Elaboration of a benzofuran scaffold and evaluation of binding affinity and inhibition of Escherichia coli DsbA: A fragment-based drug design approach to novel antivirulence compounds

Luke F. Duncan, Geqing Wang, Olga V. Ilyichova, Rabeb Dhouib, Makrina Totsika, Martin J. Scanlon, Begoña Heras, Belinda M. Abbott

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7 Citations (Scopus)

Abstract

Bacterial thiol-disulfide oxidoreductase DsbA is essential for bacterial virulence factor assembly and has been identified as a viable antivirulence target. Herein, we report a structure-based elaboration of a benzofuran hit that bound to the active site groove of Escherichia coli DsbA. Substituted phenyl groups were installed at the 5- and 6-position of the benzofuran using Suzuki-Miyaura coupling. HSQC NMR titration experiments showed dissociation constants of this series in the high µM to low mM range and X-ray crystallography produced three co-structures, showing binding in the hydrophobic groove, comparable with that of the previously reported benzofurans. The 6-(m-methoxy)phenyl analogue (2b), which showed a promising binding pose, was chosen for elaboration from the C-2 position. The 2,6-disubstituted analogues bound to the hydrophobic region of the binding groove and the C-2 groups extended into the more polar, previously un-probed, region of the binding groove. Biochemical analysis of the 2,6-disubsituted analogues showed they inhibited DsbA oxidation activity in vitro. The results indicate the potential to develop the elaborated benzofuran series into a novel class of antivirulence compounds.

Original languageEnglish
Article number116315
Number of pages13
JournalBioorganic & Medicinal Chemistry
Volume45
DOIs
Publication statusPublished - 1 Sept 2021

Keywords

  • Antivirulence
  • Benzofuran
  • DsbA
  • Enzyme inhibition
  • Fragment-based drug discovery
  • Oxidoreductase

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