Synthesis and anticonvulsant activity evaluation of 8-alkoxy-5-(4H-1,2,4- triazol-4-yl)quinoline derivatives

Article abstract of DOI:10.1007/s12272-013-0006-9

Two series of 8-alkoxy-5-(4H-1,2,4-triazol-4-yl)quinolines and 8-alkoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinolines were synthesized. The anticonvulsant activity of these compounds was evaluated with maximal electroshock seizure test and rotarod test. Among the synthesized compounds, 8-octoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4g) was the most active compound with ED₅₀ of 8.80 mg/kg, TD₅₀ of 176.03 mg/kg and protective index of 20.0. Its neurotoxicity was lower than all other synthesized compounds and also markedly lower than that of the reference drug carbamazepine. In addition, the potency of compound 4g against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline suggested its broad spectrum activity, and the mechanisms of action including inhibition of voltage-gated ion channels and modulation of GABAergic activity might involve in its anticonvulsant activity.

Full text of DOI:10.1007/s12272-013-0006-9

Arch. Pharm. Res. (2013) 36:32–40
DOI 10.1007/s12272-013-0006-9
RESEARCH ARTICLE
Synthesis and anticonvulsant activity evaluation
of 8-alkoxy-5-(4H-1,2,4-triazol-4-yl)quinoline derivatives
•
Shi-Ben Wang Xian-Qing Deng Yan Zheng
•
•
•
Hong-Jian Zhang Zhe-Shan Quan
Published online: 18 January 2013
Ó The Pharmaceutical Society of Korea and Springer Science+Business Media Dordrecht 2013
Abstract Two series of 8-alkoxy-5-(4H-1,2,4-triazol-4-
yl)quinolines and 8-alkoxy-5-(2H-1,2,4-triazol-3-one-4-
yl)quinolinesweresynthesized.Theanticonvulsantactivityof
these compounds was evaluated with maximal electroshock
seizure test and rotarod test. Among the synthesized com-
pounds, 8-octoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4g)
was the most active compound with ED50 of 8.80 mg/kg,
TD50 of 176.03 mg/kg and protective index of 20.0. Its
neurotoxicity was lower than all other synthesized com-
pounds and also markedly lower than that of the reference
drugcarbamazepine. In addition, the potency of compound4g
against seizures induced by pentylenetetrazole, 3-mercapto-
propionic acid, and bicuculline suggested its broad spectrum
activity, and the mechanisms of action including inhibition of
voltage-gated ion channels and modulation of GABAergic
activity might involve in its anticonvulsant activity.
McNamara 2001). It often has devastating effects on
patient’s quality of life, many of them suffer from epilepsy
over their lifetime (Yogeeswari et al. 2007; Brown and
Holmes 2001). In spite of the large therapeutic arsenal of
old and new antiepileptic drugs (AEDs), about 30 % of
epileptic patients are not seizure-free (Perucca et al. 2007).
Much efforts devoted in the recent years for the develop-
ment of novel therapeutics resulted in the availability of
several newer drugs (such as pregabalin, stiripentol, zon-
isamide, tiagabine, lamotrigine, levetiracetam, topiramate)
as promising anticonvulsants (Stefan and Feuerstein 2007;
Pollard and French 2006; Donner and Snead 2006). These
drugs have proven to be effective in reducing seizure,
whilst their therapeutic efficacy is overcome by some
undesirable side effects. The search for antiepileptic agents
with more selectivity and lower toxicity continues to be an
area of investigation in medicinal chemistry.
Keywords Synthesis ꢀ Anticonvulsant ꢀ Quinoline ꢀ
Triazole ꢀ Triazolone ꢀ Maximal electroshock
The insufficient information on the cellular mechanism
of epilepsy in human and the complex mechanism of action
of most of the AEDs makes it difficult to use rational
methodologies in the field of drug discovery. Fortunately,
an another design of new antiepileptics is based on the
existence of different pharmacophores that were estab-
lished through the analysis of structural characteristics of
clinically effective drugs as well as other antiepileptic
compounds (Deng et al. 2010; Karakurt et al. 2010; Alam
et al. 2010). In the literatures (Blanch et al. 2003; Estrada
and Pena 2000), it is well documented that one of the
important core fragments is defined by presence of a
hydrophobic unit (A), an electron donor group (D), a
hydrogen donor/acceptor unit (HAD) (Fig. 1). Much
efforts devoted in the recent years based on the pharma-
cophore model for the development of novel therapeutics
resulted in the availability of several newer drugs (such as
tiagabine, lamotrigine, pregabalin, stiripentol, zonisamide,
Introduction
Epilepsy is a chronic neurological disorder characterized
by the periodic and unpredictable occurrence of seizures
that affects the people of all ages (Prasad and Prasad 2001;
S.-B. Wang ꢀ X.-Q. Deng ꢀ Y. Zheng ꢀ H.-J. Zhang ꢀ
Z.-S. Quan (&)
College of Pharmacy, Yanbian University, No. 977 Park Road,
Yanji 133002, Jilin, China
e-mail: zsquan@ybu.edu.cn
X.-Q. Deng
Medical College, Jinggangshan University, Ji’an,
JiangXi 343009, China
123

Quinoline derivatives as anticonvulsant agents
33
Fig. 1 Pharmacophoric pattern
of well known antiepileptics and
target compounds with they
vital structural features
1
topiramate, levetiracetam) as promising antiepileptics
(Stefan and Feuerstein 2007).
Their structures were characterized using IR, H NMR,
13C NMR, MS and elemental analysis techniques. In
additional, their anticonvulsant activity was evaluated
using the maximal electroshock seizure (MES) test. Their
neurotoxicity (NT) was evaluated using the rotarod test in
mice. For explaining the possible mechanism of action,
compound 4g was tested in pentylenetetrazole (PTZ),
3-mercaptopropionic acid (3-MP) and bicuculline (BIC)
induced seizure tests. In the same condition, the anti-MES
activity and the NT of the marketed agent carbamazepine
were evaluated in our laboratory taken as comparison.
In previous work we have reported the synthesis and anti-
convulsant activity evaluation of some compounds containing
triazole and triazolone. All of them exhibited certain anti-
convulsant activity (Jin et al. 2006, 2007; Wei et al. 2007; Sun
et al. 2006; Xie et al. 2005; Guo et al. 2009; Zhang et al. 2009,
2010; Deng et al. 2010a, b, c; Song et al. 2010; Cui et al. 2009).
A series of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-tri-
azole derivatives (I) were found outstanding in respect of their
anticonvulsant activities (Cui et al. 2009). As part of our
continuous efforts to find better anticonvulsant agents in this
area, two series of 8-alkoxy-5-(4H-1,2,4-triazol-4-yl)quino-
lines and 8-alkoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinolines
were designed and synthesized using the compounds I (Fig. 2)
as leading compound. A pyridine ring was introduced at the
second and third positions of compound I. Assigning the
fragments of the target compounds using the above mentioned
model given the following results, that the phenyl group and
the substituents on it is the A unit, the oxygen atom is the D
unit, and the triazole is the HAD unit (Fig. 1).
Materials and methods
Chemistry
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on IR-
Prestige-21. 1H NMR spectra were measured on an AV-300
(Bruker, Switzerland), and all chemical shifts were given in
ppm relative to tetramethylsilane. Mass spectra were mea-
sured on an HP1100LC (Agilent Technologies, USA). Ele-
mental analyses were performed on a 204Q CHN (Perkin
Elmer, USA). Microanalyses of C, N, and H were performed
using a Heraeus CHN Rapid Analyzer. The major chemicals
were purchased from Aldrich Chemical Corporation.
Synthesis of 8-hydroxy-5-nitroquinoline (1)
8-Hydroxyquinoline (14.5 g, 100 mmol) was dissolved in
90 mL of 10 % HCl. A solution of NaNO2 (9 g,
Fig. 2 Structures of leading compounds I and target compounds II,
III
123

34
S.-B. Wang et al.
8-Ethoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4a) Yield:
1
130.4 mmol) in 25 mL of water was added dropwise to the
mixture in an ice-bath, ensuring that the reaction temper-
ature was below 0 °C. The mixture was stirred for 0.5 h,
then the precipitate was filtered and washed with water.
The solid was dissolved in 25 mL glacial acetic acid,
30 mL of 65 % HNO3 was added dropwise to the mixture
in an ice-bath, and then the mixture was heated at
35–37 °C for 40 min. After the reaction was complete,
oxalic acid (1.5 g, 16.6 mmol) was added to the mixture,
and a solution of 20 % NaOH was added to adjust the pH
to 7–8. Finally, glacial acetic acid was added to adjust the
pH to 3–4. The precipitate was filtered and washed with
water to produce a yellow solid.
30 %, mp: 215–217 °C. H NMR (CDCl3, 300 MHz) d:
1.68 (t, 3H, J = 6.9 Hz, –CH3), 4.40 (q, 2H, J = 6.9 Hz,
–OCH2–), 7.10–9.08 (m, 5H, Ar–H), 8.40 (s, 2H, –N=CH–).
IR (KBr) cm-1: 1616 (C=N), 1122 (N–N); MS-EI m/z 241
(M??1). Anal. calcd for C13H12N4O: C, 64.99; H, 5.03; N,
23.32. Found: C, 64.75; H, 5.23; N, 23.12.
8-Propoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4b) Yield:
1
35 %, mp: 178–181 °C. H NMR (CDCl3, 300 MHz) d:
1.15 (t, 3H, J = 7.3 Hz, –CH3), 2.10 (m, 2H, –CH2–), 4.28
(t, 2H, J = 7.2 Hz, –OCH2–), 7.10–9.08 (m, 5H, Ar–H),
8.40 (s, 2H, –N=CH–). IR (KBr) cm-1: 1616 (C=N), 1122
(N–N); MS-EI m/z 255 (M??1). Anal. calcd for
C14H14N4O: C, 66.13; H, 5.55; N, 20.03. Found: C, 66.35;
H, 5.35; N, 19.89.
Synthesis of 8-alkoxy-5-nitroquinoline (2)
A mixture of 8-hydroxy-5-nitroquinoline (2 g, 10.5 mmol),
K2CO3 (11.5 mmol) and alkyl halides (11.5 mmol) were
placed into a round-bottomed flask containing 30 mL
DMF, then the mixture was stirred and heated at 120 °C for
24 h. After the reaction was complete, the solvent was
evaporated under reduced pressure. The residue was dis-
solved in dichloromethane (30 mL), washed with water
(10 mL 9 3), dried over anhydrous MgSO4, and purified
using silica-gel column chromatography with metha-
nol:dichloromethane (1:40) to give the compound 2.
8-Butoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4c) Yield:
1
46 %, mp: 202–204 °C. H NMR (CDCl3, 300 MHz) d:
1.03 (t, 3H, J = 7.3 Hz, –CH3), 1.60–2.05 (m, 4H, –CH2–),
4.32 (t, 2H, J = 6.8 Hz, –OCH2–), 7.10–9.07 (m, 5H,
Ar–H), 8.40 (s, 2H, –N=CH–). IR (KBr) cm-1: 1616
(C=N), 1124 (N–N); MS-EI m/z 269 (M??1). Anal. calcd
for C15H16N4O: C, 67.15; H, 6.01; N, 20.88. Found: C,
67.35; H, 6.19; N, 20.69.
8-Pentoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4d) Yield:
1
50 %, mp: 198–202 °C. H NMR (CDCl3, 300 MHz) d:
Synthesis of 8-alkoxyquinolin-5-amine (3)
0.95 (t, 3H, J = 6.7 Hz, –CH3), 1.49–2.07 (m, 6H, –CH2–),
4.30 (t, 2H, J = 7.0 Hz, –OCH2–), 7.09–9.07 (m, 5H,
Ar–H), 8.40 (s, 2H, –N=CH–). IR (KBr) cm-1: 1616
(C=N), 1124 (N–N); MS-EI m/z 283 (M??1). Anal. calcd
for C16H18N4O: C, 68.06; H, 6.43; N, 19.84. Found: C,
68.31; H, 6.33; N, 19.69.
Iron powder (2 g, 35.7 mmol) and NH4Cl (35.7 mmol)
were placed into a round-bottomed flask containing 30 mL
ethanol. The mixture was stirred and heated at 80 °C for
1 h, and then 8-alkoxy-5-nitroquinoline (8.9 mmol) was
added and the mixture was stirred for 3 h. After the reac-
tion was complete, the mixture was filtered immediately
with a hot filter under reduced pressure. Evaporation of the
solvents gave a crude product, which were used without
purified in further synthesis.
8-Hexoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4e) Yield:
1
48 %, mp: 199–204 °C. H NMR (CDCl3, 300 MHz) d:
0.92 (t, 3H, J = 6.3 Hz, –CH3), 1.38–2.07 (m, 8H, –CH2–),
4.31 (t, 2H, J = 6.8 Hz, –OCH2–), 7.11–9.08 (m, 5H,
Ar–H), 8.40 (s, 2H, –N=CH–). IR (KBr) cm-1: 1616
(C=N), 1120 (N–N); MS-EI m/z 297 (M??1). Anal. calcd
for C17H20N4O: C, 68.89; H, 6,80; N, 18.90. Found: C,
68.75; H, 6.92; N, 19.11.
General procedure for synthesis
of 8-alkoxy-5-(4H-1,2,4-triazol-4-yl)quinolines (4a–l)
A mixture of compound 3 (3.0 mmol), formyl hydrazine
(0.2 g, 3.3 mmol), 0.5 mL glacial acetic acid, and triethyl
orthoformate (3.3 mmol) were placed into a round-bot-
tomed flask containing 30 mL anhydrous alcohol. The
mixture was heated at 80 °C for 18 h. The solvent was
evaporated under reduced pressure, and purified using sil-
ica-gel column chromatography with methanol:dichloro-
methane (1:40) to give compound 4a–l. The yield, melting
point and spectral data of each compound were given
below.
8-Heptoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4f) Yield:
1
38 %, mp: 198–202 °C. H NMR (CDCl3, 300 MHz) d:
0.88 (t, 3H, J = 6.6 Hz, –CH3), 1.32–2.07 (m, 10H, –CH2–),
4.30 (t, 2H, J = 7.0 Hz, –OCH2–), 7.09–9.06 (m, 5H, Ar–
H), 8.40 (s, 2H, –N=CH–). IR (KBr) cm-1: 1616 (C=N),
1122 (N–N); MS-EI m/z 311 (M??1). Anal. calcd for
C18H22N4O: C, 69.65; H, 7.14; N, 18.05. Found: C, 69.77; H,
6.98; N, 18.19.
123

Quinoline derivatives as anticonvulsant agents
35
8-Octoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4g) Yield:
1
41 %, mp: 200–204 °C. H NMR (CDCl3, 300 MHz) d:
General procedure for synthesis of 8-alkoxy-5-(2H-1,2,4-
triazol-3-one-4-yl)quinolines (5a–g)
0.88 (t, 3H, J = 6.6 Hz, –CH3), 1.35–2.06 (m, 12H, –CH2–),
4.30 (t, 2H, J = 7.0 Hz, –OCH2–), 7.09–9.07 (m, 5H,
Ar–H), 8.40 (s, 2H, –N=CH–). IR (KBr) cm-1: 1616 (C=N),
1125 (N–N); MS-EI m/z 325 (M??1). Anal. calcd for
C19H24N4O: C, 70.34; H, 7.46; N, 17.27. Found: C, 70.15; H,
7.32; N, 17.49.
Compound 3 (3.0 mmol) and methyl hydrazinocarboxylate
(4.5 mmol) with triethyl orthoformate (4.5 mmol) were
placed into a round-bottomed flask containing 30 mL
anhydrous alcohol, and refluxed for 24 h, then sodium
methylate (4.5 mmol) was added and refluxed for 24 h.
After the reaction was completed, the solvent was evapo-
rated under reduced pressure, the residue was dissolved in
8-Decyloxy-5-(4H-1,2,4-triazol-4-yl)quinoline
(4h)
dichloromethane
(30 mL),
washed
with
water
Yield: 47 %, mp: 200–203 °C. 1H NMR (CDCl3,
300 MHz) d: 0.87 (t, 3H, J = 7.5 Hz, –CH3), 1.26–2.10
(m, 16H, –CH2–), 4.30 (t, 2H, J = 6.0 Hz, –OCH2–),
7.09–9.06 (m, 5H, Ar–H), 8.38 (s, 2H, –N=CH–). IR (KBr)
cm-1: 1616 (C=N), 1124 (N–N); MS-EI m/z 353 (M??1).
Anal. calcd for C21H28N4O: C, 71.56; H, 8.01; N, 15.90.
Found: C, 71.35; H, 7.92; N, 15.69.
(10 mL 9 3) and dried over anhydrous MgSO4, which was
purified by silica-gel column chromatography with meth-
anol:dichloromethane (1:50) to give compound 5a–g. The
yield, melting point and spectral data of each compound
were given below.
8-Propoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinoline (5a)
Yield: 41 %, mp: 252–254 °C. 1H NMR (CDCl3, 300 MHz)
d: 1.12 (t, 3H, J = 7.4 Hz, –CH3), 2.08 (m, 2H, –CH2–), 4.26
(t, 2H, J = 6.9 Hz, –OCH2–), 7.10–9.06 (m, 5H, Ar–H),
7.58 (s, 1H, –N–CH–), 10.79 (s, 1H, –NHCO–). IR (KBr)
cm-1: 3070 (N–H), 1712 (C=O); MS-EI m/z 270 (M??1).
Anal. calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73.
Found: C, 62.33; H, 5.36; N, 20.55.
8-Dodecyloxy-5-(4H-1,2,4-triazol-4-yl)quinoline
(4i)
Yield: 51 %, mp: 206–209 °C. 1H NMR (CDCl3, 300 MHz)
d: 0.88 (t, 3H, J = 6.0 Hz, –CH3), 1.26–2.11 (m, 20H,
–CH2–), 4.31 (t, 2H, J = 6.0 Hz, –OCH2–), 7.10–9.07 (m,
5H, Ar–H), 8.39 (s, 2H, –N=CH–). IR (KBr) cm-1: 1616
(C=N), 1125 (N–N); MS-EI m/z 381 (M??1). Anal. calcd
for C23H32N4O: C, 72.60; H, 8.48; N, 14.72. Found: C, 72.41;
H, 8.25; N, 14.49.
8-Butoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinoline
(5b)
Yield: 36 %, mp: 252–254 °C. 1H NMR (CDCl3,
300 MHz) d: 1.03 (t, 3H, J = 6.9 Hz, –CH3), 1.57–2.05
(m, 4H, –CH2–), 4.31 (t, 2H, J = 6.6 Hz, –OCH2–),
7.10–9.06 (m, 5H, Ar–H), 7.58 (s, 1H, –N–CH–), 10.92 (s,
1H, –NHCO–). IR (KBr) cm-1: 3070 (N–H), 1713 (C=O);
MS-EI m/z 284 (M??1). Anal. calcd for C15H16N4O2: C,
63.37; H, 5.67; N, 19.71. Found: C, 62.33; H, 5.36; N,
20.55.
8-Phenoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4j) Yield:
1
29 %, mp: 224–230 °C. H NMR (CDCl3, 300 MHz) d:
5.51 (s, 2H, –OCH2–), 7.06–9.08 (m, 9H, Ar–H), 8.36 (s,
2H, –N=CH–). IR (KBr) cm-1: 1614 (C=N), 1126 (N–N);
MS-EI m/z 289 (M??1). Anal. calcd for C18H14N4O: C,
70.82; H, 4.20; N, 19.43. Found: C, 70.65; H, 4.32; N,
19.29.
8-Pentoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinoline
(5c)
Yield: 30 %, mp: 198–202 °C. 1H NMR (CDCl3,
300 MHz) d: 0.95 (t, 3H, J = 6.8 Hz, –CH3), 1.42–2.07
(m, 6H, –CH2–), 4.29 (t, 2H, J = 6.6 Hz, –OCH2–),
7.10–9.05 (m, 5H, Ar–H), 7.58 (s, 1H, –N–CH–), 10.76 (s,
1H, –NHCO–). IR (KBr) cm-1: 3070 (N–H), 1712 (C=O);
MS-EI m/z 298 (M??1). Anal. calcd for C16H18N4O2: C,
64.41; H, 6.08; N, 18.78. Found: C, 64.33; H, 5.86; N,
20.02.
8-(3-Fluorophenoxy)-5-(4H-1,2,4-triazol-4-yl)quinoline
1
(4k) Yield: 46 %, mp: 226–230 °C. H NMR (CDCl3,
300 MHz) d: 5.51 (s, 2H, –OCH2–), 7.03–9.11 (m, 9H,
Ar–H), 8.38 (s, 2H, –N=CH–). IR (KBr) cm-1: 1618
(C=N), 1128 (N–N); MS-EI m/z 307 (M??1). Anal. calcd
for C18H13N4OF: C, 66.66; H, 3.62; N, 18.29. Found: C,
66.85; H, 3.77; N, 18.49.
8-(4-Fluorophenoxy)-5-(4H-1,2,4-triazol-4-yl)quinoline
(4l) Yield: 36 %, mp: 252–254 °C. 1H NMR (CDCl3,
300 MHz) d: 5.46 (s, 2H, –OCH2–), 7.07–9.09 (m, 9H,
Ar–H), 8.38 (s, 2H, –N=CH–). IR (KBr) cm-1: 1618
(C=N), 1128 (N–N); MS-EI m/z 307 (M??1). Anal. calcd
for C18H13N4OF: C, 66.66; H, 3.62; N, 18.29. Found: C,
66.83; H, 3.80; N, 18.45.
8-Hexoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinoline
(5d)
Yield: 33 %, mp: 201–204 °C. 1H NMR (CDCl3,
300 MHz) d: 0.91 (t, 3H, J = 6.1 Hz, –CH3), 1.36–2.07
(m, 8H, –CH2–), 4.29 (t, 2H, J = 6.9 Hz, –OCH2–),
7.10–9.06 (m, 5H, Ar–H), 7.58 (s, 1H, –N–CH–), 10.98 (s,
1H, –NHCO–). IR (KBr) cm-1: 3071 (N–H), 1710 (C=O);
MS-EI m/z 312 (M??1). Anal. calcd for C17H20N4O2: C,
123

36
S.-B. Wang et al.
65.37; H, 6.45; N, 17.94. Found: C, 65.11; H, 6.25; N,
18.12.
corneal electrodes for 0.2 s. Protection against the spread
of MES-induced seizures was defined as the abolition of
the hind leg and tonic maximal extension component of the
seizure. 30 min after the administration of the compounds,
the activities were evaluated in MES test.
8-Heptoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinoline (5e)
Yield: 33 %, mp: 204–206 °C. 1H NMR (CDCl3, 300 MHz)
d: 0.89 (t, 3H, J = 6.3 Hz, –CH3), 1.30–2.07 (m, 10H,
–CH2–), 4.29 (t, 2H, J = 6.9 Hz, –OCH2–), 7.10–9.06 (m,
5H, Ar–H), 7.58 (s, 1H, –N–CH–), 11.11 (s, 1H, –NHCO–).
IR (KBr) cm-1: 3070 (N–H), 1710 (C=O); MS-EI m/z 326
(M??1). Anal. calcd for C18H22N4O2: C, 66.24; H, 6.79; N,
17.17. Found: C, 66.11; H, 6.65; N, 17.42.
NT screening (Loscher and Schmidt 1988)
¨
The NT of the compounds was measured in mice by the
rotarod test. The mice were trained to stay on an accelerating
rotarod of diameter 3.2 cm that rotates at 10 rpm. Trained
animals were given ip injection of the test compounds. NT
was indicated by the inability of the animal to maintain
equilibrium on the rod for at least 1 min in each of the trials.
8-Octoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinoline
(5f)
Yield: 28 %, mp: 205–208 °C. 1H NMR (CDCl3,
300 MHz) d: 0.88 (t, 3H, J = 6.6 Hz, –CH3), 1.29–2.07
(m, 12H, –CH2–), 4.29 (t, 2H, J = 7.0 Hz, –OCH2–),
7.10–9.06 (m, 5H, Ar–H), 7.58 (s, 1H, –N–CH–), 10.84 (s,
1H, –NHCO–). IR (KBr) cm-1: 3070 (N–H), 1712 (C=O);
MS-EI m/z 340 (M??1). Anal. calcd for C19H24N4O2: C,
67.04; H, 7.11; N, 16.46. Found: C, 66.91; H, 6.95; N,
16.22.
sc-PTZ-induced seizures (Krall et al. 1978; Poter et al.
1984)
At 0.5 h after the administration of the test compound,
85 mg/kg PTZ dissolved in saline was administered sc. The
animals (10 mice in one group) placed in individual cages
and observed for 0.5 h. The numbers of clonic seizure
(range from exaggerated twitches of the limbs to violent
shaking or vibrating of the stiffened extremities) and tonic
seizure (the extremities pull towards the body or rigidly
push away from it, usually maximal extension of the hind
leg) as well as the number of deaths were noted.
8-(4-Fluorophenoxy)-5-(2H-1,2,4-triazol-3-one-4-yl)quin-
oline (5g) Yield: 38 %, mp: 252–255 °C. 1H NMR
(CDCl3, 300 MHz) d: 5.45 (s, 2H, –OCH2–), 7.04–9.08 (m,
9H, Ar–H), 7.58 (s, 1H, –N–CH–), 10.96 (s, 1H, –NHCO–).
IR (KBr) cm-1: 3070 (N–H), 1708 (C=O); MS-EI m/z 336
(M??1). Anal. calcd for C18H13N4FO2: C, 64.28; H, 3.90; N,
16.66. Found: C, 64.41; H, 3.75; N, 16.42.
3-MP-induced seizures test (Arnoldi et al. 1990)
Pharmacology
At 0.5 h after the administration of the test compound,
60 mg/kg of 3-MP in saline solution was injected sc to mice
(10 mice in one group). The mice were placed in individual
cages and observed for 0.5 h. The numbers of clonic and
tonic seizures as well as the number of deaths were noted.
The MES test and rotarod test were carried out by the stan-
dard described in the Antiepileptic Drug Development Pro-
gram (ADD) of the National Institutes of Health following
previously described testing procedures (USA) (Hamilton
et al. 1977; Hester and Voigtlander 1979). All compounds,
which were dissolved in DMSO, were evaluated for anti-
convulsant activities with Kun-Ming mice in the 18–25 g
weight range. Groups of five mice were given a range of
intraperitoneal (ip) doses of the test drug until at least three
points were established in the range of 10–90 % seizure
protection or minimal observed NT. From the plots of these
data, the respective ED50 and TD50 values, 95 % confidence
intervals, slopes of the regression line and the standard error
of the slopes were calculated by means of a computer pro-
gram (Hester et al. 1980) written by the National Institute of
Neurological Disorders and Stroke (NINDS).
BIC-induced seizures test (Bernasconi et al. 1988)
At 0.5 h after the administration of compounds, the ani-
mals (10 mice in one group) were given a subcutaneous
dose of 5.4 mg/kg for BIC (within 15–45 min after prep-
aration due to instability). Individual mice were then
placed in isolation cages and observed for at least 0.5 h for
the presence or absence of clonic seizures, and tonic sei-
zures, and lethality was also recorded.
Results and discussion
MES test (Loscher and Nolting 1991; Arnoldi et al. 1990)
¨
Chemistry
Seizures were elicited with a 60 Hz alternating current of
50 mA intensity in mice. The current was applied via
The synthesis of target compounds 4a–l and 5a–g were
accomplished as presented in Scheme 1. 8-Hydroxy-5-
123

Quinoline derivatives as anticonvulsant agents
37
nitroquinoline (1) was prepared by nitrosation of
8-hydroxyquinoline with NaNO2 and further oxidated with
concentrated HNO3. Compound 1 was reacted with alkyl
halides in DMF to afford the compound 2. Then compound
2 reacted with Iron powder and NH4Cl in ethanol to obtain
compound 3. The target compounds 4a–l were synthesized
through the reaction of compounds 3 with formyl hydra-
zine and triethyl orthoformate in anhydrous alcohol (Yi
et al. 2003). Compounds 5a–g were synthesized through
the reaction of compounds 3 with methyl hydrazinocarb-
oxylate and triethyl orthoformate in anhydrous alcohol in
the presence of sodium methylate (Shao et al. 2006).
Table 1 Phase I anticonvulsant data in mice (ip)
N N
N
N NH
N
O
N
N
OR
4a-4l
R
OR
5a-5g
Compounds
MES (mg/kg)a
30
100
300
4a
4b
4c
4d
4e
4f
n-C2H5
0/3b
0/3
0/3
2/3
3/3
3/3
3/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
3/3
3/3
3/3
3/3
1/3
0/3
0/3
1/3
0/3
0/3
0/3
0/3
1/3
1/3
0/3
0/3
1/3
1/3
3/3
3/3
3/3
3/3
3/3
3/3
1/3
0/3
3/3
0/3
0/3
0/3
0/3
3/3
3/3
0/3
0/3
n-C3H7
Pharmacology
n-C4H9
n-C5H11
Pharmacological testing of the compounds listed in
Tables 1 and 2 have been provided by the ADD Program,
Epilepsy Branch, Neurological Disorders Program, NINDS
(Hamilton et al. 1977; Hester and Voigtlander 1979). Phase
I evaluation of the reported compounds using the most
adopted seizure model: MES test, and neurologic toxicity
(NT) test in mice. Some compounds possessed better
activity were quantified their anticonvulsant activity and
NT, and the best one 4g was tested in PTZ, 3-MP, and BIC-
induced seizure tests.
n-C6H13
n-C7H15
4g
4h
4i
n-C8H17
n-C10H19
n-C12H25
–CH2C6H5
–CH2C6H4(m-F)
–CH2C6H4(p-F)
n-C3H7
4j
4k
4l
5a
5b
5c
5d
5e
5f
n-C4H9
In this study, the MES seizure model was used for pre-
liminary (phase I) screening of compounds 4a–l and 5a–g. All
the compounds were administrated ip into the mice using
the dose of 30, 100 and 300 mg/kg and the observations
were taken at 0.5 h. And the results were presented in
Table 1. As show in Table 1, in series of 4a–l, most of the
compounds were active in the MES test, indicative of their
ability to prevent seizure spread, among which four com-
pounds 4d–g showed protection against MES-induced
seizure at the dose of 30 mg/kg. At a dose of 100 mg/kg,
n-C5H11
n-C6H13
n-C7H15
n-C8H17
5g
–CH2C6H4(p-F)
a
Maximal electroshock: doses of 30, 100 and 300 mg/kg were
administrated ip in mice. The animals were examined 0.5 h after
administration
b
n1/n2: the animals protected/the animals tested
Scheme 1 Synthetic route of target compounds (4a–l and 5a–g)
123

38
S.-B. Wang et al.
Table 2 Phase II quantitative anticonvulsant data in mice (ip)
Compounds
ED50 (MES)
TD50 (NT)
PI
4d
34.08 (29.54–39.31)a
25.65 (23.80–27.64)
23.63 (20.48–27.26)
8.80 (7.62–10.15)
11.8 (8.5–16.4)
170.42 (147.72–196.6)
157.79 (136.77–182.0)
176.69 (163.96–190.3)
176.03 (152.58–203.0)
76.1 (55.8–103.7)
5.0
6.2
4e
4f
7.5
4g
20.0
6.4
Carbamazepine
ED50 median effective dose affording anticonvulsant protection in 50 % of animals, the dose is measured in mg/kg, TD50 median toxic dose
eliciting minimal neurological toxicity in 50 % of animals, the dose is measured in mg/kg, PI protective index (TD50/ED50)
a
95 % confidence intervals given in parentheses
Table 3 Effects of compound 4g on chemical-induced seizures in mice (ip)
Chemical substances
PTZ
Compounds
Doses (mg/kg)
Test time (h)a
Clonic seizures (%)b
Tonic seizures (%)
Lethality (%)
DMSO
–
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
100
100
100
100
100
100
100
80
100
0
100
10
Carbamazepine
4g
30
30
–
0
70
3-MP acid
DMSO
100
0
100
0
Carbamazepine
4g
30
30
–
0
60
BIC
DMSO
100
0
100
60
Carbamazepine
4g
30
30
100
0
80
a
At 0.5 h after the administration of the test compound, chemical substances were administered in mice
b
The number of mice clonic seizures, tonic seizures, deaths/the number of animals were test 9 100 %
most compounds showed protection except 4a, b, i, j, and
activity relationships (SARs) were observed. Among 4a–l,
compounds 4a–i were introduced different alkoxyl group
from ethoxy group to dodecyloxy group. The length of the
alkyl chain appeared to have an impact on anticonvulsant
activity of the derivatives. From 4a to g, as the alkyl chain
length increased, anticonvulsant activity gradually
increased. From 4g to i, as the alkyl chain length increased,
anticonvulsant activity decreased. Compound 4g was the
most active compound with the ED50 of 8.80 mg/kg.
Obviously, in this study the activity curve of the alkyl
chain substituted derivatives is bell-shaped with a maxi-
mum activity peak. Compound 4g with the maximum
activity peak, probably reflected the optimal partition
coefficient associated with the easiest crossing of the bio-
logical membranes. In those benzyloxy substituted deriv-
atives 4j–l, the activity of them was comparatively weaker
than that of the compounds mentioned above. The SARs of
compounds 5a–g were not similar to that of 4a–l. Most of
the compounds showed no anticonvulsant activity except
5d and e.
l. At a dose of 300 mg/kg, all compounds showed protec-
tion except 4j and l. In series of 5a–g, none of the com-
pounds showed protection at a dose of 30 mg/kg.
Compound 5d and e showed anti-MES activity at the dose
of 100 mg/kg.
As a result of preliminary screening, compounds 4d–
g were subjected to phase II trials for quantification of their
anticonvulsant activity (indicated by ED50) and NT (indi-
cated by TD50) in mice. The data were also compared with
the marketed anticonvulsant drug carbamazepine, which
were shown in Table 2. Among the tested compounds
(4d–g), 8-octoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4g),
which gave an ED50 value of 8.80 mg/kg and a TD50 value of
176.03 mg/kg, resulting in a protective index (PI) of 20.0,
was the most active and promising compound in this study.
Compounds 4d–f possessed anti-MES activity with ED50 of
34.08, 25.65, 23.63 mg/kg, respectively. The standard car-
bamazepine gave an ED50 value of 11.8 mg/kg and a TD50
value of 76.1 mg/kg, resulting in a PI of 6.4 under the same
condition. Obviously, compound 4g resulted a higher safety
compared with anticonvulsant drug carbamazepine.
To further investigate the effects of the anticonvulsant
activity in several different models and speculate about the
possible mechanism of anticonvulsant action, compounds
4g was tested against convulsions induced by chemical
Analyzing the activities of the synthesized compounds
4a–l and 5a–g in Tables 1 and 2, the following structure–
123

Quinoline derivatives as anticonvulsant agents
39
substances, including PTZ, 3-MP, and BIC. Compounds 4g
was administered into mice ip at a dose of 30 mg/kg, which
was higher than four times its ED50 value and far below its
TD50 value. The reference drug carbamazepine was also
administered ip at a dose of 30 mg/kg.
Conclusion
Two series of compounds, 8-alkoxy-5-(4H-1,2,4-triazol-4-
yl)quinolines and 8-alkoxy-5-(2H-1,2,4-triazol-3-one-4-
yl)quinolines, were synthesized. The anticonvulsant activ-
ity of these compounds was evaluated with MES test and
rotarod test. Among the synthesized compounds, com-
pound 8-octoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4g)
was the most active compound with ED50 of 8.80 mg/kg,
TD50 of 176.03 mg/kg and PI of 20.0. Its NT was lower
than all other synthesized compounds and also markedly
lower than that of the reference drug carbamazepine. In
addition, the potency of compound 4g against seizures
induced by PTZ, 3-MP acid, and BIC suggested its broad
spectrum activity, and the mechanisms of action including
inhibition of voltage-gated ion channels and modulation of
GABAergic activity might involve in its anticonvulsant
activity.
In the sc-PTZ model, carbamazepine inhibited the clonic
seizures, tonic seizures and death at the rates of 0 %,
100 %, and 90 %, respectively. While compound 4g
inhibited the clonic seizures, tonic seizures and lethality at
the rates of 0 %, 100 %, and 30 % induced by sc-PTZ,
respectively (Table 3). The data showed that compound 4g
and carbamazepine can protect the mice from tonic sei-
zures and death, which revealed that compound 4g pos-
sessed excellent activity against sc-PTZ. PTZ has been
reported to produce seizures by inhibiting c-aminobutyric
acid (GABA) neurotransmission (Okada et al. 1989; Olsen
1981). GABA is the main inhibitory neurotransmitter in the
brain, and is widely implicated in epilepsy. Inhibition of
GABAergic neurotransmission or activity has been shown
to promote and facilitate seizures (Gale 1992), while
enhancement of GABAergic neurotransmission is known
to inhibit or attenuate seizures. The findings of the present
study suggest that the newly synthesized compound 4g
might inhibit or attenuate PTZ-induced seizures in mice by
enhancing GABAergic neurotransmission.
Acknowledgments This work was supported by the National Nat-
ural Science Foundation of China (No. 81160382) and National
Science and Technology Major Project of China (No. 2011ZX09102-
003-03).
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