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Consequently, drug development has shifted from single\u2010target approaches to multi\u2010faceted strategies that emphasize early intervention rather than late\u2010stage treatment. One promising target is glycogen synthase kinase\u20103\u03b2 (GSK\u20103\u03b2), an enzyme implicated in tau hyperphosphorylation and A\u03b2 plaque formation. Based on our earlier work, we synthesized 25 2\u2010thioxo\u20101,2,3,4\u2010tetrahydropyrimidine derivatives designed as GSK\u20103\u03b2 inhibitors, tau phosphorylation inhibitors, and A\u03b2 accumulation. Two compounds emerged as particularly effective: compound 63 (IC<jats:sub>50<\/jats:sub>\u2009=\u20091.69\u2009\u00b5M) and compound 66 (IC<jats:sub>50<\/jats:sub>\u2009=\u20090.90\u2009\u00b5M), with compound 66 identified as an ATP\u2010competitive inhibitor of GSK\u20103\u03b2. Further pharmacokinetic studies and in vitro drug metabolism assessments were conducted, followed by in vivo efficacy studies using <jats:italic>Caenorhabditis elegans<\/jats:italic>. Notably, these compounds reduced phosphorylated tau levels in the BR5706 strain and decreased A\u03b2 aggregate deposition in the CL2006 strain. Molecular Dynamic (MD) simulations were also performed on both compounds. These findings provide valuable insights into GSK\u20103\u03b2 drug development and highlight the potential of these inhibitors as therapeutic candidates for AD by targeting both tau and A\u03b2, the two pathological hallmarks of AD.<\/jats:p>","DOI":"10.1002\/ddr.70112","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T10:14:07Z","timestamp":1750068847000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploring 2\u2010Thioxo\u20101,2,3,4\u2010tetrahydropyrimidines as Dual Acting GSK\u20103\u03b2\/A\u03b2 Aggregation Inhibitors: Implications for Alzheimer's Disease Treatment"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9877-6349","authenticated-orcid":false,"given":"Sukanya","family":"Sukanya","sequence":"first","affiliation":[{"name":"Department of Pharmacy Central University of Rajasthan, Bandarsindari Ajmer Rajasthan India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aina","family":"Bellver\u2010Sanchis","sequence":"additional","affiliation":[{"name":"Pharmacology Section, Department of Pharmacology, Toxicology, and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience University of Barcelona (NeuroUB) Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5098-7681","authenticated-orcid":false,"given":"Bhanwar Singh","family":"Choudhary","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Central University of Rajasthan, Bandarsindari Ajmer Rajasthan India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Central University of Rajasthan, Bandarsindari Ajmer Rajasthan India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Therapeutics and Toxicology, Institute of Neuroscience Autonomous University of Barcelona Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f3n Leandro Mart\u00ednez","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Innopharma Screening Platform, Biofarma Research Group. 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