One‐Pot Green Microwave Synthesis and Computational Study of 1,4‐Benzodiazepine Derivatives: Docking, ADME ‐Tox, Dynamics, and DFT

ABSTRACT A one‐pot, green, and microwave‐assisted method has been efficiently developed for the synthesis of 1,4‐benzodiazepine derivatives via the reaction of various aldehydes, ethyl acetoacetate, and o‐phenylenediamine in the presence of Bi(NO 3 ) 3 ·5H 2 O as an effective catalyst. Biological activity of synthesized compounds was tested against antibacterial, antifungal, and antimalarial strains. Compound 4b showed excellent activity 62.5 and 25 μg/mL against Escherichia coli and Candida albicans , respectively. Compound 4f showed good activity 100 μg/mL against Pseudomonas aeruginosa . Also Compounds 4d and 4 g shown significant activity, with IC 50 values of 0.19 μg/mL and 0.17 μg/mL, respectively, in comparison with the reference drug quinine. Furthermore, computational investigations were performed to support the biological findings. Molecular docking studies were carried out to evaluate the binding interactions of the synthesized compounds with the target protein (PDB ID: 3DGA), followed by molecular dynamics simulations to assess the stability of the protein–ligand complexes. ADME‐Tox analyses were conducted to predict the pharmacokinetic and toxicity profiles of the compounds. In addition, quantum chemical calculations, including frontier molecular orbital (FMO) analysis, were performed. Electronic descriptors such as HOMO energy (E_HOMO), LUMO energy (E_LUMO), energy gap (Δ E ), dipole moment ( μ ), electronegativity ( χ ), and global hardness ( η ) were calculated to evaluate the electronic properties, chemical reactivity, and potential bioactivity of the synthesized molecules.