Computational Grasp on Thiadiazole–Oxadiazole Schiff Bases: DFT, ADMET, Molecular Docking, Molecular Dynamics and In Vitro Evaluation of Antibacterial and Cytotoxic Activities

Two novel Schiff bases, PGPS and PGPO, were synthesized using phenyl glyoxal with substituted thiodiazole/oxadiazole, and their molecular structures were substantiated through a combination of spectral analysis, such as FT‐IR, NMR spectroscopy ( 1 H and 13 C), and HRMS. Density functional theory (DFT) (B3LYP/ 6‐31G (d,p)) was used to compute molecular electrostatic potential (MEP) and frontier molecular orbital (FMO). Quantum reactivity descriptors from B3LYP calculations helped to understand stability and chemical reactivity, while ADMET and Lipinski's results supported their biocompatibility. Molecular docking indicated strong binding affinities of PGPS and PGPO versus Escherichia coli (PDB ID: 3T88) with binding energies of −7.68 and −7.93 kcal/mol, and against Staphylococcus aureus (PDB ID: 3Q8U) having −8.31 and −8.41 kcal/mol, respectively. MD (molecular dynamics) and MM‐PBSA studies confirmed stable interactions, with PGPS showing a high binding energy of −102 kcal/mol against E. coli . In vitro antibacterial screening against ESKAP pathogens presented evidence that PGPS has strong bactericidal efficacy, displaying an MIC of 64 µg/mL against S. aureus and E. coli . Cytotoxicity evaluation further displayed an IC 50 value of 30.20 µM for PGPS. Computational and biological assessment indicated that PGPS has significant potential for therapeutic purposes.