Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors
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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.
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 . DOI: 10.1002/cmdc.201402272
© 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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