Molecular Diversity

, Volume 22, Issue 4, pp 893–906 | Cite as

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

  • Lu Kang
  • Xiao-Hui Gao
  • Hao-Ran Liu
  • Xue Men
  • Hong-Nian Wu
  • Pei-Wu Cui
  • Eric Oldfield
  • Jian-Ye Yan
Original Article


Chalcones containing tertiary amine side-chains have potent activity as acetylcholinesterase (AChE) inhibitors. However, the effects of the location of the tertiary amine groups as well as of other groups on AChE and butyrylcholinesterase (BChE) activity have not been reported. Here, we report the synthesis and testing of 36 new coumarin–chalcone hybrids (5d7j, 9d11f, 12k13m) against AChE and BChE. The nature and position of the chalcone substituents had major effects on inhibitory activity as well as selectivity for AChE over BChE. Compounds with para-substituted chalcone fragments in which the substituents were choline-like had potent activity against AChE and poor activity against BChE, while ortho-substituted analogs exhibited an opposite effect. Replacement of the terminal amine groups by amide, alkyl or alkenyl groups abrogated activity. Compound 5e showed potent inhibitory activity \((\hbox {IC}_{50} = 0.15 \pm 0.01\, \upmu \hbox {mol}{/}\hbox {L}\)) and good selectivity for AChE over BChE (ratio 27.4), and a kinetic study showed that 5e exhibited mixed-type inhibition against AChE. Computational docking results indicate that 5e binds to Trp 279, Tyr334 and Trp 84 in AChE, but only to Trp 82 in BChE. Overall, the results show that coumarin–chalcone hybrids with choline-like side-chains have promising activity and selectivity against AChE and be promising therapeutic leads for Alzheimer’s disease.


Coumarin Chalcone Cholinesterase inhibitors Structure–activity relationship Tertiary amine group 



This work was supported by the Natural science foundation of Hu’nan Province” (Grants Nos. 2017JJ2050, 2018JJ3572) and in part by the United States Public Health Service (NIH Grant GM065307).

Supplementary material

11030_2018_9839_MOESM1_ESM.doc (14.9 mb)
Supplementary material 1 (doc 15240 KB)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of Chemistry and Chemical EngineeringHu’nan UniversityChangshaChina
  2. 2.College of PharmacyChangsha Medical UniversityChangshaChina
  3. 3.College of PharmacyHu’nan University of Chinese MedicineChangshaChina
  4. 4.Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaUSA

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