Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors.

Zhi-Qiang Cheng,Kongkai Zhu,Jia-Li Song,Hua Zhang,Juan Zhang,Cheng-Shi Jiang

doi:10.3390/md16090293

Zhi-Qiang Cheng, Kongkai Zhu + Show 4 more

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https://doi.org/10.3390/md16090293

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Journal: Marine Drugs	Publication Date: Aug 21, 2018
Citations: 19	License type: CC BY 4.0

Affiliation: University of Jinan, Universidade de Brasília

Abstract

A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aβ aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer’s disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development.

Highlights

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that has become the third leading death cause behind cancer and cardiovascular diseases
Cholinergic hypothesis is undoubtedly the earliest approved, which believes that increasing the level of acetylcholine (ACh) to enhance cholinergic neurotransmission in the brain is an efficacious approach for AD treatment [7]
We describe the total synthesis to the terminal quaternary amine of 1

Summary

Introduction

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that has become the third leading death cause behind cancer and cardiovascular diseases. The cause of AD is still poorly understood nowadays, many pathogenic hypotheses have been proposed over the last three decades [5,6]. Cholinergic hypothesis is undoubtedly the earliest approved, which believes that increasing the level of acetylcholine (ACh) to enhance cholinergic neurotransmission in the brain is an efficacious approach for AD treatment [7]. ACh can be hydrolyzed by two types of cholinesterase (ChE): acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) [8]. AChE is the key enzyme for the termination of neurotransmission in cholinergic pathways via its rapid hydrolysis of ACh, almost 103 -fold more active than BChE [9]

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