The chemical biology of Cu(II) complexes with imidazole or thiazole containing ligands: Synthesis, crystal structures and comparative biological activity

•CuThiazole (CuTh) species act as potent nucleases at low conc. and short incubation times.•CuImidazole (CuIm) complexes exhibit much lower nuclease activity.•Both CuIm and CuTh complexes utilize an oxidative mechanism.•O2− is key in the mechanism for CuIm species while 1O2 is utilized by CuTh.•CuIm complexes exhibit greater antibacterial properties.

The synthesis and characterization of two copper(II) complexes containing 2-(2-pyridyl)benzimidazole (PyBIm) are reported with the biological activity of these two complexes and a third Cu(II) complex containing 2-(2-pyridyl)benzothiazole (PyBTh). Complex 1, [Cu(PyBIm)(NO3)(H2O)](NO3), is a four coordinate, distorted square planar species with one ligand (N,N), nitrate and water bound to Cu(II). The [Cu(PyBIm)3](BF4)2 complex (2) has distorted octahedral geometry with a 3:1 Py(BIm) ligand to metal ratio. The distorted trigonal bi-pyramidal geometry of compound 3, [Cu(PyBTh)2(H2O)](BF4)2, is comprised of two PyBTh ligands and one water. Biological activity of 1–3 has been assessed by analyzing DNA interaction, nuclease ability, cytotoxic activity and antibacterial properties. Complex 3 exhibits potent concentration dependent SC-DNA cleavage forming single- and double-nicked DNA in contrast to the weak activity of complexes 1 and 2. Mechanistic studies indicate that all complexes utilize an oxidative mechanism however 1 and 2 employ O2− as the principal reactive oxygen species while the highly active 3 utilizes 1O2. The interaction between 1–3 and DNA was investigated using fluorescence emission spectroscopy and revealed all complexes strongly intercalate DNA with Kapp values of 2.65 × 106, 1.85 × 106 and 2.72 × 106 M− 1, respectively. Cytotoxic effects of 1–3 were examined using HeLa and K562 cells and show cell death in the micromolar range with the activity of 1 ≈ 2 and were slightly higher than 3. Similar reactivity was observed in the antibacterial studies with E. coli and S. aureus. A detailed comparative analysis of the three complexes is presented.

Graphical abstractCu(II) complexes containing a benzimidazole (PyBIm) or benzothiazole (PyBTh) within the ligand are reported. The PyBIm complexes were weak nucleases and relied on O2− as the principal reactive oxygen species. The PyBTh compound exhibited strong nuclease activity and relied on 1O2. In contrast, compounds containing PyBIm exhibited greater cell toxicity.Figure optionsDownload full-size imageDownload as PowerPoint slide