Synthesis and In Vitro Screening of Novel Heterocyclic β-d-Gluco- and β-d-Galactoconjugates as Butyrylcholinesterase Inhibitors.

Krešimir Baumann,Marko Močibob,Lorena Kordić,Srđanka Tomić,Goran Šinko

doi:10.3390/molecules24152833

Abstract

The development of selective butyrylcholinesterase (BChE) inhibitors may improve the treatment of Alzheimer’s disease by increasing lower synaptic levels of the neurotransmitter acetylcholine, which is hydrolysed by acetylcholinesterase, as well as by overexpressed BChE. An increase in the synaptic levels of acetylcholine leads to normal cholinergic neurotransmission and improved cognitive functions. A series of 14 novel heterocyclic β-d-gluco- and β-d-galactoconjugates were designed and screened for inhibitory activity against BChE. In the kinetic studies, 4 out of 14 compounds showed an inhibitory effect towards BChE, with benzimidazolium and 1-benzylbenzimidazolium substituted β-d-gluco- and β-d-galacto-derivatives in a 10–50 micromolar range. The analysis performed by molecular modelling indicated key residues of the BChE active site, which contributed to a higher affinity toward the selected compounds. Sugar moiety in the inhibitor should enable better blood–brain barrier permeability, and thus increase bioavailability in the central nervous system of these compounds.

Highlights

Alzheimer’s disease (AD) is a chronic and progressive age-related neurological disorder, and the most common form of dementia in the industrialised part of the world
The analysis performed by molecular modelling indicated key residues of the BChE active site, which contributed to a higher affinity toward the selected compounds
The development of AD is related to several abnormal elements, such as the aggregation of neurofibrillary tangles (NFTs), senile, tau and β-amyloid plaques, and, exposure to aluminium and brain inflammation [2]

Summary

Introduction

Alzheimer’s disease (AD) is a chronic and progressive age-related neurological disorder, and the most common form of dementia in the industrialised part of the world. The development of AD is related to several abnormal elements, such as the aggregation of neurofibrillary tangles (NFTs), senile, tau and β-amyloid plaques, and, exposure to aluminium and brain inflammation [2]. Genetic factors that play a significant role in AD progression are associated with the brain-derived neurotrophic factor (BDNF) and butyrylcholinesterase gene (BCHE) [3]. It has been reported that cholinesterases, butyrylcholinesterase (BChE, EC 3.1.1.8.), are associated with the pathogenesis and progression of AD [5,6]. Neurofibrillary tangles and β-amyloid plaques accumulate in brain cells, resulting in the loss of cholinergic neurons [1,7]. BChE inhibitors may have a greater role in the treatment of AD in the future. Though a cure has not yet been found, cholinesterase inhibitors (ChEI) have been used as an effective palliative treatment for AD symptoms

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