Combined In Vitro and In Silico analysis of ferrocenylmethylaniline derivatives: Antibacterial potential, DFT calculations, and molecular dynamics insights

The rise of antimicrobial resistance poses a major public health threat by reducing the efficacy of treatments against infections in humans, animals, and plants. This study evaluates the antibacterial potential of three ferrocenylmethylaniline derivatives: Ferrocenylmethylaniline (FMA), N-Ferrocenylmethyl-N-acetylaniline (FMAA), and N-Ferrocenylmethyl-N-benzoylaniline (FMBA) against four clinically relevant bacterial strains (Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneumoniae (K. pneumoniae), and Staphylococcus aureus (S. aureus)). In vitro assays revealed FMBA as the most potent compound, with IC50 values of 26.18 mg/mL (E. coli), 34.33 mg/mL (P. aeruginosa), and 42.08 mg/mL (S. aureus), comparable to amoxicillin (AXL).

Molecular docking against twelve bacterial drug targets showed FMBA exhibited superior binding affinities, particularly with peptide deformylase, anthranilate-CoA ligase, peptidoglycan D,D-transpeptidase, dehydrosqualene synthase, and penicillin-binding protein 2a . DFT analysis, including thermodynamic parameters and non-covalent interactions (Reduced Density Gradient, Electron Localization Function, Localized Orbital Locator), provided deeper insights into electronic structures, stability, and binding interactions. Molecular dynamics simulations confirmed the stability of FMBA-protein complexes, reinforcing its potential as a promising antimicrobial lead compound. These findings suggest FMBA as a strong candidate for the development of novel antibacterial agents targeting drug-resistant pathogens.