The influence of linkages between 1-Hydroxy-2(1H)-pyridinone Coordinating Groups and a Tris(2-aminoethyl)amine core in a novel series of synthetic Hexadentate Iron(III) Chelators on antimicrobial activity

David G. Workman, Michael Hunter, Shuning Wang, Jeremy Brandel, Veronique Hubscher, Lynn Dover, David Tetard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)
27 Downloads (Pure)

Abstract

Resistance of pathogens to antimicrobials is a major current healthcare concern. In a series of linked studies, we have investigated synthetic iron chelators based on hydroxy-pyridinone ligands as novel bacteriostatic agents. Herein we describe our synthesis of several useful building blocks based on the 1-hydroxy-2(1H)-pyridinone moiety, including a novel formyl derivative, which were combined with a tris(2-aminoethyl)amine core to obtain a series of new high-affinity hexadentate Fe(III) chelators. The design principle examined by this series is the size and flexibility of the linker between the core and the metal ligands. Measurement of the pKa and stability constants (Fe3+ and Cu2+) of representative coordinating groups was performed to help rationalise the biological activity of the chelators. The novel chelators were tested on a panel of representative microorganisms with some effectively inhibiting microbial growth. We demonstrate that the nature and position of the linker between the hydroxypyridinone and the tris(2-aminoethyl)amine core has considerable impact upon microbial growth inhibition and that both amide or amine linkages can give efficacious chelators.
Original languageEnglish
Article number103465
Number of pages18
JournalBioorganic Chemistry
Volume95
Early online date2 Dec 2019
DOIs
Publication statusPublished - 1 Jan 2020

Keywords

  • siderophore
  • chelator
  • bacterial agent
  • bacterial growth
  • 1-Hydroxy-2(1H)-pyridinone

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