Design And Biological Evaluation Of New 1,3-Oxazepine,4,7-Dione Based Heterocycles As Potential Antibacterial And Anticancer Agents

Abstract

Heterocyclic scaffolds play a crucial role in drug discovery, as their versatile structures interact strongly with biological targets. This study aims to synthesize Schiff base derivative S precursor by condensing

 1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-imidazol-2-amine with

2-hydroxy-4-methylbenzaldehyde under reflux in ethanol with glacial acetic acid as a catalyst. This schiff base derivative was cyclized with malic, phthalic, succinic, or glutaric anhydride in dry benzene under reflux for 14-15 hours to of four 1,3-oxazepine-4,7-dione derivatives (OI-OIV). The products were purified by recrystallization in dry 1,4-dioxane and confirmed using FTIR, ¹H NMR, and ¹³C NMR spectroscopy. The antibacterial activity was evaluated using the cup-plate diffusion method against Staphylococcus spp., Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa at concentrations of 0.1, 0.001, and 0.00001 mg mL⁻¹, these derivatives OI-OIII, inhibited Staphylococcus at 29 mm and 28 mm zones of inhibition, respectively, at 0.1 mg mL⁻¹, approaching the zone of inhibition of azithromycin (28 mm), while Gram-negative strains showed weaker responses. Cytotoxic activity against the MCF-7 breast cancer cell line revealed dose-dependent reductions in cell viability, with derivative OIII have an IC50 as 48.88 and derivative OIV had an IC50 as 45.99. In silico, molecular docking study against dihydrofolate reductase (PDB ID: 4P66) by using MOE software showed that derivative OI (ligand A) in pose 1 achieved a binding affinity of (-7.48 kcal/mol) and formed four hydrogen bond interactions SER49, ASP27, and MET20, which that supported by favorable placement and refinement energies, while ADMET predictions by using swissADMET indicated high gastrointestinal absorption, good solubility, and moderate bioavailability.