Design, synthesis, and insilico evaluation of 2-aminothiazole derivatives as potential mTOR and EGFR inhibitors

A series of 14 novel 2-aminothiazole (1a-1 g, 2a-2 g) derivatives were synthesized effectively and in silico evaluation was performed to find lead candidates as potential inhibitors targeting breast cancer receptors. One-pot three-component synthesis was carried out using different methods, by employing β-diketones, arylamines, and sodium thiocyanate under iodine-mediated condition. The compounds were characterized using FT-IR, ¹H-NMR, ¹³C-NMR, and LC-MS spectroscopic techniques, confirming their purity and molecular structures. Optimization of reaction was carried out employing different methods, which resulted in enhanced reaction efficiency by sonication technique, making it a superior alternative for rapid and high-yield synthesis compared to other techniques. ADMET evaluation revealed favorable pharmacokinetic and toxicity profiles for all compounds, with no Lipinski’s rule violations, suggesting good drug-likeness and oral bioavailability. Furthermore, Molecular docking study was carried out on 2-aminothiazole derivatives against mTOR (PDB: 4DRH) and EGFR (PDB: 4RJ3), two key targets in breast cancer progression. Compounds 1a and 2a emerged as lead candidates, showing stronger binding affinities than the FDA-approved drug, doxorubicin and rapamycin. The molecular dynamics simulations results demonstrated the stability and flexibility interactions between proteins and ligands, supporting their potential efficacy as lead candidates. DFT study provided electronic, and reactive properties for lead candidates which revealed the compound’s chemical behavior, stability, and potential biological activity against the targets. These results highlight the therapeutic actions of synthesized 2-aminothiazole derivatives through comprehensive in-silico studies which lays the groundwork for further in-vitro and in-vivo evaluations in anti-breast cancer drug discovery.