Design, Hemisynthesis, Computational, and Biological Evaluation of Novel Totarol‐1,3‐Thiazol Derivatives as Anticancer Agents

ABSTRACT The current study reports the design and synthesis of novel totarol‐based 1,3‐thiazole derivatives DBT 2 ‐ 9 and evaluates their anticancer potential. The synthesis involved the reaction of totarol derivatives with thiosemicarbazone derivatives under optimized conditions. Structural characterization of the synthesized compounds was accomplished using high‐resolution mass spectrometry (HRMS), infrared spectroscopy (IR), and nuclear magnetic resonance (NMR) spectroscopy, confirming their chemical identities and purity. The antitumor activity of these compounds was evaluated using the in vitro MTT and apoptosis assays. The compounds demonstrated selective anti‐proliferative effects against MCF‐7 breast cancer cells, and compound DBT 9 had an IC 50 value comparable to those of reference anticancer drugs. By activating caspases 4 and 8, which mediate the stress‐mediated and extrinsic apoptosis pathways, respectively, compound DBT 9 caused MCF‐7 cell death. Furthermore, density functional theory (DFT) was carried out to study the electronic properties and the chemical reactivity of the synthesized compounds. Furthermore, molecular docking studies revealed that DBT 9 displayed the highest binding affinity toward multiple cancer‐associated target proteins, including EGFR, VEGFR‐2, and FGFR1. These findings indicate that DBT 9 showed the best cytotoxic activity through the induction of apoptosis via caspase 4 and 8 pathways, indicating its potential as a promising bioactive compound.