DFT-based investigation of structural, optoelectronic and molecular docking analysis of thiosemicarbazone derivatives

A comprehensive theoretical investigation was carried out on two thiosemicarbazone Schiff base compounds: ( E )-2-(2,4-dihydroxybenzylidene)thiosemicarbazone (Compound 1) and ( E )-2-[(1H-indol-3-yl)methylene]thiosemicarbazone (Compound 2). Density Functional Theory (DFT) calculations were performed using B3LYP and HSEH1PBE hybrid functionals with the 6–311 + +G(d,p) basis set to explore their structural, electronic, vibrational, and nonlinear optical (NLO) properties. The HOMO-LUMO energy gaps were found to be 2.57 eV (Compound 1, HSEH1PBE) and 2.45 eV (Compound 2, B3LYP), indicating distinct reactivity profiles. Vibrational analysis reproduced experimental IR spectra, while UV-Vis studies revealed absorption maxima at 347 nm (Compound 1) and 331 nm (Compound 2), consistent with π→π* and n→π* transitions. The first-order hyperpolarizability (β tot ) values were calculated as 5.47 × 10 −30 esu for Compound 1 and 6.12 × 10 −30 esu for Compound 2, suggesting strong potential for optoelectronic applications. NMR calculations further validated the optimized geometries, with B3LYP showing lower RMSE values compared to HSEH1PBE. Molecular docking against HMGCS2 (PDB ID: 2WYA) revealed binding affinities of −6.7 kcal/mol for Compound 1 and −7.3 kcal/mol for Compound 2, stabilized by hydrogen bonding and hydrophobic interactions. PASS analysis confirmed promising pharmacological potential. These results highlight the dual applicability of the studied Schiff bases as candidates for both drug discovery and advanced NLO materials. • DFT/B3LYP and HSEH1PBE functionals were used to investigate two Schiff base derivatives. • Electronic, structural, vibrational, UV-Vis, and NLO properties were analyzed. • Compound 2 showed superior NLO behavior with higher parameter values. • Molecular docking revealed strong binding affinities with the HMGCS2 ketogenesis enzyme. • The impact of functional choice on NLO-pharmacological duality predictions was explored.