Simplifying nature : towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins
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The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the worlds very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity- several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor.
Gould , E R , King , E F B , Menzies , S K , Fraser , A L , Tulloch , L B , Zacharova , M K , Smith , T K & Florence , G J 2017 , ' Simplifying nature : towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins ' Bioorganic & Medicinal Chemistry , vol 25 , no. 22 , pp. 6126-6136 . DOI: 10.1016/j.bmc.2017.01.021
Bioorganic & Medicinal Chemistry
© 2017 Elsevier Ltd. All rights reserved. This work has been 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: https://doi.org/10.1016/j.bmc.2017.01.021
This work was funded by the Leverhulme Trust. The research data supporting this publication can be accessed at http://dx.doi.org/10.17630/1dd8b881-17c2-48e4-a72f-53af938f4537.
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