New α‐Tocopherol‐Isoxazole Hybrids: Synthesis, in Vitro Anticancer and Antioxidant Evaluation, and Molecular Docking Insights

Abstract A new library of α‐tocopherol‐based hybrids by incorporating aryl/heterocyclic moieties through an isoxazole linker was designed and synthesized. The synthetic route involved O‐alkylation of α‐tocopherol followed by a Cu(I)‐catalyzed 1,3‐dipolar cycloaddition to yield target compounds (5a‐j). All the final compounds were identified through FT‐IR, 1 H NMR, 13 C NMR, and HRMS spectral techniques. Biological evaluation revealed that several synthesized compounds exhibited promising antiproliferative activity on MCF‐7, HepG2, and Hepa cancer cell lines, but very low cytotoxicity on normal CHO cell line and also displayed good antioxidant efficacy in DPPH assay. Among them, compound 5d displayed moderate anticancer effect on Hepa cell line with an IC 50 of 13.0 µM, and compound 5c featuring vanillyl substituent demonstrated highest antioxidant capacity. The biological activity is further supplemented with molecular docking studies against target proteins, Caspase3, PARP, EFGR, BAX, and BCL2 to understand the binding interactions and mechanistic insights.