5′-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target

Authors

  • Dr. Elena Casanova,

    1. Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006, Madrid (Spain)
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  • Dr. David Moreno,

    1. Departamento de Bioquímica y Biología Molecular, Unidad Asociada de I+D+i al CSIC, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid (Spain)
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  • Alba Gigante,

    1. Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006, Madrid (Spain)
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  • Dr. Eva Rico,

    1. Departamento de Bioquímica y Biología Molecular, Unidad Asociada de I+D+i al CSIC, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid (Spain)
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  • Carlos Mario Genes,

    1. Departamento de Bioquímica y Biología Molecular, Unidad Asociada de I+D+i al CSIC, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid (Spain)
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  • Cristina Oliva,

    1. Departamento de Bioquímica y Biología Molecular, Unidad Asociada de I+D+i al CSIC, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid (Spain)
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  • Prof. María-José Camarasa,

    1. Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006, Madrid (Spain)
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  • Prof. Federico Gago,

    1. Departamento de Farmacología, Unidad Asociada de I+D+i al CSIC, Campus Universitario, Universidad de Alcalá, Alcalá de Henares (Spain)
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  • Prof. Antonio Jiménez-Ruiz,

    1. Departamento de Bioquímica y Biología Molecular, Unidad Asociada de I+D+i al CSIC, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid (Spain)
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  • Prof. María-Jesús Pérez-Pérez

    Corresponding author
    1. Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006, Madrid (Spain)
    • Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006, Madrid (Spain)
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Abstract

Two series of 5′-triphenylmethyl (trityl)-substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3′-O-(isoleucylisoleucyl)-5′-O-(3,3,3-triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds.

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