Design, Synthesis, Biological Evaluation and In-Silico Investigation, Molecular Docking, Molecular Dynamics Simulations, and ADMET Profiling of Novel Thiazole-Based Derivatives

In the present study, the design of 2-aminothiazole and 2-(1-phenylethylidene)hydrazine-1-carbothioamide (1) were reacted with different reagents such as α-bromocarbonyl derivatives, chloroacetone, and ethyl-2-cloroacetoacetate 1-chloro-1-(aryldiazenyl) propan-2-one, and ethyl 2-chloro-2-(aryldiazenyl) acetate to produce the corresponding thiazole products 4, 5, 9a-d, 10, 13a,b, and 15a-h, respectively. The synthesized compounds were screened for breast cancer cell lines MCF7 and MDA-MB231 using MTT assay and doxorubicin was used as the standard drug. The biological studies showed that compounds 9a, 9d, 10, and 15d had notable cytotoxic activity against MCF-7 cell line. Furthermore, compound 9d displayed the good cytotoxic activity against both the MCF7 and MDA-MB231 cell lines. These findings led to the synthetic chemical 9d being chosen for biological research as an antioxidant and anti-breast cancer agent comparing with the standard compound. The apoptosis/necrosis assay showed significantly higher apoptosis levels in the treated samples (9d/MCF7 and 9d/MDA-MB231) compared to the controls. Molecular docking was employed to examine how the most promising compounds interacted with key anticancer target proteins. The docking results showed that compounds 9a, 9d, 15b, 15d, and 17b displayed strong binding energies and effectively engaged with the active sites of the CDK2, ERα, EGFR, and VEGFR2 receptors. These interactions encompassed a range of molecular contacts highlighting the compounds’ potential to block enzyme activity and deliver significant anticancer effects. Additionally, the silico-ADMET analysis of compounds 9a, 9d, 15b, 15d, and 17b showed compliance with Lipinski guidelines, indicating favorable physicochemical characteristics. These compounds are expected to exhibit good oral bioavailability, and minimal toxicity risks.