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...
| Autores: | , , , , , , , |
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| 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 |
| Sumario: | 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. |
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