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The development of new therapeutic agents for glioblastoma and hepatocellular carcinoma (HCC) remains a priority due to poor prognosis, limited treatment options, and high recurrence rates. Herein, we report a one-pot synthesis of aromatic aminopropyl lactams (ArAPLs) via hydrolysis of bicyclic amidines (DBN, DBU), followed by reductive amination with aromatic aldehydes. These compounds were designed to target histamine H₃ receptors (H₃R), which are often overexpressed in these malignancies. Docking studies suggested that compounds 3a and 4a may act as H₃R antagonists, showing favorable binding through hydrophobic and hydrogen-bonding interactions. Biological evaluation identified 3a and 4a as the most promising compounds, exhibiting micromolar antiproliferative activity in glioblastoma and HCC cell models. Compound 3a showed the best balance between potency and selectivity, including activity in 3D spheroid models and modulation of cell cycle-related markers. In coculture systems, spheroids displayed reduced size and density, although a slight increase in viability was observed, particularly with 4a. Variations in peripheral cell layers suggest a role for macrophage behavior. Overall, these findings support the cytotoxic potential of ArAPLs, although further studies are required to confirm their role as H₃R antagonists.