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 leishmanicidal activities. The cytotoxic activity of these derivatives wa...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2019-05, Vol.63 (5)
Main Authors: Díaz, Marta, de Lucio, Héctor, Moreno, Esther, Espuelas, Socorro, Aydillo, Carlos, Jiménez-Ruiz, Antonio, Toro, Miguel Ángel, Gutiérrez, Killian Jesús, Martínez-Merino, Victor, Cornejo, Alfonso, Palop, Juan Antonio, Sanmartín, Carmen, Plano, Daniel
Format: Article
Language:English
Subjects:
Antiprotozoal Agents
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - therapeutic use
Biosynthesis
Chemistry
Chemistry
Biosynthesis
Editor's Pick
Humans
Leishmania infantum
Leishmania infantum - drug effects
Leishmania infantum - pathogenicity
Macrophages - parasitology
NADH, NADPH Oxidoreductases - metabolism
Organoselenium Compounds
Organoselenium Compounds - chemistry
Parasitic Sensitivity Tests
Structure-Activity Relationship
Thiourea
Thiourea - chemistry
Urea
Urea - analogs & derivatives
Urea - chemistry
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Summary: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 leishmanicidal activities. The cytotoxic activity of these derivatives was tested against 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 (EC ) values lower than that for the reference drug miltefosine (EC , 2.84 μM). In addition, the derivatives 9, 11, 42, and 47, with EC between 1.1 and 1.95 μM, 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 EC 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 leishmanicidal 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.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.02200-18