Design, synthesis, anticancer, antioxidant and computational evaluation of curcumin-benzodiazepine derivatives

This work reported synthesis of curcumin benzodiazepine derivatives using aryl diamine with curcumin in the presence of acetic acid under microwave irradiation (MWI). The synthesized compounds homogeneity was verified using various spectral analysis. Some of the selected derivatives (3a, 3b, 3c, 3d & 3e) screened for anticancer activity studies against human breast cancer MCF-7 cells. and tested derivatives 3d (2.85 ± 0.57), 3e (4.26 ± 0.82), and 3c (5.64 ± 1.09) showed comparable activities to the reference Doxorubicin (1.80 ± 0.21). Further investigated in vitro antioxidant activity by DPPH method, compounds 3a and 3b showed significant antioxidant properties in comparison to standard ascorbic acid. Furthermore, synthesized derivatives are evaluated for their physiochemical, lipophilicity, pharmacokinetics, and drug-likeliness of the derivatives. It specifically highlights the Boiled-Egg model and radar graph representation. The docking study of such protein-ligand complexes showed different binding affinities and different interaction profiles with the key residues of the target protein. Among them, complex 1PY5-3a had the highest binding affinity with a docking score of - 7.4, Complex 1PY5-3b, a docking score of - 5.9, complex 1PY5-3c has a docking score of - 6.0, 1PY5-3d has a score of -6.2, and 1PY5-3e has the lowest docked score of -5.5. RMSD values for the reference protein complex is 1PY5-APO is 0.28 ± 0.02 nm, derivative complexes 1PY5-3c 0.27 ± 0.03 nm, and 1PY5-3d (0.29 ± 0.03 nm). RMSF values for reference protein complex 1PY5-APO is 0.12 ± 0.06 nm, and derivative complexes 1PY5-3c (0.13 ± 0.08 nm), 1PY5-3d (0.13 ± 0.07 nm) and 1PY5-3e (0.13 ± 0.06 nm). The average Rg value for 1PY5-APO (1.94 ± 0.01 nm), and derivative complex 1PY5-3c (1.96 ± 0.01 nm). The molecular dynamic simulation investigated for structural dynamic determination of proteins interaction with ligands at an atomic level.

The online version contains supplementary material available at 10.1007/s13205-026-04823-x.