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The structural integrity and purity of the obtained compounds were confirmed by their spectroscopic techniques including\n                    <jats:sup>1<\/jats:sup>\n                    H-NMR,\n                    <jats:sup>13<\/jats:sup>\n                    C-NMR, mass spectroscopy and elemental analyses. The synthesized tetrahydroacridine (THA) derivatives were initially screened for antidiabetic potential through a glucose diffusion assay, where compound\n                    <jats:bold>4b<\/jats:bold>\n                    (100\u00a0mg\/kg) exhibited the highest inhibition rate (34.00%) at the lowest concentration tested, outperforming the reference drug Gliclazide. To deepen biological understanding, molecular docking studies were conducted against key diabetic targets: DPP-IV, SGLT1, and GLUT2. The docking results demonstrated that several compounds, particularly compound\n                    <jats:bold>4a<\/jats:bold>\n                    , compound\n                    <jats:bold>5a<\/jats:bold>\n                    , and compound\n                    <jats:bold>4c<\/jats:bold>\n                    , achieved excellent binding affinities and interactions with critical active-site residues, showing potential as dual or triple inhibitors. ADMET and drug-likeness evaluations based on Lipinski\u2019s rule of five and computational pharmacokinetic modeling indicated acceptable oral bioavailability, metabolic stability, and low toxicity for selected lead candidates.\n                    <jats:italic>In-vivo<\/jats:italic>\n                    studies were conducted in streptozotocin-induced diabetic Wistar rats over a 4-week period. Compounds\n                    <jats:bold>5b<\/jats:bold>\n                    ,\n                    <jats:bold>7a<\/jats:bold>\n                    , and\n                    <jats:bold>8b<\/jats:bold>\n                    (100\u00a0mg\/kg) significantly decreased blood glucose level during fasting, approaching or surpassing the efficacy of Gliclazide. Compound\n                    <jats:bold>5b<\/jats:bold>\n                    showed the most pronounced effect, lowering glucose to 180.5\u2009\u00b1\u200912.3\u00a0mg\/dL by week 4. These integrated findings highlight the potential of tetrahydroacridine derivatives as promising scaffolds for the development of new antidiabetic candidates with multitarget activity, favorable drug-like properties and minimal toxicity risk. Further in-depth SAR, enzyme inhibition, and pharmacodynamic studies are warranted to advance these candidates toward clinical relevance.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-28702-2","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T03:17:40Z","timestamp":1765595860000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthesis and antidiabetic evaluation of novel Tetrahydroacridine derivatives with computational insights"],"prefix":"10.1038","volume":"15","author":[{"given":"Asmaa M.","family":"Kadry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafaa A.","family":"Abdellah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mounir A. 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