Synthesis and pharmacokinetic profiling of a novel pyrimidine imidazole based thiosemicarbazone derivative for BRAF inhibition in lung cancer therapy

This study presents the design, synthesis, and comprehensive evaluation of a novel thiosemicarbazone derivative containing a pyrimidine-imidazole (C11H11N8SCl) as a potential BRAF inhibitor for the treatment of non-small cell lung cancer. The compound was synthesized by a condensation reaction and characterized by elemental analysis, molar conductivity, SEM-EDS, FT-IR, 1H, and 13C-NMR spectral techniques. DFT calculations at the B3LYP/6-311 + + G(d, p) level revealed a HOMO-LUMO gap of 2.8 eV, indicating appropriate molecular stability and reactivity. Molecular docking studies with BRAF (PDB ID: 1UWH) demonstrated favorable binding affinity (-6.85 kcal/mol) with key interactions at ILE512, HIS509, HIS584, GLN529, GLU585, LYS590, VAL510, and LEU587 residues. In vitro cytotoxicity assays revealed that the compound possesses anticancer potential against H-460 cells, with a significant inhibitory effect observed at a concentration of 200 µg/mL. Combined with its favorable binding affinity toward BRAF kinase, these results suggest that the pyrimidine-imidazole thiosemicarbazone may serve as a potential lead scaffold for further development in targeted lung cancer therapy.ADME profiling confirmed the compound’s compliance with Lipinski’s rule of five parameters, supporting its potential as an orally active drug candidate. These findings suggest that our pyrimidine-imidazole thiosemicarbazone represents a promising scaffold for the development of targeted BRAF inhibitors for lung cancer therapy.