Evaluation of the antitrypanosoma activity and SAR study of novel LINS03 derivatives.

Bioorg Chem 2019 Aug 18;89:102996. Epub 2019 May 18.

Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, 09913-030 Diadema, SP, Brazil. Electronic address:

Chagas' disease is a parasitic infection caused by Trypanosoma cruzi that is still treated by old and toxic drugs. In the search for novel alternatives, natural sources are an important source for new drug prototypes against T. cruzi to further structural exploitation. A set of natural-based compounds (LINS03) was designed, showing promising antitrypanosoma activity and low cytotoxicity to host cells. In this paper, nine novel LINS03 derivatives were evaluated against T. cruzi trypomastigotes and amastigotes. The selectivity was assessed through cytotoxicity assays using NCTC mammalian cells and calculating the CC/IC ratio. The results showed that compounds 2d and 4c are noteworthy, due their high activity against amastigotes (IC 13.9 and 5.8 µM) and low cytotoxicity (CC 107.7 µM and >200 µM, respectively). These compounds did not showed alteration on plasma membrane permeability in a Sytox green model. SAR analysis suggested an ideal balance between hydrosolubility and lipophilicity is necessary to improve the activity, and that insertion of a meta-substituent is detrimental to the activity of the amine derivatives but not to the neutral derivatives, suggesting different mechanisms of actions. The results presented herein are valuable for designing novel compounds with improved activity and selectivity to be applied in future studies.

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Source
https://linkinghub.elsevier.com/retrieve/pii/S00452068183138
Publisher Site
http://dx.doi.org/10.1016/j.bioorg.2019.102996DOI Listing
August 2019
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