Synthesis and evaluation of novel 1,2,3-triazole-based acetylcholinesterase inhibitors with neuroprotective activity

Jia-Cheng Li; Juan Zhang; Mosar Corrêa Rodrigues; De-Jun Ding; João Paulo Figueiró Longo; Ricardo Bentes Azevedo; Luis Alexandre Muehlmann; Cheng-Shi Jiang

doi:10.1016/j.bmcl.2016.07.017

Synthesis and evaluation of novel 1,2,3-triazole-based acetylcholinesterase inhibitors with neuroprotective activity

Bioorg Med Chem Lett. 2016 Aug 15;26(16):3881-5. doi: 10.1016/j.bmcl.2016.07.017. Epub 2016 Jul 7.

Authors

Jia-Cheng Li¹, Juan Zhang², Mosar Corrêa Rodrigues², De-Jun Ding³, João Paulo Figueiró Longo², Ricardo Bentes Azevedo², Luis Alexandre Muehlmann⁴, Cheng-Shi Jiang⁵

Affiliations

¹ Department of Pharmaceutical Engineering, School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
² Institute of Biological Sciences, University of Brasília, Brasilia 70910900, Brazil.
³ College of Pharmacy, Weifang Medical University, Weifang 261042, China.
⁴ Institute of Biological Sciences, University of Brasília, Brasilia 70910900, Brazil; Faculty of Ceilandia, University of Brasilia, Brasilia 72220-900, Brazil.
⁵ Department of Pharmaceutical Engineering, School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: jiangchengshi-20@163.com.

PMID: 27426301
DOI: 10.1016/j.bmcl.2016.07.017

Abstract

A series of new 1,2,3-triazole derivatives were synthesized and evaluated for anticholinesterase and neuroprotective activities. Some synthetic derivatives, especially compound 32, exhibited improved acetylcholinesterase (AChE) inhibitory activity by comparison with the hit 1, high selectivity toward AChE over butyrylcholinesterase (BuChE), and suitable in vitro neuroprotective effect against amyloid-β25-35 (Aβ25-35)-induced neurotoxicity in SH-SY5Y cells. Furthermore, these molecules have desired physicochemical properties in the range of CNS drugs and showed no cytotoxicity against two normal cells, including human keratinocytes HaCaT and murine fibroblasts NIH-3T3. The preliminary bioassay results and docking study indicated that compound 32 might be a promising lead compound with dual action for the treatment of Alzheimer's disease.

Keywords: 1,2,3-Triazole; Acetylcholinesterase; Alzheimer’s disease; Amyloid-β-peptide; Neuroprotective.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Amyloid beta-Peptides / toxicity
Animals
Binding Sites
Blood-Brain Barrier / metabolism
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Catalytic Domain
Cell Line
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology
Humans
Hydrogen Bonding
Mice
Molecular Docking Simulation
NIH 3T3 Cells
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology
Peptide Fragments / toxicity
Triazoles / chemical synthesis
Triazoles / chemistry*

Substances

Amyloid beta-Peptides
Cholinesterase Inhibitors
Neuroprotective Agents
Peptide Fragments
Triazoles
amyloid beta-protein (25-35)
Acetylcholinesterase
Butyrylcholinesterase