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Issue 21, 2020
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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., 2020,49, 6980-6988
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, 49, 6980
DOI: 10.1039/D0DT01123A

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