Water-Solvated SNAr Synthesis of N-(3-Substituted-phenyl)-4,6-dimethoxypyrimidin-2-amine Derivatives as Potent A549 Inhibitors: Anticancer and Molecular Dynamics Studies

Objective: This study presents the aqueous-based synthesis of 2-aminopyrimidine derivatives (IVa–IVf) via aromatic nucleophilic substitution (SNAr), followed by Suzuki coupling with halogenated derivatives. Methods: Characterization of the synthesized compounds was carried out using NMR spectroscopy and mass spectrometry analysis. Further computational studies, including molecular docking against the B-Raf protein, highlighted favorable binding interactions. Results and Discussion: Anticancer activity showed that certain compounds demonstrated significant potency against the A549 lung cancer cell line, with IC50 values indicating moderate to high efficacy. Notably, compounds IVa, IVc, and IVf exhibited IC50 values of 8.14, 9.46, and 8.6 µM, respectively. Further computational studies, including molecular docking against the B-Raf protein, highlighted favorable binding interactions, with docking scores of –8.053 for IVa and –7.617 for IVc. These findings suggest potential mechanisms of action for these compounds. Conclusions: This green synthetic approach, together with promising biological and computational results, underscores the therapeutic potential of pyrimidine derivatives as environmentally sustainable cancer treatment candidates.