ABSTRACT Through applying the hybridization technique, new coumarin derivatives ( 2–17 ) were prepared with substitution at coumarin C‐3 utilizing various heterocyclic derivatives, aiming to afford multi‐target carbonic anhydrases (CAs) IX/XII and topoisomerase II (Topo II) inhibitors with potent antiproliferative activity. Eight different cell lines were used to evaluate the growth inhibition percentages (GI%) of cancer cells determined by coumarin analogues 1–17 . Analogues 16 and 17 had the most substantial cytotoxic effects, achieving mean GI% of 86.59% and 85.74%, respectively, exceeding doxorubicin (Dox), which demonstrated a mean GI% of 69.15. Furthermore, the CAs IX/XII and Topo II inhibitory potentials for compound 17 were evaluated according to the protein expression analysis in the MG‐63 cancer cells. Analogue 17 downregulated the expression of CA IX, CA XII, and Topo II proteins by 0.43‐, 0.51‐, and 0.56‐fold change, respectively, indicating frontier inhibitory potentials. Additionally, analogue 17 achieved upregulation of apoptotic proteins (Caspases 3, 7, and 9, and BAX by 1.52‐, 3.10‐, 1.67‐, and 1.90‐fold change, respectively). On the contrary, compound 17 induced downregulation of the antiapoptotic proteins BCL‐2, MMP2, and MMP9 by 0.44‐, 0.38‐, and 0.45‐fold change, respectively. Besides, compound 17 achieved an arrest at the G0–G1 phase of the cell cycle and elevated the cellular levels from 65.75% of the control cells to 92.54%. Finally, three molecular docking processes of the superior analogue 17 toward CA IX, CA XII, and Topo II targets were performed to investigate its molecular interactions.
Al‐Karmalawy et al. (Mon,) studied this question.