Investigation of heterocycle-fused 2,5-dihydro-1H-benzo[b][1,4]diazepine conjugate as potential anti-cancer agents: Design, synthesis and in silico docking activity

The evolution of novel anti-cancer agents continues to be a critical focus of research, aiming to improve therapeutic efficacy and address the growing challenges in cancer treatment. In this work, a novel series of 2,5-dihydro-1H-benzo[b][1,4]diazepine-3-carboxylate derivatives (4a–4e) were synthesized by condensation of o-phenylenediamine, ethyl acetoacetate, and different substituted aryl aldehydes via a convenient one-pot, multicomponent, under catalytic and solvent free condition synthetic protocol. The synthesized benzo[b][1,4]diazepine compounds were characterized for their elemental analysis, 1H NMR, 13C NMR, FT-IR spectroscopy, mass spectroscopy and UV-visible spectroscopy. Anti-cancer activity of synthesized compounds was evaluated on lung cancer cell line (A549) by MTT assay. The synthesized compounds showed promising cytotoxic effects with IC50 values ranging from 16.89 ± 0.01 µg/mL to 37.22 ± 0.07 µg/mL. Notably, compound 4a and 4e are comparable with standard drug such as cisplatin (15.49 µg/mL), carboplatin (> 111.37 µg/mL), Methotrexate (11.82 ± 1.22 µg/mL) and oxaliplatin (22.66 µg/mL). In molecular docking (PDB ID: 5GWK), as a human topoisomerase IIα in complex with DNA and etoposide analysis, intercalative between protein-DNA base pairs contacts to protein residues. The docking scores of compounds ranged from −8.4 to −9.5 kcalmol−1, comparable with etoposide standard drug binding energy is −12.2 kcalmol−1. In silico pharmacokinetic parameters have been used for the drug-likeness and bioactive potential of compounds (4a-4e). The consequences mention that these benzo[b][1, 4]diazepine conjugates hold important possible as novel anti-cancer agents, particularly in A549 cell-line. Anti-bacterial activity of compounds has screened against Gram-positive and Gram-negative bacteria and compound 4a and 4e have been exhibited higher Minimum Inhibitory Concentration (MIC) value as compare to other compounds (4b, 4c and 4d).