Synthesis and in silico studies of hexahydroacridine derivatives as potential antitumor agents

Abstract Despite advances in targeted cancer therapies, drug resistance and off-target toxicity remain major challenges, underscoring the need for new multi-targeted agents with improved selectivity. 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 -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 π-π 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, 1 H/ 13 C NMR, and LC–MS. Guided by structure-based design principles, five derivatives ( 4a, 4d, 4f., 5a, 5b ) were evaluated for cytotoxicity against HSF, H460, A431, A549, and MDA-MB-231 cell lines. Compound 4d emerged as the most potent, with an IC₅₀ of 17.91 ± 2.8 µg/mL against H460 lung cancer cells and a high selectivity index (SI = 20.7), in addition to exhibiting a considerable anti-telomerase activity. Molecular docking revealed strong binding affinities of 4d with TOP2B (− 7.02 kcal/mol), p38 MAPK (− 7.05 kcal/mol), p53 (− 7.25 kcal/mol), and EGFR (− 6.55 kcal/mol), supported by MM-GBSA binding free energies (ΔG bind ≈ − 42 kcal/mol for 4d–EGFR). Furthermore, 100-ns Molecular Dynamics simulations confirmed the stability of the 4d -EGFR complex (RMSD ≈ 1.31 Å; persistent H-bonds with CYS773/GLN767). These findings establish compound 4d as a promising multi-target lead scaffold, warranting further optimization toward selective anticancer therapeutics.