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Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

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cmdc201402272rev_OA_PURE.pdf (2.328Mb)
Date
11/2014
Author
Florence, Gordon J.
Fraser, Andrew L.
Gould, Eoin R.
King, Elizabeth F. B.
Menzies, Stefanie K.
Morris, Joanne C.
Tulloch, Lindsay B.
Smith, Terry K.
Keywords
Acetogenin
Neglected diseases
HAT
T. brucei
Stereochemistry
Human African Trypanosomiasis (HAT)
Natural product analogues
Trypanosoma brucei
QD Chemistry
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Abstract
Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure–activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti-HAT agents.
Citation
Florence , G J , Fraser , A L , Gould , E R , King , E F B , Menzies , S K , Morris , J C , Tulloch , L B & Smith , T K 2014 , ' Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors ' , ChemMedChem , vol. 9 , no. 11 , pp. 2548-2556 . https://doi.org/10.1002/cmdc.201402272
Publication
ChemMedChem
Status
Peer reviewed
DOI
https://doi.org/10.1002/cmdc.201402272
ISSN
1860-7179
Type
Journal article
Rights
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at http://dx.doi.org/10.1002/cmdc.201402272
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/7289

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