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

TY - JOUR

T1 - Structure‐based design, synthesis and biological evaluation of bis‐tetrahydropyran furan acetogenin mimics targeting the trypanosomatid F1 component of ATP synthase

AU - Zacharova, Marija K.

AU - Tulloch, Lindsay B.

AU - Gould, Eoin R.

AU - Fraser, Andrew L.

AU - King, Elizabeth F.

AU - Menzies, Stefanie K.

AU - Smith, Terry K.

AU - Florence, Gordon J.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

KW - Biological activity

KW - Drug design

KW - FoF1-ATP synthase

KW - Homogeneous catalysis

KW - Trypanosomatid

UR - https://www.scopus.com/pages/publications/85066630767

U2 - 10.1002/ejoc.201900541

DO - 10.1002/ejoc.201900541

M3 - Article

SN - 1434-193X

VL - 2019

SP - 5434

EP - 5440

JO - European Journal of Organic Chemistry

JF - European Journal of Organic Chemistry

IS - 31-32

ER -