Research paperDesign, synthesis and anticholinesterase activity of novel benzylidenechroman-4-ones bearing cyclic amine side chain
Graphical abstract
A series of AChE/BuChE inhibitors namely 3-(4-(aminoalkoxy)benzylidene)-chroman-4-ones 7a-r were synthesized as homoisoflavonoid analogs. The obtained results revealed that compounds bearing piperidinylethoxy residue showed potent activity against AChE at sub-micromolar level.
Introduction
Dementia is one of the most rapidly growing diseases. The number of people living with dementia worldwide is currently estimated at 35.6 million. This number will double by 2030 and more than triple by 2050 [1], [2]. Alzheimer's disease (AD), the most common type of dementia is a progressive neurodegenerative disorder which is regarded the most common illness of over-60-year old people [3]. Although the exact cause of the disease is unknown, several factors are thought to play a role in the cause of AD. These include amyloid β (Aβ) deposits, τ-protein aggregation, oxidative stress and low levels of acetylcholine (ACh) in the hippocampus and cortex areas [4], [5]. Based on the cholinergic hypothesis, a possible cause of AD is the reduced synthesis of ACh, a neurotransmitter which is involved in memory and learning [6]. Acetylcholinesterase (AChE), is a hydrolase enzyme that hydrolyzes the neurotransmitter ACh, and serves to terminate synaptic transmission more quickly. Application of acetylcholinesterase inhibitors (AChEIs) has become the foundations for the treatment of AD. Up to now, several AChEIs have been approved for the treatment of symptomatic AD such as tacrine, donepezil, rivastigmine and galantamine (Fig. 1) [7]. However some of the limitations that exist for this drugs, including hepatoxicity, non-selectivity, poor bioavailability, adverse cholinergic side effects in the peripheral, necessitate further research in this area [8], [9].
Structurally, AChE possesses two binding sites: the catalytic active site (CAS) and the peripheral anionic site (PAS) connected by a gorge [10]. In addition, AChE interacts with β-amyloid through PAS and accelerates the formation of stable β-amyloid aggregates [11].
According to these findings, designing the new agents that are able to interact with both sites (CAS and PAS) of AChE would be an effective approach for management of AD's symptoms [12].
Flavonoids (including chalcones, flavones, flavanones, and isoflavone), and homoisoflavonoid (3-benzylidenechroman-4-ones) are well known natural products possessing a diverse pharmacological properties related to AD, such as anti-AChE activity [13], Aβ fibril formation inhibitory activity [14], MAO-B inhibitory effect [15] and neuroprotection capability [16].
In continuation of our previous studies for developing new AChE inhibitors [17], [18], [19], we designed new homoisoflavonoid derivatives by introduction of various amino alkyl groups at the para position of 7-substituted 3-benzylidenechroman-4-one. In the designed compounds, the 3-benzylidenechroman-4-one scaffold was expected to bind the PAS of AChE, and the nitrogen atom of amine side chain would interact with the catalytic site of AChE. The cyclic aminoalkoxyphenyl part of designed molecule is found in some reported AChE inhibitors as exemplified by ebselen analog (Fig. 2) [20].
Section snippets
Chemistry
The synthesis of target compounds 7a-r was accomplished using the pathways illustrated in Scheme 1. The aldehyde intermediates 2a,b and 4a-c were prepared starting from 4-hydroxybenzaldehyde (1). The reaction of compound 1 with proper aminoethyl chloride in the presence of K2CO3 and KI in CH3CN afforded corresponding O-alkylated derivatives 2a,b. On the other hand, O-alkylation of compound 1 with 1-bromo-3-chloropropane gave 3-chloropropoxy analog 3. Subsequently, the reaction of appropriate
Cholinesterase inhibitory activity
The in vitro anti-cholinesterase activity of designed compounds 7a-r was evaluated against AChE and BuChE, in comparison with tacrine as reference drug. The IC50 values of compounds are listed in Table 1. The obtained IC50 values against AChE demonstrated that most compounds had potent inhibitory activity. Among them, the piperidinylethoxy derivatives 7d, 7f, 7j and 7p with IC50 values of 0.122–0.207 μM were more potent than standard drug tacrine against AChE.
In general, compounds with two
Conclusion
Since the homoisoflavonoids (3-benzylidenechroman-4-ones) were well known natural products with diverse pharmacological properties related to AD, we designed a series of 3-(4-(aminoalkoxy)benzylidene)-chroman-4-ones 7a-r as potent AChE inhibitors. The in vitro anti-cholinesterase activity of designed compounds 7a-r against AChE and BuChE, revealed that compounds bearing piperidinylethoxy residue showed high activity against AChE at sub-micromolar level (IC50 values = 0.122–0.207 μM), more
Chemistry
Melting points of compounds are determined using Kofler hot stag apparatus and are uncorrected. IR spectra were taken using Nicolet FT-IR Magna 550 spectrographs (KBr disks). The NMR spectra were recorded by using Bruker 400 or 500 spectrometers. The chemical shifts (δ) are reported in part per million (ppm) down field from TMS as internal standard. Coupling constant (J) values are presented in Hz and spin multiplicities are given as follows: s (singlet), d (doublet), t (triplet), m
Acknowledgments
This research has been supported by grants from the Research Council of Tehran University of Medical Sciences and Iran National Science Foundation (INSF).
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