Biological Evaluation and Computational Modelling Studies on N-acyl Hydrazone and 2,5-Disubstituted 1,3,4-Oxadiazole Derivatives as Non-toxic Antimicrobial Agents.

Introduction: The increasing use of antibiotics coupled with the lack of innovative and effective antimicrobial agents has increased the development of antimicrobial resistance (AMR) worldwide. To overcome the AMR-associated prolonged disease duration and increased mortality rates, new antimicrobial agents are in high demand. In this context, hydrazone and oxadiazole derivatives are endowed with remarkable biocidal activity, becoming profitable scaffolds in the design of antimicrobial candidates.

Methods: In this study, the antimicrobial effects of N-acyl hydrazones 1-15 and 2,5-disubstituted 1,3,4- oxadiazoles 16-27 against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29213, Bacillus subtilis ATCC 6633, and clinically isolated Shigella sonnei, Klebsiella pneumoniae, and Candida albicans were evaluated. For this purpose, Kirby-Bauer disc diffusion and MIC tests were carried out, indicating that most of these compounds were active against tested microorganisms. Particularly, several compounds proved active against E. coli, whereas S. aureus showed higher resistance. The genotoxic potential of most active compounds was determined by in vitro alkaline comet assay, and they were found to be non-toxic at studied concentrations.

Results: Finally, molecular docking and dynamics (MD) studies identified four compounds as potential inhibitors of bacterial DNA gyrase B (GyrB).

Conclusion: Further exploration of molecular determinants revealed favourable drug-like properties, highlighting the potential of these molecules for subsequent hit-to-lead optimization studies.