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Despite the availability of preventive options such as vaccines and monoclonal antibodies, effective antiviral therapies for acute infections remain limited. Therefore, we investigated small\u2010molecule entry inhibitors identified in a high\u2010throughput campaing and evaluated the most promising candidates in detail by performing resynthesis and determining their antiviral activity. Unfortunately,\u00a0analytical investigations by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography\u2013mass spectrometry (LC\u2013MS) revealed discrepancies between the screening samples and the resynthesized compounds for two compound classes, highlighting the complexity of hit validation and the potential influence of impurities. By publishing these results, we aim not only to underscore the importance of rigorous analytical and biological validation in screening campaigns but also to support the development of improved strategies for identifying reliable RSV inhibitors. We also believe it is important to publish false\u2010positive hits to avoid time efforts on projects that assume such compounds as genuine hits.<\/jats:p>","DOI":"10.1002\/cmdc.70501","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:12:34Z","timestamp":1792649554000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Validation of Small\u2010Molecule Entry Inhibitors Targeting the Respiratory Syncytial Virus"],"prefix":"10.1002","volume":"21","author":[{"given":"Christina","family":"Karhan","sequence":"first","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) \u2013 Helmholtz Centre for Infection Research (HZI) Department of Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja M.","family":"Sake","sequence":"additional","affiliation":[{"name":"TWINCORE, Centre 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