The antimicrobial efficacy and DNA binding activity of the copper(II) complexes of 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline and 1,2-diaminocyclohexane

• Published in: Journal of inorganic biochemistry 2016-09, Vol.162, p.62-72
• Main Authors: Ng, Neville S, Wu, Ming J, Jones, Christopher E, Aldrich-Wright, Janice R
• Format: Article
• Language: English
• Subjects: Ampicillin - pharmacology; Animals; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - pharmacology; Candida - drug effects; Candida - growth & development; Cattle; Coordination Complexes - chemical synthesis; Coordination Complexes - pharmacology; Copper - chemistry; Cyclohexylamines - chemistry; DNA - chemistry; Enterococcus faecalis - drug effects; Enterococcus faecalis - growth & development; Ethidium - chemistry; Flucytosine - pharmacology; Microbial Sensitivity Tests; Microbial Viability - drug effects; Phenanthrolines - chemistry; Staphylococcus aureus - drug effects; Staphylococcus aureus - growth & development; Structure-Activity Relationship
• ISSN: 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.06.006

Four copper(II) complexes of the general structure [Cu(L )(L )] , where L is (1S,2S)-diaminocyclohexane or (1R,2R)-diaminocyclohexane and L is 3,4,7,8-tetramethyl-1,10-phenanthroline (TMP) or 4,7-diphenyl-1,10-phenanthroline (DIP), have been investigated in this study for their antimicrobial activity, short-term antimicrobial efficacy, and in vitro DNA-binding affinity. Against an expanded panel of bacterial and fungal strains in 12 species, minimal inhibitory concentrations (MIC) for these metallocomplexes were determined. The data confirmed our previous finding that they are effective against Gram-positive bacteria (MIC 5.6-13.1μM), with DIP coordinated complexes more so than TMP counterparts. Additionally, novel and significant findings were obtained here for these copper(II) complexes. While the four metallocomplexes exhibited high anti-Candida yeast activity (MIC 13.1-26.1μM), they demonstrated stronger anti-fungal activity against the drug-resistant Candida krusei (MIC 13.1μM and 22.6μM for TMP and DIP complexes, respectively) than the anti-fungal agent, 5-fluorocytosine. Fluorescence cell viability assays revealed that these complexes exert faster antibacterial effect than ampicillin as their inhibition against Staphylococcus aureus and Enterococcus faecalis were significantly evident within 0.5h of exposure compared to ampicillin. Similarly, these complexes but not ampicillin demonstrated bactericidal activity in non-proliferating conditions. All complexes exhibited DNA binding affinities similar to that of the known DNA intercalator, ethidium bromide (K ~10 M ) in linear dichroism binding studies and fluorescent dye displacement assays. Taken together, these findings imply that the four copper(II) complexes have different modes of action to the established antibiotics such as ampicillin and 5-fluorocytosine, and provide further insight into development of effective antimicrobial metallocomplexes.