Design, synthesis and molecular dynamics simulations of thiazole-based hydrazones targeting MDA-MB-231 breast cancer...

This study presents the design, synthesis of thiazole-based Hydrazones as potential inhibitors targeting in MDA-MB-231 triple-negative breast cancer cells. A series of quinazoline-thiazole and isatin-thiazole derivatives were synthesized and evaluated for their anti-proliferative activity. Compounds 12d and 12f (quinazoline-thiazole) demonstrated significant inhibitory effects, with IC₅₀ values of 1.90 ± 1.69 μM and 2.55 ± 1.26 μM, outperforming toceranib (IC₅₀: 2.28 ± 0.17 μM). Similarly, compounds 5m and 5l (isatin-thiazole) exhibited strong activity with IC₅₀ values of 0.86 ± 1.19 μM and 0.73 ± 1.05 μM, respectively. To explore the compound induced cell apoptosis, flow cytometry analysis revealed compound 5l to be inducing apoptosis potential twice as compared to 12d compound. Additionally, the regulation of key cancer-related proteins, including EGFR, NFKB1, PIK3CB, and others, was predicted, shedding light on the molecular mechanisms underlying their anti-cancer activity and molecular docking studies revealed interactions with critical amino acids in the EGFR binding pocket, such as MET793, PHE795, and CYS775. These interactions were further supported by molecular dynamics simulations, which assessed the stability and conformational behavior of the compounds within the binding site. MM/GBSA and DFT calculations confirmed the stability and energy profiles of these hybrids. The study predicts the regulation of proteins involved in cancer pathways, suggesting that compounds 5m, 5l, 12d and 12f are promising candidates for EGFR-targeted therapies in breast cancer treatment.