Benzimidazotriazines as adenosine receptor-targeting anticancer agents: Synthesis, cytotoxicity, DFT, and docking studies

Benzimidazotriazines are heterocyclic compounds with notable anticancer potential. In this work, a novel series of benz[4,5]imidazo[2,1-c][1,2,4]triazines was synthesized via a one-pot reaction of 2-hydrazinobenzimidazole with hydrazonoyl chlorides. Structural elucidation of that series was confirmed by spectral data and DFT calculations to support regioselectivity and thermodynamic stability. The biological evaluation using MTT assay against HEPG2-1 liver carcinoma cells revealed that methyl-substituted compounds, particularly 10b (IC₅₀ = 0.29 µM), showed greater cytotoxicity than doxorubicin (IC₅₀ = 0.32 µM). Molecular docking studies against the 1E1V receptor indicated strong binding for compounds 7b , 10a , and 10b , involving hydrogen bonding and arene interactions. ADMET (absorption, distribution, metabolism, excretion, toxicity) profiling predicted good pharmacokinetic properties, including high intestinal absorption and metabolic stability. These findings suggest that specific structural modifications enhance anticancer activity and receptor interaction, making these compounds promising leads for further in vivo validation.