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This study synthesizes novel 5\u2010benzylidene hydantoin derivatives (24\u201338) via benzylation and condensation, characterized by\u00a0nuclear magnetic resonance (NMR), mass spectrometry, and fourier\u2010transform infrared (FTIR). Anticancer activity was evaluated against eight receptor tyrosine kinases at 10\u2009\u03bcM. Six compounds\u201424 (34%), 25 (45%), 28 (57%), 32 (60%), 34 (49%), and 38 (56%)\u2014show moderate HER2 inhibition (%enzyme activity \u2264 60%). Compound 38 additionally inhibits VEGFR2 (27%), PDGFR\u03b1 (32%), and PDGFR\u03b2 (25%). Molecular docking reveals interactions with HER2 residues Met801, Leu726, Leu852, Phe1004, Val734, and Leu796, suggesting a structural basis for selectivity. The HER2\u2010targeting 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\u2010targeted therapy. These findings underscore the therapeutic relevance of the 5\u2010benzylidene hydantoin scaffold, warranting further optimization to enhance potency and selectivity against HER2 and other oncogenic kinases.<\/jats:p>","DOI":"10.1002\/open.202500158","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:39:17Z","timestamp":1760031557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design, Synthesis, Bioevaluation, and Bioinformatics Study of 5\u2010Benzylidene Hydantoin Derivatives as Novel Tyrosine Kinase Inhibitors"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0211-7539","authenticated-orcid":false,"given":"Muhammad","family":"Naufal","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Mathematics and Natural Sciences Universitas Padjadjaran  Jl. 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