Experimental and theoretical studies of isoniazid hydrazone Schiff base ligands: Synthesis, single crystal X-ray diffraction, spectral characterization, DFT, and molecular docking calculations

Abstract

Three isoniazid hydrazone Schiff base ligands containing ONO donor groups were synthesized by refluxing isoniazid with 3,5-dichlorosalicylaldehyde (IC2), 3,5-dibromosalicylaldehyde (IB2), and 3,5-diiodosalicylaldehyde (II2) in ethanol. The resulting compounds were characterized using Fourier transform infrared (FT-IR), Nuclear magnetic resonance (1H and 13C NMR), elemental analysis (CHN), and single-crystal X-ray diffraction (SC-XRD) analysis. Density Functional Theory (DFT), implemented via Gaussian 09 software, was used to optimize the geometric configurations of the ligands. Subsequent computational analyses employed this optimized geometry as a basis, and the interactions were elucidated using AutoDock Vina software. Furthermore, docking simulations identified the most favorable binding sites of the ligands with deoxyribonucleic acid (DNA) and Bovine Serum Albumin (BSA), revealing key interactions at the active sites. Among the synthesized compounds, IC2 exhibited the lowest Gibbs free energy of binding (-8.2 kcal/mol) for both DNA and BSA, likely due to the presence of a more electronegative substituent. Key interactions at the designated active sites were uncovered, highlighting various bonding types such as hydrogen bonds, hydrophobic contacts, π–π stacking, π–σ, T-shaped, and van der Waals interactions between the ligands and receptors. These findings offer valuable insights into the ligand-mediated modulation of biochemical pathways. © 2025 Elsevier B.V.