Ferulic acid-carbazole hybrid compounds: Combination of cholinesterase inhibition, antioxidant and neuroprotection as multifunctional anti-Alzheimer agents

Lei Fang; Mohao Chen; Zhikun Liu; Xubin Fang; Shaohua Gou; Li Chen

doi:10.1016/j.bmc.2016.01.010

Ferulic acid-carbazole hybrid compounds: Combination of cholinesterase inhibition, antioxidant and neuroprotection as multifunctional anti-Alzheimer agents

Bioorg Med Chem. 2016 Feb 15;24(4):886-93. doi: 10.1016/j.bmc.2016.01.010. Epub 2016 Jan 7.

Authors

Lei Fang¹, Mohao Chen², Zhikun Liu³, Xubin Fang², Shaohua Gou⁴, Li Chen⁵

Affiliations

¹ Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
² Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
³ Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
⁴ Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
⁵ Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: chenliduo12@gmail.com.

PMID: 26795115
DOI: 10.1016/j.bmc.2016.01.010

Abstract

In order to search for novel multifunctional anti-Alzheimer agents, a series of ferulic acid-carbazole hybrid compounds were designed and synthesized. Ellman's assay revealed that the hybrid compounds showed moderate to potent inhibitory activity against the cholinesterases. Particularly, the AChE inhibition potency of compound 5k (IC50 1.9μM) was even 5-fold higher than that of galantamine. In addition, the target compounds showed pronounced antioxidant ability and neuroprotective property, especially against the ROS-induced toxicity. Notably, the neuroprotective effect of 5k was obviously superior to that of the mixture of ferulic acid and carbazole, indicating the therapeutic effect of the hybrid compound is better than the combination administration of the corresponding mixture.

Keywords: AChE inhibitor; Anti-Alzheimer; Antioxidant; Hybrid compounds.

Publication types

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

MeSH terms

Acetylcholinesterase / chemistry*
Acetylcholinesterase / metabolism
Amino Acid Motifs
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / pharmacology
Animals
Antioxidants / chemical synthesis
Antioxidants / pharmacology*
Binding Sites
Biphenyl Compounds / antagonists & inhibitors
Carbazoles / chemical synthesis
Carbazoles / pharmacology*
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / pharmacology*
Coumaric Acids / chemical synthesis
Coumaric Acids / pharmacology*
Drug Design
Electrophorus
Galantamine / pharmacology
Hydrogen Peroxide / antagonists & inhibitors
Hydrogen Peroxide / pharmacology
Molecular Docking Simulation
Molecular Sequence Data
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / pharmacology*
PC12 Cells
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / pharmacology
Picrates / antagonists & inhibitors
Protein Binding
Rats
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Antioxidants
Biphenyl Compounds
Carbazoles
Cholinesterase Inhibitors
Coumaric Acids
Neuroprotective Agents
Peptide Fragments
Picrates
amyloid beta-protein (1-42)
Galantamine
ferulic acid
Hydrogen Peroxide
1,1-diphenyl-2-picrylhydrazyl
Acetylcholinesterase