Design, Synthesis, Biological Evaluation, Molecular Docking, Pharmacophore Modelling and 3D-QSAR Analysis of Novel Substituted Imidazolidine Derivatives as Potential Antimicrobial Agents

The present study reports the combined experimental and computational approaches to investigate the antimicrobial potential of 104 structurally diverse substituted imidazolidine derivatives. Selected compounds were synthesized based on their docking results and characterized by IR, 1H NMR and 13C NMR spectroscopy and mass spectrometry. Their antimicrobial activity was assessed in vitro against selected bacterial and fungal strains. Among the tested compounds, derivatives 47 and 52 exhibited the strongest activity, with compound 47 showing antibacterial activity comparable to that of amoxicillin. Molecular docking studies against lanosterol 14α-demethylase (CYP51; PDB ID: 1E9X) were performed to explore the possible interactions of the compounds within the enzyme-binding pocket. Compounds 47 and 52 achieved docking scores of -10.4 and -10.3 kcal/mol, respectively, while compounds 15, 18 and 21 each recorded a score of -10.2 kcal/mol. The docked complexes exhibited hydrogen bonding, π-π stacking, π-cation, π-alkyl and hydrophobic interactions. Pharmacophore modelling identified one hydrogen-bond acceptor feature, one hydrophobic feature and three aromatic-ring features associated with the activity profile. The optimized three-dimensional quantitative structure–activity relationship (3D-QSAR) model yielded an (R2) value of 0.6682, a (Q2) value of 0.3463, a Pearson correlation coefficient of 0.7497 and a stability value of 0.847. Analysis of the steric, electrostatic and hydrophobic contour maps provided further insight into the influence of substituent identity and spatial arrangement on antimicrobial activity. The experimental findings identify compounds 47 and 52 as promising candidates for further optimization of imidazolidine-based antimicrobial agents.