Structure-Based Design, Synthesis and Biological Evaluation of Bis-Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase

Zacharova, Marija K. and Tulloch, Lindsay B. and Gould, Eoin R. and Fraser, Andrew L. and King, Elizabeth F. and Menzies, Stefanie K. and Smith, Terry K. and Florence, Gordon 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, 2019 (31-32). pp. 5434-5440. ISSN 1434-193X

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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 hypothesised 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.

Item Type:
Journal Article
Journal or Publication Title:
European Journal of Organic Chemistry
Additional Information:
Publisher Copyright: © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1600/1606
Subjects:
?? biological activitydrug designfof1-atp synthasehomogeneous catalysistrypanosomatidphysical and theoretical chemistryorganic chemistry ??
ID Code:
219875
Deposited By:
Deposited On:
17 May 2024 15:10
Refereed?:
Yes
Published?:
Published
Last Modified:
17 May 2024 15:10