Synthesis of Novel Cu(II), Co(II), Fe(II), and Ni(II) Hydrazone Metal Complexes as Potent Anticancer Agents: Spectroscopic, DFT, Molecular Docking, and MD Simulation Studies

Metal complexes [FeL], [NiL]·H₂O, [CuL], and [CoL]·H₂O were formed by the ligand (<b>L</b>, 4-fluoro-<i>N</i>'-(2-hydroxybenzylidene)benzohydrazide) reacting with Fe(OAc)₂, Ni(OAc)₂·4H₂O, Cu(OAc)₂·H₂O, and Co(OAc)₂·4H₂O. The produced compounds were characterized using a variety of methods, such as NMR, UV-vis, FT-IR, magnetic susceptibility, elemental analysis, and molar conductivity. The spectrum of the data indicates that the geometry of the complex molecular structures is octahedral with six coordination sites. The ligand and its different metal complexes were tested in a human lung cancer cell line and a normal embryonic kidney cell line. A cytotoxic assay revealed that <b>L-Cu</b> is the most potent chelate against cancer cell lines. A computational study was performed to rationalize this finding. The binding potential of relatively active compounds to a suitable target was analyzed. For this purpose, a target that is known to be inhibited by small compounds with a scaffold similar to that of the synthesized compounds, lysine-specific demethylase 1 (LSD1), was first determined. Molecular docking studies demonstrated that <b>L-Cu</b> has a high binding potential to LSD1 at a level comparable to that of a standard ligand. Molecular dynamics (MD) simulations revealed that <b>L-Cu</b> and <b>L</b> form stable complexes with the enzyme. Furthermore, the MD simulation study showed that <b>L-Cu</b> remained inside the binding pocket of the enzyme during the 200 ns simulation period. Density functional theory (DFT) studies demonstrated that the chemical stability of <b>L</b> was higher than that of its chelate form, <b>L-Cu</b>.