Novel ferulic amide derivatives with tertiary amine side chain as acetylcholinesterase and butyrylcholinesterase inhibitors: The influence of carbon spacer length, alkylamine and aromatic group

Article abstract of DOI:10.1016/j.ejmech.2016.12.003

Based on our recent investigations on chalcone derivatives as AChE inhibitors, a series of ferulic acid (FA) tertiary amine derivatives similar to chalcone compounds were designed and synthesized. The results of bioactivity evaluation revealed that most of new synthesized compounds had comparable or more potent AChE inhibitory activity than the control drug Rivastigmine. The alteration of carbon chain linking tertiary amine groups and ferulic acid scaffold markedly influenced the inhibition activity against AChE. Among them the inhibitory activity of compound 6d (IC₅₀: 0.71 ± 0.09 μmol/L) and 6e (IC₅₀: 1.11 ± 0.17 μmol/L) was equal to 15-fold and 9-fold than that of Rivastigmine against AChE (IC₅₀: 10.54 ± 0.86 μmol/L), respectively. Moreover, compound 6d shows the highest selectivity for AChE over butyrylcholinesterase(BuChE) (ratio: 18.3). The kinetic study suggested that compound 6d revealed a mixed-type inhibition against AChE. The result of molecular docking showed that compound 6d combines to AChE with three amino acid sites(Trp84, Tyr334 and Trp279), while combines to BuChE with two amino acid sites (Tyr67 and Gly66) in enzyme domains, respectively. Compound 6d might act as a potential agent for the treatment of Alzheimer's diseases (AD).

Full text of DOI:10.1016/j.ejmech.2016.12.003

European Journal of Medicinal Chemistry 126 (2017) 810e822
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Novel ferulic amide derivatives with tertiary amine side chain as
acetylcholinesterase and butyrylcholinesterase inhibitors: The
influence of carbon spacer length, alkylamine and aromatic group
,
Haoran Liu a, Linbo Liu a, Xiaohui Gao b, Yingzi Liu c *, Wanjun Xu c, Wei He c, Hong Jiang c,
Jingjing Tang a, Haoqun Fan a, Xinhua Xia b
a College of Chemistry and Chemical Engineering, Hu'nan University, Changsha 410082, China
b College of Pharmacy, Hu'nan University of Chinese Medicine, Changsha 410208, China
c College of Medicine, Hu'nan Normal University, Changsha 410013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on our recent investigations on chalcone derivatives as AChE inhibitors, a series of ferulic acid (FA)
tertiary amine derivatives similar to chalcone compounds were designed and synthesized. The results of
bioactivity evaluation revealed that most of new synthesized compounds had comparable or more
potent AChE inhibitory activity than the control drug Rivastigmine. The alteration of carbon chain linking
tertiary amine groups and ferulic acid scaffold markedly influenced the inhibition activity against AChE.
Received 16 September 2016
Received in revised form
20 November 2016
Accepted 1 December 2016
Available online 2 December 2016
Among them the inhibitory activity of compound 6d (IC50: 0.71
1.11 0.17 mol/L) was equal to 15-fold and 9-fold than that of Rivastigmine against AChE (IC50
10.54 0.86
0.09
m
mol/L) and 6e (IC50
:
:
m
m
Keywords:
Alzheimer's disease
Ferulic acid
Acetylcholinesterases
Molecular docking
a,b-Unsaturated carbonyl
mol/L), respectively. Moreover, compound 6d shows the highest selectivity for AChE over
butyrylcholinesterase(BuChE) (ratio: 18.3). The kinetic study suggested that compound 6d revealed a
mixed-type inhibition against AChE. The result of molecular docking showed that compound 6d com-
bines to AChE with three amino acid sites(Trp84, Tyr334 and Trp279), while combines to BuChE with two
amino acid sites (Tyr67 and Gly66) in enzyme domains, respectively. Compound 6d might act as a po-
tential agent for the treatment of Alzheimer's diseases (AD).
© 2016 Published by Elsevier Masson SAS.
1. Introduction
that the presence of an a,b-unsaturated carbonyl group in chalcone
scaffold was essential for AChE inhibitory activity.
Ferulic acid, a natural product containing a,b-unsaturated
Chalcone, a special natural product containing
a
,b
-unsaturated
carbonyl group, is thought as a reasonable scaffold to develop novel
drugs via structure modification [1e3]. AChE inhibitors from nat-
ural products or their derivatives are considered as possible new
resources for the treatment of Alzheirmer's diseases (AD). In our
laboratory more than one hundred Mannich base derivatives
originated from natural products were screening for the bioactivity
in inhibiting AChE in the past several years. Fortunately Fla-
vokawain Mannich base derivatives containing chalcone scaffold
were discovered with potent AChE inhibiting effect two years ago
[4]. Afterwards, a lot of chalcone nitrogen-containing derivatives
were synthesized and confirmed as potent AChE inhibitors in our
further investigations [5e7]. According to these results, it seemed
carbonyl group, had versatile application prospects in medicine
[8e10]. In the present investigation, a series of ferulic acid benza-
mide derivatives coupled with tertiary amines side chain were
synthesized, and evaluated the biological activity in inhibiting
AChE and BuChE. In order to explore whether the benzamide
groups were essential for the bioactivity, some ferulic acid ester or
free ferulic acid derivatives were synthesized and evaluated,
compared with that of ferulic acid benzamide derivatives (Fig. 1).
For the purpose of exploring the inhibition profile and mechanism,
enzyme kinetic and molecular docking studies were carried out.
2. Results and discussion
2.1. Chemistry
* Corresponding author.
E-mail address: liuyingzi111@sina.com (Y. Liu).
In the beginning the amide derivative of ferulic acid (compound
http://dx.doi.org/10.1016/j.ejmech.2016.12.003
0223-5234/© 2016 Published by Elsevier Masson SAS.

H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
811
Fig. 1. Design strategy of the ferulic acid derivatives.
5) was planned to synthesize from ferulic acid and phenylamine
2.2. In vitro inhibition against AChE and BuChE
directly, but only poor-yield product was gained. Then it was syn-
thesized from ferulic acid chloride as the intermediate, but the
impurity of the final product is not easy to remove. So new syn-
thesis route was applied to prepared acetyl ferulic acid(compound
2) firstly [11], and then acetyl ferulic acid chloride (compound 3)
was synthesized as an intermediate to gain compound 4 with
previous reported method [12,13]. Finally, the acetyl group was
hydrolyzed by ammonium hydroxide at room temperature to
achieve compound 5 with a good yield. The synthesis route above is
summarized in Scheme 1.
Compounds 2b-2e were generated by compound 5 with four
commercially available compounds (chloroethyldimethylamine
hydrochloride, chloroethyldiethylamine hydrochloride, chlor-
oethylpiperidine hydrochloride, or chloroethylpyrrolidine hydro-
chloride) in the presence of K2CO3 and NaI. Then compounds 3b-8e
were synthesized from compounds 3a-8a which were prepared
from compound 5 with different dibromoalkanes (Scheme 1).
In order to further investigate the influence of benzamide group
in inhibiting AChE, the derivatives of four compounds possessing
higher AChE inhibitory activity (compounds 6c, 7c, 6d and 6e) were
synthesized by removing benzamide group or introducing ethyl
ester group,respectively (Scheme 2).
The half maximal inhibitory concentration (IC50 values) of new
synthesized compounds in inhibiting AChE and BuChE as well as
the selectivity for AChE were shown in Table 1. The results revealed
that all of test compounds showed perfect inhibition activity
against AChE and BuChE, compared to compound
(IC50 > 500 mol/L).
5
m
The variation of the spacer linking ferulic acid scaffold and ter-
minal amine groups dramatically influenced the anti-
cholinesterase activity (Table 1). The compounds with six methy-
lenes spacer showed better inhibition activity against AChE (6b:
8.40 0.09; 6c: 1.83 0.22; 6d: 0.71 0.09; 6e: 1.11 0.17 mmol/L)
than the others. The inhibitory activity against AChE also markedly
changed with the alteration of tertiary amine groups. For com-
pounds with the same methylene spacer, most compounds con-
taining piperidine group have more potent inhibition activity
against AChE than other derivatives. But for those compounds with
eight or ten methylenes spacer, the compounds containing dime-
thylamine or diethylamine group (compounds 7c and 8b)
possessed higher activity than the others (Table 1).
Among new synthesized compounds, nine compounds showed
better inhibitory activity (IC50 ¼ 0.71e8.40
drug Rivastigmine (IC50: 10.54 mol/L). The most promising com-
pound 6d (IC50: 0.71 0.09 mol/L) and 6e (IC50: 1.11 0.17 mol/L)
mmol/L) than the control
The final products were purified by silica gel chromatog-
raphy. The structures of the compounds were characterized by
proton nuclear magnetic resonance spectroscopy (1H NMR, 13C
NMR), infrared spectrum (IR) and mass spectrum (MS). Repre-
sentative 1H and 13C NMR spectra were outlined in Supplement
Materials.
m
m
m
possessed 15-fold or 9-fold of inhibitory activity against AChE than
that of Rivastigmine, respectively. Moreover, compound 6d showed
the highest selectivity for AChE over BuChE (IC50
12.97 0.13 mol/L; ratio: 18.3).
Among new synthesized compounds, compounds 6c, 7c, 6d and
:
m

812
H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
Scheme 1. Synthesis route of the tertiary derivatives of ferulic acid phenylamine. Reagents and conditions: (a) acetic anhydride, NaOH(aq), HCl(aq), RT; (b) oxalyl chloride, DMF,
DCM, 40 ꢀC; (c) aniline, TEA, acetonitrile, 60 ꢀC; (d) ammonium hydroxide, ethanol, RT; (e) R1R2N(CH2)2Cl, K2CO3, NaI, acetone, reflux; (f) Br(CH2)nBr, K2CO3, NaI, acetone, reflux; (g)
second amine, K2CO3, NaI, acetone, reflux.
6e had higher inhibitory activity against AChE. Further study
showed that if the benzamide group was removed or replaced by
ethyl ester group, the activity in inhibiting AChE decreased signif-
icantly. This result suggested that an aromatic group such as ben-
zamide group was possible important for the activity in inhibiting
AChE.
In order to study whether the new synthesized compounds had
specific inhibitory activity on cholinesterases, the effects of these
compounds on carboxylesterase(CaE) was assayed. CaE is thought
to detoxicate ester-containing xenobiotics, and the inhibition of CaE
could lead to the enhancing toxicity of some exogenous substances
[14]. The data showed that all the compounds exhibited high spe-
for the development of potent or selective AChE inhibitors for
the further.
2.3. LogP measurement
Log P was an important physical chemistry parameter to predict
the ability to cross blood brain barrier (BBB), and the optimum logP
of compounds for central nervous system (CNS) penetration was
around 2 0.7 according to the report [19]. As shown in Table 1, log
P values of new synthesized compounds ranged from 1.29 to 1.98,
which suggested that most of the compounds possess enough lip-
ophilicify to pass the BBB in vivo.
cific inhibition against cholinesterase over CaE (IC50 > 500
mmol/L)
compared
IC50 ¼ 31.1 1.20
to
control
mol/L).
drug
Rivastigmine
(for CaE
2.4. Kinetic studies
m
Some previous investigations reported some ferulic acid de-
rivatives incorporated with structure fragment of clinic applied
drugs such as Tarcine or Donepezil revealed AChE inhibitory
activity, but no detail structure-activity relationship study was
carried out further [15e18]. In the present investigation, primary
structure-activity relationship about ferulic acid derivatives as
AChE inhibitors was elucidated, which was possible beneficial
Compound 6d was selected for kinetic study to evaluate the
profile in inhibiting AChE. The linear LineweavereBurk equation
was applied in this experiment. The graphical analysis of the
steady-state inhibition data of compound 6d was shown in
Supplement Fig. 2. According to the analysis, the kinetic profile of
compound 6d revealed a mixed-type inhibition. It suggested that
compound 6d could bind with the catalytic site and the non-

H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
813
Scheme 2. Synthesis route of the tertiary amine derivatives of ferulic acid and ethyl ferulate. Reagents and conditions: (h) acetylchloride, absolute ethanol, RT; (i) Br(CH2)nBr, K2CO3,
NaI, acetone, reflux; (j) second amine, K2CO3, NaI, acetone, reflux; (k) 10%NaOH, ethanol, RT.
catalytic site of the AChE with different equilibrium constants, and
the competitive constant (Ki) and the non-competitive constant
(Ki’) are 0.48 and 0.92 mmol/L, respectively (Supplement Table 2).
tertiary amines side chain were synthesized and evaluated in
inhibiting AChE and BuChE. The alteration of carbon chain linking
side chain and ferulic acid scaffold as well as the difference of
tertiary amine side chain markedly influenced the inhibition ac-
tivity against AChE. Among them, compound 6d with IC50 value of
2.5. Molecular modeling studies
0.71
0.09 mmol/L exhibited the best inhibitory effect and the
highest selectivity for AChE over BuChE. Further study showed that
If the benzamide group in compound 6d was removed or replaced
by ethyl ester group, the inhibitory activity against AChE would
decrease by 3.7 or 64 folds, respectively. Enzyme kinetic and mo-
lecular docking study revealed that compound 6d presented a
mixed-type inhibition against AChE. It might act as a potential
agent for the treatment of AD.
In order to explore possible binding mechanism to AChE and
BuChE, a further computational study was performed for com-
pound 6d using Molecular Operating Environment (MOE). The re-
sults from the docking on AChE and BuChE illustrated in
Supplement Fig. 3. The results showed that Compound 6d bind
with AChE via multiple sites. The quaternary nitrogen of piperidine
ring binds to the catalytic active site (CAS) via the
p-cation inter-
action with Trp84 (4.21 Å), and. the aromatic rings at the top of
peripheral anionic site (PAS) interact with Tyr334 (4.26 Å) and
4. Experimental
Trp279 (4.07 Å) through a
p-p stacking effect (Supplement Fig. 3,
A). While compound 6d revealed a weaker affinity in binding to
4.1. Chemistry
BuChE, only.Gly66 (4.15 Å) and Tyr67 (4.07 Å) combined with
1H NMR spectra were recorded on a Bruker 400 MHz instrument
using trimethylsilyl (TMS) as the internal standard. Mass spectra
were obtained by Finnigan LCQ Advantage MAX with electrospray
ionization (ESI-MS) method. Infrared spectrum was obtained by
Shimadzu Infinity-1 infrared spectrometer. The purity of com-
pounds was checked by Shimadzu LC-20A high performance liquid
chromatography. The melting points were measured by a WRS-lA
melting point detector. All chemicals and reagents were of
analytical reagent grade and used without further purification.
BuChE via a
p-cation interaction (Supplement Fig. 3, B). Based on
these results above, the weak affinity of compound 6d binding to
BuChE may be partially explained the high selectivity in inhibiting
AChE.
3. Conclusions
Based on our investigations of chalcone derivatives as AChE
inhibitors, a series of novel ferulic acid amide derivatives with

814
H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
Table 1
Cholinesterase inhibitory activity and selectivity of synthesized compounds.
Selective for AChEb
logP
a
Compound
R
n
IC50
CaE
(
m
mol/L)
AChE
BuChE
5
2b
3b
4b
5b
6b
7b
8b
2c
3c
4c
5c
6c
7c
8c
9c
11c
10c
12c
2d
3d
4d
5d
6d
7d
8d
9d
11d
2e
3e
4e
5e
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
e
1.42
1.50
1.55
1.57
1.61
1.69
1.74
1.80
1.53
1.57
1.59
1.63
1.70
1.75
1.83
1.80
1.29
1.98
1.51
1.56
1.58
1.61
1.65
1.77
1.79
1.83
1.81
1.32
1.54
1.57
1.60
1.64
1.76
1.78
1.86
1.82
1.29
1.68
2
3
4
5
6
8
10
2
3
4
5
6
8
10
6
6
8
8
2
3
4
5
6
8
10
6
6
2
3
4
5
6
8
10
6
6
23.20 0.44
33.86 0.55
100.50 1.92
33.02 3.29
8.40 0.09
8.95 0.19
9.93 0.46
41.06 0.08
23.72 2.26
41.63 1.42
18.98 2.74
1.83 0.22
1.36 0.10
14.92 0.83
1.94 0.12
2.67 0.15
1.56 0.27
3.18 0.29
19.40 1.10
14.48 1.82
7.14 0.18
4.80 0.31
0.71 0.08
4.12 0.28
11.11 0.83
2.65 0.33
45.55 1.42
35.13 0.33
37.14 2.84
24.35 1.58
6.21 0.45
1.11 0.17
2.91 0.07
13.52 0.65
5.05 0.35
69.91 4.90
10.54 0.86
23.28 0.44
20.02 0.86
25.90 0.28
12.08 0.26
6.72 0.59
10.41 0.51
20.58 1.04
11.46 0.01
16.88 0.50
25.07 1.78
22.15 0.64
4.86 0.28
3.98 0.26
8.47 0.38
11.38 1.06
263.11 1.88
13.05 1.71
302.45 2.16
2.34 0.15
4.78 0.76
5.69 0.01
5.90 0.67
12.97 0.13
5.45 0.49
4.84 0.64
41.76 1.23
145.69 2.94
12.68 1.12
14.19 0.70
3.83 0.42
4.78 0.35
2.23 0.18
4.03 0.09
2.99 0.07
376.71 1.83
286.72 2.16
0.26 0.08
1.00
0.59
0.26
0.37
0.80
1.16
2.07
0.28
0.71
0.60
1.17
2.66
2.93
0.57
5.87
98.6
8.37
95.1
0.12
0.33
0.80
1.23
18.3
1.32
0.44
15.8
3.20
0.36
0.38
0.16
0.77
2.01
1.38
0.22
74.6
4.10
0.02
6e
7e
8e
9e
11e
Rivastigminec
e
e
31.12 1.21
a
IC50: 50% inhibitory concentration (means SD of three experiments).
Selectivity for AChE is defined as IC50 (BuChE)/IC50 (AChE).
Used for positive control.
b
c
4.2. Synthesis of (E)-3-(4-acetoxy-3-methoxyphenyl) acrylic acid
(2)
4.4. (E)-2-methoxy-4-(3-oxo-3-(phenylamino)prop-1-en-1-yl)
phenyl acetate(4)
Ferulic acid (1) (3.88 g, 20 mmol) was added into 10% NaOH
solution (20 mL), then the mixture was place in ice bath, adding
acetic anhydride (2.54 g, 25 mmol). The mixture was stirred
keeping at 20 ꢀC for 10 min and placed at room temperature for
20 min. Then the pH value was adjusted to 4e5 by adding dilute
hydrochloric acid. The mixture was filtered and the precipitate was
gained after washing by water. Finally compound 2 (colorless
needles crystal, 3.12 g, yield 66%) was gained by re-crystallization
from ethanol.
Phenylamine (1 mL, 11 mmol) was dropped slowly to a solution
of compound 3 (2.5 g, 10 mmol) in acetonitrile (20 mL) in ice bath.
The mixture was stirred for 8 h at room temperature until the re-
action was completed. After the solvent was removed under
reduced pressure, the light yellow viscous liquid was obtained, and
this material was used for the next reaction without further
purification.
4.5. (E)-3-(4-hydroxy-3-methoxyphenyl)-N-phenylacrylamide(5)
Compound 4 was hydrolyzed by ammonium hydroxide. After
the solvent was removed under reduced pressure, the crude
product was added into 20% sodium hydroxide solution. The so-
lution was cooled to 5e6ꢀС and then filtered. A solution containing
10% hydrochloric acid was slowly added to the filtrate, adjusting the
pH of solution to 3e4, and the yellow precipitate produced with a
yield of 55%, which was proved as the intermediate compound 5.
4.3. (E)-4-(3-chloro-3-oxoprop-1-en-1-yl)-2-methoxyphenyl
acetate (3)
Oxalyl chloride (2.55 mL, 30 mmol) was added to a suspension
of compound 2 (2.36 g, 10 mmol) in CH2Cl2 (40 mL) containing a
catalytic amount of dimethylformamide (DMF). The mixture was
refluxed and stirred for 6 h. After the solvent and excess oxalyl
chloride was removed under reduced pressure, pale yellow crystals
were obtained. This material was used directly for the next reaction
without further purification.
4.6. General procedure for the synthesis of 2be2e
The mixture containing compound 5 (1.5 mmol), K2CO3 (1.055 g,

H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
815
7.5 mmol) and NaI (0.012 g, 0.05 mmol) in acetone (20 mL) was
stirred for 30 min at 56ꢀС, then aminoethyl chloride (4.5 mmol)
were added into the mixture and kept refluxing for 10 h until the
reaction was completed. Then the reaction mixture was cooled to
room temperature and filtered. The filtrate was concentrated under
reduced pressure and partitioned between brine and CH2Cl2. The
separated organic phase was washed by 10% NaOH, dried with
anhydrous Na2SO4. After the solvent was removed in vacuum, the
crude product was gained and purified by silica-gel column chro-
matography with methanol/dichloromethane as eluting solution.
Compound 2b-2e was gained with the yield of 45e60%,
respectively.
pyrrolidine-H), 3.82 (3H, s, OCH3), 4.02e4.06 (2H, t, J ¼ 12.0 Hz,
OCH2CH2), 6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.02e7.07
(2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H),
7.30e7.34 (2H, t, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-
CH¼CH), 7.68e7.70 (2H, d, 8.0 Hz, Ar-H), 10.10 (1H, s, NH). 13C NMR
(400 MHz, CDCl3)
d (ppm): 11.69(2), 47.7, 51.6(2), 55.9, 67.2, 110.3,
112.4(2), 119.9, 122.1, 124.3, 127.7, 129.1(2), 138.3, 142.2, 149.3(2),
150.1, 164.4. IR (KBr) m/cmꢂ1: 3435, 1663, 1595, 1541, 1490, 1436,
1259, 1161. MS m/z (ESI): 367 [MþH]þ. Purity: 98.8% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
4.7. General procedure for the synthesis of intermediate 3ae8a
A mixture of compound 5 (1.353 g, 5 mmol) with an appropriate
4.6.1. (E)-3-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl)-N-
phenylacrylamide (2b)
Light yellow viscous liquid, yield: 46.2%. 1H NMR (400 MHz,
of a,u-dibromoalkanes (15 mmol) and anhydrous K2CO3 (3.4371 g,
25 mmol) in acetone was refluxed and stirred for 4e10 h until the
reaction was completed with TLC examination. After cooling, the
reaction mixture was filtered and the solvent was evaporated under
reduced pressure, then the residue was partitioned between H2O
and CH2Cl2. The separated organic layer was washed with brine,
dried over anhydrous Na2SO4, and filtered. The solvent was
concentrated in vacuum and the residue was purified by silica gel
chromatography with ethyl acetate/petroleum ether (15:1, v/v) as
eluant to achieve product 3a-8a, and the yield ranged 70%e85%.
DMSO-d6)
d
(ppm): 2.22 (6H, s, 2 ꢁ NCH3), 2.62e2.65 (2H, t,
J ¼ 12.0 Hz, OCH2CH2), 3.83 (3H, s, OCH3), 4.07e4.10 (2H, t,
J ¼ 12.0 Hz, OCH2CH2), 6.69e6.73 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.03e7.07 (2H, m, Ar-H), 7.16e7.18 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.22 (1H,
s, Ar-H), 7.31e7.35 (2H, t, J ¼ 16.0 Hz, Ar-H), 7.51e7.55 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.14 (1H, s,
NH). 13CNMR (400 MHz, CDCl3)
d (ppm): 27.3, 45.5(2), 56.2, 67.3,
110.4, 112.4, 112.7, 122.2(2), 127.6, 129.1(2), 138.2, 142.3, 146.7,
149.7(2), 150.4, 164.4. IR (KBr) m/cmꢂ1: 3373, 1654, 1549, 1516,
1489, 1442, 1261, 1184. MS m/z (ESI): 341 [MþH]þ. Purity: 98.3% by
HPLC (MeOH/0.1% TEA 85:15 (v/v)).
4.7.1. (E)-3-(4-(3-bromopropoxy)-3-methoxyphenyl)-N-
phenylacrylamide (3a)
4.6.2. (E)-3-(4-(2-(diethylamino)ethoxy)-3-methoxyphenyl)-N-
phenylacrylamide (2c)
White solid, yield:76.4%, mp: 154.6e155.9ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d (ppm): 1.84e1.88 (2H, m, OCH2CH2CH2),
Yellow viscous liquid, yield: 56.3%. 1H NMR (400 MHz, DMSO-
2.33e2.37 (2H, t, J ¼ 16.0 Hz, OCH2CH2CH2), 3.83 (3H, s, OCH3),
4.01e4.05 (2H, t, J ¼ 16.0 Hz, OCH2CH2CH2), 6.69e6.73 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.00e7.06 (2H, m, Ar-H), 7.16e7.18 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.22 (1H, s, Ar-H), 7.30e7.34 (2H, t, J ¼ 16.0 Hz, Ar-
H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d,
J ¼ 8.0 Hz, Ar-H), 10.13 (1H, s, NH). MS m/z (ESI): 391 [MþH]þ.
Purity: 97.6% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
d6)
d
(ppm): 0.96e0.99 (6H, t, J ¼ 12.0 Hz, 2 ꢁ NCH2CH3), 2.52e2.58
(4H, m, 2 ꢁ NCH2CH3), 2.77e2.80 (2H, t, J ¼ 12.0 Hz, OCH2CH2), 3.82
(3H, s, OCH3), 4.02e4.06 (2H, t, J ¼ 12.0 Hz, OCH2CH2), 6.68e6.72
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.02e7.07 (2H, m, Ar-H), 7.15e7.17
(1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H), 7.30e7.34 (2H, t,
J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.68e7.70 (2H, d, 8.0 Hz, Ar-H), 10.10 (1H, s, NH). 13C NMR
(400 MHz, CDCl3)
d (ppm): 11.7(2), 47.7(2), 51.6, 55.9, 67.2, 110.3,
112.4(2), 119.9, 122.1, 124.3, 127.7, 129.1(2), 138.3, 142.2, 149.3(2),
150.1, 164.4. IR (KBr) m/cmꢂ1: 3376, 1647, 1598, 1541, 1490, 1442,
1259, 1182. MS m/z (ESI): 369 [MþH]þ. Purity: 97.9% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
4.7.2. (E)-3-(4-(4-bromobutoxy)-3-methoxyphenyl)-N-
phenylacrylamide (4a)
White solid, yield:79.3%, mp: 149.1e150.7ꢀС; 1H NMR
(400 MHz, DMSO-d6) d (ppm): 1.67e1.69 (2H, m, OCH2CH2CH2CH2),
1.74e1.75 (2H, m, OCH2CH2CH2CH2), 2.70 (2H, t, J ¼ 16.0 Hz,
OCH2CH2CH2CH2), 3.83 (3H, s, OCH3), 4.01e4.04 (2H, t, J ¼ 16.0 Hz,
OCH2CH2CH2CH2), 6.71e6.75 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.01e7.07 (2H, m, Ar-H), 7.16e7.18 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.22 (1H,
s, Ar-H), 7.30e7.34 (2H, t, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, J ¼ 8.0 Hz, Ar-H), 10.14
(1H, s, NH). MS m/z (ESI): 405 [MþH]þ. Purity: 98.3% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
4.6.3. (E)-3-(3-methoxy-4-(2-(piperidin-1-yl)ethoxy)phenyl)-N-
phenylacrylamide (2d)
Yellow viscous liquid, yield: 47.9%. 1H NMR (400 MHz, DMSO-d6)
d
(ppm): 1.48e1.49 (4H, m, piperidine-H), 1.56 (2H, m, piperidine-
H), 2.42 (4H, m, piperidine-H), 2.68e2.71 (2H, t, J ¼ 12.0 Hz,
OCH2CH2), 3.84 (3H, s, OCH3), 3.91 (2H, t, J ¼ 12.0 Hz, OCH2CH2),
6.75e6.79 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.04e7.11 (2H, m, Ar-H),
7.22e7.24 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.28 (1H, s, Ar-H), 7.31e7.35 (2H,
t, J ¼ 16.0 Hz, Ar-H), 7.52e7.56 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.18 (1H, s, NH). 13C NMR
4.7.3. (E)-3-(4-((5-bromopentyl)oxy)-3-methoxyphenyl)-N-
phenylacrylamide (5a)
(400 MHz, CDCl3)
d (ppm): 20.2, 25.8(2), 53.5(2), 54.7, 55.7, 60.3,
100.0, 109.4, 114.4(2), 119.9, 128.8, 129.3(2), 130.2, 139.4, 147.6,
148.2(2),149.5,164.6.IR (KBr) m/cmꢂ1: 3421,1652,1585,1539,1498,
1456, 1195, 1195. MS m/z (ESI): 381 [MþH]þ. Purity: 98.1% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
White solid, yield:80.3%, mp: 144.6e145.2ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d
(ppm): 1.49e1.56 (4H, m,
OCH2CH2CH2CH2CH2), 1.79e1.86 (2H, m, OCH2CH2CH2CH2CH2),
2.29e2.32 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2), 3.91 (3H, s,
OCH3), 4.07e4.10 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2),
6.77e6.81 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.09e7.16 (2H, m, Ar-H),
7.24e7.26 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.30 (1H, s, Ar-H), 7.39e7.43 (2H,
J ¼ 16.0 Hz, Ar-H), 7.59e7.63 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.77e7.79 (2H, d, J ¼ 8.0 Hz, Ar-H), 10.19 (1H, s, NH). MS m/z (ESI):
419 [MþH]þ. Purity: 96.9% by HPLC MeOH/0.1% TEA 85:15 (v/v).
4.6.4. (E)-3-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-
phenylacrylamide (2e)
Yellow viscous liquid, yield: 59.2%. 1H NMR (400 MHz, DMSO-
d6)
pyrrolidine-H), 1.87e1.94 (2H, m, OCH2CH2), 2.50 (4H, m,
d d (ppm): 1.69 (4H, m,
(ppm): 1H NMR (400 MHz, DMSO-d6)

816
H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
4.7.4. (E)-3-(4-((6-bromohexyl)oxy)-3-methoxyphenyl)-N-
phenylacrylamide (6a)
H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d,
8.0 Hz, Ar-H), 10.13 (1H, s, NH). 13CNMR (400 MHz, CDCl3)
(ppm):
27.3, 45.5(2), 56.0, 56.2, 67.3, 110.4, 112.4, 112.7, 122.2(2), 127.6,
129.1(2), 138.2, 142.3, 146.7, 149.7(2), 150.4, 164.2.IR (KBr) m/cmꢂ1
d
White solid, yield: 85.3%, mp: 133.5e134.9ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d
(ppm): 1.32e1.36 (2H, m,
:
OCH2CH2CH2CH2CH2CH2), 1.41e1.44 (4H, m, OCH2CH2CH2CH2
CH2CH2), 1.69e1.76 (2H, m, OCH2CH2CH2CH2CH2CH2), 2.23e2.26
(2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2), 3.82 (3H, s, OCH3),
4.00e4.03 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2), 6.69e6.72 (1H,
d, J ¼ 12.0 Hz, Ar-CH¼CH), 7.00e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H),
7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d,
J ¼ 8.0 Hz, Ar-H), 10.11 (1H, s, NH). MS m/z (ESI): 433 [MþH]þ.
Purity: 97.1% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
3411, 1656, 1597, 1581, 1498, 1442, 1288, 1180. MS m/z (ESI): 355
[MþH]þ. Purity: 97.2% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
4.8.2. (E)-3-(4-(3-(diethylamino)propoxy)-3-methoxyphenyl)-N-
phenylacrylamide(3c)
White solid, yield: 78.5%, mp:104.8e106.2ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d
(ppm): 0.93e0.97 (6H, t, J ¼ 16.0 Hz,
2 ꢁ NCH2CH3), 1.81e1.84 (2H, m, OCH2CH2CH2), 2.46e2.50 (6H, m,
3 ꢁ NCH2), 3.82 (3H, s, OCH3), 4.02e4.05 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2), 6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.00e7.07
(2H, m, Ar-H), 7.16e7.18 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H),
7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-
CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.10 (1H, s, NH). 13C NMR
4.7.5. (E)-3-(4-((8-bromooctyl)oxy)-3-methoxyphenyl)-N-
phenylacrylamide (7a)
White solid, yield: 82.8%, mp: 126.8e128.5ꢀС; 1H NMR
(400 MHz, DMSO-d6)
OCH2CH2CH2CH2CH2CH2CH2CH2), 1.70e1.74 (2H, m, OCH2CH2
CH2CH2CH2CH2CH2CH2), 2.33 (2H, t, 16.0 Hz,
d
(ppm): 1.28e1.48 (10H, m,
(400 MHz, CDCl3)d (ppm): 11.7(2), 26.6, 46.9(2), 49.7, 55.9, 67.5,
110.4, 112.7, 119.9, 122.2(2), 124.3, 127.6, 129.1(2), 138.3, 142.3,
149.5(2), 150.4, 164.3.IR (KBr) m/cmꢂ1:3446, 1660, 1581, 1541, 1490,
1438, 1296, 1199. MS m/z (ESI): 383 [MþH]þ. Purity: 98.1% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
J
¼
OCH2CH2CH2CH2CH2CH2CH2CH2), 3.82 (3H, s, OCH3), 3.97e4.01
(2H, t, J ¼ 16.0 Hz, OCH2CH2 CH2CH2CH2CH2CH2CH2), 6.68e6.72
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.99e7.07 (2H, m, Ar-H), 7.15e7.17
(1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H), 7.30e7.34 (2H,
J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.10 (1H, s, NH). MS m/z (ESI): 461
[MþH]þ. Purity: 97.9% by HPLC MeOH/0.1% TEA 85:15 (v/v).
4.8.3. (E)-3-(3-methoxy-4-(3-(piperidin-1-yl)propoxy)phenyl)-N-
phenylacrylamide(3d)
Light yellow solid, yield: 72.2%, mp: 81.8e83.6ꢀС; 1H NMR
(400 MHz, DMSO-d6) d (ppm): 1.38 (2H, m, piperidine-H), 1.50 (4H,
m, piperidine-H), 1.88 (2H, m, OCH2CH2CH2), 2.34 (6H, m,
3 ꢁ NCH2), 3.82 (3H, s, OCH3), 4.02e4.05 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2), 6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.01e7.07
(2H, m, Ar-H), 7.16e7.18 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H),
7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-
CH¼CH), 7.68e7.70 (2H, d, 8.0 Hz, Ar-H), 10.11 (1H, s, NH). 13C NMR
4.7.6. (E)-3-(4-((10-bromodecyl)oxy)-3-methoxyphenyl)-N-
phenylacrylamide (8a)
White solid, yield: 83.5%, mp: 115.3e116.6ꢀС; 1H NMR
(400 MHz, DMSO-d6)
OCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2), 1.70e1.73
J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2), 3.83 (3H, s,
OCH3), 3.97e4.00 (2H, t, 12.0 Hz,
d
(ppm): 1.24e1.50 (16H, m,
(2H, t,
(400 MHz, CDCl3)
d (ppm): 11.7(2), 26.6, 46.9, 49.2(2), 55.9, 61.0,
J
¼
67.5, 110.4, 112.7, 119.2, 122.2(2), 124.3, 127.6, 129.1(2), 138.3, 142.9,
149.5(2), 150.4,164.3.IR (KBr) m/cmꢂ1: 3441, 1662, 1597, 1583, 1489,
1442, 1178, 1165. MS m/z (ESI): 395 [MþH]þ. Purity: 97.3% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
OCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2), 6.68e6.72 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 6.99e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H),
7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.68e7.70 (2H, d,
J ¼ 8.0 Hz, Ar-H), 10.10 (1H, s, NH). MS m/z (ESI): 489 [MþH]þ.
Purity: 98.2% by HPLC MeOH/0.1% TEA 85:15 (v/v).
4.8.4. (E)-3-(3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-N-
phenylacrylamide(3e)
Light yellow solid, yield: 75.8%, mp: 91.7e93.6ꢀС; 1H NMR
4.8. General procedure for the synthesis of 3b-8e
(400 MHz, DMSO-d6) d (ppm): 1.69 (4H, m, pyrrolidine-H),
1.87e1.94 (2H, m, OCH2CH2CH2), 2.50 (4H, m, pyrrolidine-H),
2.55e2.58 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2), 3.82 (3H, s, OCH3),
4.03e4.06 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2), 6.69e6.73 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.00e7.07 (2H, m, Ar-H), 7.16e7.18 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H),
7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz,
A mixture of compound 3a (1 mmol) with secondary amines
(dimethylamine, diethylamine, piperidine, pyrrolidine), anhydrous
K2CO3 (0.6822 g, 7.5 mmol), NaI (0.011 g, 0.05 mmol) in acetone
(20 mL) was refluxed and stirred for 8 h. After cooling to the room
temperature, the reaction mixture was filtered. The filtrate was
evaporated in vacuum and the residue was dissolved with CH2Cl2
(30 mL). Then the organic phase was washed by saturated NaCl
solution (2 ꢁ 20 mL), dried over anhydrous Na2SO4 and evaporated
in vacuum. The residue was purified by silica gel chromatography
with different ratio of CH2Cl2/MeOH as eluant to achieve target
compound 3b. The other compounds were synthesized by similar
method as mentioned above.
Ar-H), 10.11 (1H, s, NH). 13C NMR (400 MHz, CDCl3)
d
(ppm): 11.7(2),
26.6, 46.9, 49.2(2), 55.9, 67.5, 110.4, 112.7, 119.2, 122.2(2), 124.3,
127.6, 129.1(2), 138.3, 142.9, 149.5(2), 150.4, 164.3. IR (KBr) m/cmꢂ1
:
3649, 1627, 1500, 1544, 1465, 1421, 1184, 1165. MS m/z (ESI): 381
[MþH]þ. Purity: 98.0% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
4.8.5. (E)-3-(4-(4-(dimethylamino)butoxy)-3-methoxyphenyl)-N-
phenylacrylamide(4b)
4.8.1. (E)-3-(4-(3-(dimethylamino)propoxy)-3-methoxyphenyl)-N-
phenylacrylamide (3b)
Light yellow solid, yield: 81.2%, mp: 90.2e92.6ꢀС; 1H NMR
(400 MHz, DMSO-d6) d (ppm): 1.67e1.69 (2H, m, OCH2CH2CH2CH2),
White solid, yield: 78.2%, mp: 99.7e101.2ꢀС; 1H NMR (400 MHz,
1.74e1.75 (2H, m, OCH2CH2CH2CH2), 2.45 (6H, s, 2 ꢁ NCH3), 2.70
(2H, t, J ¼ 16.0 Hz, OCH2CH2CH2CH2), 3.83 (3H, s, OCH3), 4.01e4.04
(2H, t, J ¼ 16.0 Hz, OCH2CH2CH2CH2), 6.71e6.75 (1H, d, J ¼ 16.0 Hz,
Ar-CH¼CH), 7.01e7.07 (2H, m, Ar-H), 7.16e7.18 (1H, d, J ¼ 8.0 Hz, Ar-
H), 7.22 (1H, s, Ar-H), 7.30e7.34 (2H, t, J ¼ 16.0 Hz, Ar-H), 7.50e7.54
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H),10.14
DMSO-d6)
d (ppm): 1.84e1.88 (2H, m, OCH2CH2CH2), 2.14 (6H, s,
2 ꢁ NCH3), 2.33e2.37 (2H, t, J ¼ 16.0 Hz, OCH2CH2CH2), 3.83 (3H, s,
OCH3), 4.01e4.05 (2H, t, J ¼ 16.0 Hz, OCH2CH2CH2), 6.69e6.73 (1H,
d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.00e7.06 (2H, m, Ar-H), 7.16e7.18 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.22 (1H, s, Ar-H), 7.30e7.34 (2H, t, J ¼ 16.0 Hz, Ar-

H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
817
(1H, s, NH). 13CNMR (400 MHz, CDCl3)
d
(ppm): 27.3, 45.5(2), 56.0,
7.24e7.26 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.30 (1H, s, Ar-H), 7.39e7.43 (2H,
J ¼ 16.0 Hz, Ar-H), 7.59e7.63 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.77e7.79 (2H, d, 8.0 Hz, Ar-H), 10.19 (1H, s, NH). 13C NMR
56.2, 66.8, 67.3, 110.4, 112.4, 112.7, 122.2(2), 127.6, 129.1(2), 138.2,
142.3, 146.7, 149.7(2), 150.4, 164.2. IR (KBr) m/cmꢂ1: 3460, 1600,
1595, 1544, 1490, 1469, 1184, 1165. MS m/z (ESI): 369 [MþH]þ.
Purity: 98.5% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
(400 MHz, CDCl3) d (ppm): 23.9, 27.3, 29.0, 45.4(2), 55.9, 59.5, 68.6,
100.0, 110.3, 112.4(2), 119.9, 122.2, 127.5, 129.1(2), 138.3, 142.2,
149.4(2), 150.4, 164.5.IR (KBr) m/cmꢂ1: 3298, 1668, 1627, 1600,
1556, 1489, 1188, 1097. MS m/z (ESI): 383 [MþH]þ. Purity: 98.7% by
HPLC (MeOH/0.1% TEA 85:15 (v/v)).
4.8.6. (E)-3-(4-(4-(diethylamino)butoxy)-3-methoxyphenyl)-N-
phenylacrylamide(4c)
Yellow solid, yield: 83.4%, mp: 94.0e95.6ꢀС; 1H NMR (400 MHz,
DMSO-d6)
1.50e1.56 (2H, m, OCH2CH2CH2CH2), 1.69e1.76 (2H, m,
OCH2CH2CH2CH2), 2.44e2.46 (6H, m, NCH2 and
d
(ppm): 0.93e0.96 (6H, t, J ¼ 12.0 Hz, 2 ꢁ CH3),
4.8.10. (E)-3-(4-((5-(diethylamino)pentyl)oxy)-3-methoxyphenyl)-
N-phenylacrylamide(5c)
3
ꢁ
White solid, yield: 85.1%, mp: 93.8e95.3ꢀС; 1H NMR (400 MHz,
OCH2CH2CH2CH2), 3.82 (3H, s, OCH3), 4.00e4.03 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2CH2), 6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.00e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H,
s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.68e7.70 (2H, d, 8.0 Hz, Ar-H), 10.10 (1H, s,
DMSO-d6)
d
(ppm): 1.06e1.09 (6H, t, J ¼ 12.0 Hz, 2 ꢁ NCH2CH3),
1.42e1.48 (2H, m, OCH2CH2CH2CH2CH2), 1.84e1.87 (2H, m,
OCH2CH2CH2CH2CH2), 1.73e1.80 (2H, m, OCH2CH2CH2CH2CH2),
2.81 (6H, t, J ¼ 12.0 Hz, 3 ꢁ NCH2), 3.83 (3H, s, OCH3), 4.00e4.03
(2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2), 6.70e6.74 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.01e7.08 (2H, m, Ar-H), 7.16e7.18 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.22 (1H, s, Ar-H), 7.31e7.35 (2H, J ¼ 16.0 Hz, Ar-H),
7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz,
NH). 13C NMR (400 MHz, CDCl3)
d (ppm): 23.9(2), 27.3, 29.0, 45.4(2),
55.9, 59.5, 68.6, 100.0, 110.3, 112.4(2), 119.9, 122.2, 127.5, 129.1(2),
138.3, 142.2, 149.4(2), 150.4, 164.5.IR (KBr) m/cmꢂ1: 3433, 1670,
1595, 1556, 1519, 1469, 1184, 1099. MS m/z (ESI): 369 [MþH]þ.
Purity: 98.1% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
Ar-H), 10.13 (1H, s, NH). 13C NMR (400 MHz, CDCl3)
d (ppm):
10.25(1), 23.9, 25.2, 28.8, 46.7(2), 52.2, 55.9, 68.7, 99.9, 110.4, 112.6,
122.1(2), 124.2, 127.7(2), 129.0, 138.3, 149.4(2), 150.2, 154.2, 164.3. IR
(KBr) m/cmꢂ1: 3399, 1668, 1600, 1581, 1544, 1456, 1165, 1066. MS
m/z (ESI): 411 [MþH]þ. Purity: 97.1% by HPLC (MeOH/0.1% TEA
85:15 (v/v)).
4.8.7. (E)-3-(3-methoxy-4-(4-(piperidin-1-yl)butoxy)phenyl)-N-
phenylacrylamide(4d)
Light yellow solid, yield: 85.1%, mp: 92.3e94.1ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d (ppm): 1.23 (2H, m, OCH2CH2CH2CH2), 1.40
(2H, m, piperidine-H), 1.52 (4H, m, piperidine-H), 1.60 (2H, m,
OCH2CH2CH2CH2), 1.70e1.75 (2H, m, OCH2CH2CH2CH2), 2.42 (4H,
m, piperidine-H), 3.82 (3H, s, OCH3), 4.00e4.03 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2CH2), 6.69e6.74 (1H, dd, J ¼ 4.0 Hz, J ¼ 12.0 Hz, Ar-
CH¼CH), 7.00e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H),
7.21 (1H, s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H,
d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H),10.14 (1H,
4.8.11. (E)-3-(3-methoxy-4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)-
N-phenylacrylamide(5d)
Light yellow solid, yield: 76.1%, mp: 190.9e192.3ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d
(ppm): 1.42e1.47 (4H, m,
OCH2CH2CH2CH2CH2), 1.64 (6H, m, piperidine-H), 1.73e1.78 (2H, m,
OCH2CH2CH2CH2CH2), 2.67e2.73 (6H, m, 3 ꢁ NCH2), 3.83 (3H, s,
OCH3), 4.00e4.03 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2),
6.70e6.74 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.01e7.07 (2H, m, Ar-H),
7.16e7.18 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.22 (1H, s, Ar-H), 7.31e7.34 (2H,
J ¼ 12.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.69e7.71 (2H, d, 8.0 Hz, Ar-H),10.11 (1H, s, NH). 13C NMR (400 MHz,
s, NH). 13C NMR (400 MHz, CDCl3)
d (ppm): 11.5, 23.4(2), 27.1, 29.7,
46.7(2), 52.5, 56.9, 68.8, 110.3, 112.5, 119.9, 122.2(2), 124.3, 127.6,
129.1(2), 138.3, 142.2, 149.5(2), 150.1, 164.4. IR (KBr) m/cmꢂ1: 3394,
1647, 1597, 1541, 1490, 1467, 1182, 1078. MS m/z (ESI): 409 [MþH]þ.
Purity: 96.4% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
CDCl3)
d (ppm): 10.2(2), 23.8, 25.2, 28.7, 46.7(2), 52.2, 53.5, 55.9,
68.7, 110.5, 112.5, 119.9, 122.0(2), 124.1, 127.8, 128.9(2), 138.5, 141.8,
149.3(2), 150.1, 164.6. IR (KBr) m/cmꢂ1: 3298, 1668, 1627, 1600,
1556, 1489, 1188, 1097. MS m/z (ESI): 423 [MþH]þ. Purity: 97.9% by
HPLC (MeOH/0.1% TEA 85:15 (v/v)).
4.8.8. (E)-3-(3-methoxy-4-(4-(pyrrolidin-1-yl)butoxy)phenyl)-N-
phenylacrylamide(4e)
Light yellow solid, yield: 85.0%, mp: 93.7e95.2ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d (ppm): 1.23 (2H, m, OCH2CH2CH2CH2), 1.69
(4H, m, pyrrolidine-H), 1.76 (2H, m, OCH2CH2CH2CH2), 2.50 (4H, m,
pyrrolidine-H), 2.55e2.58 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2),
3.82 (3H, s, OCH3), 4.00e4.03 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2),
6.69e6.74 (1H, dd, J ¼ 4.0 Hz, J ¼ 12.0 Hz, Ar-CH¼CH), 7.00e7.07
(2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H),
7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-
CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.14 (1H, s, NH). 13C NMR
4.8.12. (E)-3-(3-methoxy-4-((5-(pyrrolidin-1-yl)pentyl)oxy)
phenyl)-N-phenylacrylamide(5e)
Light yellow solid, yield: 70.5%, mp: 198.9e200.3ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d
(ppm): 1.42e1.47 (4H, m,
OCH2CH2CH2CH2CH2), 2.68 (4H, m, pyrrolidine-H), 1.73e1.78 (2H,
m, OCH2CH2CH2CH2CH2), 2.54 (4H, m, pyrrolidine-H), 2.55e2.58
(2H, t, J ¼ 12.0 Hz, OCH2CH2CH2 CH2CH2), 3.83 (3H, s, OCH3),
4.00e4.03 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2), 6.70e6.74 (1H,
d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.01e7.07 (2H, m, Ar-H), 7.16e7.18 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.22 (1H, s, Ar-H), 7.31e7.34 (2H, J ¼ 12.0 Hz, Ar-H),
7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz,
Ar-H), 10.11 (1H, s, NH).
(400 MHz, CDCl3)
d (ppm): 23.8(2), 27.2, 28.9, 45.3(2), 55.9, 59.5,
68.6, 99.9, 110.3, 112.4(2), 119.9, 122.2, 127.5, 129.1(2), 138.3, 142.2,
149.2(2),150.3,164.5. IR (KBr) m/cmꢂ1: 3315,1670,1581,1558,1487,
1463, 1188, 1091. MS m/z (ESI): 395 [MþH]þ. Purity: 98.5% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
13C NMR (400 MHz, CDCl3)
d (ppm): 10.2(2), 23.8, 28.7, 46.7(2),
4.8.9. (E)-3-(4-((5-(dimethylamino)pentyl)oxy)-3-
methoxyphenyl)-N-phenylacrylamide(5b)
52.2, 53.5, 55.9, 68.7, 110.5, 112.5, 119.9, 122.0(2), 124.1, 127.8,
128.9(2), 138.5, 141.8, 149.3(2), 150.1, 164.6.IR (KBr) m/cmꢂ1: 3346,
1687, 1598, 1581, 1541, 1498, 1172, 1078. MS m/z (ESI): 410 [MþH]þ.
Purity: 95.5% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
White solid, yield: 83.0%, mp: 94.7e95.1ꢀС; 1H NMR (400 MHz,
DMSO-d6)
d (ppm): 1.49e1.56 (4H, m, OCH2CH2CH2CH2CH2),
1.79e1.86 (2H, m, OCH2CH2CH2CH2CH2), 2.21 (6H, s, 2 ꢁ NCH3),
2.29e2.32 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2), 3.91 (3H, s,
OCH3), 4.07e4.10 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2),
6.77e6.81 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.09e7.16 (2H, m, Ar-H),
4.8.13. (E)-3-(4-((6-(dimethylamino)hexyl)oxy)-3-
methoxyphenyl)-N-phenylacrylamide(6b)
White solid, yield: 78.1%, mp: 110.9e112.3ꢀС; 1H NMR

818
H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
(400 MHz, DMSO-d6)
d
(ppm): 1.32e1.36 (2H, m,
127.8(2), 129.0, 138.6, 141.7, 149.4(2), 150.2, 164.7.IR (KBr) m/cmꢂ1
:
3340, 1672, 1602, 1558, 1541, 1398, 1166, 1031. MS m/z (ESI): 423
[MþH]þ. Purity: 96.8% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
OCH2CH2CH2CH2CH2CH2), 1.41e1.44 (4H, m, OCH2CH2CH2CH2
CH2CH2), 1.69e1.76 (2H, m, OCH2CH2CH2CH2CH2CH2), 2.15 (6H, s,
2 ꢁ NCH3), 2.23e2.26 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2),
3.82 (3H, s, OCH3), 4.00e4.03 (2H, t,
J
¼
12.0 Hz,
4.8.17. (E)-3-(4-((8-(dimethylamino)octyl)oxy)-3-methoxyphenyl)-
N-phenylacrylamide (7b)
OCH2CH2CH2CH2CH2), 6.69e6.72 (1H, d, J ¼ 12.0 Hz, Ar-CH¼CH),
7.00e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H,
s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.11 (1H, s,
Light yellow solid, yield: 65.9%, mp: 89.1e90.6ꢀС; 1H NMR
(400 MHz, DMSO-d6)
OCH2CH2CH2CH2CH2CH2CH2CH2),
OCH2CH2CH2CH2CH2CH2 CH2CH2), 2.15 (6H, s,
d
(ppm): 1.28e1.48 (10H, m,
1.70e1.74
(2H,
m,
NH). 13C NMR (400 MHz, CDCl3)
d
(ppm): 25.9, 27.2, 27.5, 29.0,
2
ꢁ
NCH3),
45.4(2), 56.0, 59.7, 68.9, 110.3, 112.5, 118.5, 119.8, 122.3(2), 127.5,
129.1(2), 138.2, 142.4(2), 149.5, 150.5, 157.7. IR (KBr) m/cmꢂ1: 3396,
1672, 1583, 1558, 1514, 1490, 1188, 1080. MS m/z (ESI): 433 [MþH]þ.
Purity: 96.1% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
2.23e2.26 (2H, t, J ¼ 16.0 Hz, OCH2CH2CH2CH2CH2CH2CH2CH2),
3.82 (3H, s, OCH3), 4.00e4.03 (2H, t,
J
¼
12.0 Hz,
OCH2CH2CH2CH2CH2CH2), 6.69e6.72 (1H, d, J ¼ 12.0 Hz, Ar-
CH¼CH), 7.00e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H),
7.21 (1H, s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H,
d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.11 (1H,
4.8.14. (E)-3-(4-((6-(diethylamino)hexyl)oxy)-3-methoxyphenyl)-
N-phenylacrylamide(6c)
s, NH). 13C NMR (400 MHz, CDCl3)
d (ppm): 25.8, 26.4, 27.2, 28.9,
Light yellow solid, yield: 78.1%, mp: 147.7e149.3ꢀС; 1H NMR
29.2, 29.3(2), 44.5(2), 51.5, 56.0, 59.2, 68.9, 110.4, 112.5, 119.9,
122.2(2), 124.2, 127.6(2), 129.0,138.4,142.0,149.5(2),150.4,164.4. IR
(KBr) m/cmꢂ1: 3387,1664,1600,1583,1544,1467, 1182, 1080. MS m/
z (ESI): 425 [MþH]þ. Purity: 97.8% by HPLC (MeOH/0.1% TEA 85:15
(v/v)).
(400 MHz, DMSO-d6)
d
(ppm): 1.06e1.09 (6H, t, J ¼ 12.0 Hz,
2
ꢁ
NCH2CH3), 1.32e1.36 (2H, m, OCH2CH2CH2CH2CH2CH2),
1.41e1.44 (4H, m, OCH2CH2CH2CH2CH2CH2), 1.69e1.76 (2H, m,
OCH2CH2CH2CH2CH2CH2), 2.81 (6H, t, J ¼ 12.0 Hz, 3 ꢁ NCH2), 3.82
(3H, s, OCH3), 4.00e4.03 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2
CH2CH2), 6.69e6.72 (1H, d, J ¼ 12.0 Hz, Ar-CH¼CH), 7.00e7.07 (2H,
m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H),
7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-
CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.11 (1H, s, NH). 13C NMR
4.8.18. (E) -3-(4-((8-(diethylamino)octyl)oxy)-3-methoxyphenyl)-
N-phenylacrylamide (7c)
Light yellow solid, yield: 63.8%, mp: 95.3e96.5ꢀС; 1H NMR
(400 MHz, DMSO-d6d (ppm): 1.06e1.09 (6H, t, J ¼ 12.0 Hz,
(400 MHz, CDCl3)
d
(ppm): 10.9(2), 25.0, 25.7, 26.9, 28.9, 46.8(2),
2
ꢁ
NCH2CH3), 1.28e1.48 (10H, m, OCH2CH2CH2CH2
52.1, 56.0, 68.7, 110.4, 112.5(2), 119.9, 122.1, 124.1, 127.8(2), 129.0,
138.6, 141.7, 149.4(2), 150.2, 164.7. IR (KBr) m/cmꢂ1: 3340, 1674,
1598, 1560, 1516, 1492, 1166, 1095. MS m/z (ESI): 425 [MþH]þ. Pu-
rity: 97.3% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
CH2CH2CH2CH2), 1.70e1.74 (2H, m, OCH2CH2CH2CH2CH2
CH2CH2CH2), 2.33 (6H, m, 3 ꢁ NCH2), 3.82 (3H, s, OCH3), 3.97e4.01
(2H, t, J ¼ 16.0 Hz, OCH2CH2CH2CH2CH2CH2CH2CH2), 6.70e6.74
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.01e7.08 (2H, m, Ar-H), 7.16e7.18
(1H, d, J ¼ 8.0 Hz, Ar-H), 7.22 (1H, s, Ar-H), 7.31e7.35 (2H,
J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.13 (1H, s, NH). 13C NMR
4.8.15. (E)-3-(3-methoxy-4-((6-(piperidin-1-yl)hexyl)oxy)phenyl)-
N-phenylacrylamide(6d)
White solid, yield: 71.8%, mp: 103.2e104.9ꢀС; 1H NMR
(400 MHz, CDCl3) d (ppm): 11.3(2), 25.9, 26.5, 27.7, 29.0, 29.3, 29.4,
(400 MHz, DMSO-d6)
d
(ppm): 1.37e1.48 (12H, m, piperidine-H and
29.5, 29.6, 46.8(2), 52.0, 55.9, 69.0, 110.3, 112.4, 119.9, 122.2(2),
124.2, 127.5(2), 129.0, 138.3, 142.2, 149.4(2), 150.4, 164.5. IR (KBr) m/
cmꢂ1: 3394, 1678, 1602, 1583, 1552, 1498, 1161, 1080. MS m/z (ESI):
453 [MþH]þ. Purity: 98.2% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
OCH2CH2CH2CH2CH2CH2), 1.70e1.73 (2H, m, OCH2CH2CH2
CH2CH2CH2), 2.19e2.23 (2H, m, OCH2CH2CH2CH2CH2CH2), 2.29
(4H, m, piperidine-H), 3.82 (3H, s, OCH3), 3.97e4.00 (2H, t,
J
¼
12.0 Hz, OCH2CH2 CH2CH2CH2CH2), 6.68e6.72 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 6.99e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H),
7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz,
4.8.19. (E) -3-(4-((8-(piperidin-1-yl)octyl)oxy)3-methoxyphenyl)-
N-phenylacrylamide (7d)
Light yellow solid, yield: 78.1%, mp: 113.4e115.1ꢀС; 1H NMR
Ar-H), 10.10 (1H, s, NH). 13C NMR (400 MHz, CDCl3)
d
(ppm): 24.4,
(400 MHz, DMSO-d6) d (ppm): 1.28e1.48 (20H, m, piperidine-H and
25.9(2), 25.9, 26.7, 27.5, 29.0, 54.6(2), 56.0, 59.5, 68.9, 110.3,
112.4(2), 119.9, 122.2, 124.3, 127.5, 129.1(2), 138.3, 142.3, 149.4(2),
150.5, 164.4. IR (KBr) m/cmꢂ1: 3377, 1674, 1598, 1543, 1516, 1492,
1184, 1095. MS m/z (ESI): 437 [MþH]þ. Purity: 98.8% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
OCH2CH2CH2CH2CH2CH2CH2 CH2), 1.70e1.74 (2H, m, OCH2CH2
CH2CH2CH2CH2 CH2 CH2), 2.33 (6H, m, 3 ꢁ NCH2), 3.82 (3H, s,
OCH3), 3.97e4.01 (2H, t, J ¼ 16.0 Hz, OCH2CH2 CH2CH2CH2CH2 CH2
CH2), 6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.00e7.07 (2H, m,
Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H),
7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz,
4.8.16. (E)-3-(3-methoxy-4-((6-(pyrrolidin-1-yl)hexyl)oxy)
phenyl)-N-phenylacrylamide(6e)
Ar-CH¼CH), 7.68e7.70 (2H, d, 8.0 Hz, Ar-H), 10.10 (1H, s, NH). 13
C
NMR (400 MHz, CDCl3) d (ppm): 24.2, 25.5(2), 25.9, 26.5, 27.6, 28.9,
White solid, yield: 70.6%, mp: 120.2e121.9ꢀС; 1H NMR
29.3, 29.4, 29.5, 53.5, 54.5(2), 56.0, 59.4, 69.0, 110.3, 112.4, 119.9,
122.3(2), 124.3, 127.4(2), 129.1, 138.3, 142.3, 149.5(2), 150.5, 165.0.IR
(KBr) m/cmꢂ1: 3412, 1666, 1598, 1556, 1512, 1498, 1184, 1095. MS m/
z (ESI): 465 [MþH]þ. Purity: 98.9% by HPLC (MeOH/0.1% TEA 85:15
(v/v)).
(400 MHz, DMSO-d6)
d
(ppm): 1.42e1.47 (6H, m,
OCH2CH2CH2CH2CH2 CH2), 2.68 (4H, m, pyrrolidine-H), 1.73e1.78
(2H, m, OCH2CH2CH2CH2 CH2CH2), 2.54 (4H, m, pyrrolidine-H),
2.55e2.58 (2H, t, J ¼ 12.0 Hz, OCH2CH2 CH2CH2 CH2CH2), 3.82
(3H, s, OCH3), 3.97e4.00 (2H, t,
J
¼
12.0 Hz,
OCH2CH2CH2CH2CH2CH2), 6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-
CH¼CH), 6.99e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H),
7.21 (1H, s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H,
d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H),10.10 (1H,
4.8.20. (E) -3-(3-methoxy-4-((8-(pyrrolidin-1-yl)octyl)oxy)
phenyl)-N-phenylacrylamide(7e)
Light yellow solid, yield: 78.1%, mp: 101.6e102.7ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d (ppm): 1.28e1.48 (14H, m, pyrrolidine-H
s, NH). 13C NMR (400 MHz, CDCl3)
d
(ppm): 10.8(2), 25.0, 25.7, 26.9,
and OCH2CH2CH2CH2CH2CH2CH2 CH2), 1.70e1.74 (2H, m,
OCH2CH2 CH2CH2CH2CH2 CH2CH2), 2.33 (6H, m, 3 ꢁ NCH2), 3.82
28.9, 46.8(2), 52.1, 56.0, 68.7, 110.4, 112.5(2), 119.9, 122.1, 124.1,

H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
819
(3H, s, OCH3), 3.97e4.01 (2H, t,
J
¼
16.0 Hz, OCH2CH2
4.8.24. (E)-3-(3-methoxy-4-((10-(pyrrolidin-1-yl)decyl)oxy)
phenyl)-N-phenylacrylamide (8e)
CH2CH2CH2CH2CH2CH2), 6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
6.99e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H,
s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.10 (1H, s,
Pink solid, yield: 53.2%, mp: 99.7e101.5ꢀС; 1H NMR (400 MHz,
DMSO-d6)
d (ppm): 1.24e1.50 (24H, m, OCH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2 and pyrrolidine-H), 1.70e1.73 (2H, t,
J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2), 3.82 (3H, s,
OCH3), 3.97e4.00 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2),
6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.99e7.07 (2H, m, Ar-H),
7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21 (1H, s, Ar-H), 7.30e7.34 (2H,
J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.10 (1H, s, NH). 13C NMR
NH). 13C NMR (400 MHz, CDCl3)
d (ppm): 11.3(2), 25.9, 26.6, 27.7,
29.0, 29.3, 29.4, 29.5, 29.6, 16.8(2), 52.8, 55.9, 69.0, 110.3, 112.4,
119.8, 122.2(2), 124.2127.5(2), 129.1, 138.3, 142.2, 149.4, 150.1, 165.9.
IR (KBr) m/cmꢂ1: 3356, 1664, 1598, 1583, 1550, 1498, 1182, 1099. MS
m/z (ESI): 451 [MþH]þ. Purity: 97.1% by HPLC (MeOH/0.1% TEA
85:15 (v/v)).
(400 MHz, CDCl3)
d (ppm): 11.3(2), 25.9, 26.6, 27.7, 29.0, 29.3, 29.4,
4.8.21. (E) -3-(4-((10-(dimethylamino)decyl)oxy)-3-
methoxyphenyl)-N-phenylacrylamide (8b)
29.5, 29.6, 16.8(2), 52.8, 55.9, 69.0, 110.3, 112.4, 119.8, 122.2(2),
124.2127.5(2), 129.1, 138.3, 142.2, 149.4, 150.1, 165.9.IR (KBr) m/
cmꢂ1: 3284, 1695, 1602, 1583, 1552, 1498, 1176, 1080. MS m/z (ESI):
479 [MþH]þ. Purity: 98.5% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
Light yellow solid, yield: 67.3%, mp: 79.2-80.5ꢀС; 1H NMR (400
MHz,
OCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2), 2.15 (6H, s, 2ꢁNCH3),
2.23-2.26 (2H, t, 12.0 Hz, OCH2CH2CH2CH2CH2CH2
DMSO-d6)
d
(ppm):
1.24-1.50
(16H,
m,
J
¼
4.9. Synthesis of compound 9a-9c, and 10c
CH2CH2CH2CH2), 3.83 (3H, s, OCH3), 3.97-4.00 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2), 6.68-6.72 (1H, d, J ¼ 16.0
Hz, Ar-CH¼CH), 6.99-7.07 (2H, m, Ar-H), 7.15-7.17 (1H, d, J ¼ 8.0 Hz,
Ar-H), 7.21 (1H, s, Ar-H), 7.30-7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50-7.54
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 7.68-7.70 (2H, d, J ¼ 8.0 Hz, Ar-H),
4.9.1. (E)-ethyl 3-(4-((6-bromohexyl)oxy)-3-methoxyphenyl)
acrylate (9a)
Ethyl ferulate (compound 6) was synthesized as described
previously [20]. Then compound
6 was treated with 1,6-
10.10 (1H, s, NH). 13C NMR (400 MHz, CDCl3)
d
(ppm): 25.8, 26.4,
dibromohexane (2.8 mL, 15 mmol) according to the general pro-
27.2, 28.9, 29.2, 29.3(2), 44.5(2), 51.5, 56.0, 59.2, 68.9, 110.4, 112.5,
119.9, 122.2(2), 124.2, 127.6(2), 129.0, 138.4, 142.0, 149.5(2), 150.4,
164.4. IR (KBr) m/cm-1: 3360, 1681, 1602, 1585, 1554, 1489, 1174,
1078. MS m/z (ESI): 453 [MþH]þ. Purity: 97.7% by HPLC (MeOH/
0.1% TEA 85:15 (v/v)).
cedure to achieve compound 9a with a yield of 90%. 1H NMR
(400 MHz, CDCl3)
CH2CH2CH2CH2 and
d
(ppm): 1.30e1.40 (5H, m, OCH2CH2
CH3CH2O), 1.45e1.50 (4H, m,
OCH2CH2CH2CH2CH2CH2), 1.83e1.90 (2H, m, OCH2CH2CH2CH2
CH2CH2), 2.43e2.46 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2),
3.89 (3H, s, OCH3), 4.03e4.06 (2H, t,
J
¼
12.0 Hz,
4.8.22. (E) -3-(4-((10-(diethylamino)decyl)oxy)-3-
methoxyphenyl)-N-phenylacrylamide(8c)
OCH2CH2CH2CH2CH2CH2), 4.23e4.28 (2H, t, CH3CH2O), 6.28e6.32
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.84e6.86 (1H, d, J ¼ 8.0 Hz, Ar-H),
7.05e7.07 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.09 (1H, s, Ar-H), 7.60e7.64 (1H,
d, J ¼ 16.0 Hz, Ar-CH¼CH). MS m/z (ESI): 385 [MþH]þ. Purity: 97.1%
by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
Light yellow solid, yield: 54.2%, mp: 76.3e78.2ꢀС; 1H NMR
(400 MHz, DMSO-d6)
d
(ppm): 1.06e1.09 (6H, t, J ¼ 12.0 Hz,
2
ꢁ
NCH2CH3), 1.24e1.50 (16H, m, OCH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2), 2.81 (6H, t, J ¼ 12.0 Hz, 3 ꢁ NCH2), 3.83 (3H, s,
OCH3), 3.97e4.00 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2
CH2CH2CH2CH2), 6.70e6.74 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
7.01e7.08 (2H, m, Ar-H), 7.16e7.18 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.22 (1H,
s, Ar-H), 7.31e7.35 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.69e7.71 (2H, d, 8.0 Hz, Ar-H), 10.13 (1H, s,
4.9.2. (E)-ethyl 3-(4-((8-bromooctyl)oxy)-3-methoxyphenyl)
acrylate (10a)
Compound 6 was treated with 1,8-dibromooctane (3.1 mL,
15 mmol) according to the general procedure to achieve compound
10a with a yield of 90%. 1H NMR (400 MHz, CDCl3)
d
(ppm): 1.35
(5H, m, OCH2CH2CH2CH2CH2CH2CH2CH2 and CH3CH2O), 1.67 (2H,
m, OCH2CH2CH2CH2CH2CH2CH2CH2), 1.77e1.80 (2H, m,
NH). 13C NMR (400 MHz, CDCl3)
d (ppm): 11.3(2), 25.9, 26.5, 27.7,
29.0, 29.3, 29.4, 29.5, 29.6, 46.8(2), 52.0, 55.9, 69.0, 110.3, 112.4,
119.9, 122.2(2), 124.2, 127.5(2), 129.0, 138.3, 142.2, 149.4(2), 150.4,
164.5.IR (KBr) m/cmꢂ1: 3305, 1680, 1602, 1583, 1550, 1498, 1174,
1078. MS m/z (ESI): 482 [MþH]þ. Purity: 98.2% by HPLC (MeOH/
0.1% TEA 85:15 (v/v)).
OCH2CH2CH2CH2CH2CH2CH2CH2), 2.83e2.87 (4H, m, OCH2CH2CH2
CH2CH2CH2CH2CH2), 3.00e3.05 (4H, m, OCH2CH2CH2CH2CH2CH2
CH2CH2), 3.83 (3H, s, OCH3), 3.90e3.93 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2CH2CH2CH2 CH2CH2), 4.23e4.28 (2H, t, CH3CH2O),
6.38e6.42 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.68e6.70 (1H, d,
J ¼ 8.0 Hz, Ar-H), 6.96e6.98 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.04 (1H, s, Ar-
H), 7.42e7.46 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 11.25 (1H, s, COOH).
MS m/z (ESI): 413 [MþH]þ. Purity: 97.1% by HPLC (MeOH/0.1% TEA
85:15 (v/v)).
4.8.23. (E)-3-(3-methoxy-4-((10-(piperidin-1-yl)decyl)oxy)
phenyl)-N-phenylacrylamide(8d)
Pink solid, yield: 71.8%, mp: 94.2e95.5ꢀС; 1H NMR (400 MHz,
DMSO-d6)
d (ppm): 1.24e1.50 (26H, m, OCH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2 and piperidine-H), 1.70e1.73 (2H, t,
J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2CH2CH2CH2CH2), 3.83 (3H, s,
4.9.3. (E)-ethyl-3-(4-((6-(diethylamino)hexyl)oxy)-3-
methoxyphenyl)acrylate (9c)
OCH3), 3.97e4.00 (2H, t,
J
¼ 12.0 Hz, OCH2CH2CH2CH2CH2
CH2CH2CH2CH2CH2), 6.68e6.72 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH),
6.99e7.07 (2H, m, Ar-H), 7.15e7.17 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.21
(1H, s, Ar-H), 7.30e7.34 (2H, J ¼ 16.0 Hz, Ar-H), 7.50e7.54 (1H, d,
J ¼ 16.0 Hz, Ar-CH¼CH), 7.68e7.70 (2H, d, J ¼ 8.0 Hz, Ar-H), 10.10
Compound 9c was synthesized by the method mentioned
above. Pale yellow viscous liquid, 0yield 56.3%; 1H NMR (400 MHz,
CDCl3)
d
(ppm): 1.02e1.06 (6H, t, J ¼ 12.0 Hz, 2 ꢁ NCH2CH3),
1.30e1.40 (5H, m, OCH2CH2CH2CH2CH2CH2 and CH3CH2O),
1.45e1.50 (4H, m, OCH2CH2CH2CH2CH2CH2), 1.83e1.90 (2H, m,
(1H, s, NH). 13C NMR (400 MHz, CDCl3)
d (ppm): 24.2, 25.5(2),
25.9, 26.5, 27.6, 28.9, 29.3, 29.4, 29.5, 53.5, 54.5(2), 56.0, 59.4,
69.0, 110.3, 112.4, 119.9, 122.3(2), 124.3, 127.4(2), 129.1, 138.3,
142.3, 149.5(2), 150.5, 165.0. IR (KBr) m/cmꢂ1: 1678, 1598, 1581,
1552, 1498, 1178, 1078. MS m/z (ESI): 493 [MþH]þ. Purity: 97.6%
by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
OCH2CH2CH2CH2CH2CH2), 2.43e2.46 (2H, t,
OCH2CH2CH2CH2CH2CH22.53e2.58 (4H, m, 2 ꢁ NCH2CH3), 3.89
(3H, s, OCH3), 4.03e4.06 (2H, t, 12.0 Hz,
OCH2CH2CH2CH2CH2CH2), 4.23e4.28 (2H, t, CH3CH2O), 6.28e6.32
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.84e6.86 (1H, d, J ¼ 8.0 Hz, Ar-H),
J
¼
12.0 Hz,
J
¼

820
H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
7.05e7.07 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.09 (1H, s, Ar-H), 7.60e7.64 (1H,
4.10. General procedure for the synthesis of compounds 11c-11e and
12c
d, J ¼ 16.0 Hz, Ar-CH¼CH). 13C NMR (400 MHz, CDCl3)
d (ppm):
11.7(2), 14.4, 25.9, 26.9, 27.9, 29.0, 46.9(2), 52.9, 55.9, 60.3, 68.9,
110.4, 112.3, 115.8, 122.5, 127.3, 144.6, 149.5, 150.7, 167.3.IR (KBr) m/
cmꢂ1: 2935, 1770, 1598, 1581, 1510, 1257, 1161, 1093. MS m/z (ESI):
378 [MþH]þ. Purity: 98.9% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
Compounds 11c-11e and 12c were synthesized from com-
pounds 9c-9e and 10c, respectively. Compounds 9c-9e and 10c
were hydrolyzed by NaOH solution stirring on a cooled bath in
absolute ethyl alcohol. After the solvent was removed under
reduced pressure, 10% ice-hydrochloric acid was added to adjust
the solution to pH ¼ 6e7, then the crude product was partitioned
by ethyl acetate (3 ꢁ 30 mL), dried over anhydrous Na2SO4 and
evaporated in vacuum. The obtained residue was purified by silica
gel chromatography with different ratio of CH2Cl2/MeOH as eluent
to generate target compounds 11c-11e and 12c with a yield of
60e75%.
4.9.4. (E)-ethyl-3-(3-methoxy-4-((6-(piperidin-1-yl)hexyl)oxy)
phenyl)acrylate (9d)
Light yellow solid, yield 63.8%, mp: 72.6e73.8ꢀС; 1H NMR
(400
MHz,
CDCl3)
d
(ppm):
1.30e1.38
(5H,
m,
OCH2CH2CH2CH2CH2CH2 and CH3CH2O), 1.45e1.51 (4H, m,
OCH2CH2CH2CH2CH2CH2), 1.57e1.65 (6H, m, piperidine-H),
1.82e1.87 (2H, m, OCH2CH2CH2CH2CH2CH2), 2.44 (2H, t,
J
¼
12.0 Hz, OCH2CH2CH2CH2CH2CH2) 2.53e2.58 (4H, m,
4.10.1. (E)-3-(4-((6-(diethylamino)hexyl)oxy)-3-methoxyphenyl)
acrylic acid (11c)
piperidine-H), 3.89 (3H, s, OCH3), 4.02e4.05 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2CH2CH2CH2), 4.23e4.28 (2H, t, CH3CH2O), 6.28e6.32
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.84e6.86 (1H, d, J ¼ 8.0 Hz, Ar-H),
7.05e7.07 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.09 (1H, s, Ar-H), 7.60e7.64 (1H,
Light yellow solid, yield 63.4%, mp: 146.3e147.5ꢀС; 1H NMR
(400 MHz, CDCl3)
d
(ppm): 1.44e1.47 (6H, t, J ¼ 12.0 Hz,
2
ꢁ
NCH2CH3), 1.55e1.57 (4H, m, OCH2CH2CH2CH2CH2CH2),
d, J ¼ 16.0 Hz, Ar-CH¼CH). 13C NMR (400 MHz, CDCl3)
d (ppm): 14.4,
1.85e1.90 (4H, m, OCH2CH2CH2CH2CH2CH2), 3.00 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2CH2CH2CH2) 3.16 (4H, m, 2 ꢁ NCH2CH3), 3.90 (3H, s,
OCH3), 4.04e4.07 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2),
6.30e6.34 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.86e6.88 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.07 (1H, s, Ar-H), 7.10e7.12 (1H, d, J ¼ 8.0 Hz, Ar-
H), 7.69e7.73 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 10.71 (1H, s, COOH).
24.2, 25.6(2), 25.9, 26.4, 27.4, 28.9, 54.5(2), 55.9, 59.3, 60.3, 68.9,
110.1, 112.4, 115.8, 122.6, 127.3, 144.6, 149.5, 150.7, 167.3. IR (KBr) m/
cmꢂ1: 2935, 1693, 1597, 1577, 1510, 1267, 1165, 1101. MS m/z (ESI):
390 [MþH]þ. Purity: 98.2% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
13C NMR (400 MHz, CDCl3)
d (ppm): 23.3(2), 25.4, 25.5, 28.7,
4.9.5. (E)-ethyl-3-(3-methoxy-4-((6-(pyrrolidin-1-yl)hexyl)oxy)
phenyl)acrylate (9e)
53.7(2), 55.1, 59.9, 68.5, 110.3, 112.4, 114.9, 123.1, 127.0, 146.8, 149.5,
150.9, 171.7. IR (KBr) m/cm:-1: 3340, 2937, 1708, 1598, 1510, 1213,
1246, 1013. MS m/z (ESI): 350 [MþH]þ. Purity: 98.3% by HPLC
(MeOH/0.1% TEA 85:15 (v/v)).
Light yellow solid, yield 57.5%, mp: 86.8-87.6ꢀС; 1H NMR (400
MHz, CDCl3)
1.42 (2H, m, OCH2CH2CH2CH2CH2CH2), 1.46-1.49 (2H, m,
OCH2CH2CH2CH2CH2CH2), 1.55-1.58 (2H, m,
d
(ppm): 1.32-1.35 (3H, t, J ¼ 12.0 Hz, CH3CH2O), 1.38-
4.10.2. (E)-3-(3-methoxy-4-((6-(piperidin-1-yl)hexyl)oxy)phenyl)
acrylic acid (11d)
OCH2CH2CH2CH2CH2CH2), 1.79 (4H, m, pyrrolidine-H), 1.83-1.88
(2H, m, OCH2CH2CH2CH2CH2CH2), 2.43-2.47 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2CH2CH2CH2), 2.51 (4H, m, pyrrolidine-H), 3.89 (3H, s,
OCH3), 4.03-4.06 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2),
4.23-4.28 (2H, t, CH3CH2O), 6.28-6.32 (1H, d, J ¼ 16.0 Hz, Ar-
CH¼CH), 6.84-6.86 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.05-7.07 (1H, d, J ¼ 8.0
Hz, Ar-H), 7.09 (1H, s, Ar-H), 7.60-7.64 (1H, d, J ¼ 16.0 Hz, Ar-
Light yellow solid, yield 71.3%, mp: 151.0e152.9ꢀС; 1H NMR
(400
MHz,
CDCl3)
d
(ppm):
1.30e1.38
(3H,
m,
OCH2CH2CH2CH2CH2CH2), 1.45e1.51 (4H, m, OCH2CH2CH2CH2
CH2CH2), 1.57e1.65 (6H, m, piperidine-H), 1.82e1.87 (2H, m,
OCH2CH2CH2CH2CH2CH2), 2.53e2.58 (4H, m, piperidine-H),
3.57e3.60 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2), 3.90 (3H,
s, OCH3), 4.04e4.07 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2),
6.30e6.34 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.86e6.88 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.07 (1H, s, Ar-H), 7.10e7.12 (1H, d, J ¼ 8.0 Hz, Ar-
H), 7.69e7.73 (1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 10.71 (1H, s,
CH¼CH). 13C NMR (400 MHz, CDCl3)
d (ppm): 14.4, 23.4(2), 25.9,
27.5, 28.9, 29.0, 54.3(2), 55.9, 56.9, 60.4, 68.9, 110.0, 112.3, 115.8,
122.6, 127.3, 144.6, 149.5, 150.7, 167.3. IR (KBr) m/cm-1: 2935, 1747,
1597, 1577, 1510, 1247, 1165, 1101. MS m/z (ESI): 376 [MþH]þ. Purity:
99.0% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
COOH)$13C NMR (400 MHz, CDCl3)
d (ppm): 8.9(2), 23.8, 25.8, 26.9,
29.0(2), 29.1, 45.4(2), 50.7, 55.9, 68.8, 109.9, 112.4, 121.6, 122.6,
128.9, 140.1, 149.3, 149.4, 173.2.IR (KBr) m/cm-1:3331, 2937, 1738,
1577, 1523, 1226, 1218, 1013. MS m/z (ESI): 362 [MþH]þ. Purity:
98.8% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
4.9.6. (E)-ethyl-3-(4-((8-(diethylamino)octyl)oxy)-3-
methoxyphenyl)acrylate (10c)
Compound 10c was synthesized by the similar method
mentioned above. Pale yellow viscous liquid, yield 54.2%; 1H NMR
(400 MHz, CDCl3)
d
(ppm): 1.23e1.27 (6H, t, J ¼ 16.0 Hz,
4.10.3. (E)-3-(3-methoxy-4-((6-(pyrrolidin-1-yl)hexyl)oxy)phenyl)
acrylic acid (11e)
2 ꢁ NCH2CH3), 1.35 (5H, m, OCH2CH2CH2CH2CH2CH2CH2CH2 and
CH3CH2O), 1.67 (2H, m, OCH2CH2CH2CH2CH2CH2CH2CH2),
1.77e1.80 (2H, m, OCH2CH2CH2CH2CH2CH2CH2CH2), 2.83e2.87
(4H, m, OCH2CH2CH2CH2CH2CH2CH2CH2), 3.00e3.05 (4H, m,
OCH2CH2CH2CH2CH2CH2 CH2CH2), 3.12 (4H, m, 2 ꢁ NCH2CH3), 3.83
(3H, s, OCH3), 3.90e3.93 (2H, t, J ¼ 12.0 Hz, OCH2CH2CH2
CH2CH2CH2 CH2CH2), 4.23e4.28 (2H, t, CH3CH2O), 6.38e6.42 (1H,
d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.68e6.70 (1H, d, J ¼ 8.0 Hz, Ar-H),
6.96e6.98 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.04 (1H, s, Ar-H), 7.42e7.46 1H,
Light yellow solid, yield 60.5%, mp: 165.3e166.9ꢀС; 1H NMR
(400
MHz,
CDCl3)
d
(ppm):
1.38e1.42
(2H,
m,
OCH2CH2CH2CH2CH2CH2), 1.46e1.49 (2H, m, OCH2CH2CH2
CH2CH2CH2), 1.55e1.58 (2H, m, OCH2CH2CH2CH2CH2CH2), 1.79 (4H,
m, pyrrolidine-H), 1.83e1.88 (2H, m, OCH2CH2CH2CH2CH2CH2),
2.51 (4H, m, pyrrolidine-H), 3.57e3.60 (2H, t, J ¼ 12.0 Hz,
OCH2CH2CH2CH2CH2CH2), 3.90 (3H, s, OCH3), 4.03e4.06 (2H, t,
J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2), 6.29e6.33 (1H, d, J ¼ 16.0 Hz,
Ar-CH¼CH), 6.85e6.87 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.07 (1H, s, Ar-H),
7.10e7.12 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.69e7.73 (1H, d, J ¼ 16.0 Hz, Ar-
d, J ¼ 16.0 Hz, Ar-CH¼CH. 13C NMR (400 MHz, CDCl3)
d (ppm):
11.7(2), 14.4, 25.9, 26.9, 27.9, 29.0(3), 46.9(2), 52.9, 55.9, 60.3, 68.9,
110.4, 112.3, 115.8, 122.5, 127.3, 144.6, 149.5, 150.7, 167.3.IR (KBr) m/
cmꢂ1: 2937, 1708, 1625, 1599, 1512, 1263, 1180, 1018. MS m/z (ESI):
406 [MþH]þ. Purity: 98.8% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
CH¼CH), 11.25 (1H, s, COOH). 13C NMR (400 MHz, CDCl3)
d (ppm):
23.4(2), 25.4, 25.5, 28.7, 53.7(2), 55.1, 56.0, 68.5, 110.3, 112.4, 114.9,
123.1, 127.0, 146.8, 149.5, 150.9, 171.7. IR (KBr) m/cmꢂ1: 3332, 2935,

H. Liu et al. / European Journal of Medicinal Chemistry 126 (2017) 810e822
821
1732, 1635, 1579, 1541, 1213, 1138. MS m/z (ESI): 348 [MþH]þ. Pu-
4.13. Molecular docking
rity: 99.1% by HPLC (MeOH/0.1% TEA 85:15 (v/v)).
Molecular docking study was carried out using Molecular
Operating Environment (MOE) software package. The X-ray crys-
tallographic structures of AChE (PDB code: 1EVE) and BuChE (PDB
code: 1P0I) were provided by protein data bank [24]. Subsequently,
compound 6d was docked using the optimized parameters.
4.10.4. (E)-3-(4-((8-(diethylamino)octyl)oxy)-3-methoxyphenyl)
acrylic acid (12c)
Light yellow solid, yield 71.4%, mp: 86.6e88.2ꢀС; 1H NMR
(400 MHz, CDCl3)
d
(ppm): 1.23e1.27 (6H, t, J ¼ 16.0 Hz,
2 ꢁ NCH2CH3), 1.35 (2H, m, OCH2CH2CH2CH2CH2CH2CH2CH2), 1.67
(2H, m, OCH2CH2CH2CH2CH2CH2CH2CH2), 1.77e1.80 (2H, m,
OCH2CH2CH2CH2CH2CH2CH2CH2), 2.83e2.87 (4H, m, OCH2CH2CH2
CH2CH2CH2CH2CH2), 3.00e3.05 (4H, m, OCH2CH2CH2CH2CH2CH2
CH2CH2), 3.12 (4H, m, 2 ꢁ NCH2CH3), 3.83 (3H, s, OCH3), 3.90e3.93
(2H, t, J ¼ 12.0 Hz, OCH2CH2CH2CH2CH2CH2 CH2CH2), 6.38e6.42
(1H, d, J ¼ 16.0 Hz, Ar-CH¼CH), 6.68e6.70 (1H, d, J ¼ 8.0 Hz, Ar-H),
6.96e6.98 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.04 (1H, s, Ar-H), 7.42e7.46 (1H,
d, J ¼ 16.0 Hz, Ar-CH¼CH), 11.25 (1H, s, COOH). 13C NMR (400 MHz,
4.14. Log P measurement
Octanol-water partition coefficients of new synthesized com-
pounds were measured by the shake flask method described pre-
viously [25,26]. The aqueous phase was replaced by PBS (pH ¼ 7.4).
The assay mixture containing test compounds was shaken at 37 ꢀC
over night and then centrifuged at 2000 rpm for 20 min, followed
by the analysis with HPLC. A C18 column (150 nm ꢁ 4.6 mm, 5
mm)
was used with the mobile phase of methanol-0.1% triethylamine
(TEA) (85:15, v/v) at a flow rate of 1.0 mL.minꢂ1 and the detection
wavelength of 322 nm at 32 ꢀC. Experiments were conducted in
triplicate and log P values were calculated.
CDCl3)
d (ppm): 8.9(2), 23.8, 25.8, 26.9, 29.0(2), 29.1, 45.4(2), 50.7,
55.9, 68.8, 109.9, 112.4, 121.6, 122.6, 128.9, 140.1, 149.3, 149.4, 173.2.
IR (KBr) m/cmꢂ1: 3330, 2933, 1711, 1633, 1579, 1541, 1318, 1130. MS
m/z (ESI): 378 [MþH]þ. Purity: 99.1% by HPLC (MeOH/0.1% TEA
85:15 (v/v)).
Declaration of interest
4.11. Cholinesterase and carboxylesterase (CaE) inhibitory activity
assays
The authors have declared no conflict of interest.
Acknowledgment
The effects of the newly synthesized compounds on AChE/
BuChE were measured by the modified Ellmann method [21]. The
individual compound was dissolved in Tween 80 and diluted with
water to obtain five different concentrations before use. All re-
actions were performed in triplicate. The assay mixture contained
The present investigation was supported by “The innovative
investigation funds for graduated students of Hu'nan province” (No.
HN2014082 and No. CX2015B324).
100
ylthiocholine iodide, 2.76 mL phosphoric acid buffer (pH 8.0,
0.1 mol/L) and 100 L different concentrations of test compounds.
The mixture was incubated for 25 min (30 ꢀC), and terminated by
mL AChE or BuChE, 100 mL acetylthiocholine iodide or butyr-
Appendix A. Supplementary data
m
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2016.12.003.
adding 100
adding 100
m
m
L 20% sodium dodecyl sulfate (SDS), followed by
L 10 mmol/L 5,5’-dithiobis-(2-nitrobenzoic acid)
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