Coumarin‐Based Azo Derivatives With Trifluoromethyl Substituents: A Combined Experimental and Computational Approach Toward Novel Anticancer Agents

ABSTRACT Cancer's global prevalence demands novel therapeutic agents with improved efficacy and selectivity. In this study, six azo‐containing derivatives featuring trifluoromethyl (─CF 3 ) groups and a coumarin scaffold were comprehensively examined, five of which were newly synthesized. Their chemical structures were confirmed using FTIR, UV–Vis, and NMR ( 1 H and 13 C) spectroscopy. DFT calculations (B3LYP/6‐311++G(d,p)) supported the experimental data, showing strong agreement between theoretical and observed spectra. All compounds fulfilled Lipinski's rule of five, according to ADMEt studies; however, compounds 4b and 4c showed the lowest projected toxicity (LD 50 : 6480 mg/kg). High binding affinities toward cancer‐related VEGFR2 protein targets (PDB IDs: 3VO3, 6GQO, 3VHE, and 3WZD) were found via molecular docking. The compound that interacted with 3VHE the most was compound 5a (–11.2 kcal/mol). The 6GQO–4a complex was shown to be the most stable (–120.099 kJ/mol) by MM/PBSA analysis. This finding was confirmed by 100 ns molecular dynamics simulations that showed constant hydrogen bonding and stable RMSD values. These results point to compound 4a as a promising lead molecule for the development of anticancer drugs, which calls for additional in vitro and in vivo research.