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Medicinal Chemistry Research

, Volume 28, Issue 10, pp 1683–1693 | Cite as

Synthesis, in vitro assays, molecular docking, theoretical ADMET prediction, and evaluation of 4-methoxy-phenylthiazole-2-amine derivatives as acetylcholinesterase inhibitors

  • Xiao-Zhong Zhang
  • Yuan Xu
  • Meng-Meng Jian
  • Kan Yang
  • Zheng-Yue MaEmail author
Original Research
  • 42 Downloads

Abstract

Based on the cholinergic hypothesis of the reported compound, N-(4-(4-methoxy-phenyl)thiazol-2-yl)-3-(pyrrolidin-1-yl)propionamide, which had a good inhibitory activity to acetylcholinesterase (AChE), the new 4-methoxy-phenylthiazole-2-amine derivatives as AChE inhibitors (AChEIs) have been designed and synthesized in this study. Their chemical structures were confirmed by proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance, mass spectrometry, and infrared. Furthermore, their inhibitory activities against AChE in vitro were also tested by Ellman spectrophotometry, and the inhibitory activity test results showed that most of the compounds of 4-methoxy-phenylthiazole-2-amine derivatives had a certain AChE inhibitory activity in vitro, and the IC50 (half-maximal inhibitory concentration) value of compound 5g was 5.84 μmol/L, which was higher than that of the reference compound, rivastigmine. Moreover, it had almost no inhibitory effect on butyrylcholinesterase. In addition, compound 5g was subjected to enzyme inhibition kinetics experiments, and the result of Lineweaver–Burk’s V−1–[S]−1 double-reciprocal plot showed that the acting type of compound 5g was mixed inhibition type. Furthermore, the AChE inhibitory activity mechanism of compound 5g was explored by the conformational analysis and molecular docking, which was based on the principle of the four-point pharmacophore model necessary for AChE inhibition. Finally, in silico molecular property and ADMET (absorption, distribution, metabolism, excretion, and toxicity) of the synthesized compounds were predicted by using Molinspiration and PreADMET online servers, respectively. It can be concluded that the lead AChEI compound 5g presented satisfactory drug-like characteristics and ADME properties.

Keywords

Acetylcholinesterase (AChE) Phenylthiazole Molecular docking AutoDock ADMET 

Notes

Acknowledgements

This work was supported by grants from Natural Science Foundation of Hebei Province (No. H2017201075).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Xiao-Zhong Zhang
    • 1
  • Yuan Xu
    • 1
  • Meng-Meng Jian
    • 1
  • Kan Yang
    • 1
  • Zheng-Yue Ma
    • 1
    Email author
  1. 1.Key laboratory of Drug Quality Control of Hebei Province, College of pharmaceutical scienceHebei UniversityBaodingChina

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