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

• Published in: Dalton transactions : an international journal of inorganic chemistry 2020-06, Vol.49 (21), p.6980-6988
• Main Authors: Kozsup, Máté, Keogan, Donal M, Fitzgerald-Hughes, Deirdre, Enyedy, Éva A, Twamley, Brendan, Buglyó, Péter, Griffith, Darren M
• Format: Article
• Language: English
• Subjects: Amidohydrolases - antagonists & inhibitors; Amidohydrolases - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Carbonyls; Cobalt - chemistry; Cobalt - pharmacology; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Crystal structure; Crystallography; Deformation effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Hydrogen-Ion Concentration; Hydroxylamines - chemistry; Hydroxylamines - pharmacology; Inhibitors; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Peptides
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/d0dt01123a

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.