Bis- and mixed-ligand copper(II) complexes of nalidixic acid the antibacterial drug: Mode of nalidixate coordination determines DNA binding and cleavage and cytotoxicity

Abstract

The new complexes [Cu(nal)2]∙2H2O 1 and [Cu(en)2(nal)2] 2, where H(nal) is the antibacterial drug nalidixic acid, have been isolated and their X-ray structures successfully determined. The complex 1 possesses a square planar CuO4 chromophore constituted by the pyridone and carboxylate oxygen atoms of nalidixate anion. Complex 2 contains a CuN4O2 chromophore with a tetragonally distorted octahedral geometry, and the trans-axial coordination of two nalidixate anions at longer distances to the CuN4 plane constituted by ethylenediamine is stabilized by a network of H-bonding. DFT studies illustrate the structures and stabilities of complexes. The DNA binding affinity of 2 (Kb, 9.2 (±0.2) × 104 M−1) is higher than that of [Cu(en)2]2+ [Kb, 2.0 (±0.2) × 104 M−1], illustrating that bound nal¯ enhances the DNA binding affinity. DNA docking studies reveal that 2 bound to DNA undergoes interesting coordinative distortions more than 1, causing more significant changes in DNA host. Thus, 2 displays oxidative DNA cleavage (ascorbic acid) more prominent than [Cu(en)2]2+, by generating OH radicals, and shows poor cytotoxicity towards A549 lung cancer cell lines.