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

Abstract

The X-ray crystal structure and pK_a 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)_1.5Cl_0.5 (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.