Design, Synthesis, Bioevaluation, and Bioinformatics Study of 5‐Benzylidene Hydantoin Derivatives as Novel Tyrosine Kinase Inhibitors
Muhammad Agnaf Naufal, Elvira Hermawati, Ade Danova, Ika Wiani Hidayat, Jamaludin Al Anshori · ChemistryOpen · 2025
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.