Synthesis, Molecular Dynamics, and Docking Studies of Novel Phenylhydrazono‐11 H ‐Indeno[1,2‐b]Quinoxalin‐8‐yl)Methanone Derivative as Antibacterial Agent

Abstract

Some novel phenyl(11‐(2‐phenylhydrazono)‐11 H ‐indeno[1,2‐b]quinoxalin‐8‐yl)methanone derivatives were synthesized through the cyclocondensation of 3,4‐diaminobenzophenone, ninhydrin, and substituted phenylhydrazine derivatives in ethanol at room temperature. The developed protocol avoided traditional chromatographic purification and afforded the products in excellent yields up to 95%, with successful validation on gram‐scale synthesis. The method is simple, environmentally benign, avoids toxic solvents and catalysts, and provides easy work‐up conditions, highlighting its green synthetic applicability. The synthesized compounds were characterized by FT‐IR, 1H and 13C NMR, and ESI‐Mass spectroscopy. Molecular docking studies revealed strong binding interactions of the synthesized derivatives with the EGFR protein (PDB ID: 5GH8), with binding energies ranging from −8.1 to −10.2 kcal/mol. Molecular dynamics simulations and radial distribution function (RDF) analyses confirmed stable interactions between the ligand molecules and surrounding water molecules. In silico ADME prediction indicated favorable pharmacokinetic properties for all synthesized compounds. Furthermore, the quinoxaline methanone derivatives (4a–i) exhibited excellent antibacterial activity against Gram‐positive and Gram‐negative bacterial strains including Bacillus subtilis, Streptococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae . Among the synthesized derivatives, compounds showing superior antibacterial activity also exhibited better molecular docking binding scores toward the EGFR protein (PDB ID: 5GH8), indicating a positive correlation between the experimental biological activity and computational docking studies.