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Identification of potential trypanothione reductase inhibitors among commercially available \(\upbeta \)-carboline derivatives using chemical space, lead-like and drug-like filters, pharmacophore models and molecular docking

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Abstract

American trypanosomiasis or Chagas disease caused by the protozoan Trypanosoma cruzi (T. cruzi) is an important endemic trypanosomiasis in Central and South America. This disease was considered to be a priority in the global plan to combat neglected tropical diseases, 2008–2015, which indicates that there is an urgent need to develop more effective drugs. The development of new chemotherapeutic agents against Chagas disease can be related to an important biochemical feature of T. cruzi: its redox defense system. This system is based on trypanothione (\(N^{1}\),\(N^{8}\)-bis(glutathyonil)spermidine) and trypanothione reductase (TR), which are rather unique to trypanosomes and completely absent in mammalian cells. In this regard, tricyclic compounds have been studied extensively due to their ability to inhibit the T. cruzi TR. However, synthetic derivatives of natural products, such as \(\upbeta \)-carboline derivatives (\(\upbeta \)-CDs), as potential TR inhibitors, has received little attention. This study presents an analysis of the structural and physicochemical properties of commercially available \(\upbeta \)-CDs in relation to compounds tested against T. cruzi in previously reported enzymatic assays and shows that \(\upbeta \)-CDs cover chemical space that has not been considered for the design of TR inhibitors. Moreover, this study presents a ligand-based approach to discover potential TR inhibitors among commercially available \(\upbeta \)-CDs, which could lead to the generation of promising \(\upbeta \)-CD candidates.

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Acknowledgements

This research was supported by FONDECYT-11100308 (Comisión Nacional de Investigación Científica y Tecnológica, CONICYT, Chile). The authors thank FIBE 15/10 (Direccion de Investigacion - UMCE, DIUMCE, Chile), the MYS I/26 2013 Project (DIUMCE, Chile) and FONDECYT-11110421 (CONICYT, Chile).

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  1. Physical and Analytical Chemistry Laboratory, PACHEM, Departament of Chemistry, Basic Science Faculty, Universidad Metropolitana de Ciencias de la Educación, UMCE, Santiago, Chile

    Jorge Rodríguez-Becerra, Lizethly Cáceres-Jensen & José Hernández-Ramos

  2. Chemistry Faculty, Research Center for Nanotechnology and Advanced Materials, CIEN-UC, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Macul, Santiago, Chile

    Lorena Barrientos

  3. Center for the Development of Nanoscience and Nanotechnology, CEDENNA, Santiago, Chile

    Lorena Barrientos

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  1. Jorge Rodríguez-Becerra
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Rodríguez-Becerra, J., Cáceres-Jensen, L., Hernández-Ramos, J. et al. Identification of potential trypanothione reductase inhibitors among commercially available \(\upbeta \)-carboline derivatives using chemical space, lead-like and drug-like filters, pharmacophore models and molecular docking. Mol Divers 21, 697–711 (2017). https://doi.org/10.1007/s11030-017-9747-6

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