Design and Synthesis of New Coumarin Hybrids Active Against Drug-Sensitive and Drug-Resistant Neuroblastoma Cells

High-risk neuroblastoma (NB) is an aggressive pediatric tumor characterized by pronounced biological heterogeneity and frequent development of chemoresistance, which critically limits therapeutic efficacy. Identifying novel anti-NB agents remains an urgent unmet need. To address this, we designed and synthesized 17 hybrid molecules by combining natural antioxidant scaffolds (coumarin, vanillin, and isovanillin) through an acyl-hydrazone linker. Several derivatives significantly reduced the viability of MYCN-amplified NB cells (HTLA-230) and their multi-drug resistant counterpart (ER) while not affecting human keratinocytes (HaCat). Among them, compounds 5, 9 and 12 selectively inhibited HTLA and ER growth (10-25%) without affecting HaCat, accompanied by robust ROS overproduction, particularly by 9 and 12 (up to 40%). None of these compounds induced apoptosis or ferroptosis. Instead, their antiproliferative effects were associated with senescence induction and, only for compound 5, with a decrease in clonogenic potential. Moreover, to further characterize compounds 5, 9, and 12, the analysis was extended across other human neuroblastoma cell lines. In parallel, the effects of the compounds on non-malignant cell lines were assessed to obtain an indication of their selectivity toward tumor cells. Compound 17, a structural analog lacking the second aromatic ring in the ex-aldehyde portion, displayed a distinct profile with a limited anticancer activity, underscoring the importance of this structural fragment for antiproliferative efficacy.