Abstract
The first chapter of this thesis outlines the problematic era we find ourselves in with regards to antimicrobial resistance, and relevant information about antimicrobial therapy. A possible route forward is discussed, and relevant organic and inorganic compounds as well as a key synthetic reaction are presented. The second chapter covers the synthesis, characterisation and studies performed on a family of mononuclear bis-tridentate ligands and their associated metal complexes with ruthenium(II), copper(II) or iron(II), and a pair of novel dinuclear ruthenium(II) complexes as well as their associated ligand family. The mononuclear complexes were designed to have fewer isomers than the family of tris-bidentate ruthenium(II) complexes synthesised previously in the Crowley group. These complexes were shown to be antimicrobial, but were generated as mixtures of mer and fac diastereomers as well as Δ/Λ enantiomers. The bis-tridentate complexes were designed to retain the antibacterial activity of the related tris-bidentate complexes, but be synthetically easier to derive. The dinuclear complexes were synthesised with an aim to increase the potential antibacterial activity of the mononuclear complexes. The ligands and complexes were characterised through 1H NMR, 13C NMR and IR spectroscopies, HR ESIMS and elemental analysis, and the structure of [Ru(propyltripy)2](Cl)2 and [Ru(pentyltripy)2](Cl)2 supported by a pair of X-ray crystal structures. While the Ru(II) and Cu(II) complexes were stable in DMSO, the Fe(II) complex degraded immediately into free ligand. The complexes where found to be active against both the Gram positive S. aureus (ATCC 25923) and Gram negative E. coli (ATCC 25922), with the most active mononuclear complex [Ru(hexyltripy)(heptyltripy)](Cl)2 possessing MICs of 2 µg/mL and 8 µg/mL respectively. This was more potent than the previously synthesised tris-bidentate complexes against the same strain (MIC of 2 µg/mL compared to 4 µg/mL). The complexes showed a dependence on their central metal ion with the Fe(II) and Cu(II) variants having worse activity than their Ru(II) counterpart. The antibacterial activity showed dependence on the alkyl chain length of the complexes, with the best activity occurring for the three complexes in the hexyl to heptyl range of substituted ligands. The dinuclear complexes did not possess increased activity against S. aureus, but [Ru2(dihexylditripy)(hexyltripy)2](Cl)4 did possess better activity than its mononuclear counterpart against E. coli (8 µg/mL compared to 32 µg/mL). The HPLC retention times of the complexes further supported the chain length dependence of the antibacterial activity with the development of a ‘sweet spot’ of activity with the focal point at [Ru(hexyltripy)(heptyltripy)](Cl)2. Propidium iodide assays and TEM imaging showed that the mode of action of these complexes does not convincingly show that they progress through cell permeabilisation, and as such may possess a differing mode of action with bacteriostatic activity. Cytotoxic testing on the complexes showed that the complexes possess IC50 values close to their MIC values, ruling out their potential as future antibiotic agents.