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Herein, we report a one\u2010pot 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 H\n                    <jats:sub>3<\/jats:sub>\n                    receptors (H\n                    <jats:sub>3<\/jats:sub>\n                    R), which are often overexpressed in these malignancies. Docking studies suggested that compounds\n                    <jats:bold>3a<\/jats:bold>\n                    and\n                    <jats:bold>4a<\/jats:bold>\n                    may act as H\n                    <jats:sub>3<\/jats:sub>\n                    R antagonists, showing favorable binding through hydrophobic and hydrogen\u2010bonding interactions. Biological evaluation identified\n                    <jats:bold>3a<\/jats:bold>\n                    and\n                    <jats:bold>4a<\/jats:bold>\n                    as the most promising compounds, exhibiting micromolar antiproliferative activity in glioblastoma and HCC cell models. Compound\n                    <jats:bold>3a<\/jats:bold>\n                    showed the best balance between potency and selectivity, including activity in 3D spheroid models and modulation of cell cycle\u2010related markers. In coculture systems, spheroids displayed reduced size and density, although a slight increase in viability was observed, particularly with\n                    <jats:bold>4a<\/jats:bold>\n                    . 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 H\n                    <jats:sub>3<\/jats:sub>\n                    R antagonists.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70394","type":"journal-article","created":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T14:47:31Z","timestamp":1785077251000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Biological Activity of Novel Aromatic Aminopropyl Lactams in Two Cancer Cell Models"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3846-8250","authenticated-orcid":false,"given":"M. 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