Synthesis, spectroscopic characterization, DFT analysis, and EGFR docking studies of novel Schiff base derivatives

Schiff bases represent a highly reactive class of functional groups with significant biological importance and extensive chemical diversity, making them a focus of active research in both material and medicinal chemistry. This work reports the synthesis of novel Schiff base compounds through the condensation of aldehydes with aromatic amines, employing both theoretical and experimental methods. Specifically, refluxing 3-chloroaniline and 3-aminophenol with 3-nitrobenzaldehyde in ethanol yielded the compounds (E)-3-chloro-N- (3-nitrobenzylidene)aniline (SB2) and (E)-3-((nitrobenzylidene)amino)phenol (SBOH). The preliminary structural characterization of the compounds was done by Fourier-transform infrared (FT-IR) spectroscopy, and the characteristic stretching peaks at 1617.7 cm⁻¹ (SBOH) and 1625.6 cm⁻¹ (SBCL) were observed. These results are supported by ultraviolet visible (UV- Vis) and time-dependent density functional theory (TD-DFT) -based calculations, showing close agreement with experimental data. Density Functional Theory (DFT) calculations at the B3LYP level of theory using 6-31G(d) basis set were conducted in both gaseous and ethanol phases. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) gaps remained 3.19 and 2.993 for SBOH, while for SBCL, 3.268 and 3.348 energy gaps were observed in the gaseous and ethanol phase, respectively. Global reactivity indices, thermodynamic properties, Molecular electrostatic potential maps (MESPs), and frontier molecular orbitals (FMOs) were computed to evaluate the reactivity and chemical stability of the Schiff bases. Both compounds showed favorable pharmacokinetic properties, with molecular weights of 260.68 g/mol and 242.23 g/mol, zero Lipinski rule violations, good solubility, high gastrointestinal (GI) absorption, and non-P-glycoprotein (P-gp) inhibitors. In molecular docking, SBCL and SBOH showed − 6.9 and − 6.8 kcal/mol binding energy with epidermal growth factor receptor (EGFR) revealed notable binding affinities, revealing different interactions with the protein structure. This combined computational and experimental approach offers comprehensive insights into the biological, electronic, and physicochemical properties of these Schiff bases, emphasizing further experimental validation.