Acetylcholinesterase-targeted biogenic–thienopyrimidine hybrids: design, synthesis and pharmacological evaluation of compounds with anti-amnestic, anxiolytic-like and pain-modulating properties

Authors

DOI:

https://doi.org/10.15587/2519-4852.2025.346823

Keywords:

Thienopyrimidine, neurodegeneration, acetylcholinesterase, glycine, amnesia

Abstract

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

Supporting Agency

  • The research was funded by the Ministry of Health of Ukraine at the expense of the State Budget in the framework # 2301020 “Scientific and scientific-technical activity in the field of health protection” on the topic «Molecular modelling and synthesis of innovative pyrimidine derivatives as promising agents for the treatment of neurodegenerative diseases» (State registration number: 0124U002006. Order of the Ministry of Health of Ukraine of January 16, 2024, No. 82)

Author Biographies

Rita Saifudinova, National University of Pharmacy; Cherkasy Medical Academy

PhD Student

Department of Pharmaceutical Chemistry

Head of Department

Pharmaceutical Department

Hanna Severina, National University of Pharmacy

Doctor of Pharmaceutical Science, Professor

Department of Pharmaceutical Chemistry

Sergiy Vlasov, Taras Shevchenko National University of Kyiv; Enamine Ltd.

Doctor of Pharmaceutical Sciences, Professor

Department of Supramolecular Chemistry

Georgiy Yakovenko, Taras Shevchenko National University of Kyiv; Enamine Ltd.

PhD

Chemical Faculty

Andrii Khairulin, Taras Shevchenko National University of Kyiv; Enamine Ltd.

PhD

Chemical Faculty

Dmytro Kyrylov, National University of Pharmacy

Department of Pharmacology and Clinical Pharmacy

Mykyta Нutorka, National University of Pharmacy

Department of Pharmacology and Clinical Pharmacy

Sergii Shtrygol’, National University of Pharmacy

Doctor of Medical Sciences, Professor

Department of Pharmacology and Clinical Pharmacy

Victoriya Georgiyants, National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor, Head of Department

Department of Pharmaceutical Chemistry

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Acetylcholinesterase-targeted biogenic–thienopyrimidine hybrids: design, synthesis and pharmacological evaluation of compounds with anti-amnestic, anxiolytic-like and pain-modulating properties

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2025-12-30

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Saifudinova, R., Severina, H., Vlasov, S., Yakovenko, G., Khairulin, A., Kyrylov, D., Нutorka M., Shtrygol’, S., & Georgiyants, V. (2025). Acetylcholinesterase-targeted biogenic–thienopyrimidine hybrids: design, synthesis and pharmacological evaluation of compounds with anti-amnestic, anxiolytic-like and pain-modulating properties. ScienceRise: Pharmaceutical Science, (6 (58), 14–27. https://doi.org/10.15587/2519-4852.2025.346823

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No. 6 (58) (2025)

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Pharmaceutical Science

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Copyright (c) 2025 Rita Saifudinova, Hanna Severina, Sergiy Vlasov, Georgiy Yakovenko, Andrii Khairulin, Dmytro Kyrylov, Mykyta Нutorka, Sergii Shtrygol’, Victoriya Georgiyants

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