Synthesis and Evaluation of 5-(o-Tolyl)-1H-tetrazole Derivatives as Potent Anticonvulsant Agents

Article abstract of DOI:10.1002/ardp.201600389

A series of 5-(o-tolyl)-1H-tetrazole derivatives were synthesized and evaluated for their anticonvulsant activities. 1-(2-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed important anticonvulsant activity against the MES-induced seizures, as well as low

Full text of DOI:10.1002/ardp.201600389

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Full Paper
Synthesis and Evaluation of 5-(o-Tolyl)-1H-tetrazole Derivatives as
Potent Anticonvulsant Agents
Shiyang Dong1,2ꢀ, Tiantian Wang1,3ꢀ, Huayu Wang1, Kun Qian1, Zhongli Zhang1, Yueming Zuo1,
1
Guangming Luo1, Yi Jin1,3, and Zengtao Wang
1
College of Pharmacy, JiangXi University of Traditional Chinese Medicine, Nanchang, China
College of Pharmacy, Hubei University of Science and Technology, Xianning, China
The National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine,
2
3
Nanchang, China
A series of 5-(o-tolyl)-1H-tetrazole derivatives were synthesized and evaluated for their anticonvulsant
activities. 1-(2-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed important anticonvulsant activity
against the MES-induced seizures, as well as lower neurotoxicity with an ED50 value of 12.7 mg/kg
and a TD50 value of over 500 mg/kg after intraperitoneal injection into mice, providing 3h with a
high protective index (TD50/ED50) of over 39.4. The achieved results prove that the distinctive
compounds could be valuable as a model for future development, adaptation, and investigation to
construct more active analogues.
Keywords: 5-(o-Tolyl)-1H-tetrazole derivatives / Anticonvulsant / Synthesis
Received: December 22, 2016; Revised: March 18, 2017; Accepted: March 27, 2017
DOI 10.1002/ardp.201600389
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
with 1-(o-tolyl)-1H-1,2,4-triazole moiety, which showed prom-
ising anticonvulsant activities with ED50 values of 13.9 mg/kg in
Introduction
The derivatives of tetrazoles exhibit a variety of biological
activities, such as antibiotic [1], anti-allergic [2], anti-
inflammatory [2], antihypertensive [3], and antiviral activi-
ties [4]. So far, many tetrazole-based derivatives have been
successfully developed and prevalently used as clinical drugs
such as antihypertensive losartan [5], antibacterial cefora-
nide [6], anticoagulant cilostazol [7], anti-asthmatic pranlu-
kast [8], diuretic azosemide [9], and antinociceptive
alfentanil [10, 11].
MES screen and 81.6 mg/kg in scPTZ test, respectively. The
substitution in the ortho-position of the phenyl ring with
electron-donating groups was generally beneficial to activ-
ity [13], and the importance of the ortho-methyl group for
anticonvulsant activity had been depicted in many studies
[14–17] including the recently marketed drug tiagabine.
Based on the above structural characteristics, it was
assumed that the compound containing ortho-methylphenyl
group moiety in a single molecule could be beneficial to
anticonvulsant activity. In view of this structural estimation
and the important biological activity of tetrazole-based
derivatives, it has been planned to synthesize and evaluate
a series of 5-(o-tolyl)-1H-tetrazole derivatives as anticonvul-
sant agents. The structures of designed compounds along
with compound I are shown in Fig. 1.
Quite recently, Siddiqui et al. designed a series of triazole-
based anticonvulsant agents [12], which have shown consider-
able anticonvulsant activities. Especially, compound I (Fig. 1)
Correspondence: Dr. Zengtao Wang, Department of Medicinal
Chemistry, College of Pharmacy, JiangXi University of Traditional
Chinese Medicine, Nanchang 330004, China.
E-mail: zengtaowang@126.com
Fax: þ86-791-87118911
ꢀThese authors contributed equally to this article.
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In addition, all the compounds of the in vivo screening were
evaluated against the minimal motor impairment in the
rotarod test, and showed low toxicity. Especially, 3b, 3d, and
3f–h showed non-toxic behavior at the maximum dose of
300 mg/kg after both the time durations. The compounds 3a,
3c, 3e, 3i, and 3j elucidated neurotoxicity at 300 mg/kg at 0.5 h
followed by an increase in non-toxic potential except 3a and
3e after delayed absorption at 4 h by preventing minimal
motor impairment.
Figure 1. The modification of 5-(o-tolyl)-1H-tetrazole.
As a result of preliminary screening, the most active
compounds 3f and 3h were subjected to further investigations
at different doses for quantification of their anticonvulsant
activity (indicated by ED50) and neurotoxicity (indicated by
TD50) in mice (Table 2). The selected compounds 3f and 3h
displayed anticonvulsant activity against MES-induced seizure
with ED50 values of 39.9 and 12.7 mg/kg and TD50 values of
449.8 and over 500 mg/kg, respectively.
Results and discussion
Chemistry
Target compounds 3a–j were prepared according to Scheme 1.
o-Tolunitrile 1 was reacted with sodium azide (NaN3) in dry
toluene in the presence of triethylamine hydrochloride at
100°C to afford quantitative yield of 5-(o-tolyl)-1H-tetrazole
(2), which was treated with different substituted benzyl
chlorides in acetonitrile at 60°C to furnish target compounds
3a–j in a good yield.
Conclusion
Pharmacology
In summary, a series of 5-(o-tolyl)-1H-tetrazole derivatives
were synthesized and evaluated in in vivo animal models of
epilepsy. The results of this study demonstrated that some
5-(o-tolyl)-1H-tetrazole derivatives possess a good anticon-
The anticonvulsant activity of the synthesized compounds
(3a–j) was determined using two animal models of seizure
according to the standard protocols within the Antiepileptic
Drug Development (ADD) Program at National Institute of
Neurological Disorders and Stroke, National Institutes of
Health, Rockville, USA which included maximal electroshock
seizure (MES) [18] and subcutaneous pentylenetetrazole
(scPTZ) [19]. Almost all clinically significant AEDs are
protective in at least one of these two models [20–23]. In
addition to the initial anticonvulsant screen, acute neuro-
toxocity (NT) was evaluated in the rotarod test [24]. The
results of anticonvulsant activity and NT studies are summa-
rized in Table 1.
vulsant activity. Specially, 3f and 3h possess
a good
anticonvulsant activity and low toxicity in MES model.
The obtained results showed that certain compounds could
be useful as a template for future design, modification, and
investigation to produce more active analogues.
Experimental
Chemistry
As seen in Table 1, 3e, 3f, and 3h–j compounds among the
tested compounds exhibited considerable anticonvulsant activi-
ties in the MES test. The most active of these compounds were 3f
and 3h which showed 100% protection at a dose of 30 mg/kg at
0.5 and 4 h post administration. In the scPTZ screen, a test used to
identify compounds that elevate seizure threshold, 3d, 3f, 3g, 3i,
and 3j showed protection at 300 mg/kg after 0.5 h and only 3f
amongthesecompoundscontinuedtoshowactivityafter4.0 hat
300 mg/kg dose.
Melting points were determined in open capillary tubes and
were uncorrected. 1H-NMR spectra were measured on a Bruker
Avance 600 MHz NMR spectrometer, with all chemical shifts
giveninppmrelativetotetramethylsilane.Chemicalshiftvalues
are in hertz. Splitting patterns are indicated as s, singlet; d,
doublet; t, triplet; m, multiplet; dd, doublet of doublets; td,
triplet of doublets; for 1H-NMR data. High resolution
mass spectra were recorded on an AB SCIEX Triple TOFTM
5600 equipped with an electrospray ionization source. Ethyl
Scheme 1. The synthesis route of target compounds 3a–j.
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5-(o-Tolyl)-1H-tetrazoles as Anticonvulsant Agents
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Table 1. Phase I anticonvulsant activity and neurotoxocity of compounds 3a–j administered intraperitoneally to mice.
Intraperitoneal injection in micea)
MES screeningb)
0.5 h 4 h
scPTZ screeningc)
NT screeningd)
Compounds
R
0.5 h
4 h
0.5 h
4 h
3a
3b
3c
3d
3e
3f
3g
3h
4-CH3
4-C(CH3)3
4-CF3
4-NO2
4-F
3-F
2-F
2-CH3
2-Cl
2,6-di-F
–
–
100
–
–
–
–
–
300
–
300
–
–
–
–
–
300
–
–
–
100
300
30
–
300
–
–
–
300
30
–
–
300
–
300
–
300
300
–
300
–
–
–
30
100
300
30
30
30
300
30
–
–
–
3i
3j
300
300
–
–
300
300
100
–
–
–
Phenytoin
–
100
a) Doses of 30, 100, and 300 mg/kg were administered. The animals were examined 0.5 and 4.0 h after injection were made. The
dash (ꢃ) indicates the absence of activity at maximum dose administered (300 mg/kg).
b) Maximal electroshock test.
c) Subcutaneous pentylenetetrazole test.
d) Neurotoxocity screening (rotarod test).
acetate/n-hexane (1:3) (2) and ethyl acetate/n-hexane (1:9) (3a–
j) were used as developing solvent for TLC. The major chemicals
were purchased from Xiya Reagent Co., Ltd (China).
filtration, the crude solid was recrystallized from ethyl
acetate/hexane to give white crystals. Yield: 64.1%; Rf ¼ 0.52;
white solid; mp: 153–155°C. FT-IR: 3200–2300 (w, n(N–H)),
3029 (w, n(C–H)), 2970 (w, n(CH3)), 1900–1600 (w, overtones d
The 1H and MS spectra and the InChI codes of the
investigated compounds together with some biological
activity data are provided as Supporting Information.
–
–
(C–H, Ph)), 1607 (s, n(C C)), 1562 (s, d(N–H)), 1485 (s, n(C C)),
–
–
1
1463 (s, d(CH3)), 744 (s, d(C–H, Ph)) cmꢃ1; H-NMR (DMSO-d6,
600 MHz) d: 7.69 (d, 1H, ArH, J ¼ 7.8 Hz), 7.49 (td, 1H, ArH,
J ¼ 1.2, 7.2 Hz), 7.44 (d, 1H, ArH, J ¼ 7.8 Hz), 7.40 (dt, 1H, ArH,
J ¼ 1.2, 7.2 Hz), 2.48 (s, 3H, CH3). ESI–HRMS calcd. for C8H8N4
([MþH]þ): 161.0749; found: 161.0825.
Synthesis of 5-(o-tolyl)-1H-tetrazole (2)
NaN3 (0.30 g, 4.5 mmol) was added to
a mixture of
2-methylbenzonitrile
1
(0.36 g, 3 mmol) and Et3N ꢁ HCl
(0.62 g, 4.5 mmol) in toluene (10 mL) with stirring at room
temperature. The reaction temperature was raised up to
100°C for about 13 h. After completion of reaction (monitored
by thin-layer chromatography, TLC), the reaction mixture was
cooled and extracted with water (3 ꢂ 30 mL). The water layers
were combined. A total of 20% HCl was added dropwise to
the aqueous phase to precipitate the crude product. After
General procedure for the synthesis of 3a–j
A mixture of 5-(o-tolyl)-1H-tetrazole 2 (0.161 g, 1 mmol),
halides (1.2 mmol), K2CO3 (0.276 g, 2 mmol), and catalytic
amounts of KI in 10 mL acetonitrile was heated to 60°C for
about 3 h. After completion of reaction (monitored by TLC),
the mixture was poured into water and extracted with ethyl
Table 2. Phase II quantitative anticonvulsant evaluation in MES model in mice (test drug administered i.p.).
TPE (h)a)
ED50
TD50
PId)
b)
c)
Compounds
3f
3h
0.8
0.8
2
39.9 (18.6–63.8)e)
12.7 (2.9–21.0)
9.5 (8.1–10.4)
449.8 (390.1–796.9)
>500
65.5 (52.5–72.9)
69 (62.8–72.9)
11.3
>39.4
6.9
Phenytoin
Phenobarbital
1
21.8 (21.8–25.5)
3.2
a) Time to peak effect.
b) ED50: median effective dose affording anticonvulsant protection in 50% of animals; the dose is measured in mg/kg.
c) TD50: median toxic dose eliciting minimal neurological toxicity in 50% of animals; the dose is measured in mg/kg.
d) PI: protective index (TD50/ED50).
e) 95% confidence intervals given in parentheses.
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acetate. The organic layer was dried (MgSO4), concentrated
and purified by silica gel column.
1-(2-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h)
Yield: 41.6%; Rf ¼ 0.65; white solid; mp: 63–65°C; 1H-NMR
(CDCl3, 600 MHz): d 2.53 (s, 3H, Ar2–CH3), 2.64 (s, 3H, Ar1–CH3),
5.86 (s, 2H, CH2), 7.24–7.27 (m, 2H, ArH), 7.30–7.35 (m, 4H,
ArH), 7.36–7.39 (m, 1H, ArH), 8.05 (d, 1H, J ¼ 7.8 Hz, ArH).
ESI–HRMS calcd. for C16H16N4 ([MþH]þ): 265.1375; found:
265.1450.
1-(4-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3a)
Yield: 50.2%; Rf ¼ 0.53; white solid; mp: 89–91°C; 1H-NMR
(CDCl3, 600 MHz): d 2.37 (s, 3H, Ar2–CH3), 2.63 (s, 3H, Ar1–CH3),
5.80 (s, 2H, CH2), 7.21 (d, 2H, J ¼ 7.8 Hz, Ar2H), 7.30–7.33 (m,
2H, ArH), 7.35–7.38 (m, 3H, ArH), 8.01 (d, 1H, J ¼ 7.8 Hz, ArH).
ESI–HRMS calcd. for C16H16N4 ([MþH]þ): 265.1375; found:
265.1452.
1-(2-Chlorobenzylbenzyl)-5-(o-tolyl)-1H-tetrazole (3i)
Yield: 45.3%; Rf ¼ 0.61; white solid; mp: 54–56°C; 1H-NMR
(CDCl3, 600 MHz): d 2.64 (s, 3H, CH3), 6.00 (s, 2H, CH2), 7.23
(dd, 1H, J ¼ 1.2, 7.2 Hz, ArH), 7.29 (td, 1H, J ¼ 1.2, 7.8 Hz,
ArH), 7.32–7.35 (m, 3H, ArH), 7.37–7.39 (m, 1H, ArH), 7.47
(dd, 1H, J ¼ 1.2, 7.8 Hz, ArH), 8.02 (d, 1H, J ¼ 7.2 Hz, Ar1H).
ESI–HRMS calcd. for C15H13ClN4 ([MþH]þ): 285.0829; found:
285.0899.
1-(4-(tert-Butyl)benzyl)-5-(o-tolyl)-1H-tetrazole (3b)
Yield: 65.3%; Rf ¼ 0.62; colorless oily liquid; 1H-NMR (CDCl3,
600 MHz): d 1.35 (s, 9H, CH3), 2.68 (s, 3H, CH3), 5.83 (s, 2H, CH2),
7.32–7.35 (m, 2H, ArH), 7.37–7.40 (m, 1H, ArH), 7.42–7.46 (m,
4H, ArH), 8.06 (d, 1H, J ¼ 7.2 Hz, ArH). ESI–HRMS calcd. for
C
19H22N4 ([MþH]þ): 307.1844; found: 307.1915.
1-(2,6-Difluorobenzyl)-5-(o-tolyl)-1H-tetrazole (3j)
Yield: 53.1%; Rf ¼ 0.44; white solid; mp: 80–82°C; 1H-NMR
(CDCl3, 600 MHz): d 2.61 (s, 3H, CH3), 5.94 (s, 2H, CH2), 7.01 (t,
2H, J ¼ 7.8 Hz, ArH), 7.29–7.32 (m, 2H, J ¼ 7.8 Hz, ArH),
7.35–7.38 (m, 1H, ArH), 7.40–7.42 (m, 1H, ArH), 8.01 (d, 1H,
J ¼ 7.8 Hz, ArH). ESI–HRMS calcd. for C15H12F2N4 ([MþH]þ):
287.1030; found: 287.1102.
1-(4-(Trifluoromethyl)benzyl)5-(o-tolyl)-1H-tetrazole (3c)
Yield: 25.2%; Rf ¼ 0.48; colorless oily liquid; 1H-NMR (CDCl3,
600 MHz): d 2.64 (s, 3H, CH3), 5.90 (s, 2H, CH2), 7.32–7.34 (m,
2H, ArH), 7.37–7.40 (m, 1H, ArH), 7.54 (t, 1H, J ¼ 7.8, 15.6 Hz,
ArH), 7.63–7.67 (m, 2H, ArH), 7.76 (s, 1H, ArH), 8.05 (d, 1H,
J ¼ 7.8 Hz, ArH). ESI–HRMS calcd. for C16H13F3N4 ([MþH]þ):
319.0192; found: 319.1164.
Pharmacology
1-(4-Nitrobenzyl)-5-(o-tolyl)-1H-tetrazole (3d)
Maximal electroshock test (MES)
Yield: 41.4%; Rf ¼ 0.26; white solid; mp:101–103°C; 1H-NMR
(CDCl3, 600 MHz): d 2.63 (s, 3H, CH3), 5.96 (s, 2H, CH2), 7.34 (d,
2H, J ¼ 7.8 Hz, ArH), 7.39 (t, 1H, J ¼ 7.8 Hz, ArH), 7.60 (d, 2H,
J ¼ 7.8 Hz, ArH), 8.02 (d, 1H, J ¼ 7.2 Hz, ArH), 8.28 (d, 2H,
J ¼ 8.4 Hz, ArH). ESI–HRMS calcd. for C15H12N5O2 ([MþH]þ):
296.1069; found: 296.1154.
The maximal electroshock seizure test was carried out
according to the standard protocol [18, 19]. Male mice
(Kunming, China), weighing 20–25 g, were used as experi-
mental animals. Mice were housed under temperature-
controlled conditions (25–30°C) and a 12-h light/dark cycle.
They were allowed to acclimatize with free access to food
and water for a 24-h period before testing except during
the experiment. Abolition of hind limb tonic extension
spasm was recorded as anticonvulsant activity. The test
compounds were dissolved in an aqueous solution of 50%
polyethylene glycol. In preliminary screening, each com-
pound was administered as an ip injection at three dose
levels (30, 100, 300 mg/kg body mass) and the anticonvul-
sant activity was assessed after 0.5 and 4 h intervals of
administration.
1-(4-Fluorobenzyl)-5-(o-tolyl)-1H-tetrazole (3e)
Yield: 37.3%; Rf ¼ 0.41; white solid; mp: 45–47°C; 1H-NMR
(CDCl3, 600 MHz): d 2.63 (s, 3H, CH3), 5.81 (s, 2H, CH2),
7.08–7.11 (m, 2H, ArH), 7.31–7.34 (m, 2H, ArH), 7.37–7.39 (m,
1H, Ar1H), 7.45–7.47 (m, 2H, ArH), 8.02 (d, 1H, J ¼ 8.4 Hz, ArH).
ESI–HRMS calcd. for C15H13FN4 ([MþH]þ): 269.1124; found:
269.1188.
1-(3-Fluorobenzyl)-5-(o-tolyl)-1H-tetrazole (3f)
Yield: 47.8%; Rf ¼ 0.47; white solid; mp: 34–35°C; 1H-NMR
(CDCl3, 600 MHz): d 2.65 (s, 3H, CH3), 5.83 (s, 2H, CH2), 7.08 (td,
1H, J ¼ 2.4, 8.4 Hz, ArH), 7.16 (d, 1H, J ¼ 9.6 Hz, ArH), 7.22 (d,
1H, J ¼ 7.8 Hz, Ar1H), 7.32–7.35 (m, 2H, ArH), 7.36–7.40 (m, 2H,
ArH), 8.05 (d, 1H, J ¼ 7.8 Hz, ArH). ESI–HRMS calcd. for
Subcutaneous pentylenetetrazole seizure test (scPTZ)
This test involved treating the mice with metrazol
(pentylenetetrazole, 85 mg/kg in mice). This produced
clonic seizures lasting for a period of at least 5 s in 97%
of the animals tested. At the anticipated time of testing,
the convulsant was subcutaneously administered. The test
compound was intraperitoneally administered in mice and
the animals were observed over a 30-min period. Mice were
tested 30 min and 4 h after doses of 100 and 300 mg/kg of
the test compound were administered. The absence of
clonic spasms over the period of observation indicated the
compound’s ability to abolish the effect of pentylenetetra-
zol on the seizure threshold.
C
15H13FN4 ([MþH]þ): 269.1124; found: 269.1189.
1-(2-Fluorobenzyl)-5-(o-tolyl)-1H-tetrazole (3g)
Yield: 37.8%; Rf ¼ 0.61; white solid; mp: 66–68°C; 1H-NMR
(CDCl3, 600 MHz): d 2.64 (s, 3H, CH3), 5.92 (s, 2H, CH2),
7.13–7.18 (m, 2H, Ar2H), 7.30–7.33 (m, 2H, ArH), 7.35–7.40 (m,
3H, Ar1H), 8.06 (d, 1H, J ¼ 7.2 Hz, ArH). ESI–HRMS calcd. for
C
15H13FN4 ([M þ H]þ): 269.1124; found: 269.1196.
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Neurotoxicity screening
[6] J. L. Lefrock, W. Holloway, B. B. Carr, R. F. Schell, Am. J.
Med. Sci. 1984, 287, 21–25.
[7] R. Vardanyan, V. Hruby, Synthesis of Best-Seller Drugs,
Academic Press, Boston 2016, pp. 383–412.
[8] H. Kanazawa, T. Yoshikawa, K. Hirata, J. Yoshikawa,
Chest 2004, 125, 1700–1705.
The rotarod test was used to evaluate neurotoxicity. The mice
were trained to stay on an accelerating rotarod that rotated
at six revolutions per minute. The rod diameter was 3.2 cm.
Trained animals were given ip injection of the test compounds
in doses of 100 and 300 mg/kg. Neurotoxicity was indicated by
the inability of the animal to maintain equilibrium on the rod
for at least 1 min in each of the three trials.
[9] K. Y. Choi, Y. C. Kim, M. G. Lee, Life Sci. 2006, 78,
1057–1062.
[10] H. F. Hill, B. A. Coda, A. M. Mackie, K. Iverson, Pain 1992,
49, 301–310.
Quantification studies
The ED50 was calculated using the Bliss method [25, 26]. The
ED50 values were presented as the mean with 95%
confidence intervals. Neurotoxicity was indicated by the
inability of the animals to maintain equilibrium on the rod
for at least 1 min in each of the three trials. Neurotoxicity was
expressed as the median toxic dose (TD50 in mg/kg) eliciting
minimal neurological toxicity in 50% of animals. The
quantitative determination of ED50 and TD50 values were
performed at the previously estimated time of peak effect
after ip injection into mice.
[11] D. Mehta, E. L. Bradley, I. Kissin, J. Clin. Anesth. 1991, 3,
280–284.
[12] N. Siddiqui, W. Ahsan, Eur. J. Med. Chem. 2010, 45,
1536–1543.
[13] M. R. Pavia, S. J. Lobbestael, C. P. Taylor,
F. M. Hershenson, D. L. Miskell, J. Med. Chem. 1990,
33, 854–861.
[14] S. Moreau, P. Coudert, C. Rubat, D. Gardette, D. Vallee-
Goyet, J. Couquelet, P. Bastide, P. Tronche, J. Med. Chem.
1994, 37, 2153–2160.
[15] V. Bailleux, L. Vallee, J. P. Nuyts, J. Vamecq, Biomed.
Pharmacother. 1994, 48, 95–101.
[16] S. N. Pandeya, J. R. Dimmock, Pharmazie 1993, 48,
659–666.
[17] P. Yogeeswari, R. Thirumurugan, R. Kavya, J. S. Samuel,
J. Stables, D. Sriram, Eur. J. Med. Chem. 2004, 39,
729–734.
This work was supported by the Science and Technology
Research Project of Jiangxi Provincial Education Department
(No. GJJ150845), the Traditional Chinese Medicine Research
Project of Jiangxi Provincial Health and Family Planning
Commission (No.2016A035), and PhD Start-up Fund of Jiangxi
University of Traditional Chinese Medicine (No. 2014BS016).
[18] R. J. Porter, J. J. Cereghino, G. D. Gladding, B. J. Hessie,
H. J. Kupferberg, B. Scoville, B. G. White, Cleve. Clin. Q.
1984, 51, 293–305.
The authors have declared no conflict of interest.
[19] R. L. Krall, J. K. Penry, B. G. White, H. J. Kupferberg,
E. A. Swinyard, Epilepsia 1978, 19, 409–428.
[20] S. Ulloora, R. Shabaraya, S. Aamir, A. V. Adhikari, Bioorg.
Med. Chem. Lett. 2013, 23, 1502–1506.
[21] M. Dawidowski, F. Herold, A. Chodkowski, J. Kleps,
Eur. J. Med. Chem. 2012, 48, 347–353.
[22] H.-J.Zhang,P.Jin,S.-B.Wang,F.-N.Li,L.-P.Guan,Z.-S.Quan,
Arch. Pharm. 2015, 348, 564–574.
[23] H. N. Deepakumari, B. K. Jayanna, M. K. Prashanth,
H. D. Revanasiddappa, B. Veeresh, Arch. Pharm. 2016,
349, 566–571.
[24] N. W. Dunham, T. S. Miya, J. Am. Pharm. Assoc. Am.
Pharm. Assoc. 1957, 46, 208–209.
[25] C. I. Bliss, Quart. J. Pharm. Pharmaco. 1938, 11, 192–216.
[26] M. M. Schaper, R. D. Thompson, C. S. Weil, Arch. Toxicol.
1994, 68, 332–337.
References
[1] M. Bondaryk, E. Łukowska-Chojnacka, M. Staniszewska,
Bioorg. Med. Chem. Lett. 2015, 25, 2657–2663.
[2] T. Ikeda, H. Kakegawa, H. Miyataka, H. Matsumoto,
T. Satoh, Bioorg. Med. Chem. Lett. 1992, 2, 709–714.
[3] R. R. Wexler, W. J. Greenlee, J. D. Irvin, M. R. Goldberg,
K. Prendergast, R. D. Smith, P. B. Timmermans, J. Med.
Chem. 1996, 39, 625–656.
[4] S. J. Wittenberger, Org. Prep. Proced. Int. 1994, 26,
499–531.
[5] J. M. Flack, E. Saunders, A. Gradman, W. E. Kraus,
F. M. Lester, J. H. Pratt, M. Alderman, S. Green, R. Vargas,
M. Espenshade, P. Ceesay, J. Alexander, A. Goldberg,
Clin. Ther. 2001, 23, 1193–1208.
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