Halogen-tuned tripodal Schiff base ligands: synthesis, antibacterial activity, and DFT-guided mechanistic insights

Two halogenated tripodal Schiff base ligands, H₃L1 and H₃L2, were synthesized via condensation of tris(2-aminoethyl)amine with 3,5-dichlorosalicylaldehyde and 3,5-diiodosalicylaldehyde, respectively, in ethanol using a 1 : 3 amine-to-aldehyde molar ratio. The ligands were isolated as stable solids in good yields and characterized by FTIR, UV-vis, ¹H and ¹³C NMR, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction (SCXRD). Spectroscopic analyses confirmed successful Schiff base formation through the appearance of characteristic azomethine ν(C[double bond, length as m-dash]N) bands and resonances, disappearance of aldehydic signals, and the presence of intramolecularly hydrogen-bonded phenolic OH groups. Comparative studies revealed pronounced substituent-dependent electronic effects, with the iodinated ligand H₃L2 exhibiting enhanced aromatic deshielding, characteristic shielding of carbon atoms bonded to iodine, and bathochromically shifted absorption bands resulting from increased polarizability and electronic delocalization. The antibacterial activities of the ligands were evaluated against selected Gram-positive and Gram-negative bacterial strains using agar diffusion and broth microdilution methods. Both ligands displayed concentration-dependent antibacterial activity; however, H₃L2 consistently showed superior efficacy, exhibiting minimum inhibitory concentration (MIC) values of 4-8 µg mL^-1, compared to 16-64 µg mL^-1 for H₃L1. The enhanced activity of H₃L2 is attributed to the greater lipophilicity, polarizability, and electronic delocalization imparted by iodine substitution. Density functional theory calculations further supported this observation, revealing a lower HOMO-LUMO energy gap (ΔE = 6.718 eV) for H₃L2, indicative of higher chemical reactivity. Molecular docking and molecular dynamics simulations suggested favourable interactions with key bacterial targets, including DNA gyrase B and penicillin-binding protein 2a (PBP2a), highlighting H₃L2 as a promising antibacterial scaffold.