Synthesis of aminoalkyl-substituted coumarin derivatives as acetylcholinesterase inhibitors

Seung Ok Nam; Dong Hyun Park; Young Hun Lee; Jong Hoon Ryu; Yong Sup Lee

doi:10.1016/j.bmc.2014.01.010

Synthesis of aminoalkyl-substituted coumarin derivatives as acetylcholinesterase inhibitors

Bioorg Med Chem. 2014 Feb 15;22(4):1262-7. doi: 10.1016/j.bmc.2014.01.010. Epub 2014 Jan 11.

Authors

Seung Ok Nam¹, Dong Hyun Park¹, Young Hun Lee¹, Jong Hoon Ryu², Yong Sup Lee³

Affiliations

¹ Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea.
² Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea; Department of Oriental Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Republic of Korea.
³ Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701, Republic of Korea; Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Republic of Korea. Electronic address: kyslee@khu.ac.kr.

PMID: 24485122
DOI: 10.1016/j.bmc.2014.01.010

Abstract

Alzheimer's disease, one of the most common forms of dementia, is a progressive neurodegenerative disorder symptomatically characterized by declines in memory and cognitive abilities. To date, the successful therapeutic strategy to treat AD is maintaining levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, coumarin derivatives were designed and synthesized as AChE inhibitors based on the lead structure of scopoletin. Of those synthesized, pyrrolidine-substituted coumarins 3b and 3f showed ca. 160-fold higher AChE inhibitory activities than scopoletin. These compounds also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2 mg/kg.

Keywords: Acetylcholinesterase inhibitor; Alzheimer’s disease; Coumarin; Galantamine; Memory; Scopoletin.

Publication types

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

MeSH terms

Acetylcholinesterase / chemistry*
Acetylcholinesterase / metabolism
Animals
Cholinesterase Inhibitors / chemical synthesis*
Cholinesterase Inhibitors / pharmacology
Cholinesterase Inhibitors / therapeutic use
Coumarins / chemical synthesis*
Coumarins / chemistry*
Coumarins / pharmacology
Coumarins / therapeutic use
Disease Models, Animal
Enzyme Activation / drug effects
Male
Memory / drug effects
Memory Disorders / chemically induced
Memory Disorders / drug therapy
Mice
Mice, Inbred ICR
Protein Binding
Pyrrolidines / chemical synthesis*
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Pyrrolidines / therapeutic use
Scopoletin / chemistry
Scopoletin / pharmacology
Scopoletin / therapeutic use
Structure-Activity Relationship

Substances

7-hydroxy-6-(3-(pyrrolidin-1-yl)propoxy)-2H-chromen-2-one
Cholinesterase Inhibitors
Coumarins
Pyrrolidines
coumarin
Acetylcholinesterase
Scopoletin
pyrrolidine