Synthesis and anticonvulsant activity of 5-phenyl-[1,2,4]-triazolo[4,3-a] quinolines

Article abstract of DOI:10.1002/ardp.200800116

A series of novel 5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline derivatives was synthesized by the cyclization of 2-chloro-4-phenyl-1,2-dihydronaphthalene with formohydrazide. The starting material 2-chloro-4-phenyl-1,2-dihydronaphthalene was synthesized from ethyl-3-oxo-3-phenylpropanoate and substituted aniline. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The maximal electroshock test showed that 7-hexyloxy-5-phenyl-[1,2,4]- triazolo[4,3-a]quinoline 4f was found to be the most potent compound with an ED₅₀ value of 6.5 mg/kg and a protective index (PI = ED ₅₀/TD₅₀) value of 35.1, which was much higher than the PI of the reference drug phenytoin.

Full text of DOI:10.1002/ardp.200800116

774
Arch. Pharm. Chem. Life Sci. 2008, 341, 774–779
Full Paper
Synthesis and Anticonvulsant Activity of
5-Phenyl-[1,2,4]-triazolo[4,3-a]quinolines
Li-Ping Guan1, 2, Qing-Hao Jin2, Shou-Feng Wang3, Fu-Nan Li1, and Zhe-Shan Quan1, 2
1 Key Laboratory of Organism Functional Factors of the Changbai Mountain (Yanbian University), Ministry of
Education, Yanji, Jilin, P. R. China
2 College of Pharmacy, Yanbian University, Yanji, Jilin, P. R. China
3 Department of Chemistry, Yanbian University, Yanji, Jilin, P. R. China
A series of novel 5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline derivatives was synthesized by the cycli-
zation of 2-chloro-4-phenyl-1,2-dihydronaphthalene with formohydrazide. The starting material
2-chloro-4-phenyl-1,2-dihydronaphthalene was synthesized from ethyl-3-oxo-3-phenylpropanoate
and substituted aniline. Their anticonvulsant activities were evaluated by the maximal electro-
shock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox).
The maximal electroshock test showed that 7-hexyloxy-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline
4f was found to be the most potent compound with an ED50 value of 6.5 mg/kg and a protective
index (PI = ED50 /TD50) value of 35.1, which was much higher than the PI of the reference drug
phenytoin.
Keywords: Anticonvulsant activity / Maximal electroshock / Synthesis / [1,2,4]Triazolo[4,3-a]quinoline /
Received: June 13, 2008; accepted: July 30, 2008
DOI 10.1002/ardp.200800116
In our previous study [6], a series of derivatives of 5-sub-
Introduction
stituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3-a]quino-
lines was first found to have anticonvulsant activities,
but they showed weaker anticonvulsant effects than the
reference drug phenytoin in the maximal electroshock
(MES) test. It is possible that the phenyl ring in the 5-posi-
tion of the compound I can not conjugate with the tria-
zole nucleus. In order to obtain compounds with better
anticonvulsant activity, according to structure-activity
relationships (SAR), we noted that two structural modifi-
cations of compound I, i. e. the introduction of a double
bond into the 4- and 5-position, and the additional intro-
duction of a methoxy group in the 7-position on the phe-
nyl ring, which in turn gave compound II and 4a, respec-
tively, resulted in markedly enhance anticonvulsant
activity. On the basis of our recent investigation [7, 8] on
the relationship of the anticonvulsant activity and the
structure of 5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline II,
we thought that the triazole ring C might be the main
receptor-binding structure. So, increasing the electron-
cloud density at the triazole nucleus might enhance com-
pound binding with the receptor. The introduction of a
double bond into the 4- and 5-position could possibly pro-
Epilepsy, a ubiquitous disease characterized by recurrent
seizures, inflicts more than 60 million people worldwide
according to epidemiological studies [1]. For epilepsy
treatment, nearly 95% of clinically available drugs were
approved before 1985 and they could provide satisfactory
seizure control for 60–70% of the patients. These drugs,
however, also cause notable adverse side effects such as
drowsiness, ataxia, gastrointestinal disturbance, hepato-
toxicity, megaloblastic anaemia [2–4], and even life-
threatening conditions [5]. Therefore, the continued
search for safer and more effective new antiepileptic
drugs (AEDs) is imperative and challenging in medicinal
chemistry.
Correspondence: Zhe-Shan Quan, College of Pharmacy, Yanbian Uni-
versity, No. 121, JuZi Street, Yanji City, Jilin Province, P.R. China
E-mail: zsquan@ybu.edu.cn
Fax: + 86 433 2660568
Abbreviations: maximal electroshock (MES); structure-activity relation-
ships (SAR)
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Arch. Pharm. Chem. Life Sci. 2008, 341, 774–779
Synthesis and Anticonvulsant Activity of 5-Phenyl[1, 2, 4]triazolo[4, 3-a]quinolines
775
mote the conjugation of the phenyl ring in the 5-position
of ring B with the triazole nucleus, which enhances elec-
tron-cloud density at the triazole nucleus. The other aro-
matic ring A enhances the hydrophobicity of the target
compounds, thus make them more permeable to the
blood-brain barrier and enhance their anticonvulsant
activity. Therefore, we thought that the presence of A-
and C-rings was essential for the anticonvulsant activity.
Furthermore, to understand the structure-activity rela-
tionship of ring A, we designed and synthesized a novel
series of substituted ring-A derivatives of 5-phenyl-[1,2,4]-
triazolo[4,3-a]quinoline. Their anticonvulsant activities
were evaluated by the maximal electroshock (MES) test
and their neurotoxicity was evaluated by the rotarod
neurotoxicity test (Tox).
Results and discussion
Synthesis
The synthesis of the target compounds 4a–r were accom-
plished according to the reaction sequence illustrated in
Scheme 1. Compounds 1 were prepared according to a
reported procedure [9]. Briefly, they were obtained by acy-
lation of ethyl-3-oxo-3-phenylpropanoate and substituted
aniline with good yield. Compounds 2 were prepared
with compounds 1 in the presence of polyphosphoric
acid as the catalyst with high yield [9, 10]. Compounds 3
were obtained [11, 12] by chlorization of compounds 2
with phosphorus oxychloride (POCl3). Then, 5-phenyl-
[1,2,4]-triazolo[4,3-a]quinoline 4a–r were prepared by
cyclizing compounds 3 with formic hydrazide [11]. In the
first step reaction, the reaction time of compounds 1
with groups like -OCH3, -OC2H5, -CH3 etc. was 1 h, and
with groups like -F, -Cl, and –Br, it was 7 h. In the last
step reaction, the reaction time of compounds 4a–r with
groups like -OCH3, -OC2H5, -CH3 etc. was 7 h, and with
groups like -F, -Cl, and –Br, it was 40 h. These differences
in reaction time might be due to the electron-donating
(-OCH3, -CH3) and electron-absorbing (-F, -Cl) property of
the R groups which increases or decreases, respectively,
the electron-cloud density of the N atom near the phenyl
ring or quinoline ring.
Reagents and conditions: (a) 1 h or 7 h, 140 – 1508C; (b) PPA, 1408C, 30 min; (c)
POCl3, 7 h, 1208C; (d) HCONHNH2, n-butyl alcohol, 10 h or 40 h, 140 – 1508C.
Scheme 1. The synthesis route of compounds 4a–r.
exhibited strong anticonvulsant activity at a dose of
30 mg/kg against MES-induced seizures. In contrast, in
the former study [6], only two target compounds showed
anticonvulsant activity at a dose of 30 mg/kg.
In the phase-II pharmacology test (Table 2), in the for-
mer study [6, 8], the compound II (ED50 = 28.4 mg/kg)
exhibited better activity than compound I (ED50
=
54.8 mg/kg). This increase in anticonvulsant activity, as
we have mentioned earlier, might be due to the conjuga-
tion of the phenyl ring in the 5-position and the triazole
nucleus through the introduction of a double bond into
the 4- and 5-position of compound I, which increased
electron-cloud density at the triazole nucleus and then
enhanced the compound binding with its receptor. Simi-
larly, the fact that the anticonvulsant activity of com-
pound 4a (ED50 = 9.2 mg/kg) was stronger than that of
compound II (ED50 = 28.4 mg/kg) could be explained by
the introduction of a methoxyl group in the 7-position
on the phenyl ring of compound II which, through con-
jugation of the lone-pair electron at the methoxyl group,
increased electron-cloud density at triazole nucleus and
enhanced compound binding with its receptor.
Pharmacological evaluations
Pharmacological tests of the 5-phenyl-[1,2,4]-triazolo[4,3-
a]quinoline 4a–r were conducted at the Epilepsy Branch
of the National institute of Neurological Disorders and
Stroke (NINDS) following the protocol adopted by the
Antiepileptic Drug Development (ADD) program [13, 14].
The results of preliminary (phase I) screening of 4a–r
are summarized in Table 1. All synthesized compounds
All the compounds in 4a–r had anti-MES activities bet-
ter than the compound I and all except one, 4n, of these
compounds had anti-MES activities better than the com-
pound II. The following SARs were gained through ana-
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L.-P. Guan et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 774–779
Table 1. Phase-I mouse anticonvulsant activity data in mice
Table 2. Phase-II quantitative anticonvulsant data in mice (test
drug administered i. p.).
(i. p.)a).
Compound
R
MESb)
4 h
0.5 h
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
7-OCH3
30c)
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
–
–
–
–
30
–
–
–
30
–
–
–
–
–
–
–
–
d)
7-OCH2CH3
7-O(CH2)2CH3
7-O(CH2)3CH3
7-O(CH2)4CH3
7-O(CH2)5CH3
7-O(CH2)6CH3
7-O(CH2)7CH3
7-CH3
a)
b)
Compound MES, ED50
TD50
PIc) (TD50/
ED50)
I
II
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
54.8(46.3–64.8)d) 141.6 (123.7–161.6) 2.6
28.4 (21.1–38.5) 126.8 (105.5–152.4) 4.5
9.2 (7.0–12.1)
23.8 (20.0–28.8)
24.3 (22.2–26.7) 105.7 (87.9–127.1)
25.5 (21.3–26.7) 126.8 (108.2–148.6) 5.0
25.8 (17.9–30.8) 169.9 (141.6–203.8) 6.6
6.5 (4.6–9.2)
19.8 (16.4–23.9) 152.2 (126.7–183.0) 7.7
21.2 (17.8–25.7) 118.0 (98.4–141.5)
25.5 (21.4–30.3) 101.9 (84.9–122.2)
11.0 (8.4–14.5)
14.5 (10.0–20.9)
18.3 (15.0–22.4) 101.4 (89.7–116.6)
23.7 (19.5–28.4) 131.4 (109.3–158.0) 5.5
35.3 (29.4–42.4) 63.4 (52.7–76.2) 1.8
15.4 (12.9–18.3) 126.7 (107.6–149.2) 8.2
19.0 (15.8–22.9) 163.8 (136.6–196.5) 8.6
24.5 (21.0–28.6) 109.5 (91.1–131.6)
23.8 (20.0–28.8)
9.5 (8.1–10.4)
9-CH3
7,8-OCH2O-
6,9-(OCH3)2
7-OCH2C6H5
7,8-(OCH3)2
7-F
7-Cl
7-Br
6,9-Cl2
152.1(127.6–181.2) 16.6
91.3 (75.9–109.8)
3.8
4.3
228.2 (189.7–274.2) 35.1
5.6
4.0
a)
122.3 (102.0–146.7) 11.1
77.2 (70.0–86.1)
All of tested compounds were dissolved in Polyethylene gly-
col-400.
The maximal electroshock test was carried out 30 min after
administration of the test compounds.
Doses are denoted in milligrams per kilogram.
= no activity at 300 mg/kg.
5.3
5.5
b)
c)
e)
4.5
3.2
6.9
4r
76.1 (63.3–91.5)
65.5 (52.5–72.9)
lyzing the activities of synthesized compounds 4a–r.
First, the length of the alkyl chain appeared to have a
direct impact on the anticonvulsant activity of the 7-
alkyloxyl derivatives. As shown in Table 2, the compound
4a, with a methoxyl group at the 7-position, showed
stronger activity (ED50 = 9.2 mg/kg). Compounds 4b–4e,
which contain an alkyloxyl group bearing two to five car-
bon atoms at the 7-position, exhibited weaker activity
(ranging from 23.8 to 25.8 mg/kg) than compound 4a.
Phenytoin
a)
ED50-median effective dose required to assure anticonvulsant
protection in 50% animals.
TD50-median toxic dose eliciting minimal neurological toxic-
ity in 50% animals.
PI protective index (TD50 / ED50).
95% confidence limits given in parentheses.
b)
c)
d)
Compound 4f, with a hexyloxy-group substitution at the and 4j, and three compounds substituted at two posi-
7-position, exhibited the strongest anticonvulsant activ- tions, 4k, 4l, 4n, indicated that these different substitu-
ity among 4a–r (ED50 = 6.5 mg/kg) which was better than tions contributed to the anticonvulsant activity in the
the reference drug phenytoin in the MES test. It also had order of 9-CH3 (ED50 = 11.0 mg/kg) A 7,8-OCH2O– A 6,9-
a very low neurotoxicity (TD50 = 228.2 mg/kg) and thus a (OCH3)2 A 7-OCH2C6H5 A 7-CH3 A 7,8-(OCH3)2 (ED50 =
high PI value of 35.1 was gained. However, compounds 35.3 mg/kg), indicating that the position of substitution
with a 7-alkyloxyl chain having more than six carbon influences the activity. The 9-methyl-substituted deriv-
atoms, 4g and 4h, had lower activity than 4f (ED50 = 19.8 ative 4j (ED50 = 11.0 mg/kg) exhibited stronger anti-MES
and 21.2 mg/kg, respectively).
activity than the 7-methyl-substituted derivative 4i (ED50
When the substitution was a member of the halogen = 25.5 mg/kg). Similarly, substitution with two methoxyl
family, the activity order was 7-F A 7-Cl A 7-Br, and the groups at positions 6 and 9 (compound 4l, ED50 = 18.3 mg/
position of atom Cl on the phenyl ring influenced the kg) rather than positions 7 and 8 (4n, ED50 = 35.3 mg/kg)
anticonvulsant activity, with the potency order of the resulted in higher anti-MES activity. The SAR in the above
two Cl-substituted derivatives being 7-Cl A 6,9-Cl2.
two pairs of compounds might be explained by the fact
Comparing a 7-substituted compound containing a that the former compounds increased electron-cloud
phenyl ring, 4m, two methyl-substituted compounds, 4i density at the triazole nucleus.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 774–779
Synthesis and Anticonvulsant Activity of 5-Phenyl[1, 2, 4]triazolo[4, 3-a]quinolines
777
ing the solvents, the products was purified by silica gel column
chromatography (dichloromethane / methanol = 20 : 1).
Conclusions
In conclusion, a new series of 7-substituted-5-phenyl-
[1,2,4]-triazolo[4,3-a]quinoline derivatives was synthe-
sized and the pharmacological properties were eval-
uated. It was found that these compounds exhibited
remarkable anticonvulsant activity. Especially, com-
pound 4f not only has stronger anticonvulsant activity,
but also has markedly lower neurotoxicity than the refer-
ence drug phenytion, and, thus, a larger protective index
was observed for this compound in the MES test.
5-Phenyl-[1,2,4]-triazolo[4,3-a]quinoline II
Yield: 78%; m.p.: 164–1668C IR (KBr) cm– 1: 1613 (C=N), 1297 (C-
N), 1243, 1024 (C-O-C), 1151 (N-N); 1H-NMR (CDCl3 ppm) : 7.51 (s,
1H, =CH), 7.81–8.09 (m, 4H, -C6H4), 7.54–7.77 (m, 5H, -C6H5), 9.31
(s, 1H, H-1);13C-NMR (CDCl3, ppm): 114.04, 115.85, 123.40, 126.29,
128.39, 128.71, 128.75, 129.36, 129.94, 130.48, 134.56, 137.40,
141.91, 147.94; MS m/z: 246 [M + 1]. Anal..Calcd. for C16H11N3: C,
78.35; H, 4.52; N, 17.13. Found: C, 78.21; H, 4.39; N, 17.05.
7-Methoxy-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4a
Yield: 64%; m.p.: 120–1228C; IR (KBr) cm– 1: 1610 (C=N), 1300 (C-
N), 1250, 1025 (C-O-C), 1146 (N-N); 1H-NMR (CDCl3, ppm): 3.79 (s,
3H, -OCH3), 7.46 (s, 1H, =CH), 6.99–7.99 (m, 3H, -C6H3), 7.22–7.59
(m, 5H, -C6H5), 9.22 (s, 1H, H-1); 13C-NMR (CDCl3, ppm): 55.67,
110.84, 114.56, 115.02, 117.04, 117.85, 124.80, 127.06, 128.52,
129.81, 134.21, 137.52, 141.47, 147.76, 157.58; MS m/z: 276[M +
1]. Anal. Calcd. for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found:
C, 74.12; H, 4.64; N, 15.12.
This work was supported by the National Natural Science Foun-
dation of China (No. 30460151) and Foundation for Key Proj-
ects of Ministry of Education P.R. China (No. 20070422029).
The authors have declared no conflict of interest.
7-Ethoxy-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4b
Yield: 58%; m.p.: 125–1278C; IR (KBr) cm– 1: 1612 (C=N), 1301 (C-
N), 1249, 1023 (C-O-C), 1148 (N-N). 1H-NMR (CDCl3, ppm): 1.34 (t, J
= 7.2 Hz, 3H, -CH3), 3.93 (t, J = 6.9 Hz, 2H, -CH2-O-), 7.47 (s, 1H,
=CH), 7.10–7.97 (m, 3H, -C6H3), 7.27–7.55 (m, 5H, -C6H5), 9.22 (s,
1H, H-1); 13C-NMR (CDCl3, ppm): 14.36, 55.67, 110.84, 114.56,
115.02, 117.04, 117.85, 124.80, 127.06, 128.52, 129.81, 134.21,
137.52, 141.47, 147.76, 157.58; MS m/z: 290 [M + 1]. Anal. Calcd.
for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C, 74.69; H,
5.14; N, 14.39.
Experimental
Chemistry
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on a FT-
IR1730 (Bruker, Switzerland), 1H-NMR spectra were measured on
a AV-300 (Bruker), 13C-NMR spectra were measured on a AV-300
(Bruker), and all chemical shifts were given in ppm relative to
tetramethysilane. Microanalyses of C, N, and H were performed
using a Heraeus CHN Rapid Analyzer (Heraeus, Hanau, Ger-
many). Mass spectra were measured on an HP1100LC (Agilent
Technologies, USA). The major chemicals were purchased from
Alderich Chemical Corporation. All other chemicals were the
analytical grade.
5-Phenyl-7-propoxy-[1,2,4]-triazolo[4,3-a]quinoline 4c
Yield: 56%; m.p.: 129–1328C; IR (KBr) cm– 1: 1612 (C=N), 1301 (C-
N), 1251, 1024 (C-O-C), 1147 (N-N); 1H-NMR (CDCl3, ppm): 0.99 (t, J
= 6.9 Hz, 3H, -CH3), 1.76 (m, 2H, -CH2), 3.94 (m, J = 6.6 Hz, 2H, -CH2-
O-), 7.48 (s, 1H, =CH), 7.03–8.01 (m, 3H, -C6H3), 7.21–7.49 (m, 5H,
-C6H5), 9.29 (s, 1H, H-1);13C-NMR (CDCl3, ppm): 10.47, 22.40, 69.97,
111.49, 114.29, 115.76, 117.02, 118.27, 124.58, 127.46, 128.75,
129.24, 129.91, 137.51, 141.73, 147.57, 157.21; MS m/z: 304 [M +
1]. Anal. Calcd. for C19H17N3O: C, 75.23; H, 5.65; N, 13.85. Found:
C, 75.12; H, 5.54; N, 13.72.
2-Chloro-4-phenylquinoline 3
4-Phenylquinolin-2(1H)-one (1.00 g, 0.04 mol) was placed in a
round-bottomed flask, to which 10 mL POCl3 was added. The
mixture was refluxed for 7 h in a nitrogen atmosphere. After
removing the solvent under reduced pressure, the residue was
dissolved in 30 mL of water, and then extracted with CH2Cl2. The
CH2Cl2 layer was dried over anhydrous MgSO4. Evaporation of
the solvents gave a crude product that was purified by recrystal-
lization in hexane, and a yellow solid was obtained in a yield of
81%. 1H-NMR (CDCl3, ppm): 4.01 (s, 3H, -OCH3), 7.95 (s, 1H, =CH),
8.08–8.13 (m, 3H, -C6H3 ), 7.41–7.56 (m, 5H, -C6H5); MS m/z: 269
[M + 1]. Anal. Calcd. for C16H12ClNO: C, 71.25; H, 4.48; N, 5.19.
Found: C, 71.14; H, 4.36; N, 4.95.
7-Butoxy-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4d
Yield: 57%; m.p.: 172-1748C; IR (KBr) cm– 1: 1611 (C=N), 1302 (C-N),
1
1251, 1024 (C-O-C), 1148 (N-N); H-NMR (CDCl3, ppm): 0.97 (t, J =
7.5 Hz, 3H, -CH3), 1.32–1.77 (m, 4H, -(CH2)2), 3.98 (t, J = 6.6 Hz, 2H,
-CH2-O-), 7.48 (s, 1H, =CH), 6.99–7.98 (m, 3H, -C6H3), 7.21–7.50 (m,
5H, -C6H5), 9.23 (s, 1H, H-1); 13C-NMR (CDCl3, ppm): 13.80, 20.28,
31.12, 68.24, 108.38, 111.55, 115.77, 116.96, 121.49, 123.98,
125.58, 128.82, 129.25, 137.62, 140.60, 141.44, 157.19; MS m/z:
318 [M + 1]. Anal. Calcd. for C20H19N3O: C, 75.69; H, 6.03; N, 13.24.
Found: C, 75.57; H, 5.90; N, 13.09.
General procedure for the synthesis of compounds II and
4a–r
2-Chloro-4-phenylquinoline (0.04 mol) and formohydrazide
(0.04 mol) were dissolved in n-butyl alcohol in a round-bottomed
flask, and the mixture was refluxed for 20–40 h in a nitrogen
atmosphere. Solvents were removed under reduced pressure,
and the residue was extracted twice with 30 mL dichlorome-
thane. The dichloromethane layer was washed three times with
water (3630 mL) and dried over anhydrous MgSO4. After remov-
7-(Pentyloxy)-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4e
Yield: 55%; m.p.: 185–1878C; IR (KBr) cm– 1: 1608 (C=N), 1296 (C-
N), 1249, 1021 (C-O-C), 1143 (N-N); 1H-NMR (CDCl3, ppm): 0.91 (t, J
= 6.9 Hz, 3H, -CH3), 1.34-1.78(m, 6H, -(CH2)3), 3.92(t, J = 6.3 Hz, 2H,
-CH2-O-), 7.47 (s, 1H, =CH), 7.32–7.96 (m, 3H, -C6H3), 7.23-7.51 (m,
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L.-P. Guan et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 774–779
5H, -C6H5), 9.23 (s, 1H, H-1); 13C-NMR (CDCl3, ppm): 13.96, 22.40,
28.08, 28.70, 68.66, 111.52, 112.21, 117.92, 119.58, 124.15,
124.95, 128.51, 129.26, 131.09, 133.12, 136.81, 138.19, 144.91,
148.57; MS m/z: 332 [M + 1]. Anal. Calcd. for C21H21N3O: C, 76.11;
H, 6.39; N, 12.68. Found: C, 75.89; H, 6.14; N, 12.52.
7,8-Dimethylenediooxy-5-phenyl-[1,2,4]-triazolo[4,3-a]-
quinoline 4k
Yield: 75%; m.p.: 184–1868C; IR (KBr) cm– 1: 1615 (C=N), 1302 (C-
N), 1249, 1022 (C-O-C), 1149 (N-N); 1H-NMR (CDCl3, ppm): 6.14(s,
2H, -OCH2O), 7.46 (s, 1H, =CH), 7.14–7.34 (m, 2H, -C6H2), 7.36–
7.54 (m, 5H, -C6H5), 9.14 (s, 1H, H-1); 13C-NMR (CDCl3, ppm): 96.15,
102.54, 106.15, 112.07, 118.61, 126.44, 128.80, 129.24, 133.79,
137.84, 141.69, 146.83, 148.07, 149.81; MS (m/z): 290 [M + 1].
Anal. Calcd. for C16H9Cl2N3: C, 70.58; H, 3.83; N, 14.53. Found: C,
70.43; H, 3.70; N, 14.42.
7-(Hexyloxy)-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4f
Yield: 56%; m.p.: 147–1488C; IR (KBr) cm– 1: 1609 (C=N), 1298 (C-
N), 1251, 1022 (C-O-C), 1148 (N-N); 1H-NMR (CDCl3, ppm): 0.92 (t, J
= 7.2 Hz, 3H, -CH3), 1.34–1.72 (m, 8H, -(CH2)4), 4.03 (t, J = 6.6 Hz,
2H, -CH2-O-), 7.48 (s, 1H, =CH), 7.21–7.98 (m, 3H, -C6H3), 7.28–
7.55 (m, 5H, -C6H5), 9.21 (s, 1H, H-1); 13C-NMR (CDCl3, ppm): 14.04,
22.58, 25.67, 29.06, 31.57, 68.58, 111.55, 114.52, 116.95, 118.29,
123.39, 124.81, 128.75, 128.86, 129.07, 129.29, 135.54, 137.62,
141.57, 157.22; MS m/z: 346 [M + 1]. Anal. Calcd. for C22H23N3O: C,
76.49; H, 6.71; N, 12.16. Found: C, 76.36; H, 6.58; N, 12.02.
6,9-Dimethoxy-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4l
Yield: 71%; m.p.: 138–1408C; IR (KBr) cm– 1: 1614 (C=N), 1302 (C-
N), 1247, 1023 (C-O-C), 1144 (N-N); 1H-NMR (CDCl3, ppm): 3.90 (s,
3H, -OCH3), 4.06 (s, 3H, -OCH3), 7.48 (s, 1H, =CH), 6.91–7.21 (m,
2H, -C6H2), 7.51–8.15 (m, 5H, -C6H5), 9.80 (s, 1H, H-1); 13C-NMR
(CDCl3, ppm): 56.23, 56.58, 108.87, 111.75, 116.37, 122.75,
125.44, 126.86, 128.62, 129.37, 131.0, 138.98, 140.59, 142.44,
144.06, 151.25; MS m/z: 306 [M + 1]. Anal. Calcd. for C18H15N3O2:
C, 70.81; H, 4.95; N, 13.76. Found: C, 70.76; H, 4.80; N, 13.65.
7-(Heptyloxy)-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4g
Yield: 51%; m.p.: 156–1588C; IR (KBr) cm– 1: 1659 (C=N), 1301 (C-
N), 1253, 1027 (C-O-C), 1149 (N-N); 1H-NMR (CDCl3, ppm): 0.92 (t, J
= 7.5 Hz, 3H, -CH3), 1.28–1.78 (m, 10H, -(CH2)5), 3.96 (t, J = 6.9 Hz,
2H, -CH2-O-), 7.47 (s, 1H, =CH), 6.99–7.98 (m, 3H, -C6H3), 7.24–
7.51 (m, 5H, -C6H5), 9.22 (s, 1H, H-1); 13C-NMR (CDCl3; ppm): 14.05,
22.57, 28.68, 28.97, 31.73, 32.24, 68.83, 109.15, 111.43, 115.40,
115.96, 119.34, 121.21, 123.39, 125.08, 129.09, 129.88, 135.37,
135.75, 142.97, 149.20. MS m/z: 360 [M + 1]. Anal. Calcd. for
C23H25N3O: C, 76.85; H, 7.01; N, 11.69. Found: C, 76.62; H, 6.87; N,
11.85.
7-Benzyl-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4m
Yield: 49%; m.p.: 119–1218C; IR (KBr) cm– 1: 1658 (C=N), 1297 (C-
N), 1248, 1021 (C-O-C), 1150 (N-N); 1H-NMR (CDCl3, ppm): 5.30 (s,
2H, -OCH2C6H5), 7.50 (s, 1H, =CH), 6.99–7.98 (m, 3H, -C6H3), 7.21–
7.53 (m, 10H, -2C6H5), 9.22 (s, 1H, H-1); 13C-NMR (CDCl3, ppm):
70.67, 112.47, 112.74, 117.15, 123.06, 124.05, 125.91, 126.11,
126.84, 127.48, 128.75, 128.86, 129.22, 130.39, 133.21, 137.64,
139.61, 142.08, 154.34; MS m/z: 336 [M + 1]. Anal. Calcd. for
C23H17N3: C, 82.36; H, 5.11; N, 12.53. Found: C, 82.22; H, 5.04; N,
12.41.
7-(Octyloxy)-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4h
Yield: 53%; m.p.: 150–1528C; IR (KBr) cm– 1: 1612 (C=N), 1301 (C-
N), 1251, 1027 (C-O-C), 1149 (N-N); 1H-NMR (CDCl3, ppm): 0.96 (t, J
= 7.4 Hz, 3H, -CH3), 1.25–1.71 (m, 12H, -(CH2)6), 3.92 (t, J = 6.6 Hz,
2H, -CH2-O-), 7.50 (s, 1H, =CH), 6.94–7.88 (m, 3H, -C6H3), 7.20–
7.39 (m, 5H, -C6H5), 9.37 (s, 1H, H-1); 13C-NMR (CDCl3, ppm): 14.11,
22.66, 25.99, 29.21, 29.32, 29.71, 31.80, 68.56, 108.25, 111.46,
115.76, 116.45, 119.81, 121.51, 123.98, 125.28, 128.83, 129.26,
134.47, 136.35, 142.57, 149.53; MS m/z: 374 [M + 1]. Anal. Calcd.
for C24H27N3O: C, 77.18; H, 7.29; N, 11.25. Found: C, 77.02; H,
7.14; N, 11.07.
7,8-Dimethoxy-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline
4n
Yield: 70%; m.p.: 94–968C; IR (KBr) cm– 1: 1611 (C=N), 1298 (C-N),
1248, 1022 (C-O-C), 1144 (N-N); 1H-NMR (CDCl3, ppm): 3.80 (s, 3H,
-OCH3), 4.13 (s, 3H, -OCH3), 7.48 (s, 1H, =CH), 6.93–7.50 (m, 2H,
-C6H2), 7.18–7.70 (m, 5H, -C6H5), 9.42 (s, 1H, H-1); 13C-NMR (CDCl3,
ppm): 56.37, 56.66, 108.62, 111.85, 116.89, 117.90, 125.39,
128.21, 129.90, 133.84, 137.85, 141.38, 145.70, 147.97, 151.39,
152.89; MS m/z: 306 [M + 1]. Anal. Calcd. for C18H15N3O2: C, 70.81;
H, 4.95; N, 13.76. Found: C, 70.72; H, 4.75; N, 13.62.
7-Methyl-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4i
Yield: 62%; m.p.: 102–1048C; IR (KBr) cm– 1: 1611 (C=N), 1297 (C-
N), 1251, 1023 (C-O-C), 1148 (N-N); 1H-NMR (CDCl3, ppm): 2.44(s,
3H, -CH3), 7.49 (s, 1H, =CH), 7.51–7.96 (m, 3H, -C6H3), 7.27–7.49
(m, 5H, -C6H5), 9.25 (s, 1H, H-1); 13C-NMR (CDCl3, ppm): 21.39,
114.0, 115.65, 123.41, 127.94, 128.11, 128.66, 129.35, 131.12,
134.54, 136.38, 137.58, 138.07, 141.89, 148.47; MS m/z: 260 [M +
1]. Anal. Calcd. for C17H13N3: C, 78.74; H, 5.05; N, 16.20. Found: C,
78.67; H, 4.94; N, 16.11.
7-Fluoro-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4o
Yield: 38%; m.p.: 197–1998C; IR (KBr) cm– 1: 1613 (C=N), 1301 (C-
N), 1253, 1027 (C-O-C), 1149 (N-N); 1H-NMR (CDCl3, ppm): 7.47 (s,
1H, =CH), 7.37–8.17 (m, 3H, -C6H3), 7.30–7.55 (m, 5H, -C6H5), 9.26
(s, 1H, H-1); 13C-NMR (CDCl3, ppm): 116.83, 115.18, 117.51,
2
124.43(d, JC-F = 23.3 Hz), 125.71, 126.72, 127.31, 128.86, 129.73,
131.19, 136.82, 141.28(d, 3JC-F = 8.3 Hz), 141.66, 147.23, 161.53(d,
1JC-F = 241.5 Hz); MS m/z: 264 [M + 1]. Anal. Calcd. for C16H10FN3: C,
72.99; H, 3.83; N, 15.96. Found: C, 72.86; H, 3.68; N, 15.82.
9-Methyl-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4j
Yield: 63%; m.p.: 148–1508C; IR (KBr) cm– 1: 1611 (C=N), 1328(C-
N), 1251, 1024 (C-O-C), 1147 (N-N); 1H-NMR (CDCl3, ppm): 3.02 (s,
3H, -OCH3), 7.48 (s, 1H, =CH), 7.35–7.67 (m, 3H, -C6H3), 7.38–7.52
(m, 5H, -C6H5), 9.59 (s, 1H, H-1); 13C-NMR (CDCl3, ppm): 27.04,
114.45, 125.18, 125.74, 126.62, 126.82, 128.57, 128.71, 129.37,
131.07, 133.16, 137.48, 138.10, 142.45, 148.87. MS m/z: 260 [M +
1]. Anal. Calcd. for C17H13N3: C, 78.74; H, 5.05; N, 16.20. Found: C,
78.67; H, 4.94; N, 16.11.
7-Chloro-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4p
Yield: 36%; m.p.: 204–2068C; IR (KBr) cm– 1: 1614 (C=N), 1302 (C-
N), 1252, 1026 (C-O-C), 1148 (N-N); 1H-NMR (CDCl3, ppm): 7.49 (s,
1H, =CH), 7.62–8.01 (m, 3H, -C6H3), 7.22–7.50 (m, 5H, -C6H5), 9.30
(s, 1H, H-1); 13C-NMR (CDCl3, ppm): 108.07, 110.82, 121.18,
124.29, 126.31, 127.67, 128.68, 129.16, 129.38, 130.71, 131.99,
134.53, 136.56, 139.44, 148.17; MS m/z: 280 [M + 1]. Anal. Calcd.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2008, 341, 774–779
Synthesis and Anticonvulsant Activity of 5-Phenyl[1, 2, 4]triazolo[4, 3-a]quinolines
779
for C16H10ClN3: C, 68.70; H, 3.60; N, 15.02. Found: C, 68.65; H,
3.51; N, 14.96.
(Table 2). Anticonvulsant activity was expressed in terms of the
median effective dose (ED50), and neurotoxicity was expressed as
the median toxic dose (TD50). For the determination of the ED50
and TD50 values, groups of ten mice were given a range of intra-
peritoneal doses of the tested compound until at least three
points were established in the range of 10–90% seizure protec-
tion or minimal observed neurotoxicity. From the plot of this
data, the respective ED50 and TD50 values, 95% confidence inter-
vals, slope of the regression line, and the standard error of the
slope were calculated by means of a computer program written
at National Institute of Neurological Disorders and Stroke.
7-Bromo-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4q
Yield: 41%; m.p.: 198–2018C; IR (KBr) cm– 1: 1613 (C=N), 1305 (C-
N), 1253, 1027 (C-O-C), 1149 (N-N); 1H-NMR (CDCl3, ppm): 7.48 (s,
1H, =CH), 7.76–8.19 (m, 3H, -C6H3), 7.23–7.54 (m, 5H, -C6H5), 9.59
(s, 1H, H-1); 13C-NMR (CDCl3, ppm): 114.97, 118.46, 124.98,
127.47, 128.14, 128.77, 129.32, 129.60, 130.32, 132.86, 135.66,
136.76, 140.73, 147.48; MS m/z: 324 [M + 1]. Anal. Calcd. for
C16H10BrN3: C, 59.28; H, 3.11; N, 12.96. Found: C, 58.93; H, 3.04;
N, 12.87.
6,9-Dichloro-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4r
Yield: 32%; m.p.: 192–1948C; IR (KBr) cm– 1: 1611 (C=N), 1301 (C-
N), 1252, 1026 (C-O-C), 1149 (N-N); 1H-NMR (CDCl3, ppm): 7.47 (s,
1H, =CH), 7.54–7.97 (m, 3H, -C6H2), 7.29–7.51 (m, 5H, -C6H5), 9.28
(s, 1H, H-1); 13C-NMR (CDCl3, ppm): 117.47, 122.24, 124.65,
126.23, 127.94, 129.63, 130.65, 132.47, 134.86, 138.01, 139.32,
145.67, 152.12; MS m/z: 314 [M + 1]. Anal. Calcd. for C16H9Cl2N3:
C, 61.17; H, 2.89; N, 13.38. Found: C, 60.12; H, 2.69; N, 13.22.
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i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com