Structure‐based design, synthesis and biological evaluation of bis‐tetrahydropyran furan acetogenin mimics targeting the trypanosomatid F1 component of ATP synthase

Marija Zacharova, Lindsay Tulloch, Eoin Gould, Andrew Fraser, Elizabeth King, Stefanie Menzies, Terry K. Smith, Gordon J. Florence

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
7 Downloads (Pure)

Abstract

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.
Original languageEnglish
Pages (from-to)5434-5440
Number of pages8
JournalEuropean Journal of Organic Chemistry
Volume2019
Issue number31-32
Early online date29 May 2019
DOIs
Publication statusPublished - 1 Sept 2019

Keywords

  • Trypanosomatid
  • Neglected tropical disease
  • Drug design
  • FoF1-ATP synthase
  • Ruthenium/xantphos-catalysed heterocyclisation

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