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This study develops a quantitative structure\u2013activity relationship (QSAR) model to accelerate the optimization of lead compounds. Using pharmacophore modeling against different cancer targets,\u200989 flavone analogs with varied substitution patterns were designed and synthesized. Biological evaluation revealed promising candidates with enhanced cytotoxicity against breast cancer (MCF\u20107)\u2009and liver cancer (HepG2)\u2009cell lines, along with low toxicity toward normal Vero cells.\u2009A machine learning (ML)\u2010driven QSAR approach was employed, comparing random forest (RF), extreme gradient boosting, and artificial neural network (ANN) models. The RF model exhibits superior performance, achieving\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    of 0.820 for (MCF\u20107 and 0.835 for HepG2, with cross\u2010validation (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    cv) of 0.744 and 0.770, respectively. Validation using 27 test compounds yielded root mean square error test values of 0.573 (MCF\u20107) and 0.563 (HepG2). SHapley Additive exPlanations analysis highlighted key molecular descriptors influencing anticancer activity. This work presents a robust ML\u2010driven QSAR model that supports the rational design of flavone derivatives and advances the development of selective, potent anticancer agents.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500143","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T22:16:16Z","timestamp":1748643376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Machine Learning\u2010Driven QSAR Modeling of Anticancer Activity from a Rationally Designed Synthetic Flavone Library"],"prefix":"10.1002","volume":"20","author":[{"given":"Natthanan","family":"Vijara","sequence":"first","affiliation":[{"name":"Center of Excellence in Natural Products Chemistry Department of Chemistry Faculty of Science Chulalongkorn University  Bangkok 10330 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borwornlak","family":"Toopradab","sequence":"additional","affiliation":[{"name":"Program in Bioinformatics and Computational Biology Graduate School Chulalongkorn University  Bangkok 10330 Thailand"},{"name":"Center of Excellence in Structural and Computational Biology Department of Biochemistry Faculty of Science Chulalongkorn University  Bangkok 10330 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7961-7836","authenticated-orcid":false,"given":"Jantana","family":"Yahuafai","sequence":"additional","affiliation":[{"name":"Clinical Research Section Division of Research and Academic Support National Cancer Institute  Bangkok 10400 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taweesak","family":"Gulchatchai","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Science Chulalongkorn University  Bangkok 10330 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4422-3831","authenticated-orcid":false,"given":"Rita","family":"Hairani","sequence":"additional","affiliation":[{"name":"Center of Excellence in Natural Products Chemistry Department of Chemistry Faculty of Science Chulalongkorn University  Bangkok 10330 Thailand"},{"name":"Department of Chemistry Faculty of Mathematics and Natural Sciences Mulawarman University  Samarinda 75123 East Kalimantan Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apinya","family":"Patigo","sequence":"additional","affiliation":[{"name":"Center of Excellence in Natural Products Chemistry Department of Chemistry Faculty of Science Chulalongkorn University  Bangkok 10330 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0133-3818","authenticated-orcid":false,"given":"Thanyada","family":"Rungrotmongkol","sequence":"additional","affiliation":[{"name":"Program in Bioinformatics and Computational Biology Graduate School Chulalongkorn University  Bangkok 10330 Thailand"},{"name":"Center of Excellence in Structural and Computational Biology Department of Biochemistry Faculty of Science Chulalongkorn University  Bangkok 10330 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6940-1329","authenticated-orcid":false,"given":"Sumrit","family":"Wacharasindhu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Science Chulalongkorn University  Bangkok 10330 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5201-1324","authenticated-orcid":false,"given":"Warinthorn","family":"Chavasiri","sequence":"additional","affiliation":[{"name":"Center of Excellence in Natural Products Chemistry Department of Chemistry Faculty of Science Chulalongkorn University  Bangkok 10330 Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyi","family":"Shi","sequence":"additional","affiliation":[{"name":"Research Center of Nano Science and Technology Department of Chemistry College of Sciences Shanghai University  Shanghai 200444 P. 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