Synthesis, Molecular Docking, Molecular Dynamics, DFT and Antimicrobial Activity Studies of 5-substituted-2-(p-methylphenyl)benzoxazole Derivatives

Abstract

In this study, new 2-(p-methylphenyl)-5-(2-substitutedacetamido)benzoxazole derivatives were synthesized, and antimicrobial activities on six bacteria and their twelve drug-resistant isolates and one fungus and its two drug-resistant isolates were investigated by microdilution method. B1 against Staphylococcus aureus isolate, and B1 and B2 against Escherichia coli isolate showed more potent antimicrobial activity with MIC value of 16 µg/mL than some of the reference drugs. The compounds' interactions on the DNA gyrase enzyme were evaluated by molecular docking and molecular dynamics simulations. Docked compounds have demonstrated superimposition in the DNA gyrase ATP binding site with similar protein-ligand interactions. With 50 ns duration molecular dynamics simulations, the average RMSD value of the DNA gyrase subunit B protein and B1, B2, B3, and B4 complexes were measured at about 0.15 nm. The ligands-bound DNA gyrase subunit B protein is a little less RMSF value and more stable than the apoprotein form between 45-49 residues in the active site amino acids region. Geometric optimization parameters, HOMO-LUMO orbital energies, and other electronic parameters derived from these energies, MEP, and NBO analysis were performed the DFT/B3LYP theory and 6-311G (d,p) basis set. The ΔE: LUMO-HOMO of the two most active compounds B1 and B2 are 4.2928 and 4.3219, respectively. The compounds' predicted ADME profiles were in line with Lipinski and other limiting rules.