2. Academic Validation
  3. Design and evaluation of substituted cinnamoyl piperidinyl acetate derivatives as potent cholinesterase inhibitors

Design and evaluation of substituted cinnamoyl piperidinyl acetate derivatives as potent cholinesterase inhibitors

  • Sci Rep. 2025 Jun 2;15(1):19346. doi: 10.1038/s41598-025-04266-z.
Maryam Esmkhani 1,  Shahrzad Javanshir 2 3,  Aida Iraji 4 5,  Mohammad Mahdavi 6
Affiliations

Affiliations

  • 1 Pharmaceutical and Heterocyclic Compounds Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran.
  • 2 Pharmaceutical and Heterocyclic Compounds Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran. shjavan@iust.ac.ir.
  • 3 Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, 16846-13114, Iran. shjavan@iust.ac.ir.
  • 4 Research Center for Traditional Medicine and History of Medicine, Department of Persian Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. iraji@sums.ac.ir.
  • 5 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. iraji@sums.ac.ir.
  • 6 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
PMID: 40456843 DOI: 10.1038/s41598-025-04266-z
Abstract

In the pursuit of therapeutic agents for Alzheimer's disease (AD), this study employed a molecular hybridization strategy to design and synthesize substituted cinnamoyl piperidinyl acetates. A total of 17 novel derivatives were evaluated for their inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), key Enzymes implicated in AD pathogenesis. Notably, compound 5b, featuring a 2-chloro substitution, emerged as the most potent AChE Inhibitor (IC50 = 19.74 ± 0.96 µM), while compound 5q, possessing a 4-ethoxy-3-methoxy moiety, demonstrated superior BChE inhibition (IC50 = 13.49 ± 0.44 µM). Kinetic studies revealed mixed-type inhibition for compound 5b (Ki = 10.03 µM, Kis = 36.16 µM), and molecular docking confirmed its stable interactions with AChE's catalytic and peripheral anionic sites. These findings underscore the potential of cinnamoyl piperidinyl acetate derivatives as promising scaffolds for further optimization and development into effective AD therapeutics.

Keywords

Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitor; Cinnamoyl; Drug-Likeness; Molecular dynamics; Piperidinyl.

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