Design, synthesis and biological assessment of new 1-benzyl-4-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium derivatives (BOPs) as potential dual inhibitors of acetylcholinesterase and butyrylcholinesterase

Samaneh Zarei,Mohammad Shafiei,Maryam Firouzi,Loghman Firoozpour,Kouros Divsalar,Ali Asadipour,Tahmineh Akbarzadeh,Alireza Foroumadi

doi:10.1016/j.heliyon.2021.e06683

Abstract

Alzheimer's disease (AD), is among the most growing neurodegenerative diseases, which is mainly caused by the acetylcholine neurotransmitter loss in the hippocampus and cortex. Emerging of the dual Acetylcholinesterase (AChE)/Butyrylcholinesterase (BuChE) inhibitors has increased for treating Alzheimer disease. In this study, we would like to report the design and synthesis of a new sequence of 1-benzyl-4-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium derivatives (BOPs) assessed as BuChE and AChE inhibitors. Ellman's approach was used for the evaluation of AChE and BuChE inhibitory activities. Moreover, docking research was conducted to predict the action mechanism. Among all synthesized compounds, 1-(3-bromobenzyl)-3-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium bromide (BOP-1) was found to be the most active compound with dual activity for inhibition of AChE (IC50 = 5.90 ± 0.07μM), and BuChE (IC50 = 6.76 ± 0.04μM) and 1-(4-chlorobenzyl)-3-((6,7-dimethoxy-4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium chloride (BOP-8) showed the highest AChE inhibitory activity (IC50s = 1.11 ± 0.09 μM). The synthesized compounds BOP-1 and BOP-8 could be proposed as valuable lead compounds for further drug discovery development against AD.

Highlights

Alzheimer's disease (AD) is a progressive neurodegenerative problem, prevalent in elder people [1]
Based on to the World Alzheimer Report (2019), about 50 million people were living with AD in 2019 worldwide, and it is estimated that this number will have risen to 152 million by 2050 [2]
The 1H nuclear magnetic resonance (NMR) spectra for all derivatives were documented by tetramethylsilane (TMS), which is the internal standard on a Bruker FT-500 MHz spectrometer

Summary

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative problem, prevalent in elder people [1]. Among diverse hypotheses proposed for the mechanism of AD, cholinergic hypothesis plays a determining role in leading the scientists to discover viable strategies to overcome the disease [4,5,6]. Based on this theory, a dramatic decline in the acetylcholine neurotransmitter levels in the hippocampus and cortex is accountable for memory loss, learning impairments and cognitive dysfunction [6]. Galantamine, donepezil and rivastigmine are three widely-available FDA-approved drugs for AD (Figure 1) [9] Among these drugs, Rivastigmine reveals dual inhibition against BuChE and AChE [10]. In comparison to other AChEIs, donepezil reveals higher cognitive enhancement and more desirable Pharmacokinetic, pharmacodynamic and safety profile [11]

Methods

Results

Conclusion