Simplifying nature : Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins

Gould, Eoin R. and King, Elizabeth F.B. and Menzies, Stefanie K. and Fraser, Andrew L. and Tulloch, Lindsay B. and Zacharova, Marija K. and Smith, Terry K. and Florence, Gordon J. (2017) Simplifying nature : Towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins. Bioorganic and Medicinal Chemistry, 25 (22). pp. 6126-6136. ISSN 0968-0896

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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 world's 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.

Item Type:
Journal Article
Journal or Publication Title:
Bioorganic and Medicinal Chemistry
Uncontrolled Keywords:
?? acetogeninsnatural productsneglected tropical diseasestetrahydropyranbiochemistrymolecular medicinemolecular biologypharmaceutical sciencedrug discoveryclinical biochemistryorganic chemistrygeneral medicinemedicine(all) ??
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25 Jun 2024 08:20
Last Modified:
16 Jul 2024 12:18