Cytotoxicity and Antibacterial Potentials of Mixed Ligand Cu(II) and Zn(II) Complexes: A Combined Experimental and Computational Study

Abstract

[Cu(C₁₅H₉O₄)(C₁₂H₈N₂)O₂C₂H₃]·3H₂O (1) and [Zn(C₁₅H₉O₄)(C₁₂H₈N₂)]O₂C₂H₃ (2) have been synthesized and characterized by ultraviolet-visible (UV-vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, mass spectrometry, thermogravimetric analysis/differential thermal analysis (TGA/DTA), X-ray diffraction (XRD), scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDX), and molar conductance, and supported by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. Square pyramidal and tetrahedral geometries are proposed for Cu(II) and Zn(II) complexes, respectively, and the XRD patterns showed the polycrystalline nature of the complexes. Furthermore, in vitro cytotoxic activity of the complexes was evaluated against the human breast cancer cell line (MCF-7). A Cu(II) centered complex with an IC₅₀ value of 4.09 μM was more effective than the Zn(II) centered complex and positive control, cisplatin, which displayed IC₅₀ values of 75.78 and 18.62 μM, respectively. In addition, the newly synthesized complexes experienced the innate antioxidant nature of the metal centers for scavenging the DPPH free radical (up to 81% at 400 ppm). The biological significance of the metal complexes was inferred from the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy band gap, which was found to be 2.784 and 3.333 eV, respectively for 1 and 2, compared to the ligands, 1,10-phenathroline (4.755 eV) and chrysin (4.403 eV). Moreover, the molecular docking simulations against estrogen receptor alpha (ERα; PDB: 5GS4) were strongly associated with the in vitro biological activity results (E _B and K _i are -8.35 kcal/mol and 0.76 μM for 1, -7.52 kcal/mol and 3.07 μM for 2, and -6.32 kcal/mol and 23.42 μM for cisplatin). However, more research on in vivo cytotoxicity is suggested to confirm the promising cytotoxicity results.

Figure 1

Structure and potential chelation sites of the ligands: (a) 1,10-phenanthroline and (b) chrysin.

Figure 2

Diagrammatic representations of the research design.

Scheme 1. Schematic Representations of 1,10-Phenathroline–Chrysin Mixed Ligand Metal Complexes

Figure 3

Experimental (a) and calculated (b) FTIR spectra of the ligands (1,10-phen, Cry) and their metal complexes (1 and 2).

Figure 4

UV–vis and TD-DFT calculated absorption spectrum of the ligands (chrysin and 1,10-phenanthroline).

Figure 5

UV–vis (black) and TD-DFT (red) absorption spectra of complex 1.

Figure 6

UV–vis (black) and TD-DFT (red) absorption spectra of complex 2.

Figure 7

PXRD patterns for Cu(II)(1) and Zn(II) (2) mixed ligand complexes.

Figure 8

Graphical presentation of the TGA/DTA of complexes 1 (top) and 2 (bottom).

Figure 9

EDX (Left) and SEM (right) images of complexes 1 (top) and 2 (bottom).

Figure 10

Cell viability of the MCF-7 cell line at different concentrations with respect to control cells.

Figure 11

Photomicrographs of the cellular morphology of (a) untreated MCF-7 and the changes induced by complex 1 (b), cisplatin (c), and 2 (d) at 50 μM.

Figure 12

Antibacterial activity of 1,10-phenathroline and chrysin mixed ligand complexes (1 and 2).

Figure 13

Antioxidant activity of the synthesized metal complexes (1 and 2) against DPPH radicals.

Figure 14

Graphical presentations of quantum chemical descriptors.

Figure 15

Optimized geometry, HOMO–LUMO, and Eigen values of Cu(II) (1) and Zn(II) (2) metal complexes.

Figure 16

Binding interactions of 2 against estrogen receptor alpha (ERα; PDB: 5GS4).

Figure 17

Binding interactions of complex 1 against S. aureus (Dihydrofolate reductase) (PDB: 2w9h).