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The present study evaluated the anticancer potential of newly synthesized hexahydro-1,8-acridinedione derivatives featuring strategic structural modifications at positions 9 and 10. The novelty of this work lies in the introduction of\n                    <jats:italic>N<\/jats:italic>\n                    -aryl substituents combined with C-9 biphenyl or 4-bromophenyl groups, a structural motif not previously reported for this chemotype. This dual modification was rationally designed to enhance \u03c0-\u03c0 stacking interactions with kinase ATP-binding pockets while improving metabolic stability through fluorine substitution. Compounds were synthesized via a one-pot multicomponent reaction catalyzed by PTSA and characterized by IR,\n                    <jats:sup>1<\/jats:sup>\n                    H\/\n                    <jats:sup>13<\/jats:sup>\n                    C NMR, and LC\u2013MS. Guided by structure-based design principles, five derivatives (\n                    <jats:bold>4a, 4d, 4f., 5a, 5b<\/jats:bold>\n                    ) were evaluated for cytotoxicity against HSF, H460, A431, A549, and MDA-MB-231 cell lines. Compound\n                    <jats:bold>4d<\/jats:bold>\n                    emerged as the most potent, with an IC\u2085\u2080 of 17.91\u2009\u00b1\u20092.8\u00a0\u00b5g\/mL against H460 lung cancer cells and a high selectivity index (SI\u2009=\u200920.7), in addition to exhibiting a considerable anti-telomerase activity. Molecular docking revealed strong binding affinities of\n                    <jats:bold>4d<\/jats:bold>\n                    with TOP2B (\u2212\u20097.02\u00a0kcal\/mol), p38 MAPK (\u2212\u20097.05\u00a0kcal\/mol), p53 (\u2212\u20097.25\u00a0kcal\/mol), and EGFR (\u2212\u20096.55\u00a0kcal\/mol), supported by MM-GBSA binding free energies (\u0394G\n                    <jats:sub>bind<\/jats:sub>\n                    \u2248 \u2212\u200942\u00a0kcal\/mol for 4d\u2013EGFR). Furthermore, 100-ns Molecular Dynamics simulations confirmed the stability of the\n                    <jats:bold>4d<\/jats:bold>\n                    -EGFR complex (RMSD \u2248 1.31\u00a0\u00c5; persistent H-bonds with CYS773\/GLN767). These findings establish compound\n                    <jats:bold>4d<\/jats:bold>\n                    as a promising multi-target lead scaffold, warranting further optimization toward selective anticancer therapeutics.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-68544-0","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T06:34:15Z","timestamp":1788935655000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and in silico studies of hexahydroacridine derivatives as potential antitumor agents"],"prefix":"10.1038","volume":"16","author":[{"given":"Eman A. 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