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Pyrazolopyrimidinones are fused nitrogen\u2010containing heterocyclic systems which are a scaffold in several bioactive drugs and drug candidates. Here, a structure\u2013activity relationship (SAR) study was performed where 23 substituted pyrazolo[1,5\u2010<jats:italic>\u03b1<\/jats:italic>]pyrimidinones were screened for cytotoxicity against the GBM U\u2010251\u2009MG cell line and the noncancerous embryonic kidney HEK293 cell line to assess their potential as antiGBM agents capable of selectivity for cancer cells. Through analog synthesis of preliminary HIT compounds with varied structural substituents, a lead compound, <jats:bold>22<\/jats:bold>, has been identified, which proved capable of inducing significant GBM cell death while having a marginal cytotoxicity against the noncancerous cells. The mode of cell death studies suggested that the structurally varied HIT compounds induced cell death through differential mechanisms including cell membrane permeabilization and mitochondria membrane depolarization\u2010dependent mechanisms such as necrosis or apoptosis. The results highlight the potential of pyrazolo[1,5\u2010<jats:italic>\u03b1<\/jats:italic>]pyrimidinones derivatives as a novel anti\u2010GBM therapy, capable of selectively killing cancer cells. Furthermore, pyrazolo[1,5\u2010<jats:italic>\u03b1<\/jats:italic>]pyrimidinones provide a scaffold for further development of selective GBM therapies.<\/jats:p>","DOI":"10.1002\/cmdc.202500337","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T10:20:29Z","timestamp":1751970029000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Development of Novel Anticancer Pyrazolopyrimidinones Targeting Glioblastoma"],"prefix":"10.1002","volume":"20","author":[{"given":"Kate","family":"Byrne","sequence":"first","affiliation":[{"name":"School of Food Science and Environmental Health Technological University Dublin  Grangegorman Lower, Dublin 7 Dublin D07 ADY7 Ireland"},{"name":"Sustainability and Health Research Hub (SHRH) Technological University Dublin  Grangegorman Lower, Dublin 7 Dublin D07 ADY7 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