Design, Synthesis, and Anticancer Evaluation of Novel Chalcone Derivatives Bearing Piperazine and Morpholine Moieties

Cancer remains one of the leading causes of mortality worldwide, highlighting the need for novel anticancer agents with improved efficacy and selectivity. In this study, a series of chalcone derivatives bearing phenylpiperazine, 2-fluorophenylpiperazine, and morpholine moieties (1a-g, 2a-g, and 3a-g) were designed, synthesized, and evaluated for their anticancer potential. The target compounds were synthesized via Claisen-Schmidt condensation under basic conditions and characterized by ¹H NMR, ¹³C NMR, and elemental analysis. Their cytotoxic activities were assessed against PC-3, PANC-1, A549, and MCF-7 cancer cell lines using the MTT assay, with HEK-293 cells serving as a non-cancerous control. Most compounds exhibited notable antiproliferative activity and favorable selectivity compared with doxorubicin, cisplatin, and gemcitabine. Among the tested cell lines, A549 cells were the most sensitive. Compounds 2d, 2b, 2c, 2e, 2g, and 2a showed particularly potent activity against A549 cells, with IC₅₀ values of 5.35 ± 0.08, 5.71 ± 0.09, 5.95 ± 0.09, 5.83 ± 0.09, 5.94 ± 0.09, and 5.96 ± 0.09 µM, respectively. Notably, 2c exhibited the highest selectivity toward A549 cells (SI = 3.26). SAR analysis indicated that the 2-fluorophenylpiperazine moiety enhanced anticancer activity, while halogen substitution generally improved potency and selectivity. Induced Fit Docking and Glide XP simulations supported these findings, suggesting that 2d and 2c achieve their activity through key hinge-region anchoring and isoform-specific interactions with PI3K-α and PI3K-γ. Overall, these findings identify fluorinated chalcone derivatives, particularly 2d, as promising leads for further anticancer drug development.