo, Carlos | |
| dc.contributor.author | Jiménez Ruiz, Antonio | |
| dc.contributor.author | Toro, Miguel Ángel | |
| dc.contributor.author | Gutiérrez, Killian Jesús | |
| dc.contributor.author | Martínez Merino, Víctor | |
| dc.contributor.author | Cornejo Ibergallartu, Alfonso | |
| dc.contributor.department | Ciencias | es_ES |
| dc.contributor.department | Zientziak | eu |
| dc.date.accessioned | 2020-01-27T09:50:37Z | |
| dc.date.available | 2020-01-27T09:50:37Z | |
| dc.date.issued | 2019 | |
| dc.description.abstract | 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. | en |
| dc.description.sponsorship | 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). | en |
| dc.format.extent | 50 p. | |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.doi | 10.1128/AAC.02200-18 | |
| dc.identifier.issn | 0066-4804 | |
| dc.identifier.uri | https://academica-e.unavarra.es/handle/2454/36162 | |
| dc.language.iso | eng | en |
| dc.publisher | American Society for Microbiology | en |
| dc.relation.ispartof | Antimicrobial Agents and Chemotherapy, 63 e02200-18 | en |
| dc.relation.projectID | info:eu-repo/grantAgreement/MINECO//SAF2015-64629-C2-1-R/ES/ | |
| dc.relation.publisherversion | https://doi.org/10.1128/AAC.02200-18 | |
| dc.rights | © 2019 American Society for Microbiology | en |
| dc.rights.accessRights | info:eu-repo/semantics/openAccess | |
| dc.subject | Selenium | en |
| dc.subject | Selenourea | en |
| dc.subject | Thiourea | en |
| dc.subject | Trypanothione reductase | en |
| dc.subject | Urea | en |
| dc.title | Synthesis and Leishmanicidal activity of novel urea, thiourea, and selenourea derivatives of diselenides | en |
| dc.type | info:eu-repo/semantics/article | |
| dc.type.version | info:eu-repo/semantics/acceptedVersion | |
| dspace.entity.type | Publication | |
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| relation.isAuthorOfPublication.latestForDiscovery | 7bca4c38-21d4-4c54-a683-843613ad2d61 |