Heterocyclic acyl-phosphate bioisostere-based inhibitors of Staphylococcus aureus biotin protein ligase

William Tieu; Angie M Jarrad; Ashleigh S Paparella; Kelly A Keeling; Tatiana P Soares da Costa; John C Wallace; Grant W Booker; Steven W Polyak; Andrew D Abell

doi:10.1016/j.bmcl.2014.08.030

Heterocyclic acyl-phosphate bioisostere-based inhibitors of Staphylococcus aureus biotin protein ligase

Bioorg Med Chem Lett. 2014 Oct 1;24(19):4689-4693. doi: 10.1016/j.bmcl.2014.08.030. Epub 2014 Aug 19.

Authors

William Tieu¹, Angie M Jarrad², Ashleigh S Paparella², Kelly A Keeling³, Tatiana P Soares da Costa², John C Wallace², Grant W Booker², Steven W Polyak², Andrew D Abell⁴

Affiliations

¹ School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: william.tieu@adelaide.edu.au.
² School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia.
³ School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia 5005, Australia.
⁴ School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: andrew.abell@adelaide.edu.au.

PMID: 25193234
DOI: 10.1016/j.bmcl.2014.08.030

Abstract

Inhibitors of Staphylococcus aureus biotin protein ligase (SaBPL) are generated by replacing the acyl phosphate group of biotinyl-5'-AMP with either a 1,2,3-triazole (see 5/10a/10b) or a 1,2,4-oxadiazole (see 7) bioisostere. Importantly, the inhibitors are inactive against the human BPL. The nature of the 5-substituent in the component benzoxazolone of the optimum 1,2,3-triazole series is critical to activity, where this group binds in the ATP binding pocket of the enzyme.

Keywords: Antibiotics; Bioisosteres; Drug design; Inhibitors; Ligases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Biotin / antagonists & inhibitors*
Biotin / metabolism
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Humans
Ligases / antagonists & inhibitors*
Ligases / metabolism
Models, Molecular
Molecular Structure
Organophosphates / chemical synthesis
Organophosphates / chemistry
Organophosphates / pharmacology*
Staphylococcus aureus / enzymology

Substances

Bacterial Proteins
Enzyme Inhibitors
Heterocyclic Compounds
Organophosphates
Biotin
Ligases