Synthesis and antidepressant activity of di substituted-5-Aryl-1,2,4- triazoles

Article abstract of DOI:10.1007/s00044-011-9902-z

A series of 5-Aryl-1H-1,2,4-triazole-3-thiol (3) were synthesized. Alkylation of thiol group with N,Ndimethyl/ diethyl/dicyclo hexyl-(2-chloro ethyl) amine gave compounds N,N-disubstituted-2-(5-Aryl-1H-1,2,4-triazol-3- ylthio)ethanamine (4). These compounds were characterized on the basis of IR, ¹H NMR, Mass spectral data, and elemental analysis. The newly synthesized compounds were screened for their antidepressant activity by using tail suspension test in mice. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9902-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3509–3513
DOI 10.1007/s00044-011-9902-z
ORIGINAL RESEARCH
Synthesis and antidepressant activity of di substituted-5-aryl-
1,2,4-triazoles
•
C. Radhika A. Venkatesham Manda Sarangapani
•
Received: 26 June 2011 / Accepted: 9 November 2011 / Published online: 20 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 5-aryl-1H-1,2,4-triazole-3-thiol (3)
were synthesized. Alkylation of thiol group with N,N-
dimethyl/diethyl/dicyclo hexyl-(2-chloro ethyl) amine gave
compounds N,N-disubstituted-2-(5-aryl-1H-1,2,4-triazol-3-
ylthio)ethanamine (4). These compounds were character-
contain N,N-di alkyl ethyl side chain in their structures (Foye,
1989; John et al., 2005). Keeping these observations in view,
we incorporated this side chain in the 1,2,4-triazole ring and we
report the synthesis of N,N-disubstituted-2-(5-aryl-1H-1,2,4-
triazol-3-ylthio)ethanamine and their antidepressant screening
studies. Among the synthesized compounds, compound 4l has
shown most promising activity.
1
ized on the basis of IR, H NMR, Mass spectral data, and
elemental analysis. The newly synthesized compounds
were screened for their antidepressant activity by using tail
suspension test in mice.
Chemistry
Keywords 1,2,4-Triazole Á Thiol Á
Antidepressant activity Á Aroyl thiosemicarbazide
Aroyl thiosemicarbazide (2) was obtained by the reaction of
Aroyl chloride with thiosemicarbazide (Plumitallo et al.,
2004). The cyclization of compound (2) in the presence of 2 M
NaOH resulted in the formation of 5-aryl-1H-1,2,4-triazole-3-
thiol (3) (Khosrow et al., 2003; Birsen et al., 2007). These were
reacted in acetone in the presence of anhydrous K2CO3 and a
catalytic amount of KI with dimethyl (2-chloro ethyl) amine/di
ethyl (2-chloro ethyl) amine/di cyclo hexyl (2-chloro ethyl)
amine to give desired products (4). (Scheme 1).
Introduction
1,2,4-triazole and their derivatives constitute an important
class of heterocyclic organic compounds with diverse phar-
macological and biological activities including antimicrobial,
sedative, anticonvulsant, anti-inflammatory, antidepressant,
antihypertensive etc. (Monazza et al., 2009; Hussain et al.,
2005; Loredana et al., 2004; Katica et al., 2001; Mohammad
et al., 2006; Aniket Kshirsagar et al. 2009).
The structures of compounds 4 were established on the
basis of IR, NMR, mass spectral data and C, H, N analysis.
The physical data and analytical data was given in Table 1.
Literature survey reveals that N,N-di alkyl ethyl chain is
important for antidepressant activity. For instance, tricyclic
antidepressants like Imipramine, Amitriptyline, Clomipra-
mine, Doxepin which are used for the treatment of depression,
Results and discussion
The IR spectrum of compound 3a showed an absorption
band at 3450.8 cm-1 indicating the presence of NH
stretching. The absorption band at 2,360 cm-1 indicating
the presence of SH functional group. When compound 3
was converted to alkyl derivative 4 the SH peak disap-
peared, while new signal due to C–S group was observed at
C. Radhika (&)
RBVRR Women’s College of Pharmacy, Barkathpura,
Hyderabad 500027, Andhra Pradesh, India
e-mail: cradhika8@gmail.com
A. Venkatesham Á M. Sarangapani
University College of Pharmaceutical Sciences, Kakatiya
University, Warangal 506009, Andhra Pradesh, India
1010.2 cm-1
.
123

3510
Med Chem Res (2012) 21:3509–3513
O
C
S
S
C
O
C
Pyridine
N
H
N
H
C
NH2
Ar
NH2
NH
NH2
+
Cl
Ar
Sub.Aroyl chloride
Aroyl thiosemicarbazide
Thiosemicarbazide
2% NaOH
R2
N
HN
ClCH2CH2N
N
HN
R1
SH
R2
CH2CH2N
R1
Ar
Ar
S
N
anhyd K2CO3,Acetone
N
5-aryl-1H-1,2,4-triazole-3-thiol
(3a-u)
N,N-disubstituted-2-(5-aryl-1H-1,2,4-triazol-
3-ylthio)ethanamine (4a-u)
Scheme 1 Synthesis of N,N-disubstituted-2-(5-aryl-1H-1,2,4-triazol-3-ylthio)ethanamine
In the 1H NMR spectra of compound 3a, NH signal was
observed at 13.6 ppm. Additional signals (5H) belonging
to phenyl ring were observed in the aromatic region at 7.3
to 8.0 ppm. The signal due to –SH group was observed at
(P \ 0.001) decrease in immobility time when compared
with the control group animals. This significant reduced
immobility time displayed by mice indicates that the
investigational compounds having the potential anti-
depressant properties. Compound 4l with 2,4-di chloro and
dicyclohexyl substitution showed most significant activity
as compared to other test compounds and are comparable
with standard drug (imipramine 10 mg/kg). Compound 4i
with 4-chloro substitution, compound 4o with 4-methoxy
substitution, compound 4j with 2,4-dichloro substitution
also showed good activity. Compounds 4a, 4b, 4c, 4g, 4h,
4k, 4m, 4n showed slight activity. Compounds 4d, 4e, 4f,
4p, 4q showed no activity. From above results it is revealed
that compound with dicyclohexyl substitution have shown
good activity due to lipophilic nature of the dicyclohexyl
group. (Table 2).
1
13.2 ppm in the H NMR spectra of compound 3a. When
compound 3a is converted to alkyl derivative 4a the SH
signal disappeared. In compound 4a the additional signals
were observed at 2.9 to 3.0 (S–CH2), 3.2 (N–CH2) and 2.4
(aliphatic 6H) ppm integrating for two protons, two pro-
tons, and six protons, respectively.
The molecular ion (M ? 1) for compound 3a was
recorded at m/z 178.3 while compound 4a was recorded at
m/z 249.4.
Acute toxicity studies
All the test compounds have been found to be free from
toxicity as well as toxic symptoms even at high dose of
2,000 mg/kg (b.w).
Pharmacology
Gross behavioral studies
Acute toxicity study
The gross behavioral studies reveal that all the compounds
have shown alertness.
Healthy and adult female albino Swiss mice weighing
between 20 and 25 g were used in this investigation.
The test compounds suspended in 0.1% sodium carboxy
methyl cellulose (CMC) were administered by i.p, in
doses up to 2,000 mg/kg-body weight. The control
group animals received only vehicle (0.1% sodium
CMC). The animals were observed for 1 month from
the time of administration of test compound to record
the mortality.
Tail suspension test in mice
The test compounds were screened for antidepressant
activity by using tail suspension method in mice and the
duration of immobility was recorded for a period of 5 min.
Some of the test compounds have shown significant
123

Med Chem Res (2012) 21:3509–3513
3511
Table 1 Physical and analytical data of N,N-disubstituted-2-(5-aryl-1H-1,2,4-triazol-3-ylthio)ethanamine 4a–u
Compd Ar
R1
R2
Mol. formula Mol. wt. M.P. (°C) % Yield Elemental analysis calc. (found)
C H N
4a
4b
4c
Phenyl
CH3 CH3 C12N4H16
C2H5 C2H5 C14N4H20
C22N4H32
S
S
S
248
276
384
210–212 87
216–218 82
288–290 75
58.06 (58.03) 6.45 (6.47)
60.86 (60.85) 7.24 (7.22)
68.75 (68.73) 8.33 (8.30)
22.51 (22.52)
20.28 (20.29)
14.58 (14.56)
Phenyl
Phenyl
4d
4e
4f
4-methyl phenyl
4-methyl phenyl
4-methyl phenyl
CH3 CH3 C13N4H18
C2H5 C2H5 C15N4H22
C23N4H34
S
S
S
262
290
398
234–236 68
242–244 62
59.54(59.55) 6.87 (6.85)
62.06(62.03) 7.58 (7.55)
69.34(69.35) 8.54 (8.56)
21.37 (21.35)
19.31 (19.34)
14.07 (14.09)
[300
73
4g
4h
4i
4-chloro phenyl
4-chloro phenyl
4-chloro phenyl
CH3 CH3 C12N4H15SCl 282
C2H5 C2H5 C14N4H19SCl 310
C22N4H31SCl 418
257–258 79
262–264 73
298–299 80
51.06 (51.09) 5.31 (5.30)
58.74(58.78) 6.64 (6.63)
63.15 (63.17) 7.41 (7.42)
19.85 (19.88)
19.58 (19.57)
13.39 (13.40)
4j
4k
4l
2,4-di chloro phenyl CH3 CH3 C12N4H14SCl2 316
2,4-di chloro phenyl C2H5 C2H5 C14N4H18SCl2 344
266–268 65
270–272 60
66.66 (66.69) 6.48 (6.47)
68.85 (68.88) 7.37 (7.38)
58.40 (58.38) 6.63 (6.65)
25.92 (25.93)
22.95 (22.96)
12.38 (12.40)
2,4-di chloro phenyl
C22N4H30SCl2 452
[300
72
4m
4n
4o
4-methoxy phenyl
4-methoxy phenyl
4-methoxy phenyl
CH3 CH3 C13N4OH18
C2H5 C2H5 C15N4OH22
C23N4OH34
S
S
S
278
306
414
236–238 62
240–241 63
56.11 (56.10) 6.47 (6.48)
58.82 (58.83) 7.18 (7.21)
66.66 (66.68) 8.21 (8.23)
20.14 (20.13)
18.30 (18.34)
13.52 (13.55)
[300
53
4p
4q
4r
2-OH phenyl
2-OH phenyl
2-OH phenyl
CH3 CH3 C12N4OH16
C2H5 C2H5 C14N4OH20
C22N4OH30
S
S
S
264
292
400
198–200 67
194–196 65
188–190 59
54.54 (54.55) 6.06 (6.04)
57.53 (57.55) 6.84 (6.87)
21.21 (21.25)
19.17 (19.16)
14 (13.97)
66 (66.03)
8 (8.02)
4s
4t
4-OH phenyl
4-OH phenyl
4-OH phenyl
CH3 CH3 C12N4OH16
C2H5 C2H5 C14N4OH20
C22N4OH30
S
S
S
264
292
400
170–172 75
174–176 70
178–180 68
54.54 (54.53) 6.06 (6.04) 21.21 (21.23)
57.53 (57.51) 6.84 (6.85) 19.17 (19.14)
4u
66 (66.02)
8 (7.97)
14 (14.03)
IR (KBr, cm-1): 4a, 3307.9 (NH str), 3072 (aromatic CH str), 2941.7 (aliphatic CH str), 1010.2 (C–S str) 4b: 3400(NH str), 1033 (C–S str), 800
(Ar–H str) 4f: 3490 (NH str), 2792 (CH str), 1030 (C–S), 810 (Ar–H str)
1
H NMR (DMSO): 4a, 7.4 to 8.1 (m, 5H, ArH), 2.9 to 3.0 (s, 2H, S–CH2), 3.2 (s, 2H, N–CH2), 2.4 (m, aliphatic 6H). 4c, 7.7–7.9 (m, 5H, Ar H),
3.0 (s, 2H, S–CH2), 3.4 (s, 2H, N–CH2), 6.3–6.9 (m, 11H of cyclohexyl). 4g, 7.01–8.0 (m, 4H of p-chlorophenyl), 3.2 (S–CH2), 3.2 (N–CH2), 2.5
(aliphatic 6H). 4m, 7.27–7.7 (m, 5H Ar H), 3.9 (s, 3H, OCH3), 2.7 (s, 2H, S–CH2), 3.0 (s, N–CH2), 2.3 (m, aliphatic 6H). 4a, m/z 249.4
Gross behavioral studies
(10, 30 and 100 mg/kg), and control vehicles (1% Sodium
CMC) were administered to the mice by intraperitoneal
injection 60 min before testing. Mice were suspended on
the edge of a shelf 58 cm above a table top by adhesive
tape placed approximately 1 cm from the tip of the tail.
The duration of immobility was recorded for a period of
5 min. Mice were considered immobile when they were
passively and completely motionless for at least 1 min. The
responses were noted at 60 min after the injection of the
test compound. The results were compared with control
and standard drug.
All the compounds were tested for the gross behavioral
changes continuously for 3 h starting from the adminis-
tration of test compound and 48 h intermittently and
compared with that of control group of mice. In the
behavioral profile the test animals were observed for
alertness, visual placing, vocalization, restlessness, irrita-
bility, fearfulness, reactivity, touch response, and pain
responses.
Tail suspension test in mice
Healthy adult male mice weighing between 20 and 25 g
were used as experimental animals. Animals were fasted
for over night and divided into groups of six animals each.
Standard drug (10 mg/kg of Imipramine), test compound
Conclusions
This study reports the synthesis of some N,N-disubstituted-2-
(5-aryl-1H-1,2,4-triazol-3-ylthio)ethanamine. The antidepressant
123

3512
Med Chem Res (2012) 21:3509–3513
Table 2 Antidepressant activity of test compounds by tail suspension
test in mice
Table 2 continued
Compound name
Dose (mg/kg)
Immobility (s)
Compound name
Dose (mg/kg)
Immobility (s)
4p
4q
4r
4s
4t
10
164.8 14.8
150.8 13.6
150.0 9.1
173.8 12.2
163.5 9.4
137.3 12.8
162.5 13.3
149.3 12.0
150.0 9.1
161.2 13.1
150.3 13.0
149.0 8.5
171.8 10.1
167.3 9.2
151.8 13.5
157.5 16.8
126.2 11.4*
112.7 11.9*
Control
Imipramine
4a
0.1 ml of 1% sodium CMC
169.8 13.0
95.8 11.6*
117.2 10.5*
110.3 8.1*
102.0 9.3*
145.8 14.1
120.7 12.5*
108.3 6.9*
117.0 9.1*
109.7 6.7*
101.7 9.0*
172.8 5.9
30
10
100
10
10
30
30
100
10
100
10
4b
4c
4d
4e
4f
30
30
100
10
100
10
30
30
100
10
100
10
30
168.2 8.7
30
100
10
152.8 13.2
178.3 7.7
100
10
4u
30
168.2 8.0
30
100
10
151.2 10.9
165.0 11.6
151.3 11.4
150.0 8.5
100
N = 6
30
* P \ 0.001 Compared with control
100
10
4g
4h
4i
109.2 6.8*
102.2 4.9*
96.0 11.0*
129.7 8.6*
115.0 11.5*
103.8 12.3*
96.8 10.7*
94.8 11.0*
89.2 12.2*
109.0 7.5*
101.8 4.7*
96.2 11.7*
121.8 9.0*
110.0 10.9*
103.2 12.2*
96.5 11.8*
94.5 11.7*
90.5 10.8*
116.3 9.5*
111.0 5.5*
103.8 6.0*
139.0 10.9*
118.5 9.4*
103.8 4.5*
101.3 5.8*
96.3 14.5*
94.8 12.8*
activity revealed that all the compounds screened showed
good to moderate antidepressant activities, except com-
pounds 4d, 4e, 4f, 4p, 4q. Among all the compounds, com-
pound 4l which contains dicyclohexyl ring in its structure
displayed significant activity due to high lipophilic nature.
30
100
10
30
100
10
30
Experimental
100
10
4j
Chemistry
30
100
10
Melting points were determined by open capillary using
toshiwal melting point apparatus and are uncorrected. IR
spectra were recorded in potassium bromide KBr on FTIR
4k
4l
30
100
10
1
8400 Shimadzu spectrophotometer. H NMR spectra were
recorded on 300 MHz Bruker DPX using CDCl3 and Mass
spectra were recorded on LC–MS/MS. Elemental analysis
was performed on Perkin–Elmer series 2400.
30
100
10
4m
4n
4o
All chemicals used in synthesis were purchased from
E.Merck and Aldrich. Thin layer chromatography (TLC)
was performed on silicagel G (Merck) pre-coated plates
and spots were visualized with ultraviolet light. The
chemical shifts are reported in d ppm scale. The splitting
pattern abbreviations are as follows: s, singlet; t, triplet; m,
multiplet. The synthetic pathway is given in Scheme 1.
Elemental data for C, H, and N were within 0.4% of the
theoretical values.
30
100
10
30
100
10
30
100
123

Med Chem Res (2012) 21:3509–3513
3513
Synthesis of aroyl thiosemicarbazide (2)
NMR (DMSO-d6) d ppm: 7.4 to 8.1 (m, 5H, ArH), 2.9 to
3.0 (s, S-CH2), 3.2 (s, N-CH2), 2.4 (m, aliphatic 6H);
C12N4H16S; Calc. N 22.51; Found N 22.52.
Thiosemicarbazide (0.1 mol) was suspended in dry pyri-
dine (100 ml). The reaction mixture was cooled down to
-5°C and the appropriate Aroylchloride (0.1 mol) was
added dropwise, maintaining temperature under 0°C. The
reaction was stirred overnight. The crude precipitate was
filtered off, washed several times with water, and
recrystallized.
Mass spectrum of the compound (4a, R = C6H5) was
recorded its molecular ion (M ? 1) at m/z 249.4.
Acknowledgments The authors are thankful to IICT hyderabad for
1
providing H NMR, IR, Mass spectra, and elemental analysis of the
compounds. Thanks are also to the management of Malla Reddy
group of Institutions for providing research facilities.
Synthesis of 5-aryl-1H-1,2,4-triazole-3-thiol
(3a–u) (Khosrow et al., 2003; Birsen et al. 2007)
References
Al-Amin M, Islam R (2006) Synthesis of some bis-triazole deriva-
tives as probes for cytotoxicity study. Bangladesh J Pharmacol
1:21–26
Aniket K, Toraskar MP et al (2009) Microwave assisted synthesis of
potential anti infective and anticonvulsant thiosemicarbazones.
Int J Chem Tech Res 1:696–701
Colanceska-Ragenovic K, Dimova V et al (2001) Synthesis, antimi-
crobial and antifungal activity of 4-substituted-5-aryl-1,2,4-
triazoles. Molecules 6:815–824
A mixture of compound 2 (0.1 mol) and 2 M sodium
hydroxide was refluxed for 4 h. After cooling, the solution
was acidified with hydrochloric acid and the ppt was fil-
tered. The ppt was then recrystallized by using appropriate
solvent to get TLC pure compound 3a–u.
5-phenyl-1H-1,2,4-triazole-3-thiol (3a) Yield 76%; m.p.
261–265°C; FT-IR (KBr) cm-1: 3450.8 (NH), 3053 (aro-
matic CH), 1563.3, 1508.9, 1481.2 (C=C), 2360 (SH);
1H NMR (DMSO-d6) d ppm: 7.3–8.0(m, 5H, ArH), 13.6
(s, 1H, NH), 13.2 (s, 1H, SH).
Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as
a
model for assessing antidepressant activity: review of
pharmacological and genetic studies in mice. Neurosci Biobehav
Rev 29:571–625
Mass spectrum of the compound (3a, R = C6H5) was
recorded its molecular ion (M ? 1) at m/z 178.3.
Foye WO (1989) Principles of medicinal chemistry, 3rd edn. Boston,
Massachusetts, p 288
Hussain A, Sharba K, Al-Bayati RH et al (2005) Synthesis of
oxadiazoles, thiadiazoles and triazoles derived from benzo[b]thi-
ophene. Molecules 10:1161–1168
Loredana S, Mariangela S et al (2004) Synthesis of new 5-phenyl
[1,2,4] triazole derivatives as ligands for the 5-HT1A serotonin
receptor. Arkivoc 5:312–324
Synthesis of N,N-disubstituted-2-(5-aryl-1H-1,2,4-triazol-
3-ylthio)ethanamine (4a–u)
To a mixture of 3 (0.1 mol), a solution of dimethyl-(2-
chloro ethyl)amine (0.1 mol) or diethyl-(2-chloro ethyl)a-
mine (0.1 mol) or dihexyl-(2-chloro ethyl)amine (0.1 mol)
in 10 ml of acetone and anhydrous Potassium carbonate
(K2CO3) (0.1 mol) in 25 ml of acetone was added. The
reaction was refluxed for 6 h. After cooling, the ppt was
filtered. The ppt was then recrystallized from acetone.
N,N-dimethyl-2-(5-phenyl-1H-1,2,4-triazol-3-ylthio)eth-
anamine (4a) Yield 87%; m.p. 210–212°C FT-IR (KBr)
cm-1: 3307.9 (NH), 3072 (aromatic CH), 2941.7, 2865.2,
2785.9 (aliphatic CH), 1464.8 (CH), 1010.2 (C–S); 1H
Plumitallo A, Cardia MC et al (2004) Synthesis and antimicrobial
activity evaluation of some new 1-benzoyl-isothiosemicarba-
zides. IL Farmaco 59:945–952
Serwar M, Akhtar T et al (2009) Synthesis, urease inhibition and
antimicrobial activities of some chiral 5-aryl-4-(1-phenylpro-
pyl)-2H–1,2,4-triazole-3(4H)-thiones. Arkivoc 7:210–221
Tozkoparan B, Kupeli E et al (2007) Preparation of 5-aryl-3-alkylthio-
1,2,4-triazoles and corresponding sulfones with anti-inflammatory-
analgesic activity. Bioorg Med Chem 15:1808–1814
Zamani K, Faghihi K et al (2003) Synthesis of some new substituted
1,2,4-triazole and 1,3,4-thiadiazole and their derivatives. Turk J
Chem 27:119–125
123