Novel cinnamic acid–tryptamine hybrids as potent butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study

Article abstract of DOI:10.1002/ardp.201800115

A novel series of cinnamic acid–tryptamine hybrids was designed, synthesized, and evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of the synthesized compounds displayed a clearly selective inhibition of butyrylcholinesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase (AChE) was detected. Among these cinnamic acid–tryptamine hybrids, compound 7d was found to be the most potent inhibitor of BChE with an IC₅₀ value of 0.55 ± 0.04 μM. This compound showed a 14-fold higher inhibitory potency than the standard drug donepezil (IC₅₀ = 7.79 ± 0.81 μM) and inhibited BChE through a mixed-type inhibition mode. Moreover, a docking study revealed that compound 7d binds to both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE. Also, compound 7d was evaluated against β-secretase, which exhibited low activity (inhibition percentage: 38%).

Full text of DOI:10.1002/ardp.201800115

Received: 11 April 2018
Revised: 28 August 2018
Accepted: 1 September 2018
|
|
DOI: 10.1002/ardp.201800115
FULL PAPER
Novel cinnamic acid–tryptamine hybrids as potent
butyrylcholinesterase inhibitors: Synthesis, biological
evaluation, and docking study
Shahrzad Ghafary1
Zahra Najafi2,3
Maryam Mohammadi-Khanaposhtani4
|
|
|
Hamid Nadri5
Najmeh Edraki6
Neda Ayashi7
Bagher Larijani7
|
|
|
|
Mohsen Amini1,8
Mohammad Mahdavi7
|
1 Faculty of Pharmacy, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
3 Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
4 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
5 Faculty of Pharmacy, Department of Medicinal Chemistry, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
6 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
7 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
8 Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
Correspondence
Abstract
Dr. Mohsen Amini, Department of Medicinal
Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran
71877, Iran.
A novel series of cinnamic acid–tryptamine hybrids was designed, synthesized, and
evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of
the synthesized compounds displayed a clearly selective inhibition of butyrylcho-
linesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase
(AChE) was detected. Among these cinnamic acid–tryptamine hybrids, compound 7d
was found to be the most potent inhibitor of BChE with an IC50 value of
0.55 0.04 μM. This compound showed a 14-fold higher inhibitory potency than the
standard drug donepezil (IC50 = 7.79 0.81 μM) and inhibited BChE through a mixed-
type inhibition mode. Moreover, a docking study revealed that compound 7d binds to
both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE.
Also, compound 7d was evaluated against β-secretase, which exhibited low activity
(inhibition percentage: 38%).
Email: moamini@tums.ac.ir
Dr. Mohammad Mahdavi, Endocrinology and
Metabolism Research Center, Endocrinology and
Metabolism Clinical Sciences Institute, Tehran
University of Medical Sciences, Tehran 11780,
Iran.
Email: momahdavi@tums.ac.ir
Funding information
Tehran University of Medical Sciences,
Grant number: 94-03-33-30167
K E Y W O R D S
Alzheimer's disease, butyrylcholinesterase inhibitors, cholinesterase inhibition, cinnamic
acid, docking study, tryptamine
impairment, memory loss, and a decline in language skills.[1] Several
hypotheses including cholinergic dysfunction, amyloid-beta peptide
|
1
INTRODUCTION
Alzheimer's disease (AD) is a complex, age-related, and neurodegen-
erative disorder that is characterized by irreversible cognitive
(Aβ) plaques, neurofibrillary tangles, and oxidative stress have been
proposed to explain the etiology of AD.[2] Acetylcholine (ACh), as a
|
Arch Pharm Chem Life Sci. 2018;351:e1800115.
wileyonlinelibrary.com/journal/ardp
© 2018 Deutsche Pharmazeutische Gesellschaft
1 of 10
https://doi.org/10.1002/ardp.201800115

2 of 10
GHAFARY ET AL.
|
neurotransmitter, plays an important role in memory and learning
processes. According to the cholinergic hypothesis, a reduction in the
ACh level in the basal forebrain leads to the genesis of AD.[3,4] This
hypothesis has been supported by observations indicating that
cholinesterase inhibitors (ChEIs) improve cognition and memory in
AD patients.
Also, recent findings have demonstrated that the formation of stable
Aβ-aggregates is accelerated by the PAS of both AChE and BChE.[14,15]
These findings have encouraged many researchers to develop BChE
inhibitors (BChEIs) as potential therapeutic agents for the treatment of
AD.[16]
Cinnamic acid derivatives are often found in some plant species and
have various pharmacological activities such as anti-inflammatory,
antioxidant, neuroprotective, and anti-amyloid aggregation activi-
ties.[17–20] Since the main pharmacological effects of these compounds
may be useful in the treatment of AD, their hybrids, especially with
anticholinesterase,arepromisingagentsasmulti-target-directedligands
(MTDLs) to treat AD.[21] Recently, Wang et al.[22] reported cinnama-
mide–dibenzylamine hybrids A with potent neurogenic, antioxidant,
cholinergic, and neuroprotective properties (Figure 1). Also, Estrada
et al.[23] synthesized a new series of cinnamic-N-benzylpiperidine
hybrids B as MTDLs for treatment of AD (Figure 1).
Therefore, one of the most important strategies in AD treatment is
to restore the levels of ACh by inhibiting ChE enzymes.[5–8] There are
two types of ChE enzymes: acetylcholinesterase (AChE, EC 3.1.1.7)
and butyrylcholinesterase (BChE, EC 3.1.1.8). AChE, unlike BChE, has a
predominant role in the hydrolysis of ACh in the central nervous
system (CNS) in healthy people. However, in patients with AD, AChE
activity in specific regions of the brain decreases, whereas BChE
activity progressively increases.[9] Therefore, concurrent inhibition of
both AChE and BChE may improve AD signs and symptoms.[10,11]
An X-ray crystallography study of AChE and BChE confirmed that
they have a long gorge with two separate ligand binding sites, including
a catalytic anionic site (CAS) and a peripheral anionic site (PAS).[12,13]
Tryptamine is a monoamine alkaloid containing an alkylindole
moiety that has been found in many complex natural products. It
FIGURE 1 Structures of some cholinesterase inhibitors bearing cinnamide (A and B), tryptamine (C and D), and newly designed hybrids
7a–l

GHAFARY ET AL.
3 of 10
|
possesses many biological activities, including hallucinogenic, neuro-
transmitter, antioxidant, antimicrobial, and antifungal activities.[24–27]
Furthermore, recently, derivatives of this scaffold such of tryptamine–
coumarin hybrids C and tryptamine–benzylpyridinium bromide hybrids
D have been reported that exhibited potent anti-AChE and -BChE
activities (Figure 1).[28,29]
191.68 ppm in the 13C NMR spectra. Moreover, trans-geometry of
the synthesized compounds was established based on 1H NMR
spectroscopy. In all of the synthesized compounds, coupling constant
between Hα and Hβ was around 16 Hz which indicated the trans-
geometry of the alkene group.
In this context and as a continuation of our previous works on the
synthesis of novel anti-AD compounds, here we designed a new series
of cinnamic acid–tryptamine hybrids 7a–l and evaluated their activity
against AChE and BChE.[30–34] Kinetic and docking studies of the
synthesized compounds were also performed.
|
2.2 AChE and BChE inhibitory activity
The in vitro AChE and BChE inhibitory activity of all compounds
7a–l were evaluated using Ellman's method[37] and compared with
donepezil as the reference drug. Their half maximal inhibitory
concentrations (IC50 values) for inhibition of AChE and BChE are
presented in Table 1. The synthesized compounds 7a–l showed
moderate AChE inhibitory activity with an IC50 ranging from
13.42 1.19 to 39.1 2.37 μM in comparison with the standard
drug, donepezil (IC50 = 0.027 0.0013 μM), but all of the
synthesized compounds, except compounds 7b and 7k, showed
more potent BChE inhibitory activity in comparison with donepezil
(IC50 = 7.79 0.81 μM).
|
2
RESULTS AND DISCUSSION
|
2.1 Chemistry
The synthetic route for the synthesis of cinnamic acid–tryptamine
hybrids 7a–l has been depicted in Scheme 1. It was started from the
reaction of 4-hydroxybenzaldehyde 1 and appropriate benzyl halide
derivatives 2a–f in the presence of potassium carbonate in DMF at
80°C to give 4-(benzyloxy)benzaldehydes 3a–f.[35] Compounds 3a–f
reacted with malonic acid 4 in the presence of pyridine and pyrrolidine
in ethanol at 110°C.[36] Treatment of the resulting cinnamic acid
derivatives 5a–f with tryptamine derivatives 6a and 6b, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDCI), and hydroxybenzotriazole
(HOBt) in acetonitrile at room temperature to give the corresponding
products 7a–l in good yields (62–84%).
Structurally, the synthesized compounds 7a–l could be divided
into two series: unsubstituted tryptamine derivatives 7a–f and
5-methoxytryptamine derivatives 7g–l.
Among the unsubstituted tryptamine derivatives 7a–f, compound
7a (IC50 = 14.93 1.13 μM) with an unsubstituted pendant benzyl
group was the most active compound against AChE. Introduction of
both electron-donating and electron-withdrawing substituents includ-
ing fluorine, chlorine, nitro, methyl, and methoxy into the 4-position of
the pendant benzyl group of compound 7a led to a reduced inhibitory
activity as observed in compounds 7b–f.
The target compounds 7a–l were fully characterized by physical
techniques. The synthesis of new cinnamic acid–tryptamine was
indicated in the FTIR spectra by the presence of strong peaks at 3224
(NH) and 1649 (CO) cm−1 that were assigned to amide group.
Moreover, the NH amide proton appeared at 8.11 ppm in the
1H NMR spectra and carbonyl amide carbon appeared at
Interestingly, 5-methoxytryptamine derivative 7g and its unsub-
stituted tryptamine analog 7a showed approximately the same
inhibitory activity against AChE. Furthermore, like the unsubstituted
tryptamine series, the insertion of various substituents at the
SCHEME 1 Reagents and conditions: (a) K2CO3/DMF/80°C, (b) pyrrolidine/pyridine/EtOH/reflux, (c) EDCI/HOBt/CH3CN/rt

4 of 10
GHAFARY ET AL.
|
TABLE 1 Cholinesterase inhibitory activity of compounds 7a–l
Compound
R1
R2
AChE inhibition IC50 (μM)a
14.93 1.13
32.17 1.24
24.7 1.11
BChE inhibition IC50 (μM)a
2.12 0.69
7a
H
H
7b
F
H
9.36 1.09
7c
Cl
H
0.89 0.0094
0.55 0.0016
7.73 0.69
7d
NO2
CH3
OCH3
H
H
34.49 1.71
39.1 2.37
7e
H
7f
H
34.95 2.42
14.18 1.23
29.67 1.91
13.42 1.19
31.45 2.47
31.85 2.68
25.11 2.38
0.027 0.0013
2.51 0.46
7g
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
–
6.63 0.94
7h
F
5.89 0.83
7i
Cl
2.86 0.67
7j
NO2
CH3
OCH3
–
4.28 0.27
7k
12.25 1.21
7.69 0.81
7l
Donepezil
7.79 0.81
aValues are the mean SD. All experiments were performed at least three times.
4-position of the pendant benzyl group in the 5-methoxytryptamine
series, except for the 4-chloro substituent (compound 7i), diminished
inhibitory activity against AChE.
In the 5-methoxytryptamine derivatives 7g–l, better anti-BChE
activities were obtained with the electron-withdrawing 4-chloro
(compound 7i), 4-nitro (compound 7j), and 4-fluoro (compound 7h)
substituents. In this series, compound 7g with an unsubstituted
pendant benzyl group and 4-methoxy compound 7l was almost as
potent as the standard drug donepezil against BChE. 4-Methyl
compound 7k exhibited the lowest anti-BChE activity among all of
the synthesized compounds.
The observed IC50 values of synthesized compounds 7a–l against
BChE revealed that the most active compounds were 4-nitro and 4-Cl
derivatives of the unsubstituted tryptamine series (compounds 7d and
7c) with an inhibitory activity 14.16- and 8.75-fold, respectively, higher
than donepezil.
In the unsubstituted tryptamine series (compounds 7a–l), com-
pound 7a with an unsubstituted pendant benzyl group, displayed good
BChE inhibitory activity with an IC50 value of 2.12 0.69 μM.
Introduction of a fluorine atom, as an electron-withdrawing group,
into the 4-position of the pendant benzyl group, as in compound 7b
(IC50 = 9.36 1.09 μM), led to a significant decrease in BChE inhibitory
activity. The replacement of fluorine with other electron-withdrawing
groups such as chlorine and nitro dramatically improved the anti-BChE
potency as observed in compounds 7c and 7d. Given these findings, it
seems that the potential for hydrophobic or hydrogen binding
interactions of chloro or nitro substituents with the active site of
BChE is more important than the electron-withdrawing effect of them.
In this context, it must be pointed out that replacement of the fluorine
atom at the 4-position of the pendant benzyl group with electron-
donatingsubstituentssuchasamethylormethoxy groupincreasedtheir
BChE inhibition potency (compounds 7b vs. 7e and 7f, respectively).
The comparison of IC50 values of the unsubstituted tryptamine
derivatives with their corresponding 5-methoxytryptamine analogs
against AChE and BChE revealed that the 5-methoxytryptamine
derivatives 7g–l exhibited slightly better AChE inhibitory activity than
their unsubstituted tryptamine analogs 7a–f, while all of the
unsubstituted tryptamine derivatives, except 4-fluoro derivative 7b,
were more active than their 5-methoxytryptamine analogs against
BChE.
|
2.3 Kinetic study of the BChE inhibition
To obtain insight into the mechanism of inhibition of BChE by the most
potent anti-BChE compound 7d, a kinetic study was performed using
Ellman's method.[38] As seen in Figure 2, graphical analysis of a
Lineweaver–Burk reciprocal plot confirmed a mixed type of inhibition.
This finding showed that compound 7d can interact with both the CAS

GHAFARY ET AL.
5 of 10
|
of this compound created the following interactions with PAS:
hydrogen bonds between 4-nitro substituent and Asn68, Ala277,
and Asn289 and a weak hydrophobic interaction between pendant
phenyl ring and Ala277. An important π–π interaction between the
phenyl ring connected to the acrylamide moiety of compound 7d and
Tyr332 of PAS was also observed.
|
2.5 Neuroprotective effect of compound 7d
The neuroprotective effect of compound 7d against H2O2-induced
oxidative stress and apoptosis in PC12 neuron cells was evaluated
using methylthiazol tetrazolium (MTT) assay (Figure 4). The differenti-
ated cells were pretreated with different concentrations of compound
7d at 1, 10, and 100 μM. As shown in Figure 4, the percent of cell
viabilities was determined in comparison to control group. Compound
7d demonstrated remarkable neuroprotective activity at 10 μM (cell
viability = 62.71 and p < 0.001 vs. H2O2 treatment alone). Statistical
analysis of the data was carried out using one-way analysis of
variance (ANOVA) and significance of the results was determined by
Tukey's test.
|
2.6 β-Secretase inhibitory activity of compound 7d
The β-secretase inhibitory activity of the compound 7d as most potent
compound against BChE was evaluated by fluorescence resonance
emission transfer (FRET) method. The kit consists of enzyme
β-secretase (BACE-1) and APP peptide-based substrate (Rh-
EVNLDAEFK-quencher) comparing with reference compound
OM99-2 (IC50 = 0.014 μM). Compound 7d displayed low activity
(inhibition percentage: 35%). OM99-2 was tested at 10, 1, and 0.1 nM
and compound 7d was tested at 10 μM.
FIGURE 2 (A) Lineweaver–Burk plot for the inhibition of BChE
by compound 7d; (B) secondary plot for steady-state inhibition
constant (Ki) of compound 7d
|
3
CONCLUSION
In the current study, a novel series of cinnamic acid–tryptamine
hybrids was designed, synthesized, and evaluated as possible AChE
and BChE inhibitors for treatment of AD. The in vitro assessment of all
compounds 7a–l revealed that the majority of compounds had
significant activity toward BChE. Among the synthesized compounds,
compound 7d displayed the highest anti-BChE activity. Kinetic analysis
studies revealed that compound 7d inhibited BChE via a mixed-type
inhibition mode. Furthermore, a molecular modeling study showed
that this compound is able to bind to both the CAS and PAS of BChE.
and PAS of BChE as a dual binding site inhibitor. The inhibition
constant (Ki = 0.4 μM) was calculated using secondary replots of the
slope versus concentrations of compound 7d.
|
2.4 Docking study
The molecular docking simulation was performed using AutoDock Vina
(AV) 1.1.1 program to study the binding mode of the most active
compound 7d in active site of BChE.[38] Several crystallographic
structures of BChE are available in the RCSB Protein Data Bank
(http://www.rcsb.org/pdb/home/home.do). Herein, PDB structure of
4BDS was retrieved for docking purpose.
|
4
EXPERIMENTAL
|
4.1 Chemistry
As depicted in Figure 3, compound 7d accepted an appropriate
orientation in the active site of BChE as the indole ring stacked with
Trp82 of CAS. Moreover, the indole moiety of compound 7d also
interacted with Glu197 and His438 of CAS. The pendant phenyl group
|
4.1.1 General
Melting points were measured on a Kofler hot stage apparatus. NMR
spectra (1H and 13C) were performed on a Bruker FT-500. IR spectra

6 of 10
GHAFARY ET AL.
|
FIGURE 3 The interaction mode of compound 7d in the active site of BChE
were recorded on a Nicolet Magna FTIR 550 spectrophotometer (KBr
The original spectra of the investigated compounds are provided
disks). Mass spectra were recorded on an Agilent Technology (HP)
mass spectrometer operating at an ionization potential of 70 eV.
Elemental analysis data were obtained from an Elementar Analy-
sensystem GmbH VarioEL CHNS mode.
as Supporting Information. The InChI codes and some biological
activity data of the investigated compounds are also provided as
Supporting Information.
|
4.1.2 General procedure for the synthesis of
compounds 3
A solution of 4-hydroxybenzaldehyde 1 (2 mmol) and potassium carbonate
(2.4 mmol) in DMF (5 mL) was stirred at 80°C for 1 h and then appropriate
benzyl halide derivative 2a–f(2.4 mmol) was added dropwise to the mixture.
After completion of the reaction (monitored by TLC), the mixture was
diluted with water. The precipitates 3a–f were filtered and washed with
water, dried, and used without further purification.
4-(Benzyloxy)benzaldehyde (3a)
White solid; yield: 89%, mp: 76–78°C. 1H NMR (DMSO, 500 MHz):
δ = 5.225 (s, 2H,CH2-O), 7.208(m,2H, H3, H5), 7.360–7.703 (m,5H,H4′,
H5′, H3′, H2′, H6′), 7.877 (m, 2H, H2, H6), 9.878 (s, 1H, H aldehyde) ppm.
13C NMR (DMSO, 125 MHz): δ = 70.129, 115.726, 128.283, 128.521,
128.957, 130.260, 132.245, 136.766, 163.750, 191.686 ppm.
|
4.1.3 General procedure for the synthesis of
compounds 5
A mixture of malonic acid 4 (5.5 mmol) and pyridine (1.25 mL) was
stirred at 110°C for several minutes. Next, compounds 3 (5 mmol),
pyrrolidine (0.05 mL) and ethanol (5 mL) were added and heated at
reflux for 24 h. After completion of the reaction (monitored by TLC),
FIGURE 4 Neuroprotective activity of compound 7d on PC12
cells against H2O2-induced cells death (***p < 0.001)

GHAFARY ET AL.
7 of 10
|
the mixture was cooled to room temperature and diluted with ice-
water. The precipitated solid was isolated by filtration, washed with
water, and dried to give compounds 5a–f.
(d, J = 7 Hz, 1H, H4″), 8.10 (t, J = 5.5 Hz, 1H, NH-CH2), 10.79 (s, 1H, NH)
ppm. 13C NMR (DMSO, 125 MHz): δ = 25.24, 39.44, 68.56, 111.39,
111.80, 115.20, 116.37, 118.19, 120.10, 120.88, 122.65, 123.40, 127.20,
127.81, 129.08, 130.02, 133.04, 136.23, 138.10, 159.20, 162.88,
165.14 ppm. Anal. calcd. for C26H23FN2O2: C, 75.34; H, 5.59; N, 6.76.
Found: C; 75.18, H, 5.41; N, 6.62.
(E)-3-(4-(Benzyloxy)phenyl)acrylic acid (5a)
White solid; yield: 84%, mp: 87–89°C. 1H NMR (DMSO, 500 MHz):
δ = 5.22 (s, 2H, CH2-O), 6.39 (d, J = 16 Hz, 1H, Hα), 7.21 (d, J = 8.5 Hz,
2H, H3, H5), 7.31–7.34 (m, 1H, H4′), 7.37–7.39 (m, 2H, H2′, H6′), 7.44–
7.48 (m, 2H, H3′, H5′), 7.57 (d, J = 16 Hz, 1H, Hβ), 7.63 (d, J = 8.5 Hz, 2H,
H2, H6), 12.26 (s. 1H, OH) ppm. 13C NMR (DMSO, 125 MHz):
δ = 70.134, 115.727, 117.138, 128.163, 128.279, 128.521, 128.906,
130.364, 136.745, 160.474, 163.750, 168.287 ppm.
(E)-N-(2-(1H-Indol-3-yl)ethyl)-3-(4-((4-chlorobenzyl)oxy)phenyl)-
acrylamide (7c)
Pale brown solid; yield: 65%, mp: 241–244°C. IR (KBr) υ: 3444.96, 3312.06,
3238.18, 3052.41, 2923.01, 1647.75, 1601.12, 1540.45, 1512.02 cm−1
.
1H NMR (DMSO, 500 MHz): δ = 2.88–2.89 (m, 2H, CH2), 3.46–3.47 (m, 2H,
CH2-NH), 5.14 (s, 2H, CH2-O), 6.49 (d, J = 16 Hz, 1H, Hα), 6.98 (t, J = 7 Hz,
1H, H5″), 7.03–7.08 (m, 3H, H6″, H3, H5), 7.16 (s, 1H, H2″), 7.34 (d, J = 8 Hz,
2H, H2′, H6′), 7.38 (d, J = 16 Hz, 1H, Hβ), 7.44–7.59 (m, 5H, H5′, H3′, H7″, H2,
H6), 7.55 (d, J = 7.5 Hz, H4″), 8.11 (t, J = 5.5 Hz, 1H, NH-CH2), 10.79 (s, 1H,
NH) ppm. 13C NMR (DMSO, 125 MHz): δ = 25.25, 39.47, 68.44, 111.41,
111.82, 115.23, 118.21, 120.14, 120.91, 122.67, 127.22, 127.89, 128.53,
128.98, 129.10, 129.59, 132.47, 135.88, 136.25, 138.11, 159.11,
165.18 ppm. Anal. calcd. for C26H23ClN2O2: C, 72.47; H, 5.38; N, 6.50.
Found: C, 72.32; H, 5.25; N, 6.36.
|
4.1.4 General procedure for the synthesis of
compounds 7a–l
A solution of compounds 5a–f (2 mmol), 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (2.4 mmol), and hydroxybenzotriazole (2.4 mmol)
in dry acetonitrile (5 mL) was stirred at room temperature for 1 h. Then,
tryptamine derivates 6a and 6b (2 mmol) were added to the mixture
and the reaction was continued at room temperature for 48 h. After
completion of reaction (checked by TLC), the solvent was reduced
under vacuum. The residue was dissolved in chloroform and washed
with aqueous sodium chloride (10%), sodium carbonate (10%), and
citric acid (10%). The organic phase was dried over Na2SO4 and the
solvent was evaporated. The obtained precipitates were recrystallized
by petroleum ether/ethyl acetate to give target compounds 7a–l.
(E)-N-(2-(1H-Indol-3-yl)ethyl)-3-(4-((4-nitrobenzyl)oxy)phenyl)-
acrylamide (7d)
Mustard color solid; yield: 62%, mp: 222–225°C. IR (KBr) υ: 3412.21,
3220.96, 3052.48, 2926.64, 2854.97, 1658.36, 1602.77, 1575.15,
.
1515.63 cm−1 1H NMR (DMSO, 500 MHz): δ = 2.88 (t, J = 6.5 Hz, 2H,
CH2), 3.46 (m, 2H, CH2-NH), 5.32 (s, 2H, CH2-O), 6.49 (d, J = 16 Hz, 1H,
Hα), 6.97 (t, J = 7.5 Hz, 1H, H5″), 7.06 (d, J = 7.5 Hz, 3H, H6″, H3,H5), 7.16
(s, 1H, H2″), 7.33 (d, J = 8 Hz, 1H, H7″), 7.38 (d, J = 15.5 Hz, 1H, Hβ), 7.51
(d, J = 8 Hz, 2H, H2, H6), 7.55 (d, J = 7.5 Hz, 1H, H4″), 7.72 (d, J = 8.5 Hz,
2H, H2′, H6′), 8.10 (t, J = 6 Hz, 1H, NH-CH2), 8.26 (d, J = 8 Hz, 2H, H5′,
H3′), 10.79 (s, 1H, NH) ppm. 13C NMR (DMSO, 125 MHz): δ = 25.23,
39.45, 68.08, 111.36, 111.79, 115.23, 118.18, 120.29, 120.87, 122.64,
123.53, 123.66, 127.19, 128.12, 128.22, 129.10, 136.22, 137.99,
144.75, 147.01, 158.8, 165.09 ppm. Anal. calcd. for C26H23N3O4: C,
70.74; H, 5.25; N, 9.52. Found: C, 70.62; H, 5.09; N, 9.36.
(E)-N-(2-(1H-Indol-3-yl)ethyl)-3-(4-(benzyloxy)phenyl)acrylamide
(7a)
Pale brown solid; yield: 68%, mp: 218–220°C. IR (KBr) υ: 3455.16,
3244.31, 3060.83, 2930.71, 2886.12, 1649.30, 1605.49, 1542.83,
.
1511.76 cm−1 1H NMR (DMSO, 500 MHz): δ = 2.87 (t, J = 7 Hz, 2H,
CH2), 3.45 (m, 2H, CH2-NH), 5.14 (s, 2H, CH2-O), 6.48 (d, J = 16 Hz, 1H,
Hα), 6.97 (t, J = 7.5 Hz, 1H, H5″), 7.03–7.07 (m, 3H, H6″, H3, H5), 7.16 (s,
1H, H2″), 7.33–7.36 (m, 3H, H4′, H7″, Hβ), 7.39 (t, J = 6.5 Hz, 2H, H5′,
H3′), 7.45 (d, J = 7.5 Hz, 2H, H2′, H6′), 7.50 (d, J = 8.5 Hz, 2H, H2, H6),
7.55 (d, J = 7.5 Hz, 1H, H4″), 8.11 (t, J = 5.5 Hz, 1H, NH-CH2), 10.80 (s,
1H, NH) ppm. 13C NMR (DMSO, 125 MHz): δ = 25.74, 39.47, 69.76,
111.81, 112.88, 115.67, 118.67, 120.53, 121.36, 123.09, 127.69,
128.08, 128.17, 128.22, 128.35, 128.91, 129.48, 136.71, 137.28,
138.53, 159.78, 165.63 ppm. Anal. calcd. for C26H24N2O2: C, 78.76; H,
6.09; N, 7.07. Found: C, 78.94; H, 6.21; N, 6.91.
(E)-N-(2-(1H-Indol-3-yl)ethyl)-3-(4-((4-methylbenzyl)oxy)phenyl)-
acrylamide (7e)
Pale brown solid; yield: 72%, mp: 228–230°C. IR (KBr) υ: 3444.33,
3233.35, 3048.71, 2924.57, 2857.63, 1646.79, 1600.92, 1540.42,
1512.87 cm−1. 1H NMR(DMSO, 500 MHz): δ = 2.31 (s, 3H, CH3), 2.89 (t,
J = 8.5 Hz, 2H, CH2), 3.48 (q, J = 7 Hz, 2H, CH2-NH), 5.09 (s, 2H, CH2-O),
6.51 (d, J = 16 Hz, 1H, Hα), 6.99 (t, J = 7.5 Hz, 1H, H5″), 7.01 (d,
(E)-N-(2-(1H-Indol-3-yl)ethyl)-3-(4-((4-fluorobenzyl)oxy)phenyl)-
acrylamide (7b)
J = 10.5 Hz,2H, H3, H5),7.08(t, J = 7 Hz, 1H,H6″),7.17–7.21(m, 3H, H2″
,
Pale brown solid; yield: 67%, mp: 232–235°C. IR (KBr) υ: 3451.14,
H3′, H5′), 7.33 (m, 3H, H2′, H6′, H7″), 7.38 (d, J = 15.5 Hz, 1H, Hβ), 4.49 (d,
J = 8.5 Hz, 2H, H2, H6), 7.65 (d, J = 7.5 Hz, 1H, H4″), 8.13 (t, J = 5 Hz, 1H,
NH-CH2), 10.82 (s, 1H, NH) ppm. 13C NMR (DMSO, 125 MHz):
δ = 21.22, 25.74, 39.47, 69.67, 111.82, 112.29, 115.68, 118.68, 118.73,
120.49, 121.37, 123.09, 127.69, 128.15, 128.26, 129.45, 134.23,
136.72, 137.60, 138.56, 159.82, 165.65 ppm. Anal. calcd. for
3228.88, 3052.65, 2928.09, 1647.29, 1601.30, 1540.88, 1512.84 cm−1
.
1H NMR (DMSO, 500 MHz): δ = 2.88 (t, J = 7 Hz, 2H, CH2), 3.46–3.47 (m,
2H, CH2-NH), 5.12 (s, 2H, CH2-O), 6.49 (d, J = 16 Hz, 1H, Hα), 6.98 (t,
J = 7 Hz, 1H, H5″), 7.04 (d, J = 8 Hz, 2H, H3, H5), 7.07 (t, J = 7.5 Hz, 2H, H5′,
H3′), 7.16 (s, 1H, H2″), 7.22 (t, J = 8.5 Hz, 1H, H6″), 7.34 (d, J = 8 Hz, 1H,
H7″), 7.38 (d, J = 16 Hz,1H,Hβ), 7.5 (d, J = 7.5 Hz, 4H, H2,H6,H2′, H6′), 7.55
C27H26N2O2: C, 79.00; H, 6.38; N, 6.82. Found: C, 78.88; H, 6.17; 6.53.

8 of 10
GHAFARY ET AL.
|
(E)-N-(2-(1H-Indol-3-yl)ethyl)-3-(4-((4-methoxybenzyl)oxy)-
phenyl)acrylamide (7f)
Hβ),7.46(m, 3H, H5′, H3′, H7″),7.49(d, J = 8.5 Hz, 2H, H2,H6),8.10(m, 1H,
NH-CH2),10.63(s, 1H, NH) ppm. 13CNMR(DMSO,125 MHz):δ = 25.25,
39.45, 55.28, 68.42, 100.19, 111.04, 111.65, 111.90, 115.20, 120.16,
123.34, 127.55, 128.43, 128.92, 129.06, 129.56, 131.37, 132.44,
135.86, 138.05, 152.95, 159.08, 165.14 ppm. Anal. calcd. for
Pale brown solid; yield: 79%, mp: 208–211°C. IR (KBr) υ: 3445.56,
3235.95, 3045.71, 2929.22, 2840.57, 1646.91, 1601.32, 1540.44,
1514.62 cm−1. 1H NMR (DMSO, 500 MHz): δ = 2.88 (m, 2H, CH2), 3.46
(m, 2H, CH2-NH), 3.75 (s, 1H, O-CH3 benzyl), 5.04 (s, 2H, CH2-O), 6.48
(d, J = 15.5 Hz, 1H, Hα), 0.94 (d, J = 7.5 Hz, 2H, H3, H5), 6.98–6.99 (m,
1H, H5″), 7.02 (d, J = 8 Hz, 2H, H5′, H3′), 7.04–7.07 (m, 1H, H6″), 7.16 (s,
1H, H2″), 7.33–7.38 (m, 4H, Hβ, H7″, H2′, H6′), 7.49 (d, J = 7.5 Hz, 2H,
H2, H6), 7.55 (d, J = 7.5 Hz, 1H, H4″), 8.10 (m,1H, 1H, NH-CH2), 10.79
(s, 1H, NH) ppm. 13C NMR (DMSO, 125 MHz): δ = 25.24, 39.45, 55.06,
69.06, 11.25, 111.80, 113.81, 115.20, 118.18, 119.95, 120.87,
122.52, 127.20, 127.61, 128.63, 129.03, 129.43, 129.57, 136.23,
138.05, 159.02, 159.37, 165.16 ppm. Anal. calcd. for C27H26N2O3: C,
76.03; H, 6.14; N, 6.57. Found: C, 75.85; H, 6.02; N, 6.43.
C27H25ClN2O3: C, 70.35; H, 5.47; N, 6.08. Found; C, 70.22; H, 5.41, N,
6.02.
(E)-N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-(4-((4-nitrobenzyl)-
oxy)phenyl)acrylamide (7j)
Mustard color solid; yield: 69%, mp: 202–204°C. IR (KBr) υ: 3444.85,
324.79, 3065.30, 2925.56, 2855.79, 1650.84, 1602.55, 1575.36,
1515.66 cm−1. 1H NMR (DMSO, 500 MHz): δ = 2.84 (t, J = 7.5 Hz, 2H,
CH2), 3.44 (m, 2H, CH2-NH), 3.74, (s, 3H, CH3-O), 5.32, (s, 1H, CH2-O),
6.49 (d, J = 16.5 Hz, 1H, Hα), 6.70 (d, J = 9 Hz, 1H, H6″), 7.03 (s, 1H, H2″),
7.06 (d, J = 7.5 Hz, 2 H, H3, H5), 7.11 (s, 1H, H4″), 7.38 (d, J = 16 Hz, 1H,
Hβ), 7.51 (d, J = 8.5 Hz, 2H, H2, H6), 7.72 (d, J = 8 Hz, 2H, H2′, H6′), 8.11
(t, J = 6 Hz, 1H, NH-CH2), 8.26 (d, J = 8 Hz, 2H, H5′, H3′), 10.63 (s, 1H,
NH) ppm. 13C NMR (DMSO, 125 MHz): δ = 25.25, 39.48, 55.29, 68.09,
100.19, 111.04, 111.65, 112.00, 115.25, 120.32, 123.53, 123.67,
127.55, 128.12, 128.23, 128.99, 131.37, 137.95, 144.76, 147.02,
152.95, 158.83, 165.12 ppm. Anal. calcd. for C27H25N3O5: C, 68.78; H,
5.34; N, 8.91. Found: C, 68.65; H, 5.14; N, 8.73.
(E)-3-(4-(Benzyloxy)phenyl)-N-(2-(5-methoxy-1H-indol-3-yl)-
ethyl)acrylamide (7g)
Pale brown solid; yield: 70%, mp: 183–186°C. IR (KBr) υ: 3448.26,
3239.91, 3062.93, 2929.12, 2871.23, 1647.32, 1601.12, 1545.36,
.
1510.95 cm−1 1H NMR (DMSO, 500 MHz): δ = 2.84 (t, J = 7 Hz, 2H,
CH2), 3.44 (m, 2H, CH2-NH), 3.74, (s, 3H, CH3-O), 5.14, (s, 1H, CH2-O),
6.48 (d, J = 16 Hz, 1H, Hα), 6.71 (d, J = 9 Hz, 1H, H6″), 7.03–7.05 (m, 3H,
H5, H3, H4″), 7.11 (s, 1H, H2″), 7.21 (d, J = 8.5 Hz, 1H, H7″), 7.31–7.35
(m, 2H, Hβ, H4′), 7.40–7.39 (m, 2H, H3′, H5′), 7.44 (d, J = 7.5 Hz, 2H, H2′,
H6′), 7.49 (d, J = 8 Hz, 2H, H2, H6), 8.11 (m, 1H, NH-CH2), 10.63 (s, 1H,
NH) ppm. Anal. calcd. for C27H26N2O3: C, 76.03; H, 6.14; N, 6.57.
Found: C, 75.86; H, 5.92; O, 11.06.
(E)-N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-(4-((4-methylbenzyl)-
oxy)phenyl)acrylamide (7k)
Pale brown solid; yield: 84%, mp: 191–193°C. IR (KBr) υ: 3452.31,
3237.96, 3056.36, 2924.08, 2855.79, 1647.13, 1603.15, 1541.69,
1512.50 cm−1 1H NMR (DMSO, 500 MHz): δ = 2.30 (s, 3H, CH3), 2.84
.
(E)-3-(4-((4-Fluorobenzyl)oxy)phenyl)-N-(2-(5-methoxy-1H-
indol-3-yl)ethyl)acrylamide (7h)
(m, 2H, CH2), 3.45 (m, 2H, CH2-NH), 3.74 (s, 3H, CH3-O), 5.08 (s, 2H, CH2-
O), 6.48 (d, J = 15.5 Hz, 1H, Hα), 6.0 (d, J = 8 Hz, 1H, H6″), 7.03 (m, 3H, H2,
H3, H5), 7.11 (s, 1H, H4″), 7.20 (m, 3H, H5′, H3′, H7″), 7.33 (d, J = 6.5 Hz, 2H,
H2′,H6′), 7.37(d, J = 16.5 Hz, 1H, Hβ), 7.48(d, J = 7 Hz,2H,H2,H6), 8.09(m,
1H, NH-CH2), 10.63 (s, 1H, NH) ppm. 13C NMR (DMSO, 125 MHz):
δ = 20.72, 25.25, 39.42, 55.28, 69.18, 100.17, 111.04, 111.65, 111.96,
115.22, 120.03, 123.28, 127.55, 127.84, 129.02, 130.04, 131.37, 133.76,
137.12, 138.10, 152.95, 159.33, 165.15 ppm. Anal. calcd. for
Pale brown solid; yield: 71%, mp: 175–178°C. IR (KBr) υ: 3449.16,
3243.01, 3060.53, 2926.78, 2876.73, 1647.32, 1603.42, 1540.26,
.
1512.60 cm−1 1H NMR (DMSO, 500 MHz): δ = 2.85 (t, J = 7 Hz, 2H,
CH2), 3.44 (m, 2H, CH2-NH), 3.74, (s, 3H, CH3-O), 5.11, (s, 1H, CH2-O),
6.49 (d, J = 16 Hz, 1H, Hα), 7.21 (d, J = 8.5 Hz, 1H, H6″),7.03 (d, J = 7 Hz,
2H, H5′, H3′), 7.04 (s, 1H, H4″), 7.12 (s, 1H, H2″), 7.19–7.24 (m, 3H, H3,
H5, H7″), 7.38 (d, J = 15.5 Hz, 1H, Hβ), 7.49 (d, J = 8 Hz, 4H, H2, H6, H2′,
H6′), 8.10 (t, J = 5.5 Hz, 1H, NH-CH2), 10.63 (s, 1H, NH) ppm. 13C NMR
(DMSO, 125 MHz): δ = 25.26, 39.40, 55.29, 68.56, 100.19, 111.05,
111.67, 111.98, 115.20, 116.38, 120.12, 123.34, 127.34, 127.81,
128.93, 130.00, 131.38, 133.03, 138.09, 152.96, 159.19, 162.74,
165.16 ppm. Anal. calcd. for C27H25FN2O3: C, 72.96; H, 5.67; N, 6.30;
O. Found: C, 72.77; H, 5.51; N, 6.07.
C28H28N2O3: C, 76.34; H, 6.41; N, 6.36. Found: C, 76.17; H, 6.25; N, 6.24.
(E)-N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)-3-(4-((4-nitrobenzyl)-
oxy)phenyl)acrylamide (7l)
Mustard color solid; yield: 69%, mp: 202–204°C. IR (KBr) υ: 3444.85,
3224.79, 3065.30, 2925.56, 2855.79, 1650.84, 1602.55, 1575.36,
1515.66 cm−1. 1H NMR (DMSO, 500 MHz): δ = 2.84 (t, J = 7.5 Hz, 2H,
CH2), 3.44 (m, 2H, CH2-NH), 3.74, (s, 3H, CH3-O), 5.32, (s, 1H, CH2-O),
6.49 (d, J = 16.5 Hz, 1H, Hα), 6.70 (d, J = 9 Hz, 1H, H6″), 7.03 (s, 1H, H2″),
7.06 (d, J = 7.5 Hz, 2H, H3, H5), 7.11 (s, 1H, H4″), 7.38 (d, J = 16 Hz, 1H,
Hβ), 7.51 (d, J = 8.5 Hz, 2H, H2, H6), 7.72 (d, J = 8 Hz, 2H, H2′, H6′), 8.11
(t, J = 6 Hz, 1H, NH-CH2), 8.26 (d, J = 8 Hz, 2H, H5′, H3′), 10.63 (s, 1H,
NH) ppm. 13C NMR (DMSO, 125 MHz): δ = 25.25, 39.48, 55.29, 68.09,
100.19, 111.04, 111.65, 112.00, 115.25, 120.32, 123.53, 123.67,
127.55, 128.12, 128.23, 128.99, 131.37, 137.95, 144.76, 147.02,
152.95, 158.83, 165.12 ppm.
(E)-3-(4-((4-Chlorobenzyl)oxy)phenyl)-N-(2-(5-methoxy-1H-
indol-3-yl)ethyl)acrylamide (7i)
Pale brown solid; yield: 69%, mp: 225–228°C. IR (KBr) υ: 3445.35,
3238.49, 3059.72, 2929.72, 1649.01, 1602.63, 1542.39, 1512.20 cm−1
1H NMR (DMSO, 500 MHz): δ = 2.85 (t, J = 6 Hz, 2H, CH2), 3.45–3.46
(m, 2H, CH2-NH), 3.74 (s, 3H, CH3-O), 5.13, (s, 1H, CH2-O), 6.49 (d,
J = 16 Hz, 1H, Hα), 6.71 (d, J = 8 Hz, 1H, H6″), 7.02–7.04 (m, 3H, H3, H5,
.
H4″),7.12(s,1H, H2″), 7.22(d, J = 8.5 Hz,2H, H2′, H6′), 7.38(d, J = 15.5 Hz,

GHAFARY ET AL.
9 of 10
|
|
4.2 AChE and BChE inhibitory activity
Discovery Studio 4.0 client software (Accelrys, Inc., San Diego, CA)
(http://accelrys.com/products/discovery-studio/).
The inhibitory potency of the target compounds on AChE and BChE
was evaluated using Ellman's method.[31] All compounds were
dissolved in 1 mL DMSO and 9 mL ethanol and then four different
concentrations (56.3, 11.3, 2.2, 0.45 μM per well) of each compound
were tested to obtain the range of 20–80% enzyme inhibition for
AChE/BChE. The reaction mixture included 2 mL phosphate buffer
(0.1 M, pH = 8.0), 65 mL of DTNB 0.1 M, 35 mL of enzyme (2 U/mL of
AChE (E.C. 3.1.1.7, Type V-S, lyophilized powder, from electric eel)
or BChE (E.C. 3.1.1.8, from equine serum)), and 35 mL of inhibitor
solution. The changing of the absorbance was measured at 412 nm for
2 min (30 s intervals) after addition of 10 mL of substrate (acetyl-
thiocholine iodide or butyrylthiocholine iodide, 0.15 M) to the reaction
mixture by a multi-well plate reader (Gen5, Power wave xs2, BioTek,
America). The IC50 values were determined graphically from inhibition
curves (log inhibitor concentration vs. percent of inhibition). All
experiments were performed in 24-well plates on a Synergy HTX
microplate reader in quadruplicates.
|
4.5 Neuroprotection assay
Neuroprotective activity wasevaluated as described in the literature.[31]
PC12 cell line was purchased from Pasteur institute. Cells were
cultivated in DMEM supplemented with 10% fetal calf serum, 5% horse
serum and antibiotics (100 units/mL penicillin, 100 µg/mL streptomy-
cin). To induce neuronal differentiation, PC12 cells were re-suspended
using trypsin/EDTA (0.25%) and seeded in 96 well culture plate (4000
cells/well) and cultured for
1 week in differentiation medium
(DMEM + 2% horse serum + NGF (100 ng/mL) + penicillin and strepto-
mycin). To evaluate the effect of compound 7d on survival rate of
neurons, the culture medium was changed to NGF-free medium and
different concentrations of candidate drug (10, 50, 100 µM) were
applied on cells. Quercetin (10 µM) was used as a positive control. The
compound 7d was diluted into DMEM and added to each well (10 µL).
Three hours later induction of ROS-mediated apoptosis was initiated by
adding the H2O2 (375 µM) to their medium and after 12 h, MTT assay
was performed. MTT solution (5 mg/mL) was added to each well in a
volume of 10 µL, and 3 h later 100 µL of the solubilization solution (10%
SDS in 0.01 M HCl (w/v)) was added into each well. The plates were
allowed to stand overnight in the incubator in a humidified atmosphere.
Absorbance at 570 nm was determined for each well using an ELISA
reader. Each experimental was performed in three replicates. All culture
media and supplements were purchased from Gibco.
|
4.3 Kinetic studies of BChE inhibition
To obtain estimates of the inhibition constant Ki and inhibition
mechanism of the synthesized compounds, reciprocal plots of 1/V
versus 1/[S] were constructed at three different concentrations of
substrate (acetylthiocholine 0.14, 0.33, 0.70 μM) by using Ellman's
method.[37] The experiments were performed as same as enzyme
inhibitionassay intriplicate. The rateofenzymeactivity wasmeasuredin
the presence of different concentrations of compound 7d as inhibitor (I)
(control = 0, [I1] = 0.319, [I2] = 0.638, and [I3] = 1.276 μM) for proposed
concentrations of substrate (acetylthiocholine 0.14, 0.33, 0.70 μM)
(Figure 2). For each experiment after adding substrate, progress curves
weremonitoredat412 nmfor 2 min. Thedoublereciprocalplots(1/Vvs.
1/[S]) wereconstructedusingthe slopesofprogresscurvestoobtainthe
type of inhibition. Then slopes of the reciprocal plots were plotted
against the concentration of inhibitor to evaluate Ki data. Data analysis
was performed with Microsoft Excel 2003.
|
4.6 β-Secretase inhibitory assay
β-Secretase inhibitory assay of the compound 7d was obtained
considering our previous work.[39]
ACKNOWLEDGMENT
This work wassupported by grants from the Research Council of Tehran
University of Medical Sciences with project No. 94-03-33-30167.
|
4.4 Docking study
CONFLICT OF INTEREST
Docking simulations for compound 7d was carried out by AutoDock
Vina (AV) 1.1.1 program.[34] The crystal structure of BChE (pdb code:
4BDS) was retrieved from Protein Data Bank. Thereafter, the water
molecules and inhibitors were removed and pdbqt structure of enzyme
was prepared by AutoDock Tools (ver 1.5.4) with default parameters.
3D structure of compound 7d was generated by MarvineSketch 5.8.3,
2012 and pdbqt structure of this compound was provided by
AutoDock Tools (ver 1.5.4). The AutoDock Vina parameters were
set as follow; box size: 50 × 50 × 50 Å, the center of box: x = 135.943,
y = 112.748, z = 40.693, the exhaustiveness: 10, and the other
parameters were left unchanged. The calculated geometries were
ranked in terms of free energy of binding and the best pose was
selected for further analysis. Molecular visualization was performed by
The authors have declared no conflicts of interest.
ORCID
Mohammad Mahdavi
http://orcid.org/0000-0002-4171-7310
REFERENCES
[1] M. Goedert, M. G. Spillantini, Science 2006, 314, 777.
[2] D. P. Perl, Mt. Sinai J. Med. 2010, 77, 32.
[3] P. Anand, B. Singh, Arch. Pharm. Res. 2013, 36, 375.
[4] A. Contestabile, Behav. Brain Res. 2011, 221, 334.

10 of 10
GHAFARY ET AL.
|
[5] N. A. Khan, I. Khan, S. Abid, S. Zaib, A. Ibrar, H. Andleeb, S. Hameed,
J. Iqbal, Med. Chem. 2018, 14, 74.
[30] M. Mohammadi-Khanaposhtani, M. Mahdavi, M. Saeedi,
R. Sabourian, M. Safavi, M. Khanavi, A. Foroumadi, A. Shafiee,
T. Akbarzadeh, Chem. Biol. Drug Des. 2015, 86, 1425.
[31] Z. Najafi, M. Mahdavi, M. Saeedi, E. Karimpour-Razkenari, R. Asatouri,
F. Vafadarnejad, F. H. Moghadam, M. Khanavi, M. Sharifzadeh,
T. Akbarzadeh, Eur. J. Med. Chem. 2017, 125, 1200.
[32] Z. Najafi, M. Mahdavi, M. Saeedi, R. Sabourian, M. Khanavi, M. Safavi,
M. Barazandeh Tehrani, A. Shafiee, A. Foroumadi, T. Akbarzadeh, Lett.
Drug Des. Discov. 2017, 14, 58.
[6] I. Khan, A. Ibrar, S. Zaib, S. Ahmad, N. Furtmann, S. Hameed,
J. Simpson, J. Bajorath, J. Iqbal, Bioorg. Med. Chem. 2014, 22,
6163.
[7] I. Khan, S. Zaib, A. Ibrar, N. H. Rama, J. Simpson, J. Iqbal, Eur. J. Med.
Chem. 2014, 78, 167.
[8] I. Khan, S. M. Bakht, A. Ibrar, S. Abbas, S. Hameed, J. M. White, U. A.
Rana, S. Zaib, M. Shahid, J. Iqbal, RSC Adv. 2015, 5, 21249.
[9] N. H. Greig, T. Utsuki, Q. Yu, X. Zhu, H. W. Holloway, T. Perry, B. Lee,
D. K. Ingram, D. K. Lahiri, Curr. Med. Res. Opin. 2001, 17, 159.
[10] R. M. Lane, S. G. Potkin, A. Enz, Int. J. Neuropsychopharmacol. 2006, 9,
101.
[33] S. Arab, S. E. Sadat-Ebrahimi, M. Mohammadi-Khanaposhtani,
A. Moradi, H. Nadri, M. Mahdavi, S. Moghimi, M. Asadi,
L. Firoozpour, M. Pirali-Hamedani, A. Shafiee, Arch. Pharm.
2015, 348, 643.
[11] W. J. Shan, L. Huang, Q. Zhou, F. C. Meng, X. S. Li, Eur. J. Med. Chem.
2011, 46, 5885.
[34] F. Mehrabi, Y. Pourshojaei, A. Moradi, M. Sharifzadeh, L. Khosravani,
R. Sabourian, S. Rahmani-Nezhad, M. Mohammadi-Khanaposhtani,
M. Mahdavi, A. Asadipour, H. R. Rahimi, Future Med. Chem. 2017, 9,
659.
[12] N. C. Inestrosa, J. P. Sagal, M. Colombres, Subcell. Biochem. 2005, 38,
299.
[13] G. A. Reid, S. Darvesh, Neuroscience 2015, 298, 424.
[14] M. Pera, A. Martinez-Otero, L. Colombo, M. Salmona, D. Ruiz-Molina,
A. Badia, Mol. Cell. Neurosci. 2009, 40, 217.
[35] B. R. Bhattarai, B. Kafle, J. S. Hwang, D. Khadka, S. M. Lee, J. S. Kang,
S. W. Ham, I. O. Han, H. Park, H. Cho, Bioorg. Med. Chem. Lett. 2009,
19, 6161.
[15] Q. Li, H. Yang, Y. Chen, H. Sun, Eur. J. Med. Chem. 2017, 26, 294.
[16] J. Wang, P. Cai, X. L. Yang, F. Li, J. J. Wu, L. Y. Kong, X. B. Wang, Eur. J.
Med. Chem. 2017, 139, 68.
[36] S. Chang, S. L. Yin, J. Wang, Y. K. Jing, J. H. Dong, Molecules 2009, 14,
4166.
[37] G. L. Ellman, K. D. Courtney, J. V. Andres, R. M. Feather-Stone,
Biochem. Pharmacol. 1961, 7, 88.
[17] B. Löser, S. O. Kruse, M. F. Melzig, Planta Med. 2000, 66, 751.
[18] M. Sova, Mini-Rev. Med. Chem. 2012, 12, 749.
[19] Y. Nakajima, M. Shimazawa, S. Mishima, H. Hara, Life Sci. 2007, 80,
370.
[38] O. Trott, A. J. Olson, J. Comput. Chem. 2010, 31, 455.
[39] B. Sameem, M. Saeedi, M. Mahdavi, H. Nadri, F. H. Moghadam,
N. Edraki, M. I. Khan, M. Amini, Bioorg. Med. Chem. 2017, 25,
3980.
[20] C. Mancuso, R. Santangelo, Food Chem. Toxicol. 2014, 65, 185.
[21] X. Zhang, X. He, Q. Chen, J. Lu, S. Rapposelli, R. Pi, Bioorg. Med. Chem.
2018, 26, 543.
[22] J. Wang, P. Cai, X. L. Yang, F. Li, J. J. Wu, L. Y. Kong, X. B. Wang, Eur. J.
Med. Chem. 2017, 139, 68.
SUPPORTING INFORMATION
[23] M. Estrada, C. Herrera-Arozamena, C. Pérez, D. Viña, A. Romero, J. A.
Morales-García, A. Pérez-Castillo, M. I. Rodríguez-Franco, Eur. J. Med.
Chem. 2016, 121, 376.
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
[24] D. Fontanilla, M. Johannessen, A. R. Hajipour, N. V. Cozzi, M. B.
Jackson, A. E. Ruoho, Science 2009, 323, 934.
[25] R. W. Fuller, Annu. Rev. Pharmacol. Toxicol. 1980, 20, 111.
[26] J. W. L. Van Anh Vo, J. H. Park, J. H. Kwon, H. J. Lee, S. S. Kim, Y. S.
Kwon, W. Chun, Biomol. Ther. 2014, 22, 200.
How to cite this article: Ghafary S, Najafi Z,
Mohammadi-Khanaposhtani M, et al. Novel cinnamic
acid–tryptamine hybrids as potent butyrylcholinesterase
inhibitors: Synthesis, biological evaluation, and docking
study. Arch Pharm Chem Life Sci. 2018;351:e1800115.
https://doi.org/10.1002/ardp.201800115
[27] T. Narasaiah, D. S. Rao, K. V. Ramana, S. Adam, C. N. Raju, Der Pharma
Chem. 2012, 4, 1582.
[28] S. Ghanei-Nasab, M. Khoobi, F. Hadizadeh, A. Marjani, A. Moradi,
H. Nadri, S. Emami, A. Foroumadi, A. Shafiee, Eur. J. Med. Chem. 2016,
121, 40.
[29] X. T. Luo, C. M. Wang, Y. Liu, Z. G. Huang, Eur. J. Med. Chem. 2015,
103, 302.