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Medicinal Chemistry Research

, Volume 23, Issue 6, pp 3178–3186 | Cite as

Synthesis and structure–activity relationship of nuciferine derivatives as potential acetylcholinesterase inhibitors

  • Zhongduo YangEmail author
  • Zhuwen Song
  • Weiwei Xue
  • Jie Sheng
  • Zongmei Shu
  • Yin Shi
  • Jibei Liang
  • Xiaojun Yao
Original Research

Abstract

Acetylcholinesterase inhibitors (AChEIs) are currently the best available pharmacotherapy for Alzheimer patients, but because of bioavailability issues, there is still great interest in discovering better AChEIs. The aporphine alkaloid is an important class of natural products, which shows diverse biological activity, such as acetylcholinesterase inhibitory activity. To find new lead AChEIs compounds, eight aporphine alkaloids were synthesized by O-dealkylation, N-dealkylation, and ring aromatization reactions using nuciferine as raw material. The anti-acetylcholinesterase activity of synthesized compounds was measured using modified Ellman’s method. The results showed that some synthesized compounds exhibited higher affinity to AChE than the parent compound nuciferine. Among these compounds, 1,2-dihydroxyaporphine (2) and dehydronuciferine (5) were the most active compounds (IC50 = 28 and 25 μg/mL, respectively). Preliminary analysis of structure–activity relationships suggested that aromatization of the C ring, the presence of the alkoxyl group at C1 and the hydroxy group at C2 position as well as the alkyl substituent at the N atom were favorable to the acetylcholinesterase inhibition. Molecular docking was also applied to predict the binding modes of compounds 1, 2, and 9 into the huperzine A binding site of AChE.

Keywords

Aporphine alkaloids Acetylcholinesterase inhibitors Structure–activity relationships 

Notes

Acknowledgments

The authors are grateful to the National Natural Science Foundation of China (No. 21262022), the Elitist Program of Lanzhou University of Technology (No. J201303) and Zhejiang Provincial Natural Science Foundation of China (No. LY12B02005). The authors also thank Miss Karen Tenney, a researcher of University of California, Santa Cruz, for revising the grammar errors

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Zhongduo Yang
    • 1
    Email author
  • Zhuwen Song
    • 1
  • Weiwei Xue
    • 2
  • Jie Sheng
    • 1
  • Zongmei Shu
    • 1
  • Yin Shi
    • 3
  • Jibei Liang
    • 1
  • Xiaojun Yao
    • 2
  1. 1.School of Life Science and EngineeringLanzhou University of TechnologyLanzhouPeople’s Republic of China
  2. 2.Department of ChemistryLanzhou UniversityLanzhouPeople’s Republic of China
  3. 3.Key Lab of New Animal Drug Project, Gansu Province, Key Lab of Veterinary Pharmaceutical Development, Ministry of AgricultureLanzhou Institute of Husbandry and Pharmaceutical Sciences of CAASLanzhouPeople’s Republic of China

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