Гібриди тієнопіримідинів з біогенними речовинами, таргетовані на ацетилхолінестеразу: дизайн, синтез та фармакологічна оцінка сполук з антиамнестичною, анксіолітичною дією та властивостями модуляції болю

The aim. To carry out the rational design, synthesis, and experimental evaluation of new glycine-linked thieno[2,3-d]pyrimidine hybrids as potential modulators of memory, anxiety, and pain for further correction of neurodegenerative processes, integrating in silico and in vivo investigations. Materials and Methods. Organic synthesis methods; structure confirmation by ¹H, ¹³C NMR spectroscopy, LC-MS, and elemental analysis. Molecular docking was performed using AutoDock Vina, AutoDockTools 1.5.6, and Discovery Studio Client. The pharmacological studies were carried out using a scopolamine-induced amnesia model and included the following behavioral assays: the Passive Avoidance Test, the Light-dark Transition Test, the Rotarod Test, and the Hot Plate Test. Results and Discussion. A series of newly designed glycine-linked thieno[2,3-d]pyrimidine hybrids was rationally developed, synthesized, and evaluated as potential modulators of neurodegenerative processes. The synthetic procedures for obtaining the intermediates and target 5-methylthieno[2,3-d]pyrimidin-4(3H)-one hybrids via amide coupling were optimized. Molecular docking to AChE (PDB ID: 7E3H) revealed that several derivatives, particularly 4d, 4f, and 4g, exhibited favorable binding energies (down to –12.5 kcal/mol) and formed an extensive network of hydrogen-bonding, halogen, π–π, and hydrophobic interactions within the active site of acetylcholinesterase. In vivo studies using the scopolamine-induced amnesia model demonstrated that these compounds display moderate anti-amnestic (pro-cognitive) properties and do not influence motor coordination or nociceptive sensitivity. Compound 4g showed anti-amnestic activity comparable to that of Donepezil, as well as pronounced anxiolytic effects. A correlation between the in silico predictions and the in vivo findings was established. Conclusions. The rational design, synthesis, and structural characterization of new AChE-targeted inhibitors, combined with in silico calculations and subsequent in vivo validation, enabled the identification of several thieno[2,3-d]pyrimidine derivatives with moderate anti-amnestic properties in the scopolamine-induced amnesia model, highlighting their potential as promising structures for further optimization