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  3. Novel imidazolium salts bearing 2-oxindoles scaffold as potent acetylcholinesterase inhibitors for Alzheimer's disease: Design, synthesis, in vitro and in silico studies

Novel imidazolium salts bearing 2-oxindoles scaffold as potent acetylcholinesterase inhibitors for Alzheimer's disease: Design, synthesis, in vitro and in silico studies

  • Bioorg Med Chem Lett. 2026 May:134:130560. doi: 10.1016/j.bmcl.2026.130560.
Le Quoc Tien 1,  Hien Thi Thanh Phung 2,  Huy-Hoang Do 2,  Tiep N Khac 1,  Pham Thi Ngoc Minh 1,  Vu Ngoc Hai Linh 1,  Nguyen Quoc Thang 3,  Shuai Wang 4,  Phuong-Thao Tran 5
Affiliations

Affiliations

  • 1 Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi 11021, Viet Nam.
  • 2 Faculty of Chemistry, VNU - University of Science, Vietnam National University, 19 Le Thanh Tong, Hanoi 11021, Viet Nam.
  • 3 Radiology and Nuclear Medicine Department, Vinmec Times City International Hospital, Vinmec Health Care System, Hanoi 100000, Viet Nam.
  • 4 Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Shanghai Engineering Research Center of Industrial Asymmetric Catalysis of Chiral Drugs, State Key Laboratory of Green Chemical Synthesis and Conversion, Fudan University, Shanghai, China.
  • 5 Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi 11021, Viet Nam. Electronic address: [email protected].
PMID: 41580137 DOI: 10.1016/j.bmcl.2026.130560
Abstract

In this study, a series of thirty-five novel imidazolium salts bearing a 2-oxindoles were designed and synthesized as potent acetylcholinesterase (AChE) inhibitors for Alzheimer's disease. Structural diversity was introduced through substituent variation on both the oxindole and phenyl rings to investigate structure-activity relationships. All compounds were evaluated in vitro by the modified Ellman assay, revealing several highly potent inhibitors in the nanomolar to subnanomolar range. The most active compound, 32, exhibited an IC50 of 0.17 nM, surpassing galantamine and donepezil. Enzyme kinetic study indicated that all compounds act as mixed-type AChE inhibitors. Machine learning-based binding affinity predictions (ΔGML = -10.30 to -8.18 kcal/mol) correlated well with experimental activity. Molecular docking against AChE (PDB ID: 4EY6 and 7E3H) revealed that compounds bearing electron-withdrawing substituents exhibited superior binding scores and favorable interactions with key catalytic residues and aromatic residues. Molecular dynamics (200 ns) simulations demonstrated that compound 32 maintained a highly stable conformation within the AChE active site, with consistent hydrogen bonding and low root-mean-square deviation (RMSD) fluctuations. In addition, MM-PBSA binding free energy analysis (ΔGtotal = -33.42 kcal/mol) further confirmed its strong and stable interactions compared with galantamine (-17.82 kcal/mol) and donepezil (-21.20 kcal/mol). Furthermore, in silico ADME predictions suggested favorable oral absorption and potential blood-brain barrier permeability for compound 32, while maintaining an acceptable safety profile compared to galantamine and donepezil. These promising findings highlight the potential of oxindole-imidazolium hybrids as effective AChE inhibitors and warrant further investigation for the development of novel anti-Alzheimer agents.

Keywords

2-oxindoles; AChE inhibitors; Alzheimer's disease; Fragment-based drug design; Imidazolium salts.

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