Synthesis, Characterization, Molecular Docking, and Molecular Dynamics Studies of Schiff Bases of 2-Phenoxy-1-Phenyl-Ethanone as Antibacterial Agents

Background: The development of antimicrobial resistance and reduced discovery and commercialization of newer antibiotics point to the need for the discovery of novel anti-bacterial agents. Schiff bases are reported to possess a broad range of pharmacological activi-ties, which also include antibacterial activity. With this background, novel Schiff bases were synthesized. Aim: The present study aimed to synthesize novel Schiff bases of 2-phenoxy-1-phenyl-etha-none with aryl amines and evaluate their antibacterial activity. Methods: The desired Schiff bases were synthesized by condensing various aryl amines with 2-bromo-1-phenylethanone and characterized by physicochemical and spectral methods. The antibacterial activity of the synthesized Schiff bases was determined by the cup diffusion method. Molecular docking with Staphylococcus aureus tyrosyl-t-RNA synthetase (Protein Data Bank ID: 1JIJ) was performed using Autodock. Molecular dynamics simulation studies were performed using GROMACS. ADME analysis and drug-likeliness of the synthesized compounds were predicted using SwissADME. Protein-ligand interactions were studied using BIOVIA Discovery Studio Visualizer. Results: Out of the synthesized compounds, two compounds, sb₀4 and sb₀5, exhibited fair antibacterial activity. The compounds sb₀4 and sb₀5 exhibited better binding energy values than the original ligand of the target enzyme and comparable binding energy with ampicillin. The Autodock program estimated the binding free energy and inhibition constant values of compound sb₀5 as -9. 18 kcal/mol and 187. 33 nM and for the compound sb₀4 as -8. 82 kcal/mol and 341. 59 nM, respectively. The RMSD values of the compound sb₀4 were stable throughout the duration of the simulation; however, the compound sb₀5 showed lesser sta-bility in the docked complex. Interestingly, the compound sb₀5 (-182. 754 kJ/mol) exhibited stable interaction with a lower value of total interaction energy than sb₀4 (-136. 304 kJ/mol). The synthesized Schiff bases showed no violation of Lipinski’s rule of five and a bioavailabil-ity score in the range of 55% to 85%. Conclusion: The synthesized Schiff bases present a scaffold for the development of novel antibacterial agents, in particular the compounds sb₀4 and sb₀5.