Influence of metal complex formation on the biological activity of metronidazole: spectroscopic, DFT calculation, <i>in vitro</i> and in silico biological activity

Abstract In the present study, the interaction between an ethanolic solution of metronidazole (C 6 H 9 N 3 O 3 ), hereafter denoted as MTZ, and aqueous solutions of three transition metal ions Iron(III), Cobalt(II), and Nickel(II) was investigated. This interaction led to the formation of three monomeric complexes, C1, C2, and C3, with the respective molecular formulas [Fe(C 6 H 9 N 3 O 3 ) 2 Cl 3 ·H 2 O]·H 2 O, Co(C 6 H 9 N 3 O 3 ) 4 Cl 2 , and Ni(C 6 H 9 N 3 O 3 ) 3 Cl 2 ·H 2 O. The chemical compositions of these complexes were confirmed by elemental (CHNS and metal) analysis, FTIR, Raman, 1 H NMR, magnetic susceptibility, and electronic absorption spectroscopy. The combined results indicate that all complexes are monomeric and that metronidazole coordinates to the metal center in a monodentate manner through the imidazole nitrogen. Spectroscopic and magnetic data further support an octahedral geometry for the complexes. The biological properties of the synthesized complexes were assessed through in vitro antibacterial and antifungal assays against both aerobic and anaerobic strains. Among the tested compounds, the C2 complex exhibited notable inhibitory activity against Enterococcus faecalis and Staphylococcus aureus . Additionally, in silico molecular docking studies were performed to simulate the interactions between the complexes and selected biological targets. The docking results revealed strong binding affinities toward epidermal growth factor receptor (EGFR), a tyrosine kinase enzyme implicated in several cancer types, and dihydropteroate synthase (DHPS), an essential enzyme in the bacterial folate pathway. These findings highlight the promising antibacterial and anticancer potential of the synthesized complexes. Furthermore, the molecular structures of the complexes were optimized using density functional theory (DFT) calculations to support the experimental observations.