Novel Pyrimidine Derivatives as Potent BUB1B Inhibitors for Clear Cell Renal Cell Carcinoma: From Synthesis and Characterization to Docking Insights and Therapeutic Validation

• Novel Inhibitor Design: Four pyrimidine-based derivatives of TG-101209 were synthesized, with compound 3a identified as a potent BUB1B inhibitor for ccRCC therapy. • Structural Validation: Experimental X-ray diffraction and FT-IR data showed excellent agreement with DFT calculations and Hirshfeld surface analysis. • Biological Efficacy: Compound 3a exhibited superior BUB1B inhibition compared to the other derivatives. • In silico Studies : Molecular Docking and Dynamics Analysis revealed stable and favorable binding affinity of the compound 3a within the BUB1B active site. • Using Hirshfeld surface investigations, DFT, and X-ray single crystal, the structure of the PKL-05 chemical was examined. • Fukui functions, charge analyses, and the MEP map were used to identify the electrophilic and nucleophilic areas.