Synthesis, characterisation, and solution behaviour of Ag(I) bis(phenanthroline-oxazine) complexes and the evaluation of their biological activity against the pathogenic yeast Candida albicans.

Three Ag(I) bis(phenanthroline-oxazine) complexes with varying lipophilicity were synthesised and characterised. The solution stoichiometry of 1:2 Ag(I):ligand was determined for each complex by the continuous variation Job's plot method using NMR spectroscopy. NMR studies were also carried out to investigate the fluxional behaviour of the Ag(I) complexes in solution. The biological activity of the silver(I) complexes and the corresponding ligands towards a clinical strain of Candida albicans MEN was studied using broth microdilution assays. Testing showed the choice of media and the duration of incubation were key determinants of the inhibitory behaviour towards Candida albicans, however, the difference between freshly prepared and pre-prepared solutions was insignificant in minimal media. The activity of the metal-free ligands correlated with the length of the alkyl chain. In minimal media, the methyl ester phenanthroline-oxazine ligand was effective only at 60 µM, limiting growth to 67% of the control, while a 60 µM dose of the propyl ester analogue limited fungal growth at < 20% of the control. MIC50 and MIC80 values for the propyl and hexyl ester analogues were calculated to be 45 and 59 µM (propyl), and 18 and 45 µM (hexyl). Moreover, in a study of activity as a function of time it was observed that the hexyl ester ligand maintained its activity for longer than the methyl and propyl analogues; after 48 h a 60 µM dose held fungal growth at 24% of that of the control. Complexation to Ag(I) was much more effective in enhancing biological activity of the ligands than was increasing the ester chain length. Significantly no difference in activity between the three silver(I) complexes was observed under the experimental conditions. All three complexes were substantially more active than their parent ligands against Candida albicans and AgClO4 and the three silver(I) bis(phen-oxazine) complexes have MIC80 values of < 15 µM. The ability of the silver(I) complexes to hold fungal growth at about 20% of the control even after 48 h incubation at low dosages (15 µM) showcases their superiority over the simple silver(I) perchlorate salt, which ceased to be effective at dosages below 60 µM at the extended time point.

Synthesis and characterisation of phenanthroline-oxazine ligands and their Ag(I), Mn(II) and Cu(II) complexes and their evaluation as antibacterial agents.

A series of phenanthroline-oxazine ligands were formed by a cyclisation reaction between L-tyrosine amino acid esters and 1,10-phenanthroline-5,6-dione (phendione). The methyl derivative of the phenanthroline-oxazine ligand 1 was complexed with Ag(I), Mn(II) and Cu(II) to form [Ag(1)2]ClO4, [Mn(1)3](ClO4)2 and [Cu(1)3](ClO4)2. The activity of these metal complexes was tested against the bacteria Escherichia coli and Staphylococcus aureus. Each of the metal complexes was more active than 1 against S. aureus and the Mn(II) and Cu(II) complexes also showed greater activity than 1 towards E. coli. The effect of increasing the length of the alkyl moiety on the phenanthroline-oxazine ligands and their corresponding tris homoleptic Cu(II) complexes was investigated. In all cases both the ligands and their complexes were more active against Gram-positive S. aureus than against Gram-negative E. coli. Differences in the lipophilicity of the ligands and their corresponding Cu(II) complexes did alter the antibacterial activity, with the hexyl and octyl derivatives and their complexes showing the greatest activity and comparing well with clinically used antibiotics. The most active Cu(II) complexes and their respective ligands were also active against Methicillin-resistant S. aureus (MRSA). In vivo toxicity studies, conducted using the Galleria mellonella model, showed that all of the compounds were well tolerated by the insect larvae.

Synthesis and antimicrobial activity of a phenanthroline-isoniazid hybrid ligand and its Ag+ and Mn2+ complexes.

Hydrazide ligand, (Z)-N'-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)isonicotinohydrazide, 1 forms from a 1:1 Schiff base condensation reaction between isoniazid (INH) and 1,10-phenanthroline-5,6-dione (phendione). Ag+ and Mn2+ complexes with 1:2 metal:ligand stoichiometry are prepared: [Ag(1)2]NO3, [Ag(1)2]BF4 and [Mn(1)2](NO3)2. Polymeric {[Ag(1)(NO3)]}n has 1:1 stoichiometry and forms upon infusion of CH2Cl2 into a DMSO solution of [Ag(1)2]NO3. {[Ag(1)(NO3)]}n was structurally characterized using X-ray crystallography. Metal-free 1 and its 1:2 complexes exhibit very good, broad-spectrum antimicrobial activity and are not excessively toxic to mammalian cells (A549 lineage).

(E)-6,6'-(Diazene-1,2-di-yl)bis-(1,10-phenanthrolin-5-ol) tri-chloro-methane disolvate: a superconjugated ligand.

Phenanthroline ligands are important metal-binding mol-ecules which have been extensively researched for applications in both material science and medicinal chemistry. Azo-benzene and its derivatives have received significant attention because of their ability to be reversibly switched between the E and Z forms and so could have applications in optical memory and logic devices or as mol-ecular machines. Herein we report the formation and crystal structure of a highly unusual novel diazo-diphenanthroline compound, C24H14N6O2·2CHCl3.

Tuning the reaction pathways of phenanthroline-Schiff bases: routes to novel phenanthroline ligands.

Pyrido-phenanthrolin-7-one compounds are structural analogues of the cytotoxic alkaloid, ascididemin, and would be expected to have interesting biological activities. Synthetic strategies are reported for a novel simple route to form this class of ligand. 1,10-Phenanthrolin-5,6-dione reacts with l-phenylalanine alkyl esters and their para-substituted analogues to form both a phenanthroline-oxazine and a pyrido-phenanthrolin-7-one product. The nature of the major product is dependent on the electronic properties of the para substituent. Successful metal coordination to the pyrido-phenanthrolin-7-one ligand is also presented.