Discovery of novel vanillin-2-acetylfuran hybrids through integrated design, synthesis, computational studies, and in-vitro cytotoxic evaluation

Abstract A new one-step, multicomponent Mannich base reaction was developed between vanillin, 2-acetyl furan, and amine derivatives using p-TSA as a catalyst. Synthesized compounds ( 1–26 ) have been characterised using FT-IR, 1 H NMR, 13 C NMR, GC–MS, and elemental analysis. These compounds were evaluated for cytotoxic activity, with doxorubicin as the control. Furthermore, molecular docking, density functional theory, ADME-T, and MD simulations were performed on the synthesized compounds. Compound 14 had a higher binding affinity (-10.3 kcal/mol) than doxorubicin (-7.3 kcal/mol) and other compounds. The pharmacokinetics of the newly synthesised derivatives were predicted using ADME analysis. According to the HOMO–LUMO study, compound 14 had a significant energy gap of 2.77 eV with an energy range of -8.027 eV and -5.258 eV. Simulations of the HER2 receptor (PDB ID: 5NQR) using compound 14 demonstrated stable binding, as evidenced by minimal fluctuations over 100 ns. After docking studies, compound 14 was evaluated for cytotoxicity activity against HepG-2 (IC 50 = 29.07 μg/mL), HeLa (IC 50, = 34.13 μg/mL), and MCF-7 (IC 50, = 25.40 μg/mL) cell lines. Compound 14 was moderately active in MCF-7 (IC 50, = 25.40 μg/mL) compared with other cancer cell lines. In addition to blocking cancer cell invasion, compound 14 promotes apoptosis via mitochondrial-dependent apoptosis and reactive oxygen species (ROS) generation. As a result of the aforementioned findings, vanillin derivatives may suggest useful as anticancer drugs in the future.