Non-natural Acetogenin Analogues as Potent Trypanosoma brucei Inhibitors

Florence, Gordon J. and Fraser, Andrew L. and Gould, Eoin R. and King, Elizabeth F.B. and Menzies, Stefanie K. and Morris, Joanne C. and Tulloch, Lindsay B. and Smith, Terry K. (2014) Non-natural Acetogenin Analogues as Potent Trypanosoma brucei Inhibitors. ChemMedChem, 9 (11). pp. 2548-2556. ISSN 1860-7179

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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.

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?? acetogeninhuman african trypanosomiasis (hat)natural product analoguesneglected diseasesstereochemistrytrypanosoma bruceibiochemistrymolecular medicinepharmacologydrug discoverypharmacology, toxicology and pharmaceutics(all)organic chemistry ??
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24 Jun 2024 12:35
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16 Jul 2024 01:20