Novel 2-aminobenzimidazolyl-1-hydrazones with antileukemic activity: Potent alternatives to imatinib and ibrutinib

• Novel 2-aminobenzimidazolyl-1-hydrazones designed as potential antileukemic agents. • Potent antileukemic cytotoxicity, surpassing imatinib and ibrutinib. • Rapid early apoptosis induced in both leukemic cell lines. • Favorable safety profile due to lower hepatotoxicity than ibrutinib. • Promising translational potential based on apoptosis-mediated antileukemic activity. Chronic leukemias are serious, life-threatening blood malignancies that require long-term treatment. Current drug development focuses on precise, targeted therapies to overcome the limitations of conventional chemotherapeutics, such as low efficacy and adverse side effects. In this study, we synthesized a series of novel 2-aminobenzimidazolyl-1-hydrazones through a three-step reaction and structurally characterized the compounds. Their cytotoxic activity was evaluated in K562 cells (a model of chronic myeloid leukemia) and HG-3 cells (a model of chronic lymphocytic leukemia). The mechanism of cell death, apoptosis or necrosis, was assessed by flow cytometry after 24 h of treatment with the most active compounds at their respective IC 50 values. To evaluate potential hepatotoxicity during early-stage drug development, cytotoxicity was also tested in HepG2 cells, a widely used hepatic model. Among the four compounds tested, 3-(2-amino-1H-benzo[d]imidazol-1-yl)-N′-(2,3-dihydroxybenzylidene)propanehydrazide ( 4a ) and 3-(2-amino-1H-benzo[d]imidazol-1-yl)-N′-(2-hydroxy-4-methoxybenzylidene)propanehydrazide ( 4b ) showed the most potent cytotoxic effects, matching or exceeding the activity of clinically used drugs, imatinib and ibrutinib, in their respective cell line models.