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Synthesis and characterisation of Co(iii) complexes of N-formyl hydroxylamines and antibacterial activity of a Co(iii) peptide deformylase inhibitor complex

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Abstract

The X-ray crystal structure and pKa values of GSK322, a well-known and effective peptide deformylase inhibitor and antibacterial drug candidate, are reported. The first examples of Co(III) complexes of N-formyl hydroxylamines are reported. Reaction of N-hydroxy-N-phenylformamide (HFA) with [Co(tren)Cl2]Cl and [Co(tpa)Cl2]Cl (where tren = tris(2-aminoethyl)amine, tpa = tris(2-pyridylmethyl)amine) with one equivalent of NaOH in H2O afforded [Co(tren)(HFA−1H)](PF6)1.5Cl0.5 (1) and [Co(tpa)(HFA−1H)]Cl2 (2), respectively. X-ray crystal structures of both complexes revealed that the N-formyl hydroxylamine group acts as a bidentate ligand, coordinating the Co(III) centres via the carbonyl oxygen and deprotonated hydroxy group (O,O′), a coordination mode typically observed for closely related mono-deprotonated hydroxamic acids. Reaction of the N-formyl hydroxylamine-based GSK322 with [Co(tpa)Cl2]Cl afforded the corresponding Co(III) chaperone complex of the peptide deformylase inhibitor, [Co(tpa)(GSK322−1H)](PF6)2. GSK322 and [Co(tpa)(GSK322−1H)](PF6)2 exhibited better Gram-positive activity than Gram-negative, where low MICs (1.56–6.25 μM) were determined for S. aureus strains, independent of their antibiotic susceptibility.

Graphical abstract: Synthesis and characterisation of Co(iii) complexes of N-formyl hydroxylamines and antibacterial activity of a Co(iii) peptide deformylase inhibitor complex

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Supplementary files

Article information


Submitted
25 Mar 2020
Accepted
21 Apr 2020
First published
21 Apr 2020

Dalton Trans., 2020, Advance Article
Article type
Paper

Synthesis and characterisation of Co(III) complexes of N-formyl hydroxylamines and antibacterial activity of a Co(III) peptide deformylase inhibitor complex

M. Kozsup, D. M. Keogan, D. Fitzgerald-Hughes, É. A. Enyedy, B. Twamley, P. Buglyó and D. M. Griffith, Dalton Trans., 2020, Advance Article , DOI: 10.1039/D0DT01123A

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