Synthesis and antidiabetic evaluation of novel Tetrahydroacridine derivatives with computational insights

Abstract A new series of thirty-two tetrahydroacridine (THA) derivatives were rationally designed and synthesized via efficient multistep reactions involving nucleophilic aromatic substitution and Mannich condensation. The structural integrity and purity of the obtained compounds were confirmed by their spectroscopic techniques including 1 H-NMR, 13 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 4b (100 mg/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 4a , compound 5a , and compound 4c , 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’s rule of five and computational pharmacokinetic modeling indicated acceptable oral bioavailability, metabolic stability, and low toxicity for selected lead candidates. In-vivo studies were conducted in streptozotocin-induced diabetic Wistar rats over a 4-week period. Compounds 5b , 7a , and 8b (100 mg/kg) significantly decreased blood glucose level during fasting, approaching or surpassing the efficacy of Gliclazide. Compound 5b showed the most pronounced effect, lowering glucose to 180.5 ± 12.3 mg/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.