Design, synthesis and biological evaluation of 2-acetyl-5-O-(amino-alkyl)phenol derivatives as multifunctional agents for the treatment of Alzheimer's disease

Zhipei Sang; Keren Wang; Huifang Wang; Huijuan Wang; Qianwen Ma; Xue Han; Mengyao Ye; Lintao Yu; Wenmin Liu

doi:10.1016/j.bmcl.2017.09.057

Design, synthesis and biological evaluation of 2-acetyl-5-O-(amino-alkyl)phenol derivatives as multifunctional agents for the treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2017 Nov 15;27(22):5046-5052. doi: 10.1016/j.bmcl.2017.09.057. Epub 2017 Sep 28.

Authors

Zhipei Sang¹, Keren Wang², Huifang Wang³, Huijuan Wang⁴, Qianwen Ma⁴, Xue Han⁴, Mengyao Ye⁴, Lintao Yu⁴, Wenmin Liu⁵

Affiliations

¹ College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China. Electronic address: sangzhipei@126.com.
² Nanyang Normal University Hospital, Nanyang Normal University, Nanyang 473061, China.
³ Nanyang Normal University Library, Nanyang Normal University, Nanyang 473061, China.
⁴ College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China.
⁵ College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China. Electronic address: liuwm1969@163.com.

PMID: 29033233
DOI: 10.1016/j.bmcl.2017.09.057

Abstract

A series of 2-acetyl-5-O-(amino-alkyl)phenol derivatives was designed, synthesized and evaluated as multi-function inhibitors for the treatment of Alzheimer's disease (AD). The results revealed that compound TM-3 indicated selective AChE inhibitory potency (eeAChE, IC₅₀ = 0.69 μM, selective index (SI) = 32.7). Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-3 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. And TM-3 was also a highly selective MAO-B inhibitor (IC₅₀ = 6.8 μM). Moreover, TM-3 could act as antioxidant (ORAC value was 1.5eq) and neuroprotectant, as well as a selective metal chelating agent. More interestingly, compound TM-3 could cross the blood-brain barrier (BBB) in vitro and abided by Lipinski's rule of five. Therefore, compound TM-3, a promising multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against AD.

Keywords: 2-Acetyl-5-O-(amino-alkyl)phenol derivatives; Alzheimer’s disease; Blood-brain barrier; Designed; Multi-target inhibitor; Synthesized.

Publication types

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

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Alzheimer Disease / drug therapy*
Animals
Antioxidants / chemical synthesis*
Antioxidants / pharmacology
Antioxidants / therapeutic use
Benzophenones / chemical synthesis*
Benzophenones / pharmacology
Benzophenones / therapeutic use
Binding Sites
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / pharmacology
Cholinesterase Inhibitors / therapeutic use
Drug Design*
Humans
Hydrogen Peroxide / toxicity
Inhibitory Concentration 50
Molecular Docking Simulation
Monoamine Oxidase / chemistry
Monoamine Oxidase / metabolism
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / pharmacology
Neuroprotective Agents / therapeutic use*
PC12 Cells
Permeability / drug effects
Phenols / chemistry*
Phenols / pharmacology
Phenols / therapeutic use
Piperazines / chemical synthesis*
Piperazines / pharmacology
Piperazines / therapeutic use
Protein Structure, Tertiary
Rats
Structure-Activity Relationship

Substances

1-(4-(3-(4-benzylpiperazin-1-yl)propoxy)-2-hydroxyphenyl)ethan-1-one
Antioxidants
Benzophenones
Cholinesterase Inhibitors
Neuroprotective Agents
Phenols
Piperazines
Hydrogen Peroxide
Monoamine Oxidase
Acetylcholinesterase