Novel 1,3,4-Oxadiazole Acetamide Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Biological Evaluation, and Molecular Modelling Studies

In this work, a series of novel 1,3,4-oxadiazole-acetamide analogs (3a-j) were designed and constructed. The newly synthesized compounds were characterized by ¹H NMR, ¹³C NMR, and ESI-HRMS. Compounds 3a-j were evaluated for their efficacy as antimicrobial agents against a wide range of pathogenic and fungi strains. The results revealed 3a-j possessed excellent antimicrobial activities, among them, compounds 3a-3g, 3i, and 3j showed remarkable antimicrobial activity with an MIC value of 1.95 µg/mL, superior to that of positive controls. Molecular modeling techniques, such as induced fit docking (IFD) and molecular mechanics generalized born surface area (MM-GB/SA), were utilized to elucidate the binding modes and affinities of the candidate compounds. The results suggested that the most potent candidate compounds demonstrated binding to therapeutically significant bacterial drug targets, including 1KNZ, 2XCT, and 4HOE, with ΔG binding energies ranging from −44.0 to −77.49 kcal/mol. Furthermore, geometry optimization of the structures through the application of density functional theory (DFT) was performed to simulate their electronic properties, which encompass HOMO–LUMO energies/band gaps and electrostatic potential maps. The outcomes indicated that compounds 3d, 3e, 3f, and 3h exhibit nucleophilic characteristics, with heightened HOMO energies and diminished band gap energies. These findings elucidate the forces influencing the compounds' potential to inhibit the bacterial strains under study.