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

Date

2019

Authors

Díaz, Marta
Lucio, Hector de
Moreno, Esther
Espuelas, Socorro
Aydillo, Carlos
Jiménez Ruiz, Antonio
Toro, Miguel Ángel
Gutiérrez, Killian Jesús

Director

Publisher

American Society for Microbiology
Acceso abierto / Sarbide irekia
Artículo / Artikulua
Versión aceptada / Onetsi den bertsioa

Project identifier

MINECO//SAF2015-64629-C2-1-R/ES/recolecta

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.

Description

Keywords

Selenium, Selenourea, Thiourea, Trypanothione reductase, Urea

Department

Ciencias / Zientziak

Faculty/School

Degree

Doctorate program

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© 2019 American Society for Microbiology

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