Structure‐based design, synthesis and biological evaluation of bis‐tetrahydropyran furan acetogenin mimics targeting the trypanosomatid F1 component of ATP synthase
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The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for the severely debilitating neglected Tropical diseases of African sleeping sickness, Chagas disease and leishmaniasis, respectively. As part of our ongoing programme exploring the potential of simplified analogues of the acetogenin chamuvarinin we identified the T. brucei FoF1‐ATP synthase as a target of our earlier triazole analogue series. Using computational docking studies we hypothesized that the central triazole heterocyclic spacer could be substituted for a central 2,5‐substituted furan moiety, thus diversifying the chemical framework for the generation of compounds with greater potency and/or selectivity. Here we report the design, docking, synthesis and biological evaluation of new series of trypanocidal compounds and demonstrate their on‐target inhibitory effects. Furthermore, the synthesis of furans by the modular coupling of alkyne‐ and aldehyde‐THPs to bis‐THP 1,4‐alkyne diols followed by ruthenium/xantphos‐catalysed heterocyclisation described here represents the most complex use of this method of heterocyclisation to date.
Zacharova , M , Tulloch , L , Gould , E , Fraser , A , King , E , Menzies , S , Smith , T K & Florence , G J 2019 , ' Structure‐based design, synthesis and biological evaluation of bis‐tetrahydropyran furan acetogenin mimics targeting the trypanosomatid F1 component of ATP synthase ' , European Journal of Organic Chemistry , vol. 2019 , no. 31-32 , pp. 5434-5440 . https://doi.org/10.1002/ejoc.201900541
European Journal of Organic Chemistry
Copyright © 2019 The Authors. Published by Wiley‐VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
DescriptionThis work was funded by the Leverhulme Trust (G.J.F.), Wellcome Trust ISSF support (G.J.F./T.K.S.) and the European Community’s Seventh Framework Programme under grant agreement No. 602773 [Project KINDRED] (T.K.S.).
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