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

Eoin R. Gould, Elizabeth F. B. King, Stefanie K. Menzies, Andrew L. Fraser, Lindsay B. Tulloch, Marija K. Zacharova, Terry K Smith (Lead / Corresponding author), Gordon J. Florence (Lead / Corresponding author)

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6126-6136
Number of pages11
JournalBioorganic & Medicinal Chemistry
Volume25
Issue number22
Early online date28 Jan 2017
DOIs
Publication statusPublished - 15 Nov 2017

Keywords

  • Acetogenins/chemical synthesis
  • Cell Survival/drug effects
  • Drug Design
  • Furans/chemistry
  • HeLa Cells
  • Humans
  • Leishmania major/drug effects
  • Structure-Activity Relationship
  • Triazoles/chemistry
  • Trypanocidal Agents/chemical synthesis
  • Trypanosoma cruzi/drug effects

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    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, 25(22), 6126-6136. https://doi.org/10.1016/j.bmc.2017.01.021