Antiproliferative noscapinoids bearing isoxazoles: Design, synthesis, bioevaluation and molecular docking

Natural α-noscapine is an antitussive agent approved by the FDA, known for its low cytotoxicity even at high concentrations. Recently, it has shown that noscapine and its derivatives exhibit significant anticancer effects against a variety of cancer cell lines. To improve its therapeutic potential, this study focused on the synthesis of a series of novel isoxazole-conjugated noscapinoids, which were then assessed for their cytotoxic properties in vitro. The reaction of N-propargylic noscapine with in situ generated (Z)-N-hydroxybenzimidoyl chloride yielded the desired noscapinoids containing isoxazoles. The newly synthesized compounds showed considerable cytotoxic activity, with IC₅₀ ranging from 1.2 to 21.3 μM, surpassing noscapine (IC₅₀: 31 and 65.5 μM) across all evaluated cell lines, while exhibiting minimal toxicity to normal cells (IC₅₀ > 300 μM). Molecular docking analyses of the most promising synthetic derivative, 7p (IC₅₀ ranging 1.2 and 9.4 μM across different cancer cell lines), indicated the highest binding affinity to tubulin (ΔG binding of −24.99 kcal/mol) and effectively induced apoptosis in cancer cells to a greater degree.