Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents

Alshamari, Asma K.; Magdy, Nourhan; Basiony, Ebtesam A.; Hassan, Nasser A.; Alshammari, Odeh A. O.; Abdel-Rahman, Adel A.-H.; Alsaif, Nuha O. S.; Alshammari, Mona Z.; Elrashedy, Ahmed A.; Hassan, Allam A.

doi:10.3390/ijms27146119

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Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents

by

Asma K. Alshamari

¹

,

Nourhan Magdy

^2,3,

Ebtesam A. Basiony

²,

Nasser A. Hassan

^3,*

,

Odeh A. O. Alshammari

¹

,

Adel A.-H. Abdel-Rahman

²,

Nuha O. S. Alsaif

¹

,

Mona Z. Alshammari

¹,

Ahmed A. Elrashedy

^4,5 and

Allam A. Hassan

⁶

¹

Department of Chemistry, College of Science, Ha’il University, Ha’il 81451, Saudi Arabia

²

Department of Chemistry, Faculty of Science, Menofia University, Shbien El-Kom 32511, Egypt

³

Department of Photochemistry, Synthetic Unit, Chemical Industries Research Institute, National Research Centre, 33 El Buhouth Street, Cairo P.O. Box 12622, Egypt

⁴

Natural and Microbial Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, 33 El Buhouth Street, Cairo P.O. Box 12622, Egypt

⁵

College of Pharmacy, Al-Farahidi University, Baghdad 10021, Iraq

⁶

Department of Chemistry, Faculty of Science, Suez University, Suez 43221, Egypt

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(14), 6119; https://doi.org/10.3390/ijms27146119 (registering DOI)

Submission received: 15 April 2026 / Revised: 28 June 2026 / Accepted: 28 June 2026 / Published: 8 July 2026

(This article belongs to the Special Issue Research in Alzheimer’s Disease: Advances and Perspectives)

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Abstract

Thienopyrimidine derivatives are emerging as potent scaffolds for cholinesterase inhibition in Alzheimer’s disease therapy. In this work, a novel series of substituted thieno[2,3-d]pyrimidines was synthesized via Gewald’s reaction, followed by cyclization and functionalization through nucleophilic substitution and hydrazone formation. Structural confirmation was achieved using spectroscopic techniques, and biological evaluation was performed against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with donepezil and rivastigmine as reference drugs. Compound 4 emerged as the most potent and selective AChE inhibitor (IC₅₀ = 0.58 µM), while compound 7 also showed strong AChE inhibition (IC₅₀ = 0.63 µM). Notably, compound 9 exhibited superior BChE inhibition (IC₅₀ = 3.05 µM) compared to donepezil (IC₅₀ = 8.41 µM). Dual inhibitory activity was observed for compounds 5, 6, and 11, highlighting their multitarget potential. Molecular dynamics simulations (200 ns) and MM/GBSA binding free energy calculations provided mechanistic insights. Compound 4 showed the most favorable binding energy (ΔGbind = −59.16 kcal/mol), driven by hydrogen bonds with Tyr121 and Glu199 and π-π stacking with Trp83. Residue-level decomposition identified Tyr121, Trp83, Glu199, and Tyr338 as critical contributors to binding stability. Structure–activity relationship analysis confirmed that nitrogen-containing substituents and cyclic amino moieties enhance potency, whereas bulky aromatic groups reduce activity. These findings establish thieno[2,3-d]pyrimidine derivatives as promising candidates for the development of next-generation anti-Alzheimer agents.

Keywords: β-enaminonitriles; thieno[2,3-d]pyrimidine; acetylcholinesterase inhibition; butyrylcholinesterase; MM/GBSA; SAR analysis; Alzheimer’s disease; dual inhibitors; molecular docking; molecular dynamics

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MDPI and ACS Style

Alshamari, A.K.; Magdy, N.; Basiony, E.A.; Hassan, N.A.; Alshammari, O.A.O.; Abdel-Rahman, A.A.-H.; Alsaif, N.O.S.; Alshammari, M.Z.; Elrashedy, A.A.; Hassan, A.A. Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents. Int. J. Mol. Sci. 2026, 27, 6119. https://doi.org/10.3390/ijms27146119

AMA Style

Alshamari AK, Magdy N, Basiony EA, Hassan NA, Alshammari OAO, Abdel-Rahman AA-H, Alsaif NOS, Alshammari MZ, Elrashedy AA, Hassan AA. Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents. International Journal of Molecular Sciences. 2026; 27(14):6119. https://doi.org/10.3390/ijms27146119

Chicago/Turabian Style

Alshamari, Asma K., Nourhan Magdy, Ebtesam A. Basiony, Nasser A. Hassan, Odeh A. O. Alshammari, Adel A.-H. Abdel-Rahman, Nuha O. S. Alsaif, Mona Z. Alshammari, Ahmed A. Elrashedy, and Allam A. Hassan. 2026. "Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents" International Journal of Molecular Sciences 27, no. 14: 6119. https://doi.org/10.3390/ijms27146119

APA Style

Alshamari, A. K., Magdy, N., Basiony, E. A., Hassan, N. A., Alshammari, O. A. O., Abdel-Rahman, A. A.-H., Alsaif, N. O. S., Alshammari, M. Z., Elrashedy, A. A., & Hassan, A. A. (2026). Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents. International Journal of Molecular Sciences, 27(14), 6119. https://doi.org/10.3390/ijms27146119

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Synthesis, Biological Evaluation, Molecular Docking and Molecular Dynamics of Substituted Thieno[2,3-d]pyrimidine Derivatives as Potential Anti-Alzheimer Agents

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