Design, Synthesis, Bioevaluation, and Bioinformatics Study of 5-Benzylidene Hydantoin Derivatives as Novel Tyrosine Kinase Inhibitors.

Abstract

Tyrosine kinases regulate cellular growth, differentiation, and metabolism, and their dysregulation is implicated in malignancies, making them therapeutic targets. This study synthesizes novel 5-benzylidene hydantoin derivatives (24-38) via benzylation and condensation, characterized by nuclear magnetic resonance (NMR), mass spectrometry, and fourier-transform infrared (FTIR). Anticancer activity was evaluated against eight receptor tyrosine kinases at 10 μM. Six compounds-24 (34%), 25 (45%), 28 (57%), 32 (60%), 34 (49%), and 38 (56%)-show moderate HER2 inhibition (%enzyme activity ≤ 60%). Compound 38 additionally inhibits VEGFR2 (27%), PDGFRα (32%), and PDGFRβ (25%). Molecular docking reveals interactions with HER2 residues Met801, Leu726, Leu852, Phe1004, Val734, and Leu796, suggesting a structural basis for selectivity. The HER2-targeting derivatives demonstrate potential for development as novel HER2 inhibitors. Compound 38's multikinase inhibition resembles sunitinib, a clinically approved drug for renal cell carcinoma and gastrointestinal stromal tumors, highlighting its promise for broader kinase-targeted therapy. These findings underscore the therapeutic relevance of the 5-benzylidene hydantoin scaffold, warranting further optimization to enhance potency and selectivity against HER2 and other oncogenic kinases.