Synthesis and multifaceted exploration of dibenzoxepinones: <i>in vitro</i> antimicrobial and ct-DNA binding, DFT/TD-DFT, molecular docking and simulation studies

In the present study, ten novel derivatives of dibenzoxepine-11-one, have been synthesized and thoroughly characterized using spectroscopic techniques, including ¹H and ¹³C NMR, FTIR, and HRMS. Density Functional Theory (DFT) calculations were carried out to analyze the geometrical structure and vibrational modes, enabling the identification of the most stable conformation of the lead compound. Time-Dependent DFT (TD-DFT) was employed to investigate the electronic transitions within the UV-Vis spectrum. Molecular docking studies were performed for all derivatives using various target proteins with PDB IDs:IKZN (for <i>E. coli</i>), 1IYL (for <i>C. albicans</i>), and the DNA dodecamer structure (PDB ID: 1BNA). The results revealed favorable binding interactions across all targets. Additionally, molecular dynamics (MD) simulations were conducted for 50 ns using the most promising compound, 7a, confirming the stability of its binding conformation. From <i>in vitro</i> studies, antibacterial activity was assessed for all the synthesized derivatives against Gram-positive strains (<i>B. subtilis</i>, <i>L. rhamnosus</i>) and a Gram-negative strain (<i>E. coli</i>). Compounds 7a, 7b, 7c, 7d, and 7f exhibited strong antibacterial efficacy, with minimum inhibitory concentration (MIC) values of 8 μg ml^-1 for <i>E. coli</i> and <i>L. rhamnosus</i> and 16 μg ml^-1 for <i>B. subtilis</i> bacterial strains. Additionally, compound 7a exhibited good antifungal activity, with a maximum zone of inhibition of 18 mm against the fungal strain <i>C. albicans</i>. Further UV-Vis absorption and fluorescence quenching studies, conducted for compounds 7a, 7b, and 7e with calf thymus DNA (ct-DNA), suggested a groove-binding interaction. Compound 7a demonstrated the strongest binding affinity, with a binding constant (<i>K</i> _b) of 3.61 × 10⁵ M^-1 and a Gibbs free energy change (Δ<i>G</i>) of -31.70 kJ mol^-1. Therefore, these novel dibenzoxepine-11-ones derivatives are multifaceted in their action as potential antimicrobial and DNA-binding agents, and will be useful in developing new therapeutics.