Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

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

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2548-2556
Number of pages9
JournalChemMedChem
Volume9
Issue number11
Early online date21 Aug 2014
DOIs
Publication statusPublished - Nov 2014

Keywords

  • Acetogenins/chemical synthesis
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazoles/chemistry
  • Trypanocidal Agents/chemical synthesis
  • Trypanosoma brucei brucei/drug effects

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