Synthesis and biological evaluation of novel dicarboximide-aryl/heteroarylpiperazine hybrid derivatives as anticancer agents

Dicarboximide derivatives and piperazine-containing compounds have independently demonstrated promising anticancer properties; however, limited studies explored the biological potential of their hybridization. In the present study, six novel aryl- and heteroarylpiperazine derivatives ( 1 – 6 ) were synthesized and evaluated for their antiproliferative activity. The structures of all tested compounds were confirmed by 1 H and 13 C NMR, as well as ESI–MS spectral analysis. Their cytotoxicity was assessed in vitro against a panel of hematological and solid tumor cell lines, with non-malignant keratinocytes used as the control. Compounds 1 – 3 displayed the highest anticancer activity, whereas the halogen-substituted derivatives 4 – 6 were markedly less active, suggesting a structure–activity relationship. The derivative 1 showed the broadest and most potent cytotoxic profile across the tested cancer cell lines. Mechanistic studies demonstrated that the investigated compounds induced distinct biological effects depending on the cell line, including apoptosis induction, necrotic cell death, G 0 /G 1 cell-cycle arrest, increased caspase-3/7 activity, and altered NF-κB signaling. Taken together, these findings suggest that subtle structural modifications within dicarboximide–piperazine scaffolds may influence both antiproliferative activity and cellular responses.