Structure‐based design, synthesis and biological evaluation of bis‐tetrahydropyran furan acetogenin mimics targeting the trypanosomatid F1 component of ATP synthase
| Autor: | Zacharova, Marija K., Tulloch, Lindsay B., Gould, Eoin R., Fraser, Andrew L., King, Elizabeth F., Menzies, Stefanie K., Smith, Terry K., Florence, Gordon J. |
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| Přispěvatelé: | The Wellcome Trust, The Leverhulme Trust, European Commission, University of St Andrews. School of Chemistry, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. School of Biology, University of St Andrews. EaSTCHEM |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
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Full Paper
Trypanosomatid Biological activity Neglected tropical disease Ruthenium/xantphos-catalysed heterocyclisation NDAS Full Papers Homogeneous catalysis QD Chemistry Drug design FoF1-ATP synthase FoF1‐ATP synthase SDG 3 - Good Health and Well-being parasitic diseases HAT Inhibitors | Very Important Paper QD |
| Zdroj: | European Journal of Organic Chemistry |
| Popis: | This 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.). 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. Publisher PDF |
| Databáze: | OpenAIRE |
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