Synthesis, characterization, antibacterial activity, DFT and molecular docking studies of four4-phenyldiazenyl phenyl aminophosphonates

Four 4-phenyldiazenyl phenyl aminophosphonates were successfully synthesized using an eco-friendly one-pot Kabachnik-Fields reaction. The reaction involved aromatic aldehydes, 4-(Phenyldiazenyl) aniline, and diethylphosphite, with Ni(SO4).6H2O (5 mol%) serving as an efficient catalyst. Conducted at room temperature under solvent-free conditions within 20 min, the reaction yielded excellent chemical results, with up to 90 % yields. The compounds underwent characterization through IR, UV-vis, NMR (1H, 13C, 31P), and HRMS. The antibacterial activity of the synthesized molecules was evaluated against two Gram-negative bacteria (Escherichia coli ATTC 25922, Pseudomonas aeruginosa ATTC 27853) and the Gram-positive bacterium (Staphylococcus aureus ATTC 25923) at different compound concentrations (32-128 µg/ml) compared to Cefixime. The results revealed significant antibacterial activity of molecules 4b, 4c and 4d against the two Gram-negative bacteria and 4b against S. aureus, with a minimum inhibitory concentration (MIC) of 0.5 µg/mL, surpassing the reference drug. DFT calculations at B3LYP 6-311G (2d, p) basis set were employed for geometry optimization, stability and reactivity studies, including HOMO/LUMO, ΔEGAP, dipole moment, electronegativity, electrophilicity, and calculated thermodynamic descriptors (Enthalpy and Gibbs Free Energy). The molecular docking studies confirmed strong interactions between the synthesized compounds and proteins, with binding affinities ranging from -9.6 to -6.8 kcal/mol. Notably, diethyl (4-biphenyl (4-phenyldiazenyl) phenylamino) methylphosphonate (4b) demonstrated the highest efficiency, making it a promising antibacterial candidate according to both experimental and computational assessments.