“Click” assembly of novel dual inhibitors of AChE and MAO-B from pyridoxine derivatives for the treatment of Alzheimer’s disease

Zhao Jia,Ruijie Wang,Weiming Xue,Yane Luo,Huiyun Wen,Kaikai Wan,Saipeng Huang,Juanjuan Gao

doi:10.1515/hc-2022-0002

Zhao Jia, Ruijie Wang + Show 6 more

Open Access

https://doi.org/10.1515/hc-2022-0002

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Abstract

Abstract This study fast synthesizes numerous functionalized pyridoxines using click chemistry and assayed in vitro as inhibitors of the acetylcholinesterase (AChE), butyrylcholinesterase, and two monoamine oxidase (MAO) isoforms, MAO-A and MAO-B. Most of the obtained compounds demonstrate good AChE and selective MAO-B inhibitory activities in the micromolar range, especially one compound, called 4k5, exhibits excellent inhibitory performance against AChE (IC50 = 0.0816 ± 0.075 μM) and MAO-B (IC50 = 0.039 ± 0.003 μM). Finally, a docking study is carried out, demonstrating potential binding orientations and interactions of the compounds in terms of the AChE and MAO-B active sites.

Highlights

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder with multifaceted pathogenesis [1]
Monoamine oxidase B (MAO-B) activity is increased in association with gliosis, resulting in higher levels of H2O2 and oxidative free radicals, which are a possible source of oxidative stress for vulnerable neurons affected by AD [4]
Inhibition of AChE is considered to be a key target for effective treatment of AD because it increases the availability of synaptic ACh in brain regions [9]

Summary

Introduction

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder with multifaceted pathogenesis [1]. Acetylcholinesterase (AChE) is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter ACh in numerous cholinergic pathways in the central and peripheral nervous systems [8]. In addition to AChE, MAOs has attracted attention due to its role in the treatment of AD [10]. Inhibitors of AChe and MAO-B in the treatment of Alzheimer’s disease 19 β-phenylethylamine and benzylamine [13]. Numerous functionalized pyridoxine have been presented as potent MAO and/or AChE inhibitors, and some of them have been proposed for treating AD [17]. A series of pyridoxine derivatives are designed (Figure 1), synthesized, and the biological activities of the derivatives, including the inhibition of cholinesterase and MAO, are evaluated

Chemistry

Molecular modeling studies

Materials

Preparation of alkyne blocks

Detection of enzyme inhibition