Synthesis, structural elucidation, and molecular docking of diclofenac-derived hydrazone metal complexes with...

A novel Schiff base ligand, (E)-2-(2-((2,6-dichlorophenyl)amino)phenyl)-N'-(2-hydroxynaphthalen-1-yl)methylene)acetohydrazide, was synthesized and complexed with Cu(II), Ni(II), Co(II), Gd(III), La(III), and Ag(I) ions. The resulting metal complexes were characterized using FTIR, UV-Vis, 1H NMR, ESR, XRD, thermal analysis, and magnetic susceptibility measurements. Spectroscopic and magnetic data confirmed octahedral geometries for Co(II), Ni(II), and Cu(II), square antiprismatic and tricapped trigonal prismatic geometries for Gd(III) and La(III), respectively, and a tetrahedral geometry for Ag(I). The anti-inflammatory activity was evaluated using ELISA-based COX-1/COX-2 inhibition assays. The HDN ligand exhibited potent COX-2 inhibition (IC₅₀ = 0.06 µM) with a selectivity index (SI) of 174.5, outperforming diclofenac sodium (SI = 4.52) and indomethacin (SI = 1.25), and approaching rofecoxib (SI = 725). The Cu(II) and Gd(III) complexes showed strong cytotoxicity in MTT assays against MCF-7 (IC₅₀ = 0.65 and 0.80 µM) and HepG-2 (IC₅₀ = 1.00 and 2.47 µM) cell lines, significantly surpassing the HDN ligand and standard drugs such as 5-fluorouracil (IC₅₀ = 3.95 µM, MCF-7) and cisplatin (IC₅₀ = 15.24 µM, MCF-7). In silico studies including molecular docking and ADME profiling supported the experimental findings. The HDN ligand and Cu(II) complex exhibited strong binding affinities to COX-2 (- 22.87 kcal/mol), HepG-2 (- 32.56 and - 31.76 kcal/mol), and MCF-7 (- 25.29 and - 20.20 kcal/mol) receptors. SwissADME and BOILED-Egg models predicted high gastrointestinal absorption for the HDN ligand and favorable pharmacokinetic profiles for the metal complexes. The present results provide a preclinical proof-of-concept for diclofenac-derived Schiff base metal complexes as dual anti-inflammatory and anticancer agents. However, their therapeutic potential remains to be validated through stability, mechanistic, and in vivo investigations.