Design, synthesis and biological evaluation of (E)-3-(3,4,5-trimethoxyphenyl) acrylic acid (TMCA) amide derivatives as anticonvulsant and sedative agents

Article abstract of DOI:10.1007/s00044-018-2228-3

In this article, a novel series of (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (TMCA) amide derivatives 1-18 were designed and synthesized by a facile and one-pot step, which were achieved with good yields using 1-hydroxybenzotriazole (HOBT) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as activation system. All the synthesized derivatives were biologically evaluated for their anticonvulsant, sedative activity and neurotoxicity using the maximal electroshock (MES) model, sc-pentylenetetrazol (PTZ) model, pentobarbital sodium-induced sleeping model, and locomotor activity tests, respectively. Among them, compounds 4, 9 and 16 exhibited good anticonvulsant activity in primary evaluation. Furthermore, compound 4 is the most effective anticonvulsant and sedative agent in subsequent tests, while the low threshold of toxicity of compound 4 is vigilant. Compounds 9 and 16 also performed significantly anticonvulsant activity in subsequent tests with weak toxicity. The molecular modeling experiments also predicted good binding interactions of the obtained active molecules with the GABA transferas. Therefore, it could be concluded that the synthesized derivatives 4, 9 and 16 would represent useful lead compounds for further investigation in the development of anticonvulsant and sedative agents.

Full text of DOI:10.1007/s00044-018-2228-3

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-018-2228-3
ORIGINAL RESEARCH
Design, synthesis and biological evaluation of (E)-3-(3,4,5-
trimethoxyphenyl) acrylic acid (TMCA) amide derivatives as
anticonvulsant and sedative agents
Zefeng Zhao1 Yajun Bai1,2 Xufei Chen1 Shaoping Wu1,2 Xirui He3 Yujun Bai1 Ying Sun1 Xiaohui Zheng1
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Received: 12 April 2018 / Accepted: 24 July 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
In this article, a novel series of (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (TMCA) amide derivatives 1-18 were designed
and synthesized by a facile and one-pot step, which were achieved with good yields using 1-hydroxybenzotriazole (HOBT)
and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) as activation system. All the synthesized
derivatives were biologically evaluated for their anticonvulsant, sedative activity and neurotoxicity using the maximal
electroshock (MES) model, sc-pentylenetetrazol (PTZ) model, pentobarbital sodium-induced sleeping model, and locomotor
activity tests, respectively. Among them, compounds 4, 9 and 16 exhibited good anticonvulsant activity in primary
evaluation. Furthermore, compound 4 is the most effective anticonvulsant and sedative agent in subsequent tests, while the
low threshold of toxicity of compound 4 is vigilant. Compounds 9 and 16 also performed significantly anticonvulsant
activity in subsequent tests with weak toxicity. The molecular modeling experiments also predicted good binding
interactions of the obtained active molecules with the GABA transferas. Therefore, it could be concluded that the
synthesized derivatives 4, 9 and 16 would represent useful lead compounds for further investigation in the development of
anticonvulsant and sedative agents.
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Keywords Synthesis 3,4,5-Trimethoxycinnamic acid Amide derivatives Anticonvulsant Sedative Docking
Introduction
wide attention as an important source for the treatment of
antiepileptic drugs (AEDs). Piperine (C17H19NO3; CAS: 94-
62-2), an alkaloid derivative isolated from Piper species, is
a potential anticonvulsant and sedative compound in several
pharmacological models. Briefly, piperine has performed
significant anticonvulsant activity in maximal electroshock
(MES) and pentylenetetrazol (PTZ) models, with median
effective dose (ED50) values of 47 mg/kg in MES model. γ-
Aminobutyric acid (GABA) neurotransmission, c-fos and
transient receptor potential cation channel subfamily V
member 1 (TRPV1) receptor could be the possible relative
targets (Chen et al. 2013; da Cruz et al. 2013). Additionally,
it also has been demonstrated to markedly increase
pentobarbitone-induced sleeping time in a dose-dependent
manner (Mujumdar et al. 1990). Antiepilepsirine
(C15H17NO3, CAS: 94-62-2), one of the derivatives of
piperine, has been used clinically as an efficacious antic-
onvulsant agent in the treatment of different types of epi-
lepsy in China, especially the epileptic seizures in children
(approved by H11021771, http://app2.sfda.gov.cn/) (Wang
et al. 1993, 1999). Researches on the structural modification
Epilepsy is a chronic neurological disorder characterized by
the spontaneous recurrence of seizures that disrupt periods
of more or less normal electroencephalographic (EEG)
activity and behavior. Recently, natural products attract
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00044-018-2228-3) contains supplementary
material, which is available to authorized users.
* Xiaohui Zheng
zhengxh@nwu.edu.cn
1
Key Laboratory of Resource Biology and Biotechnology in
Western China, Ministry of Education, Northwest University, 229
Taibai Road, 710069 Xi’an, China
2
College of Chemistry and Materials Science, Northwest
University, 710069 Xi’an, China
3
Honghui Hospital, Xi’an Jiaotong University, 710054
Xi’an, China

Medicinal Chemistry Research
of piperine are still ongoing; several central nervous system
(CNS) active compounds have been synthetized nowadays
(Al-Baghdadi et al. 2012; Gunia-Krzyzak et al. 2017).
3,4,5-Trimethoxycinnamic acid (TMCA) is a component
isolated from the root of Polygala tenuifolia Willd. (poly-
galaceae) and its extract has been used as a traditional
sedative medicine in China, Japan and Korea (Carreiro et al.
2014; Klein et al. 2012; May et al. 2013). TMCA is reported
to exhibit anticonvulsant and sedative activity in former
studies. Additionally, mechanism research revealed that
TMCA was an excellent GABAA/BZ receptor agonist for
antiseizure and insomnia therapy (Chen et al. 2016; Lee
et al. 2013). A lot of TMCA amide derivatives have been
synthesized and multiple bioactivities have been reported in
recent years, such as antinarcotic (Jung et al. 2013), anti-
tumor (Kamal et al. 2016) and anti-inflammatory (Seo et al.
2014). In view of the active group cinnamamide in TMCA
plays an important role in CNS (Gunia-Krzyzak et al.
2015), we speculated that TMCA amide derivatives exhibit
anticonvulsant activity.
locomotor test and pentobarbital sodium-induced sleeping
model of effective compounds are measured in vivo. The
biologically active compounds are verified in docking
analysis, GABA transferas (PDB ID: 1OHW) (Fig. 2).
Experimental
Chemistry
The chemicals and reagents were purchased from several
chemical companies such as Alfa-Aesar, Macklin and J&K
in China. The progress of the reaction was monitored by
TLC (TLC-DCM: ME −10:1) analysis using silica gel G
plates under UV chamber in 256 nm for visualization of
TLC spots. IR spectra were recorded on a Thermo Nicolet
5700 FT-IR spectrophotometer using KBr pellets. 1H NMR
and 13C NMR spectra were obtained by Varian Gemini
2000 DMX600 MHz FT NMR spectrometers using CDCl3
as a solvent and Tetramethylsilicane (TMS) as an internal
standard. The chemical shifts were expressed in ppm. Mass
spectral ESI measurements were executed on Agilent 6520
Accurate-mass Q-TOF LC/MS instruments. The spectra
were performed in the positive ion mode at a declustering
potential of 4000 V. Melting points were determined in a
WRS-1B apparatus and are uncorrected.
However, there is still limited information on the antic-
onvulsant studies of TMCA derivatives; therefore, in the
present study, we design and synthesize a series of TMCA
derivatives. Firstly, we design TMCA-piperidine amide (4)
and the reduction of double-bonded analog (18), which is
structurally similar to antiepilepsirine (Scheme 1). More-
over, heterocyclic derivatives (3–8, 17), aromatic deriva-
tives (9, 12–17) and hydrazine derivatives (10, 11) are also
synthesized using the same method. All the compounds are
identified by thin layer chromatography (TLC), melting
General experimental procedure for the synthesis of
TMCA amide derivatives (1–17): a mixture containing
trans-3,4,5-trimethoxycinnamic
4.0 mmol), 1-hydroxybenzotriazole (HOBT, 2.0 mmol), 1-
(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydro-
acid
(trans-TMCA,
1
point, IR, LC-MS, H-NMR and 13C-NMR. All the com-
pounds are primarily evaluated for anticonvulsant activity
by MES model. Furthermore, the anticonvulsant activity in
scPTZ and neurotoxicity (NT) models and sedative effect in
chloride (EDCI, 4.0 mmol) and amine (3.0 mmol) in the
presence of anhydrous dichloromethane (15 mL) was thor-
oughly stirred at room temperature for 6–10 h till the
Scheme 1 Synthetic route for target compounds 1–18

Medicinal Chemistry Research
50 mA intensity (instrument: YSD-4G, SN: ZH0056232,
Anhui, China) was applied through corneal electrodes for a
0.25-s duration. Carbamazepine (CBZ, 53 mg/kg) was dis-
solved in an aqueous Tween-80 (3% v/v, 0.9% NaCl)
solution as positive control group. Negative control groups
composed of 3% Tween-80 solution. All the tested com-
pounds were prepared as homogenized suspensions in
aqueous Tween-80 (3% v/v, 0.9% NaCl), and intraper-
itoneally (i.p.) injected in a standard volume of 0.1 mL/10 g
body weight. For the test groups, mice were respectively
administered i.p. with tested compounds at 100 mg/kg in
preliminary evaluation and 75, 50, 25, 12.5 mg/kg in further
evaluation to calculate ED50. All the mice were treated with
electrical stimulation in the preliminary evaluation after the
administration of the compounds at 0.5, 1, 2, 3 and 4 h.
Mice were considered protected if they did not exhibit tonic
hind.
Fig. 1 Structure of piperine, antiepilepsirine and the analogs 4 and 18
scPTZ-induced seizure test
After the completion of the MES test, the anticonvulsant
activities of tested compounds were carried out using the
scPTZ-induced mice seizure model. The experiments uti-
lized 85 mg/kg PTZ that produced clonic seizures lasting for
a period of at least 5 s in 97% of animals tested (Vamecq
et al. 1998), and PTZ (85 mg/kg) was dissolved in 0.9%
NaCl to subcutaneously inject into mice 30 min after the
treatment of compounds. In scPTZ test, all the selected
compounds were injected i.p. into mice at the doses of 50,
100, 150 and 200 mg/kg, and the number of protected
animals and latent time were recorded. ED50 was calculated
according to the probit analysis. CBZ (200 mg/kg) was used
as positive control in the screens.
Fig. 2 Interaction sites of compound 4
completion of reaction as indicated by TLC analysis. The
obtained product was washed with sodium bicarbonate
water solution and diluted hydrochloric acid. The organic
layer was dried over anhydrous sodium sulfate and evapo-
rated to dryness to give the crude product. Compounds 18
and antiepilepsirine were synthesized according to the steps
for the synthesis of compounds 1–17. The difference about
compound 18 and antiepilepsirine is that TMCA was
replaced with 3-(3,4,5-trimethoxyphenyl)propanoic acid
and (E)-3-(benzo[d][1,3]dioxol-5-yl)acrylic acid, respec-
tively. The target products were recrystallized from
methanol (Scheme 1).
NT screening
The acute NT of the screened compounds were measured in
mice through the rotarod test (Dunham et al. 1957). The
mice were trained to place on a 4-cm-diameter rod that
rotates at 24 rpm. Then, the trained mice were selected and
randomly divided, and administered i.p. with the different
doses of the screened compounds, as well as reference drugs
so as to obtain the median neurotoxic dose (TD50). About
0.5 h after the drug treatment, the mice were placed on a
rotarod that rotates at 24 rpm. Neurologic toxicity is defined
as the failure (drop more than three times from the rotarod
in 3 min) of the mice to remain on the rod for 3 min.
Biological activity
Animals
Male KunMing-strain mice weighing 22–26 g were used in
this study. All the mice were kept under controlled envir-
onmental conditions (22 2 °C; 50 20% humidity; 12 h
light/dark cycle) with free access to pellet food and water.
Locomotor activity
MES test
The spontaneous locomotor activities of mice were mon-
itored according to the described method by the published
researches (Chen et al. 2011; Gupta et al. 2012). Mice were
The MES test was carried out following the method of
Swinyard (1969). In the MES screen, a 60-Hz current of

Medicinal Chemistry Research
pretreated with the tested compounds (20 and 100 mg/kg, i.
p.), diazepam (20 mg/kg, i.p.) and normal saline (20 mL/kg,
i.p.). About 30 min later, the activity cage apparatus (YSL-
1A, Shandong, China) was used. Interruptions of light
beams during vertical and horizontal movements of the
animals were automatically recorded for 5 min.
Identification of compounds 1–18 and antiepilepsirine is
listed as follows:
(E)-N-butyl-3-(3,4,5-trimethoxyphenyl)acrylamide (1)
Yellow solid. Melting point (mp) 131–132 °C. Yield: 80%;
Rf = 0.5 (DCM/MeOH = 10:1, v/v); IR (KBr) 526, 604,
623, 740, 829, 985, 1126, 1212, 1238, 1277, 1321, 1417,
Pentobarbital sodium-induced sleeping
1461, 1504, 1580, 1618, 1655, 3292 cm−1 1H NMR
;
Pentobarbital sodium-induced sleeping time in mice was
determined based on previously described method with
some improvement (Yang et al. 2013). Mice were pretreated
with test compounds (10 mg/kg, i.p.), diazepam (4 mg/kg, i.
p.) or normal saline (20 mL/kg, i.p.) 30 min before injection
of pentobarbital sodium (70 mg/kg, i.p.). Then the mice
were observed for the loss of the “righting reflex”—tested
mice roll over onto their feet when they were turned on their
back. The time between the administration of pentobarbital
sodium and the loss of “righting reflex” was regarded as
latent time of sleeping, and the interval between the loss and
recovery of the righting reflex was recorded as the duration
of sleep.
(600 MHz, CDCl3) δ 7.52 (d, J = 15.5 Hz, 1H), 6.72 (s,
2H), 6.30 (d, J = 15.5 Hz, 1H), 5.67 (s, 1H), 3.87 (s, 9H),
3.42–3.36 (m, 2H), 1.55 (p, J = 7.3 Hz, 2H), 1.42–1.37 (m,
2H), 0.94 (t, J = 7.3 Hz, 3H);13C NMR (151 MHz, CDCl3)
δ 165.91, 153.53, 140.88, 130.62, 105.05, 61.08, 56.26,
39.63, 31.89, 20.25; HRMS (ESI+) m/z calculated for
C16H23NO4 ([M+H]+): 294.1705; found: 294.1751.
(E)-N-cyclohexyl-3-(3,4,5-trimethoxyphenyl)acrylamide (2)
White solid; mp 185–186 °C. Yield: 82%; Rf = 0.6 (DCM/
MeOH = 10:1, v/v); IR (KBr) 569, 611, 629, 692, 747, 824,
891, 968, 996, 1128, 1205, 1241, 1325, 1420, 1537, 1582,
1
1613, 2929, 3288 cm−1; H NMR (600 MHz, Chloroform-
Statistical analysis
d) δ 7.51 (d, J = 15.5 Hz, 1H), 6.72 (s, 2H), 6.28 (d, J =
15.5 Hz, 1H), 3.87 (d, J = 3.4 Hz, 9H), 1.99 (dd, J = 12.8,
4.3 Hz, 2H), 1.73 (dt, J = 13.7, 4.0 Hz, 2H), 1.66–1.60 (m,
2H), 1.41 (d, J = 11.9 Hz, 2H), 1.25 (s, 2H), 1.19 (dd, J =
12.0, 8.3 Hz, 2H);13C NMR (151 MHz, CDCl3) δ 164.96,
153.53, 140.81, 139.62, 130.67, 120.63, 105.03, 61.09,
56.26, 48.50, 33.45; HRMS (ESI+) m/z calculated for
C18H25NO4 ([M+H]+): 320.1856; found: 320.1901.
All data were presented as mean standard deviation. The
results were analyzed by a one-way ANOVA, followed by
Student’s two-tailed t-test for the comparison between test
and control, and Dunnett’s test when the data involved three
or more groups. The level of significance for all tests was
set at P < 0.01. ClogP was calculated by means of Chem-
Draw Ultra software, version 13.0.
(E)-1-(piperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-
Docking study
1-one (3)
The docking analysis of all molecules was performed
using module of SYBYL-X 2.0, implemented from
Surflex-dock molecular modeling module. The crystal
structures of GABA transferas (PDB ID: 1OHW) were
retrieved from the Protein Data Bank (www.rcsb.org)
(Sahu et al. 2017). The structures of ligand were generated
using ChemBioDraw Ultra (v13.0) (Cambridgesoft, Bill-
erica, MA, USA).
Yellow solid; mp 127–128 °C. Yield: 70%; Rf = 0.4 (DCM/
MeOH = 8:1, v/v); IR (KBr) 516, 584, 604, 651 682, 721,
777, 827, 979, 1118, 1252, 1449, 1586, 1981, 2954 cm−1
;
1H NMR (600 MHz, CDCl3) δ 7.55 (1H, d, J = 15.4 Hz),
6.77 (1H, d, J = 15.4 Hz), 6.73 (2H, s), 3.89 (6H, s), 3.86
(3H, s), 3.62 (4H, d, J = 43.3 Hz), 1.68 (2H, d, J = 4.9 Hz),
1.62–1.60 (2H, m); 13C NMR (151 MHz, CDCl3) δ 165.42,
153.52, 142.37, 139.57, 131.22, 117.12, 105.06, 61.07,
56.34, 26.96, 25.73, 24.77; HRMS (ESI+) m/z calculated
for C17H23NO4 ([M+H]+): 306.1705; found: 306.1757.
Results and discussion
(E)-3-(3,4,5-trimethoxyphenyl)-1-morpholinoprop-2-en-1-
one (4)
Chemistry
Yellow solid; mp 101–102 °C. Yield: 80%; Rf = 0.4 (DCM/
MeOH = 10:1, v/v); IR (KBr) 528, 548, 603, 618, 680, 720,
775, 832, 846, 900, 1120, 1269, 1339, 1368, 1456, 155,
1585, 2001, 2944, 3006 cm−1; 1H NMR (600 MHz, CDCl3)
All titled compounds 1–18 were successfully synthesized
using the synthetic protocols presented in Scheme 1. Anti-
epilepsirine was also synthesized and characterized.

Medicinal Chemistry Research
δ 7.55 (1H, d, J = 15.4 Hz), 6.78 (1H, d, J = 15.4 Hz), 6.73
(2H, s), 3.89 (6H, s), 3.87 (3H, s), 3.63 (4H, d, J =
43.7 Hz), 1.71–1.67 (2H, m), 1.64–1.60 (4H, m); 13C NMR
(151 MHz, CDCl3) δ 165.44, 153.53, 142.40, 139.59,
131.24, 117.13, 105.08, 61.09, 56.36, 47.16, 26.91, 24.79;
HRMS (ESI+) m/z calculated for C16H21NO5 ([M+H]+):
308.1492; found: 308.1493.
(E)-N-(benzo[d]thiazol-2-yl)-3-(3,4,5-trimethoxyphenyl)
acrylamide (8)
White solid; mp 171–172 °C. Yield: 86%; Rf = 0.8 (DCM/
MeOH = 10:1, v/v); IR (KBr) 507, 617, 679, 758, 826,
1003, 1126, 1276, 1324, 1445, 1503, 159, 1683, 2939 cm
−1; 1H NMR (600 MHz, CDCl3) δ 7.89 (1H, d, J = 7.9 Hz),
7.86 – 7.78 (2H, m), 7.40 (1H, t, J = 7.6 Hz), 7.33 (1H, t, J
= 8.0 Hz), 6.62–6.58 (3H, m), 3.86 (3H, s), 3.68 (6H, s);
13C NMR (151 MHz, CDCl3) δ 207.04, 160.68, 153.54,
145.36, 132.39, 129.52, 126.75, 124.11, 121.92, 120.32,
117.54, 105.70, 61.09, 56.17, 31.03; HRMS (ESI+) m/z
calculated for C19H18N2O4S ([M+H]+): 371.106; found:
371.1066.
(E)-1-(4-methylpiperazin-1-yl)-3-(3,4,5-trimethoxyphenyl)
prop-2-en-1-one (5)
Yellow solid; mp 100–101 °C. Yield: 75%; Rf = 0.3 (DCM/
MeOH = 10:1, v/v); IR (KBr) 518, 615, 776, 828, 853, 976,
1008, 1039, 1140, 1222, 1254, 1274, 1293, 1320, 1344,
1
1420, 1465, 1508, 1590, 1644, 2787, 2840, 2944 cm−1; H
NMR (600 MHz, CDCl3) δ 7.58 (d, J = 15.3 Hz, 1H), 6.74
(d, J = 16.1 Hz, 3H), 3.89 (s, 6H), 3.87 (s, 3H), 3.72 (d, J =
46.6 Hz, 4H), 2.45 (s, 4H), 2.33 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 165.59 (s, 2H), 153.68 (s, 3H), 143.14
(s, 3H), 139.84 (s, 1H), 131.07 (s, 1H), 116.54 (s, 3H),
105.23 (s, 6H), 61.18 (s, 2H), 56.44 (s, 6H), 46.25 (s, 3H);
HRMS (ESI+) m/z calculated for C17H24N2O4 ([M+H]+):
321.1809; found: 321.1858.
(E)-N,3-bis(3,4,5-trimethoxyphenyl)acrylamide (9)
White solid; mp 166–168 °C. Yield: 86%; Rf = 0.5 (DCM/
MeOH = 10:1, v/v); IR (KBr) 588, 773, 799, 839, 993,
1130, 1209, 1237, 1278, 1318, 1415, 1453, 1507, 1610,
1656, 2839, 2939, 3278 cm−1; 1H NMR (600 MHz, CDCl3)
δ 7.65 (1H, d, J = 15.4 Hz), 7.51 (1H, s), 6.95 (2H, s), 6.74
(2H, s), 6.47 (1H, d, J = 15.4 Hz), 3.88 (3H, s), 3.87 (6H,
s), 3.84 (6H, s), 3.83 (3H, s); 13C NMR (151 MHz, CDCl3)
δ 164.05, 153.61, 153.52, 142.50, 140.09, 134.94, 134.36,
130.27, 105.31, 97.71, 61.13, 56.29, 56.25; HRMS (ESI+)
m/z calculated for C21H25NO7 ([M+H]+): 404.1704; found:
404.1741.
(E)-N-(pyridin-3-yl)-3-(3,4,5-trimethoxyphenyl)acrylamide
(6)
Yellow solid; mp 185–187 °C. Yield: 70%; Rf = 0.5 (DCM/
MeOH = 10:1, v/v); IR (KBr) 513, 581, 606, 624, 648, 670,
702, 774, 821, 858, 971, 1007, 1129, 1177, 1279, 1331,
(E)-N′-(3-(3,4,5-trimethoxyphenyl)acryloyl)benzohydrazide
(10)
1
1423, 1504, 1580, 1683, 2938 cm−1; H NMR(600 MHz,
CDCl3) δ 8.65 (1H, s), 8.39–8.24 (3H, m), 7.67 (1H, d, J =
15.4 Hz), 7.36–7.27 (1H, m), 6.72 (2H, s), 6.53 (1H, d, J =
15.4 Hz), 3.88 (3H, s), 3.84 (6H, s); 13C NMR (151 MHz,
CDCl3) δ 164.86, 153.62, 145.16, 143.13, 141.18, 140.15,
135.68, 130.21, 127.52, 124.10, 119.79, 105.40, 61.18,
56.30; HRMS (ESI+) m/z calculated for C17H18N2O4 ([M
+H]+): 315.1339; found: 315.1336.
White solid; mp 162–163 °C. Yield: 76%; Rf = 0.7 (DCM/
MeOH = 5:1, v/v); IR (KBr) 603, 711, 822, 995, 1129,
1246, 1282, 1420, 1507, 1583, 3001 cm−1 1H NMR
;
(600 MHz, CDCl3) δ 10.35 (1H, s), 10.11 (1H, s), 7.90 (2H,
d, J = 7.5 Hz), 7.58 (1H, d, J = 15.5 Hz), 7.51 (1H, t, J =
7.4 Hz), 7.40 (2H, t, J = 7.7 Hz), 6.69–6.61 (3H, m), 3.85
(3H, s), 3.75 (6H, s); 13C NMR (151 MHz, CDCl3) δ
164.37, 163.31, 153.49, 142.77, 140.08, 132.63, 131.35,
130.14, 127.55, 116.76, 61.07, 56.17; HRMS (ESI+) m/z
calculated for C19H20N2O5 ([M+H]+): 357.1445;
found:357.1449.
(E)-N-(pyridin-4-yl)-3-(3,4,5-trimethoxyphenyl)acrylamide
(7)
Yellow solid; mp 155–157 °C. Yield: 70%; Rf = 0.5
(DCM/MeOH = 10:1, v/v); IR (KBr) 536, 575, 749, 774,
824, 958, 988, 1132, 1210, 1242, 1280, 1333, 1419, 1453,
(E)-N′-(3-(3,4,5-trimethoxyphenyl)acryloyl)
isonicotinohydrazide (11)
1
1507, 1560, 1691, 2940, 3425 cm−1; H NMR (600 MHz,
CDCl3) δ 8.53 (2H, d, J = 5.7 Hz), 7.71 (1H, d, J =
15.3 Hz), 7.57 (2H, d, J = 5.8 Hz), 6.78 (2H, s), 6.46 (1H,
d, J = 15.3 Hz), 3.90 (6H, s), 3.90 (3H, s); 13C NMR
(151 MHz, cdcl3) δ 164.65, 153.70, 150.88, 146.99,
134.58, 129.98, 120.30, 113.83, 105.58, 61.24, 56.42.;
HRMS (ESI+) m/z calculated for C17H18N2O4 ([M+H]+):
315.1339; found: 315.1336.
Yellow solid; mp 168–169 °C. Yield: 70%; Rf = 0.6 (DCM/
MeOH = 5:1, v/v); IR (KBr) 554, 694, 827, 981, 1128,
1241, 1284, 1327, 1417, 1509, 1586, 1627, 1665, 2951,
3423 cm−1; 1H NMR (600 MHz, CDCl3) δ 10.93 (s, 1H),
10.05 (s, 1H), 8.66 (s, 2H), 7.69 (s, 2H), 7.51 (d, J =
15.5 Hz, 1H), 6.61 (s, 2H), 6.55 (d, J = 15.4 Hz, 1H), 3.85

Medicinal Chemistry Research
(s, 3H), 3.78 (s, 7H); 13C NMR (151 MHz, cdcl3) δ 164.64,
163.50, 153.53, 150.62, 143.65, 140.42, 138.36, 129.66,
121.29, 115.99, 105.43, 61.07, 56.21, 32.04, 29.80, 29.47.;
HRMS (ESI+) m/z calculated for C18H19N3O5 ([M+H]+):
358.1397; found: 358.1405.
(E)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-3-(3,4,5-
trimethoxyphenyl)acrylamide (15)
White solid; mp 116–117 °C. Yield: 79%; Rf = 0.6 (DCM/
MeOH = 10:1, v/v); IR (KBr) 609, 815, 847, 924, 968, 996,
1039, 1128, 1190, 1243, 1282, 1320, 1503, 1582, 1619,
1
(E)-N-(4-methoxybenzyl)-3-(3,4,5-trimethoxyphenyl)
1655, 2935, 3327 cm−1; H-NMR (600 MHz, CDCl3) δ 7.53
acrylamide (12)
(1H, d, J = 15.5 Hz), 6.77 (1H, d, J = 7.8 Hz), 6.71 (3H, s),
6.67 (1H, d, J = 7.9 Hz), 6.23 (1H, d, J = 15.5 Hz), 5.95 (2H,
s), 5.57 (1H, t, J = 5.4 Hz), 3.88 (6H, s), 3.87 (3H, s), 3.62
(2H, q, J = 6.7 Hz), 2.81 (2H, t, J = 6.8 Hz); 13C NMR
(151 MHz, CDCl3) δ 165.88, 153.55, 148.04, 146.42, 141.27,
139.78, 132.74, 121.85, 120.01, 109.25, 108.58, 105.13,
101.10, 61.10, 56.30, 35.54; HRMS (ESI+) m/z calculated for
C21H23NO6 ([M+H]+): 386.1598; found: 386.1594.
White solid; mp 144–145 °C. Yield: 76%; Rf = 0.6 (DCM/
MeOH = 10:1, v/v); IR (KBr) 547, 611, 685, 717, 744,
826, 968, 998, 1030, 1135, 1214, 1241, 1279, 1322, 1416,
1508, 1551, 1581, 1615, 1651, 2930, 3292 cm−1 1H-
;
NMR (600 MHz, CDCl3) δ 7.56 (1H, d, J = 15.5 Hz), 7.24
(2H, d, J = 7.1 Hz), 6.86 (2H, d, J = 6.7 Hz), 6.70 (2H, s),
6.32 (1H, d, J = 15.5 Hz), 4.49 (2H, s), 3.85 (9H, d, J =
4.9 Hz), 3.78 (3H, s); 13C NMR (151 MHz, CDCl3) δ
165.71, 159.23, 153.52, 141.33, 141.31, 139.72, 129.41,
114.26, 105.07, 56.23, 55.44, 43.50; HRMS (ESI+) m/z
calculated for C20H23NO5 ([M+H]+): 358.1649; found:
358.1581.
(E)-N-(3,4-dimethoxyphenethyl)-3-(3,4,5-trimethoxyphenyl)
acrylamide (16)
White solid; mp 127–128 °C. Yield: 81%; Rf = 0.6 (DCM/
MeOH = 10:1, v/v); IR (KBr) 510, 610, 636, 673, 768, 802,
821, 846, 864, 965, 1001, 1025, 1129, 1214, 1241, 1452,
1
(E)-N-(4-fluorobenzyl)-3-(3,4,5-trimethoxyphenyl)
1516, 1583, 1622, 1657, 2383, 2929, 3011, 3285 cm−1; H-
acrylamide (13)
NMR (600 MHz, CDCl3) δ 7.52 (1H, d, J = 15.5 Hz), 6.81
(1H, d, J = 8.0 Hz), 6.74 (2H, s), 6.69 (2H, s), 6.24 (1H, d,
J = 15.5 Hz), 5.69 (1H, s), 3.85 (15H, d, J = 1.7 Hz), 3.64
(2H, q, J = 6.7 Hz), 2.83 (2H, t, J = 6.9 Hz); 13C NMR
(151 MHz, CDCl3) δ 165.92, 153.51, 147.86, 141.12, 139.72,
131.45, 130.46, 120.79, 112.12, 111.54, 105.07, 61.05, 56.25,
56.05, 56.02, 40.96, 35.29; HRMS (ESI+) m/z calculated for
C21H23NO6 ([M+H]+): 402.1911; found: 402.1909.
White solid; mp 152–153 °C. Yield: 85%; Rf = 0.6 (DCM/
MeOH = 10:1, v/v); IR (KBr) 563, 614, 684, 738, 829, 968,
999, 1030, 1134, 1216, 1241, 1279, 1323, 1418, 1509,
1554, 1581, 1615, 1651, 2839, 2933, 3073, 3290 cm−1; 1H-
NMR (600 MHz, CDCl3) δ 7.58 (1H, d, J = 15.5 Hz), 7.29
(1H, dd, J = 8.6, 5.4 Hz), 7.02 (1H, t, J = 8.7 Hz), 6.72 (2H,
s), 6.32 (1H, d, J = 15.5 Hz), 5.93 (1H, t, J = 4.9 Hz), 4.54
(2H, d, J = 5.8 Hz), 3.86 (9H, d, J = 1.9 Hz); 13C NMR
(151 MHz, CDCl3) δ 165.87, 163.26, 153.62, 141.78,
139.92, 134.23, 130.46, 129.77, 119.80, 115.73, 105.20,
61.17, 56.34, 43.36; HRMS (ESI+) m/z calculated for
C19H20NFO4 ([M+H]+): 396.1417; found: 396.1436.
(E)-1-(4-(4-fluorophenyl)piperazin-1-yl)-3-(3,4,5-
trimethoxyphenyl)prop-2-en-1-one (17)
Pale-yellow solid; mp 134–135 °C. Yield: 70%; Rf = 0.7
(DCM/MeOH = 10:1, v/v); IR (KBr) 519, 610, 711, 738,
824, 913, 996, 1042, 1128, 1236, 1334, 1450, 1512, 1601,
2819 cm−1; 1H-NMR (600 MHz, CDCl3) δ 7.62 (1H, d, J =
15.3 Hz), 6.99 (2H, t, J = 8.6 Hz), 6.90 (2H, dd, J = 7.9,
5.6 Hz), 6.79 (1H, d, J = 15.4 Hz), 6.75 (2H, s), 3.90 (6H,
s), 3.89 (2H, t, J = 3.1 Hz), 3.88 (3H, s), 3.84 (2H, s), 3.14
(5H, t); 13C NMR (151 MHz, CDCl3) δ 165.67, 153.67,
147.81, 143.49, 139.97, 130.95, 118.84, 118.79, 116.23,
116.03, 115.89, 105.31, 61.20, 56.47; HRMS (ESI+) m/z
calculated for C22H25FN2O4 ([M+H]+): 401.1871; found:
401.1874.
(E)-N-(4-chlorobenzyl)-3-(3,4,5-trimethoxyphenyl)
acrylamide(14)
White solid; mp 143–144 °C. Yield: 80%; Rf = 0.6 (DCM/
MeOH = 10:1, v/v); IR (KBr) 547, 611, 684, 717, 744, 826,
968, 998, 1030, 1134, 1214, 1241, 1279, 1322, 1416, 1508,
1550, 1581, 1615, 1650, 2930, 3292 cm−1
;
1H-NMR
(600 MHz, CDCl3) δ 7.60 (1H, s), 7.31 (2H, d, J =
8.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 6.73 (2H, s), 6.32 (1H, d,
J = 15.5 Hz), 5.88 (1H, t, J = 5.8 Hz), 4.55 (2H, d, J =
5.9 Hz), 3.87 (6H, s), 3.87 (3H, s); 13C NMR (151 MHz,
CDCl3) δ 165.85, 141.88, 136.90, 133.59, 130.36, 129.38,
129.04, 119.61, 105.17, 61.11, 56.29, 43.31; HRMS (ESI+)
m/z calculated for C19H20NClO4 ([M+H]+): 362.1159;
found: 362.1147.
1-(piperidin-1-yl)-3-(3,4,5-trimethoxyphenyl)propan-1-one
(18)
Pale-yellow solid; mp 76–77 °C. Yield: 62%; Rf = 0.4
(DCM/MeOH = 10:1, v/v); IR (KBr) 533, 560, 672, 748,

Medicinal Chemistry Research
Table 1 Anticonvulsant activity in the preliminary MES model
(100 mg/kg) and ClogP of compounds administered i.p. to mice
778, 839, 906, 1002, 1126, 1184, 1236, 1315, 1342, 1451,
1507, 1590, 1638, 2928, 2999, 3445 cm−1
;
1H-NMR
Com.
0.5 h
1 h
2 h
3 h
4 h
ClogPa
(600 MHz, CDCl3) δ 6.42 (s, 2H), 3.81 (d, J = 20.0 Hz,
9H), 3.54 (t, J = 5.6 Hz, 2H), 3.35 – 3.31 (m, 2H), 2.89 (dd,
J = 9.2, 6.7 Hz, 2H), 2.59 (dd, J = 8.9, 6.9 Hz, 2H), 1.59
(qd, J = 7.0, 5.9, 4.2 Hz, 2H), 1.50 (q, J = 6.4, 5.9 Hz, 2H),
1.47–1.41 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 170.46,
153.33, 137.47, 105.53, 60.97, 56.26, 46.81, 42.89, 35.38,
32.23, 26.59, 25.73, 24.66; HRMS (ESI+) m/z calculated
for C17H25NO4 ([M+H]+): 308.1856; found: 308.1874.
NS
CBZ
AER
1
0b/4c
5/6
4/4
0/4
0/4
2/4
4/4
3/4
2/4
3/4
1/4
4/4
3/4
1/4
3/4
1/4
1/4
2/4
4/4
3/4
3/4
0/4
6/6
2/4
0/4
0/4
2/4
4/4
3/4
1/4
1/4
1/4
2/4
1/4
0/4
3/4
0/4
0/4
2/4
2/4
2/4
1/4
0/4
4/6
1/4
0/4
0/4
0/4
3/4
2/4
0/4
0/4
0/4
1/4
0/4
0/4
2/4
0/4
0/4
1/4
1/4
0/4
1/4
0/4
4/6
0/4
0/4
0/4
0/4
1/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
2/6
0/4
0/4
0/4
0/4
1/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
–
2.38
2.86
2.69
3.14
1.05
2.17
1.49
2.30
2.30
3.79
2.32
2.00
1.25
2.79
3.02
3.59
3.17
2.86
3.37
1.38
2
3
4
5
(E)-3-(benzo[d][1,3]dioxol-5-yl)-1-(piperidin-1-yl)prop-2-en-
1-one (antiepilepsirine)
6
7
8
Yellow solid; mp 80–81 °C. Yield: 60%; Rf = 0.7 (DCM/
MeOH = 10:1, v/v); IR (KBr) 522, 598, 821, 857, 933, 977,
1041, 1102, 1139, 1251, 1298, 1357, 1445, 1450, 1494,
1590, 1643, 2927, 3444 cm−1; 1H-NMR (600 MHz, CDCl3)
δ 7.56 (d, J = 15.3 Hz, 1H), 7.11 – 6.94 (m, 2H), 6.85 –
6.67 (m, 2H), 5.98 (s, 2H), 3.61 (d, J = 51.0 Hz, 4H), 1.60
(q, J = 5.7 Hz, 5H), 1.53 (q, J = 5.7 Hz, 2H); 13C NMR
(151 MHz, cdcl3) δ 165.63, 149.02, 148.38, 142.14, 130.15,
123.77, 115.91, 108.68, 106.55, 101.58, 53.30, 26.13,
24.88; HRMS (ESI+) m/z calculated for C22H25FN2O4 ([M
+H]+): 260.1281; found: 260.1299.
9
10
11
12
13
14
15
16
17
18
AER antiepilepsirine
aClogP was calculated by utilizing the ChemBioDraw Ultra (v13.0)
Pharmacology
(Cambridgesoft, Billerica, MA, USA)
MES test
bProtect mice
cTotal mice
In the initial MES test, all the compounds exhibited protection
of the tested mice after 0.5 h except compounds 1 and 2
(Table 1), indicative of their ability to prevent seizure spread.
Compounds which were significantly active at 100 mg/kg
after 0.5 h in MES test included 4, 9, 16 and antiepilepsirine,
indicative of their good ability to protect from seizure. Among
these compounds, compound 4 was even effective at the same
dose after 4 h. This result revealed that these compounds have
quick onset and long duration of action at relatively higher
dose. Furthermore, we evaluated the protective effect of the
derivatives at lower dosage. The ED50 values of potent active
compounds 4, 9 and 16 were 12.2, 35.4 and 34.5 mg/kg,
respectively. The most active compound 4 was even better
than that of antiepilepsirine used as reference drug. As for the
protective index, compound 4 exhibited higher value than
CBZ and antiepilepsirine.
and latent time at the dose of 100 mg/kg, while compounds
9 and 16 showed weak anticonvulsant effect at this con-
centration. Compounds 4 and 16 significantly extended the
latent time of clonic seizure (P < 0.01). The ED50 values of
potent active compounds 4, 9 and 16 were 81.0, 198.5 and
165.1 mg/kg, respectively. Compared to reference com-
pounds CBZ and antiepilepsirine, the test compounds
showed moderate effect in this model.
NT screening
In the NT screen, compounds 9 and 16 showed weak NT in
the maximum dose administered (1000 mg/kg) (Table 2).
To our dismay, the most active compound 4 exerted marked
toxicity, and the protective index was close to reference
compounds CBZ and antiepilepsirine.
scPTZ-induced seizure test
The anticonvulsant activity of active compounds 4, 9 and 16
was further evaluated in scPTZ-induced seizure in mice
(Table 2). The result exhibited that compound 4 could
effectively inhibit the scPTZ-induced seizure in protect ratio
Locomotor activity
As shown in Table 3, i.p. administration of compounds 4, 9
and 16 at the dose of 100 kg/mg significantly reduced the

Medicinal Chemistry Research
Table 2 Further screening for some active compounds
Com.
ED50 (MES)
scPTZ (100 mg/kg)
ED50 (scPTZ)
TD50
PIa
Protect animals
Latent time (s)
MES
scPTZ
NS
CBZd
AER
4
---
0b/4c
---
170.8 23.3
---
227.3 14.5**
230.0 25.0**
174.5 22.9
221.3 21.1**
---
---
---
---
8.8 (5.5–14.1)
15.2 (8.4–30.0)
12.2 (5.2–24.4)
35.4 (19.6–67.6)
34.5 (15.8–59.4)
>100
71.6 (45.9–135.0)
80.0 (56.0–118.5)
75.2 (47.4–110.7)
>1000
8.1
5.4
6.2
28.2
21.5
0.7
1.0
0.9
5.0
4.5
3/4
3/4
1/4
1/4
83.5 (57.0–137.8)
81.0 (50.7–191.8)
198.5 (120.7–305.2)
165.1 (101.3–247.2)
9
16
743.3 (477.1–879.8)
AER antiepilepsirine
aPI: protective index (TD50/ED50)
bProtected mice
cTotal mice; **P < 0.01, 95% confidence intervals given in parentheses
dReference drug, data from Ucar et al. (1998)
Table 3 Effect of compounds 4,
9 and 16 on locomotor activity
in mice (n = 4)
Com.
Dosage (mg/kg)
Before
Locomotor activity (times, x s)
0.5 h
1 h
2 h
NS
Diazepama
143.5 9.4
169.9 32.7
149.0 7.8
134.8 52.5
158.8 38.7
160.0 15.7
94.0 24.0
159.0 11.7
134.1 39.9
0.1 0.4**
4.0 2.3**
57.5 23.9
22.3 5.7**
93.8 44.9
30.2 17.8**
112.5 23.6
135.7 19.8
0.1 0.4**
152.6 26.5
0.0 0.0**
20
4
100
20
11.8 3.7**
59.25 30.4
29.5 14.9**
74.8 19.9
29.3 3.5**
106 28.5
21.7 5.7**
47.8 30.4
36.8 19.4**
72.0 43.7
33.0 17.4**
113 22.3
9
100
20
16
100
20
aReference drug, data from Chen et al. (2011)
**P < 0.01, 95% confidence intervals given in parentheses
Table 4 Effect of compounds 4, 9 and 16 on pentobarbital sodium-
induced sleeping in mice (n = 4)
locomotor activity compared to the Normal saline (NS) group
(P < 0.01). When the dosage was adjusted to 20 mg/kg, the
decrease of locomotor activity had no statistical significance,
which indicated that the compounds exhibited a sedative
effect at the concentration of 100 mg/kg in this model.
Com.
Dosage (mg/ Latent time of
Duration time of
sleeping (min)
kg)
sleeping (min)
NS
4.0 0.2
32.8 4.6
Diazepam
4
2.8 0.3**
3.5 0.4
91.0 4.5**
82.0 7.9**
71.2 3.3**
63.8 4.0**
Pentobarbital sodium-induced sleeping
4
10
10
10
9
3.17 0.3**
3.0 0.5**
Based on our experiment data (Table 4), compounds 4, 9
and 16 significantly lengthened the duration time of sleep-
ing induced by pentobarbital sodium compared to negative
control (P < 0.01) at the dose of 10 mg/kg. Among them,
compound 4 was the most potent sedative compound in
comparison with positive control. As for the latent time of
sleeping, compounds 9 and 16 were statistically effective
while compound 4 was invalid.
16
**P<0.01, 95% confidence intervals given in parentheses
anticonvulsant compounds in this study, were selected as
ligand examples. To gain insight into the interaction of
GABA receptor with compounds 4, 9 and 16, it was docked
on to GABA transferas (PDB ID: 1OHW) using SYBYL-X
2.0 software. As shown in Table 5, total score of com-
pounds was evaluated, and vitamin B6 phosphate was used
as reference standard. When the score was >5, it indicated
that the drug could interact with the protein. The docking
result showed that compounds 4 and 16 could bond to the
Docking analysis
Based on the pharmacology evaluation results, the most
potent compounds 4,
9 and 16, our best active

Medicinal Chemistry Research
Table 5 Docking score of synthesized derivatives 4, 9 and 16
Compound
Total score Amino acid interactions
4
9.074
<0
Arg 192, Thr 353
9
16
9.922
Glu 301, Glu 270
1OHW-ligand 11.5271
Arg 192, Thr 353, Trp 354, Gln 301
Fig. 3 Docking mode of compound 4 (green) at GABA transferas
Fig. 4 Preliminary
structure–activity relationship of
TMCA amide derivatives
protein with good scores, while the compound 9 did not
interact with the protein, suggesting that compound 9 could
possess anticonvulsant effect mediated by other targets. The
intermolecular hydrogen-bonding interactions of 4 were
mainly seen with the Arg 192 and Thr 353 (dotted yellow line
in Fig. 2), which are partly similar to the original ligand of
1OHW. Compound 4 and the original ligand (purple mole-
cule in Fig. 3) could be observed in the cavity of 1OHW,
which demonstrated the rationality of the docking study.
for the anticonvulsant agents to traverse the blood–brain
barrier. Additionally, compounds 9 and 16 are the multi-
methoxyphenyl-substituted derivatives and compound 4 is
substituted by piperidine, which indicates that multi-
methoxyphenyl and piperidine could be the potential
active functional groups. Compared with the saturated
double bond derivative 18, compound 4 displayed superior
activity in in vivo anticonvulsant test, suggesting that C = C
bond is essential for the pharmacology property. Addi-
tionally, substituted 3,4,5-trimethoxyl was supposed to be
better than 3,4-dioxymethyl according to the result. 3,4-
Dioxymethyphenyl group has distributed in marketed
anticonvulsant drugs Stiripentol and antiepilepsirine, while
the 3,4,5-trimethoxyphenyl moiety has not been widely
investigated in this field. Further research should focus on
retaining effective groups and attenuating the toxicity of the
derivatives, especially heterocyclic amides, and definite
targets are needed to prove in vitro as well. Above all, it
could be concluded that compounds 4, 9 and 16 are
worthwhile precursors for further investigation in the
development of anticonvulsant and sedative agents.
Conclusion
In summary, based on the structure of the anticonvulsant
active compound antiepilepsirine and TMCA, we rationally
designed and successfully synthesized the derivatives of
TMCA amide using the reaction of coupling reagent EDCI/
HOBT as an efficient catalyst at room temperature. This
method gives high yield of pure products in a short reaction
time, and the reaction condition is also easy to control. All the
derivatives were primarily evaluated for their anticonvulsant
effect using the MES. Compounds 4, 9 and 16 exhibited
moderate activity and were tested for the activity in sc-PTZ
model, NT, locomotor activity and pentobarbital sodium-
induced sleeping model, respectively. Furthermore, the mole-
cular modeling results also predicted good binding interactions
of most active molecules with GABA transferas (1OHW).
As for the structure–activity relationship (Fig. 4), firstly,
the ClogP values of active compounds 4, 9 and 16 range
from 2 to 3, as well as positive controls CBZ and anti-
epilepsirine, revealing that appropriate polarity is necessary
Acknowledgements This work was supported by the Changjiang
Scholars and Innovative Research Team in Universities, Ministry of
Education of China (IRT_15R55), the 7th Group of Hundred-Talent
Program of Shaanxi Province (2015), and Natural Science Foundation
of Shaanxi Province, China (Grant No. 2017JM8054).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.

Medicinal Chemistry Research
References
Kamal A, Bajee S, Lakshma Nayak V, Venkata Subba Rao A,
Nagaraju B, Ratna Reddy C, Jeevak Sopanrao K, Alarifi A (2016)
Synthesis and biological evaluation of arylcinnamide linked
combretastatin-A4 hybrids as tubulin polymerization inhibitors
and apoptosis inducing agents. Bioorg Med Chem Lett
26:2957–2964
Klein Jr LC, de Andrade SF, Cechinel Filho V (2012) A pharma-
cognostic approach to the Polygala genus: phytochemical and
pharmacological aspects. Chem Biodivers 9:181–209
Lee CI, Han JY, Hong JT, Oh KW (2013) 3,4,5-Trimethoxycinnamic
acid (TMCA), one of the constituents of Polygalae Radix
enhances pentobarbital-induced sleeping behaviors via GABA(A)
ergic systems in mice. Arch Pharm Res 36:1244–1251
May BH, Lu C, Lu Y, Zhang AL, Xue CC (2013) Chinese herbs for
memory disorders: a review and systematic analysis of classical
herbal literature. J Acupunct Meridian Stud 6:2–11
Mujumdar AM, Dhuley JN, Deshmukh VK, Raman PH, Thorat SL,
Naik SR (1990) Effect of piperine on pentobarbitone induced
hypnosis in rats. Indian J Exp Biol 28:486–487
Sahu M, Siddiqui N, Iqbal R, Sharma V, Wakode S (2017) Design,
synthesis and evaluation of newer 5,6-dihydropyrimidine-2(1H)-
thiones as GABA-AT inhibitors for anticonvulsant potential.
Bioorg Chem 74:166–178
Seo YH, Kim JK, Jun JG (2014) Synthesis and biological evaluation
of piperlongumine derivatives as potent anti-inflammatory agents.
Bioorg Med Chem Lett 24:5727–5730
Swinyard EA (1969) Laboratory evaluation of antiepileptic drugs.
Review of laboratory methods. Epilepsia 10:107–119
Ucar H, Van dK, Cacciaguerra S, Spampinato S, Stables JP, Depovere
P, Isa M, Masereel B, Delarge J, Poupaert JH (1998) Synthesis
and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-
benzothiazolone derivatives. J Med Chem 41:3102
Al-Baghdadi OB, Prater NI, Van der Schyf CJ, Geldenhuys WJ (2012)
Inhibition of monoamine oxidase by derivatives of piperine, an
alkaloid from the pepper plant Piper nigrum, for possible use in
Parkinson’s disease. Bioorg Med Chem Lett 22:7183–7188
Carreiro EP, Louro P, Adriano G, Guedes RA, Vannuchi N, Costa AR,
Antunes CM, Guedes RC, Burke AJ (2014) 3-Hydroxypyrrolidine
and (3,4)-dihydroxypyrrolidine derivatives: inhibition of rat
intestinal alpha-glucosidase. Bioorg Chem 54:81–88
Chen CY, Wei XD, Chen CR (2016) 3,4,5-Trimethoxycinnamic acid,
one of the constituents of Polygalae Radix exerts anti-seizure
effects by modulating GABAAergic systems in mice. J Phar-
macol Sci 131:1–5
Chen CY, Li W, Qu KP, Chen CR (2013) Piperine exerts anti-seizure
effects via the TRPV1 receptor in mice. Eur J Pharmacol
714:288–294
Chen H, Chen H, Bai X, Li Y, Yin S (2011) Synthesis and calm
activity of helicid-pyrazoline derivatives. Chin J Org Chem
31:231–234
da Cruz GM, Felipe CF, Scorza FA, da Costa MA, Tavares AF, Menezes
ML, de Andrade GM, Leal LK, Brito GA, da Graca Naffah-
Mazzacoratti M, Cavalheiro EA, de Barros Viana GS (2013)
Piperine decreases pilocarpine-induced convulsions by GABAergic
mechanisms. Pharmacol Biochem Behav 104:144–153
Dunham NW, Miya TS, Edwards LD (1957) The pharmacological
activity of a series of basic esters of mono- and dialkylmalonic
acids. J Am Pharm Assoc Am Pharm Assoc 46:64–66
Gunia-Krzyzak A, Panczyk K, Waszkielewicz AM, Marona H (2015)
Cinnamamide derivatives for central and peripheral nervous
system disorders--a review of structure-activity relationships.
ChemMedChem 10:1302–1325
Vamecq J, Lambert D, Poupaert JH, Masereel B, Stables JP (1998)
Anticonvulsant activity and interactions with neuronal voltage-
dependent sodium channel of analogues of ameltolide. J Med
Chem 41:3307–3313
Wang L, Vieth R, Landes RC, Suzuki Y, Walson PD (1993) Anti-
epileptic effect of antiepilepsirine in pentylenetetrazol and
amygdala kindled rats. Epilepsy Res 15(1):1–5
Wang L, Zhao D, Zhang Z, Zuo C, Zhang Y, Pei YQ, Lo YQ (1999)
Trial of antiepilepsirine (AES) in children with epilepsy. Brain
Dev 21:36–40
Yang T, Kong B, Gu JW, Kuang YQ, Cheng L, Yang WT, Cheng JM,
Ma Y, Yang XK (2013) Anticonvulsant and sedative effects of
paederosidic acid isolated from Paederia scandens (Lour.) Mer-
rill. in mice and rats. Pharmacol Biochem Behav 111:97–101
Gunia-Krzyzak A, Zelaszczyk D, Rapacz A, Zeslawska E, Waszkie-
lewicz AM, Panczyk K, Sloczynska K, Pekala E, Nitek W,
Filipek B, Marona H (2017) Structure-anticonvulsant activity
studies in the group of (E)-N-cinnamoyl aminoalkanols deriva-
tives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3.
Bioorg Med Chem 25:471–482
Gupta G, Kazmi I, Afzal M, Rahman M, Saleem S, Ashraf MS,
Khusroo MJ, Nazeer K, Ahmed S, Mujeeb M, Ahmed Z, Anwar
F (2012) Sedative, antiepileptic and antipsychotic effects of
Viscum album L. (Loranthaceae) in mice and rats. J Ethno-
pharmacol 141:810–816
Jung JC, Moon S, Min D, Park WK, Jung M, Oh S (2013) Synthesis
and evaluation of a series of 3,4,5-trimethoxycinnamic acid
derivatives as potential antinarcotic agents. Chem Biol Drug Des
81:389–398