Design, Synthesis, Molecular Docking, ADME-T and In Vitro Anticancer Assessment of Phenyl-Substituted-Pyrimidin-Benzenesulfonamide Derivatives as Potential BRAFV600E /WT Inhibitors.

BRAF is one of the most commonly mutated oncogenes in human cancers. More than 90% of BRAF mutations are associated with malignant melanoma. Given the pivotal role of BRAFV600E/WT mutations in melanoma progression and therapy resistance, our study focused on the design of phenyl-substituted pyrimidin-benzenesulfonamide hybrids in the [αC-OUT/DFG-IN] conformation, inspired by previously synthesized molecules structurally related to FDA-approved BRAF inhibitors. A total of ten derivatives were synthesized, and their ADME-T properties, in silico binding affinities, in vitro cytotoxic activities against a melanoma cell line and BRAFV600E/WT kinase assay were thoroughly evaluated. All compounds exhibit selective and stronger affinity for the BRAFV600E mutant over the wild-type BRAF protein and also adhere to Lipinski's Rule of Five. Overall, both computational and biological evaluations support that the synthesized compounds, particularly VA03, exhibit greater potency and selectivity toward the BRAFV600E mutant protein. Furthermore, the presence of electron-withdrawing groups at the R1 position appears to significantly enhance the cytotoxic activity of these derivatives.