Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors

Fraser, Andrew L. and Menzies, Stefanie K. and King, Elizabeth F.B. and Tulloch, Lindsay B. and Gould, Eoin R. and Zacharova, Marija K. and Smith, Terry K. and Florence, Gordon J. (2018) Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors. ACS Infectious Diseases, 4 (4). pp. 560-567. ISSN 2373-8227

Abstract

Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photoaffinity probes capable of labeling target protein(s) in vitro. Several of these functionalized compounds maintain low micromolar activity against Trypanosoma brucei, Trypanosoma cruzi, Leishmania major, and Leishmania donovani. In addition, we demonstrate the utility of the photoaffinity probes for target identification through preliminary cellular localization studies.