Synthesis of N′-arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio) acetohydrazides as antidepressants

Article abstract of DOI:10.1007/s00044-017-1854-5

Abstract: A series of N′-arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio) acetohydrazide were synthesized. Condensation of aromatic aldehydes with 2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio) acetohydrazide gave corresponding N′ -arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio) acetohydrazide. Spectral and elemental analysis was used for structural elucidation of novel 1, 2, 4-triazole schiff bases. The newly synthesized compounds were screened for their antidepressant activity by using tail suspension test in mice. Compound 4l showed significant activity among the series. Graphical Abstract: A series of new N′-arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio)acetohydrazide have been synthesized and characterized. The results revealed that compound 4l with bromo substitution exhibited promising antidepressant activity among the series. [InlineMediaObject not available: see fulltext.].

Full text of DOI:10.1007/s00044-017-1854-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1854-5
ORIGINAL RESEARCH
Synthesis of N′-arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio)
acetohydrazides as antidepressants
Radhika Chelamalla1 Venkatesham Akena2 Sarangapani Manda2
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Received: 25 August 2015 / Accepted: 2 March 2017
© Springer Science+Business Media New York 2017
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Keywords Antidepressant activity
1, 2, 4-triazole
Abstract A series of N′-arylidene-2-(5-aryl-1H-1, 2, 4-
triazol-3-ylthio) acetohydrazide were synthesized. Con-
densation of aromatic aldehydes with 2-(5-aryl-1H-1, 2, 4-
triazol-3-ylthio) acetohydrazide gave corresponding N′
-arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio) acetohy-
drazide. Spectral and elemental analysis was used for
structural elucidation of novel 1, 2, 4-triazole schiff bases.
The newly synthesized compounds were screened for their
antidepressant activity by using tail suspension test in mice.
Compound 4l showed significant activity among the series.
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Acetohydrazide Schiff base Structure-activity
relationships
Introduction
Depression is a common mood disorder caused by improper
release of monoamine neurotransmitters such as serotonin,
noradrenaline, and dopamine in the central nervous system
with the dysfunction of dopaminergic, noradrenergic, ser-
otonergic systems. Heterocyclic compounds such as 1, 2, 4-
triazoles play a key role in the management of depression
for their safety and efficacy (McNamara 2011).
Graphical Abstract A series of new N′-arylidene-2-(5-
aryl-1H-1, 2, 4-triazol-3-ylthio)acetohydrazide have been
synthesized and characterized. The results revealed that
compound 4l with bromo substitution exhibited promising
antidepressant activity among the series.
1, 2, 4-Triazoles and their derivatives are possessed by
different biological activities such as anticonvulsant
(Kamboj et al. 2015; Plech et al. 2013; Song et al. 2011),
antimicrobial (Li et al. 2015; Maddila and Jonnalagadda
2012; Mange et al. 2013; Panda and Jain 2014), anticancer
(Kamel and Abdo 2014; Flefel et al. 2013; Singh et al.
2013), anti-inflammatory (Sarigol et al. 2015; Jiang et al.
2014). Several compounds containing 1, 2, 4-triazole rings
are well known as drugs. For example, fluconazole is used
as an antimicrobial drug, while vorozole, letrozole, and
anastrozole are non-steroidal drugs used for the treatment of
cancer. Loreclezole (anticonvulsant), alprazolam (anxioly-
tic), rizatriptan (antimigraine), and ribavirin (antiviral) are
examples of other drugs with 1, 2, 4-triazole moiety. In
addition to 1, 2, 4-triazoles, Schiff base derivatives and their
reduced derivatives have been also found to associate with
various pharmacological activities (Aouad et al. 2015; Li
et al. 2012; Sim et al. 2014).
N
HN
SCH2CONHN=CHArI
Ar
N
Ar - H, Cl, 2, 4-di chloro, 4-CH3, 2-OH, 4-OH
Ar1 - H, Cl, Br
* Radhika Chelamalla
cradhika8@gmail.com
1
2
Center for Pharmaceutical Sciences, Jawaharlal Nehru
Technological University, Kukatpally, Hyderabad 500085, India
Literature survey revealed that few reports were estab-
lished on 1, 2, 4-triazoles Schiff bases with antidepressant
University College of Pharmaceutical Sciences, Kakatiya
University, Warangal, AP 506009, India

Med Chem Res
activity (Jubie et al. 2011). Unsufficient biological data has
given a way to synthesize some new 1, 2, 4-triazole Schiff
base derivatives. It has been established that introduction of
several aromatic aldehydes to 2-(5-aryl-1H-1, 2, 4-triazol-3-
ylthio) acetohydrazide have yielded many biologically
active Schiff base structures which were screened for anti-
depressant activity by using tail suspension test in mice. The
compounds were characterized by IR, NMR, MS, and ele-
mental analysis.
and 2M sodium hydroxide was refluxed for 4 h. After
cooling, the solution was acidified with hydrochloric acid
and the precipitate was filtered. The precipitate was then re-
crystallized by using appropriate solvent to get pure
compound.
Synthesis of Ethyl 2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio)
acetate (2)
Ethyl chloroacetate (0.002 mol) was added to a solution of
compound 1 (0.001 mol) in absolute ethanol (20 ml). The
mixture was refluxed under stirring for 24 h in the presence
of potassium hydroxide (0.001 mol). Then the solvent was
removed under reduced pressure to give the solid product.
The crude product was recrystallized.
Materials and methods
Melting points were determined by open capillary using
Toshniwal melting point apparatus and are uncorrected. IR
spectra were recorded in potassium bromide (KBr) on FTIR
1
8400 Shimadzu spectrophotometer. H NMR spectra were
Synthesis of 2-(5-aryl-1H-1, 2, 4-triazol-3-ylthio)
acetohydrazide (3)
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. All chemicals
used in synthesis were purchased from E.Merck and
Aldrich. Thin layer chromatography was performed on
silicagel G (Merck) pre-coated plates and spots were
visualized with ultraviolet light. The chemical shifts are
reported in δ p.p.m. scale. The splitting pattern abbrevia-
tions are as follows: s, singlet; t, triplet; m, multiplet. The
synthetic pathway is given in Scheme 1. Elemental data for
C, H, N, O, and S were within 0.4% of the theoretical
values.
Eighty percent hydrazine hydrate (0.003 mol) was added to
compound 2 (0.002 mol) in ethanol (10 ml) and refluxed for
3 h. After cooling the appeared solid was filtered and
recrystallized with appropriate solvent.
Synthesis of N′-arylidene-2-(5-aryl-1H-1, 2, 4-triazol-3-
ylthio)acetohydrazide (4a–u)
A solution of 3 (0.001 mol) in ethanol (10 ml) the appro-
priate aromatic aldehyde (0.001 mol) and 4–5 drops of
glacial acetic acid was refluxed for 3 h. The resultant was
allowed to cool and poured into cold water. The solid was
collected by filtration and recrystallized from ethanol. By
using this total 21 compounds 4a–u were synthesized.
The physical and analytical data of all the synthesized
compounds were given in Table 1
Synthesis of 5-aryl-1H-1, 2, 4-triazole-3-thiol (1)
A mixture of compound aryl thiosemicarbazide (Tozko-
paran et al. 2007; Zamani et al. 2003) which was synthe-
sized from thiosemicarbazide and aroylchloride (0.1 mol)
Scheme 1 Synthetic pathway of
N'-arylidene-2-(5-aryl-1H-1, 2,
4-triazol-3-ylthio)
N
HN
N
HN
ClCH2COOC2H5
KOH
SH
SCH2COOC2H5
Ar
acetohydrazides
Ar
N
1
N
2
NH2NH2H2O
N
HN
N
HN
Ar1CHO
SCH2CONHNH2
Ar
SCH2CONHN=CHAr1
N
3
glacial acetic acid
Ar
N
4

Med Chem Res

Med Chem Res
N′-benzylidene-2-(5-phenyl-1H-1,2,4-triazol-3-ylthio)
acetohydrazide (4a)
(C–S),738(C–Cl); 1H NMR (CDCl3) δ p.p.m.:7.5–8.3
(m,8H, ArH), 2.47 (s, 3H, CH3), 3.62(s,2H, S–CH2), 11.5
(s,1H, CONH), 7.89(s,1H, N=CH), 13.4 (s,1H,Ar–NH);
13C NMR (CDCl3) δ p.p.m.:160.7 and 159.8(C3 and C5
triazole ring), 126.5–132.9(aromatic), 40.4 (SCH2),172.1
(C=O), 143.7(N–CH), 136.2(C–Cl),21.6(CH3); MS (70
eV) m/z: 386 (M+).
Yield 81%; m.p. 282 °C FT-IR (KBr) cm−1: 3460(NH),
1639(C=O), 1515(C=N), 1018(C–S) cmˉ1; 1H NMR
(CDCl3) δ p.p.m.:7.3–8.2(m,10H, ArH),4.06(s,2H, S–CH2),
10.6 (s,1H, CONH), 8.39 (s,1H, N=CH), 13.17 (s,1H,
Ar–NH); 13C NMR (CDCl3) δ p.p.m.: 160.1 and 159.5(C3
and C5 triazole ring), 127.4–133.2(aromatic), 40.1
(SCH2),172.4 (C=O), 143.8(N–CH);MS (70 eV) m/z: 338
(M+).
N′-(4-bromobenzylidene)-2-(5-p-tolyl-1H-1,2,4-triazol-3-
ylthio)acetohydrazide (4f)
Yield 81%; m.p. 294 °C FT-IR (KBr) cm−1:3197(NH),
3094(aromatic C–H str), 1654(C=O), 1560(C=N), 1109
(C–S),682(C–Br); 1H NMR (CDCl3) δ p.p.m.:7.3–8.0(s,8H,
ArH), 3.4(s,2H, S–CH2), 10.5 (s, 1H, CONH), 7.9(s, 1H,
N=CH), 2.51 (s, 3H, CH3), 13.1(s,1H,Ar–NH); 13C NMR
(CDCl3) δ p.p.m.:159.9 and 159.6(C3 and C5 triazole ring),
127.2–133.7(aromatic), 40.5 (SCH2),172.2 (C=O), 143.8
(N–CH), 21.3(CH3),123.9(C–Br); MS (70 eV) m/z:431
(M+).
N′-(4-chlorobenzylidene)-2-(5-phenyl-1H-1,2,4-triazol-3-
ylthio)acetohydrazide (4b)
Yield 79%; m.p. > 300 °C FT-IR (KBr) cmˉ1:3349 (NH),
3093(aromatic C–H str),1639(C=O), 1590(C=N), 1019
(C–S), 742(C–Cl); 1H NMR (CDCl3) δ p.p.m.: 7.2–8.2
(m,9H, ArH),4.15(s,2H, S–CH2), 8.29 (s, 1H, N=CH), 11.0
(s,1H, CONH), 13.2 (s,1H,Ar–NH); 13C NMR (CDCl3) δ p.
p.m.:160.5 and 159.2(C3 and C5 triazole ring), 126.8–132.6
(aromatic), 40.6 (SCH2),172.3 (C=O), 143.7(N–CH), 136.9
(C–Cl); MS (70 eV) m/z: 372 (M+).
N′-benzylidene-2-(5-(4-chlorophenyl)-1H-1,2,4-triazol-3-
ylthio)acetohydrazide (4g)
N′-(4-bromobenzylidene)-2-(5-phenyl-1H-1,2,4-triazol-3-
ylthio)acetohydrazide (4c)
Yield 75%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3250(NH),
3094(aromatic C-H str),1670(C=O), 1551(C=N), 1020(C-
1
S),743(C–Cl); H NMR (CDCl3) δ p.p.m.: 7.5–8.3(m,9H,
Yield 76%; m.p. 290 °C FT-IR (KBr) cmˉ1:3291 (NH),
3024.2 (aromatic C–H str), 1629(C=O), 1580 (C=N),1028
(C–S),690.3(C–Br);1H NMR (CDCl3) δ p.p.m.:7.3–8.2
(m,9H, ArH), 3.97 (s,2H, S–CH2), 10.9 (s,1H, CONH),
8.38 (s,1H, N=CH), 13.0 (s,1H,Ar–NH);13C NMR (CDCl3)
δ p.p.m.: 160.8 and 159.9(C3 and C5 triazole ring),
127.7–133.1(aromatic), 40.3 (SCH2),172.1(C=O), 143.2
(N–CH), 124.6 (C–Br); MS (70 eV) m/z: 417 (M+).
ArH), 3.6 (s,2H, S–CH2), 10.6 (s,1H, CONH), 8.1(s,1H,
N=CH), 13.4 (s,1H,Ar–NH);13C NMR (CDCl3) δ p.p.m.:
161.4 and 159.8(C3 and C5 triazole ring), 127.9–136.6
(aromatic), 40.0 (SCH2),172.7 (C=O), 143.1(N–CH),137.8
(C–Cl); MS (70 eV): m/z = 372 (M+).
N′-(4-chlorobenzylidene)-2-(5-(4-chlorophenyl)-1H-1,2,4-
triazol-3-ylthio)acetohydrazide (4h)
(N′-benzylidene-2-(5-p-tolyl-1H-1,2,4-triazol-3-ylthio)
acetohydrazide (4d)
Yield 71%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3270(NH),
1650(C=O), 3096(aromatic C-H str), 1564(C=N), 1100
(C–S),741(C–Cl); 1H NMR (CDCl3) δ p.p.m.: 7.4–8.2
(m,8H, ArH), 3.5 (s,2H, S–CH2), 10.1 (s,1H, CONH), 7.8
(s,1H, N=CH), 13.8 (s,1H,Ar–NH);13C NMR (CDCl3) δ p.
p.m.: 160.3 & 159.6(C3 and C5 triazole ring), 128.8–136.5
(aromatic), 40.3 (SCH2),172.9 (C=O), 143.5(N–CH),137.6
(C–Cl); MS (70 eV) m/z: 407 (M+).
Yield 78%; m.p. 291 °C FT-IR (KBr) cmˉ1: 3316 (NH),
3074(aromatic C–H str), 1647(C=O), 1591(C=N), 1023
(C–S);1H NMR (CDCl3) δ p.p.m.: 7.2–8.2(m,9H, ArH),
2.33 (s, 3H, CH3), 3.87 (s,2H, S–CH2), 11.2 (s,1H, CONH),
8.52 (s,1H, N=CH), 13.3 (s,1H,Ar–NH);13C NMR (CDCl3)
δ p.p.m.: 160.4 and 159.1(C3 and C5 triazole ring),
127.4–133.5(aromatic), 40.2 (SCH2),172.7 (C=O), 143.1
(N–CH), 21.5(CH3); MS (70 eV) m/z: 352 (M+).
N′-(4-bromobenzylidene)-2-(5-(4-chlorophenyl)-1H-1,2,4-
triazol-3-ylthio)acetohydrazide (4i)
N′-(4-chlorobenzylidene)-2-(5-p-tolyl-1H-1,2,4-triazol-3-
ylthio)acetohydrazide (4e)
Yield 78%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3260 (NH),
3086(aromatic C–H str), 1654(C=O), 1559(C=N), 1107
(C–S), 684(C–Br),747(C–Cl);1H NMR (CDCl3) δ p.p.
m.:7.5–8.0(m,8H, ArH), 3.2(s,2H, S–CH2), 10.8(s,1H,
CONH), 7.7(s,1H, N=CH), 13.1(s,1H,Ar–NH) p.p.m.;13C
Yield 72%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3275(NH),
3082(aromatic C–H str), 1754(C=O), 1570(C=N), 1010

Med Chem Res
NMR (CDCl3) δ p.p.m.:160.4 and 159.(C3 and C5 triazole
ring), 125.4–134.2 (aromatic), 40.3 (SCH2),171.9 (C=O),
143.8(N–CH),135.7(C–Cl),123.9(C–Br); MS (70 eV) m/z:
451 (M+).
N′-(4-chlorobenzylidene)-2-(5-(4-methoxyphenyl)-1H-1,2,4-
triazol-3-ylthio)acetohydrazide (4n)
Yield 79%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3294(NH),
3091 (aromatic C–H str),1648(C=O), 1562(C=N), 1107
(C–S),739(C–Cl); 1H NMR (CDCl3) δ p.p.m.: 7.1–7.9
(m,8H, ArH), 3.7(s,3H,OCH3), 4.2(s,2H, S–CH2), 10.5
(s,1H, CONH), 8.1(s,1H, N=CH), 13.1(s,1H,Ar–NH);13C
NMR (CDCl3) δ p.p.m.: 160.5 and 159.6(C3 and C5 triazole
ring), 114.9–160.6 (aromatic), 40.2 (SCH2),172.6 (C=O),
143.9(N–CH), 55.7 (OCH3),139.2(C–Cl); MS (70 eV) m/z:
402 (M+).
N′-benzylidene-2-(5-(2,4-dichlorophenyl)-1H-1,2,4-triazol-
3-ylthio)acetohydrazide (4j)
Yield 69%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3210 (NH),
3192(aromatic C–H str), 1657(C=O), 1562(C=N), 1103
(C–S),741(C–Cl); 1H NMR (CDCl3) δ p.p.m.: 7.4–7.9
(m,8H, ArH), 3.3(s,2H, S–CH2), 10.7(s,1H, CONH), 6.9
(s,1H, N=CH), 13.2(s,1H,Ar–NH);13C NMR (CDCl3) δ:
160.1 and 159.4(C3 and C5 triazole ring), 127.5–136.7
(aromatic), 40.5 (SCH2),172.7 (C=O), 143.4(N–CH),137.5
(C–Cl);MS (70 eV) m/z: 407 (M+).
N′-(4-bromobenzylidene)-2-(5-(4-methoxyphenyl)-1H-1,2,4-
triazol-3-ylthio)acetohydrazide (4o)
N′-(4-chlorobenzylidene)-2-(5-(2,4-dichlorophenyl)-1H-
1,2,4-triazol-3-ylthio)acetohydrazide (4k)
Yield 73%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3256 (NH),
3085 (aromatic C–H str),1653(C=O), 1549(C=N), 1094
(C–S),675(C–Br);1H NMR (CDCl3) δ p.p.m.: 7.0–8.1
(m,8H, ArH), 3.5(s,3H,OCH3), 4.2(s,2H, S–CH2), 10.2
(s,1H, CONH), 7.8(s,1H, N=CH), 13.3(s,1H,Ar–NH);13C
NMR (CDCl3) δ p.p.m.: 160.5 and 159.6(C3 and C5 triazole
ring), 114.2–160.2 (aromatic), 40.4 (SCH2),172.7 (C=O),
143.9(N–CH), 55.2 (OCH3),126.3(C–Br); MS (70 eV) m/z:
447 (M+).
Yield 73%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3209(NH),
3087(aromatic C–H str), 1651(C=O), 1567(C=N), 1110
(C–S),752(C–Cl);1H NMR (CDCl3) δ p.p.m.: 7.3–7.8
(m,7H, ArH), 3.6(s,2H, S–CH2), 10.7(s,1H, CONH), 7.4
(s,1H, N=CH), 13.0(s,1H,Ar–NH);13C NMR (CDCl3) δ p.
p.m.:160.8 and 159.4(C3 and C5 triazole ring), 127.3–135.6
(aromatic), 40.7 (SCH2),172.0 (C=O), 143.7(N–CH),137.2
(C–Cl);MS (70 eV) m/z: 441 (M+).
N′-benzylidene-2-(5-(2-hydroxyphenyl)-1H-1,2,4-triazol-3-
ylthio)acetohydrazide (4p)
N′-(4-bromobenzylidene)-2-(5-(2,4-dichlorophenyl)-1H-
1,2,4-triazol-3-ylthio)acetohydrazide (4l)
Yield 76%; Semisolid FT-IR (KBr) cmˉ1: 3750(OH), 3360
(NH), 3085 (aromatic C–H str), 1554(C=N),1103(C–S); 1H
NMR (CDCl3) δ p.p.m.: 7.1–7.9(m, 9H, ArH),4.1(s,2H,
S–CH2), 10.4(s,1H, CONH), 8.1(s,1H, N=CH), 13.1(s,1H,
Ar–NH), 9.6(s,1H,OH); 13C NMR (CDCl3) δ p.p.m.: 160.1
and 159.5(C3 and C5 triazole ring), 117.9–154.6 (aromatic),
40.0 (SCH2),172.5 (C=O), 143.8(N–CH) p.p.m.; MS (70
eV) m/z: 354 (M+).
Yield 81%; m.p. > 300 °C FT-IR (KBr) cmˉ1: 3346 (NH),
3106(aromatic C–H str), 1654 (C=O), 1564(C=N), 1105
(C–S),691(C–Br),742(C–Cl); 1H NMR (CDCl3) δ p.p.
m.:7.4–7.8(m,7H, ArH), 3.7(s,2H, S–CH2), 10.3(s,1H,
CONH), 7.8(s,1H, N=CH), 13.0(s,1H,Ar–NH);13C NMR
(CDCl3) δ p.p.m.: 160.1 and 159.4(C3 and C5 triazole
ring),127.4–136.7 (aromatic), 40.7 (SCH2),172.5 (C=O),
143.8(N–CH), 136.8(C–Cl),128.1(C–Br); MS (70 eV) m/z:
420 (M+).
N′-(4-chlorobenzylidene)-2-(5-(2-hydroxyphenyl)-1H-1,2,4-
triazol-3-ylthio)acetohydrazide (4q)
N′-benzylidene-2-(5-(4-methoxyphenyl)-1H-1,2,4-triazol-3-
ylthio)acetohydrazide (4m)
Yield 83%; Semisolid FT-IR (KBr) cmˉ1: 3769(OH),3275
(NH), 3076 (aromatic C–H str), 1641(C=O), 1559(C=N),
1101(C–S),739(C–Cl); 1H NMR (CDCl3) δ p.p.m.: 7.0–7.7
(m,8H, ArH), 3.5(s,2H, S–CH2), 10.5(s,1H, CONH), 7.2
(s,1H, N=CH), 13.4(s,1H,Ar–NH), 9.4(s,1H,OH);13C
NMR (CDCl3) δ p.p.m.:160.7 and 159.2(C3 and C5 triazole
ring), 117.0–136.6 (aromatic), 40.7 (SCH2),172.6 (C=O),
143.9(N–CH),137.6(C–Cl); MS (70 eV) m/z:388 (M+).
yield 73%; m.p. 298 °C FT-IR (KBr) cmˉ1: 3334 (N–H str),
3072 (aromatic C–H str), 1641 (C=O), 1517(C=N), 1018
(C–S);1H NMR (CDCl3) δ p.p.m.: 7.2–8.0 (m, 9H, ArH),
3.8 (s, 3H, OCH3), 4.1 (s, 2H, S–CH2), 8.3 (s, 1H, N=CH),
10.8 (s, 1H, CONH), 13.0(s, 1H,Ar–NH);13C NMR
(CDCl3) δ p.p.m.: 160.0 and 158.9(C3 and C5 triazole ring),
114.4–160.7(aromatic), 40.1 (SCH2),172.7 (C=O), 143.6
(N–CH), 55.8 (OCH3); MS (70 eV) m/z: 368 (M+).

Med Chem Res
N′-(4-bromo benzylidene)-2-(5-(2-hydroxy phenyl)-1H-
1,2,4-triazol-3-ylthio)acetohydrazide (4r)
Tail suspension test in mice
Healthy adult male or female mice weighing between
20–25 g were used as experimental animals. Animals were
fasted for overnight and divided into groups of six animals
each. Standard drug (10 mg/kg of Imipramine), test com-
pound (10, 30, and 100 mg/kg) and control vehicles (0.1%
Sodium CMC-Sodium Carboxy Methyl Cellulose) were
administered to the mice by intraperitoneal injection. The
tail suspension test was conducted in a silent experimental
room in which tail of the mouse was hanged to a horizontal
wooden bar located inside a yellow plastic box (40 × 46 ×
40 cm) just above 35 cm from the floor. The mouse
was fixed to the bar with the help of adhesive tape placed
1–1.5 cm from the tip of the tail, such that the mouse’s head
was laid about 20 cm above the floor. The subject was
observed with the help of video camera through a perspex
plastic coverage of the box allowed observation of the
subject with the aid of a video camera. The trial was con-
ducted for 5 min (300 s) during which a blinded observer
scored the total duration of immobility. The mouse was
considered immobile only when it hung passively and
completely motionless for at least 1 min. The responses
were noted at 60 min after the injection of the test com-
pound. The results were compared with control and stan-
dard drug (Cryan et al. 2005).
Yield 76%; Semisolid FT-IR (KBr) cmˉ1: 3709(OH), 3260
(NH), 3060(aromatic C–H str), 1649(C=O), 1541(C=N),
1123(C–S),662(C–Br); 1H NMR (CDCl3) δ p.p.m.: 7.1–7.8
(m,8H, ArH), 3.2(s,2H, S–CH2), 10.2(s,1H, CONH), 7.8
(s,1H, N=CH), 13.4(s,1H,Ar–NH), 9.5(s,1H,OH);13C
NMR (CDCl3) δ p.p.m.: 160.1 and 158.9(C3 and C5 triazole
ring), 117.7–154.3 (aromatic), 40.3 (SCH2),172.3 (C=O),
143.1(N–CH),126.9(C–Br); MS (70 eV) m/z:433 (M+).
N′-benzylidene-2-(5-(4-hydroxyphenyl)-1H-1,2,4-triazol-3-
ylthio)acetohydrazide (4s)
Yield 71%; Semisolid FT-IR (KBr) cmˉ1: 3735(OH),3249
(NH), 3059 (aromatic C–H str), 1643 (C=O), 1562(C=N),
1100(C–S); 1H NMR (CDCl3) δ p.p.m.: 7.1–7.9(m,8H,
ArH), 3.4(s,2H, S–CH2), 10.3 (s,1H, CONH), 7.6(s,1H,
N=CH), 13.0(s,1H,Ar–NH), 9.8(s,1H,OH) p.p.m.; 13C
NMR (CDCl3) δ p.p.m.: 160.1 and 159.6(C3 and C5 triazole
ring), 116.2–158.3 (aromatic), 40.2 (SCH2),170.8 (C=O),
143.2(N–CH); MS (70 eV) m/z:354 (M+).
N′-(4-chlorobenzylidene)-2-(5-(4-hydroxyphenyl)-1H-1,2,4-
triazol-3-ylthio)acetohydrazide (4t)
Yield 76%; Semisolid FT-IR (KBr) cmˉ1: 3765(OH),3280
(NH), 3074 (aromatic C–H str), 1621(C=O), 1574(C=N),
1128(C–S),741(C–Cl);1H NMR (CDCl3) δ p.p.m.: 6.8–7.9
(m,8H, ArH), 4.1(s,2H, S–CH2), 9.5(s,1H, CONH), 7.9
(s,1H, N=CH), 13.1(s,1H,Ar–NH), 9.4(s,1H,OH);13C
NMR (CDCl3) δ p.p.m.:160.5 and 159.3(C3 and C5 triazole
ring), 116.7–158.9 (aromatic), 40.4 (SCH2),170.8 (C=O),
143.3(N–CH),124.9(C–Cl); MS (70 eV) m/z: 388 (M+).
Results and discussion
Chemistry
IR spectrum of the compound 1a exhibited NH stretching at
3450.8 cm−1, the absorption band at 2360 cm−1 indicating
the presence of SH group. When triazole Schiff base was
prepared from compound 1 the SH peak was disappeared.
In the series 4, the absence of signals in the region
2300–2600 cm−1 (SH str) in IR spectral data and the pre-
sence of signal in the region of 1010–1050 cm-1 (C–S str)
and 1600–1700 cm−1 (C=O) indicates the formation of
compounds for the series 4.
N′-(4-bromobenzylidene)-2-(5-(4-hydroxyphenyl)-1H-1,2,4-
triazol-3-ylthio)acetohydrazide (4u)
Yield 83%; Semisolid FT-IR (KBr) cmˉ1:3760(OH),3292
(NH), 3097 (aromatic C–H str), 1654(C=O), 1531
(C=N),1112(C–S); 1H NMR (CDCl3) δ p.p.m.: 6.9–8.0
(m,8H, ArH), 3.2(s,2H, S–CH2), 9.6 (s,1H, CONH), 8.1
(s,1H, N=CH), 13.8(s,1H,Ar–NH), 9.6(s,1H,OH); 13C
NMR (CDCl3) δ p.p.m.: 160.3 and 159.6(C3 and C5 triazole
ring), 116.2–158.3 (aromatic), 40.7 (SCH2),172.4 (C=O),
143.1(N–CH), 129.3(C–Br); MS (70 eV) m/z: 433 (M+).
In the 1H NMR spectra of compound 1a, NH signal was
observed at 13.6 p.p.m. Additional signals (5H) belonging
to phenyl ring were observed in the aromatic region at 7.3 to
8.0 p.p.m. The signal due to –SH group was observed at
13.2 p.p.m. in the 1H NMR spectra of compound 1a. When
compound 1 is converted to Schiff base 4 the SH signal was
disappeared. In compound 4a the additional signals were
observed at 3.0 (2H, S–CH2), 8.6 (1H, CONH), 6.5 (1H,
N=CH).
Pharmacology
The synthesized compounds were evaluated for anti-
depressant activity by tail suspension test in mice.
Mass spectrum of the compound (4a, R = C6H5) was
recorded at molecular ion (M + 1) i.e. m/z 338.

Med Chem Res
Table 2 Antidepressant activity of test compounds by tail suspension
test in mice
Table 2 continued
Compound Name
Dose (mg/kg)
Immobility (in seconds)
Compound Name
Control
Dose (mg/kg)
Immobility (in seconds)
173.8 10.2
4p
4q
4r
4s
4t
10
167.2 11.2
154.3 11.6
147.0 14.6
121.5 7.6*
113.5 8.6*
102.2 9.2*
118.8 13.7*
105.2 4.3*
96.0 13.8*
166.2 11.1
155.0 10.0
153.2 8.2
0.1 ml of 0.1%
Sodium CMC
30
100
10
Imipramine
10
96.8 11.5*
176.8 10.8
167.5 8.2
4a
10
30
30
100
10
100
10
155.5 9.4
4b
4c
4d
4e
4f
172.2 5.7
30
30
167.7 12.5
158.5 9.7
100
10
100
10
156.3 9.5
30
30
146.0 14.1
121.3 12.8*
177.0 9.9
100
10
100
10
128.2 9.9*
118.0 8.7*
109.0 8.7*
119.8 8.4*
109.7 10.2*
102.5 9.9*
30
30
163.0 8.5
100
10
100
10
137.2 11.7
173.3 11.5
166.3 6.3
4u
30
30
100
100
10
155.3 9.6
158.0 16.3
117.7 6.7*
111.8 7.7*
168.2 15.1
152.0 16.2
149.7 11.2*
118.2 11.0*
112.8 7.8*
102.8 6.5*
104.0 5.1*
98.7 12.0*
95.7 9.6*
N = 6
30
*P < 0.001 Compared with control
100
10
4g
4h
4i
30
Tail suspension test in mice
100
10
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 (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 antidepressant properties.
Compound 4l with 4-bromo and 2, 4-dichloro substitution
showed most significant activity as compared to other test
compounds and is comparable with standard drug (imipra-
mine 10 mg/kg). Compounds 4f, 4h, 4i, 4k, 4n, 4q, 4r, 4t,
4u showed moderate activity. Compounds 4a, 4b, 4d, 4e,
4j, 4m, and 4p showed no activity. From above results it is
revealed that compound with bromo substitution have
shown good activity due to lipophilicity and high-molecular
weight. (Table 2).
30
100
10
30
100
10
4j
165.8 11.8
152.5 10.9
145.5 10.4
117.2 11.2*
108.0 8.1*
100.7 10.1*
97.2 11.9*
95.2 11.7*
91.0 10.0*
167.0 12.9
16.0.5 13.4
151.2 12.5
132.7 8.7*
117.0 9.6*
102.5 10.2*
131.5 13.8
116.8 9.3*
111.0 7.6*
30
100
10
4k
4l
30
100
10
30
100
10
4m
4n
4o
30
100
10
30
Conclusions
100
10
30
This study reports the synthesis of N′-arylidene-2-(5-aryl-
1H-1, 2, 4-triazol-3-ylthio) acetohydrazides. Twenty one
compounds were successfully synthesized. The anti-
depressant activity revealed that all the compounds that
were screened showed good to moderate antidepressant
100

Med Chem Res
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Piao HR (2015) Synthesis and antimicrobial evaluation of 5-aryl-
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Bioorg Med Chem Lett 25:3052–3056
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Among all the compounds, compound 4l displayed sig-
nificant activity due to high-lipophilic nature.
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Acknowledgements The authors are thankful to IICT Hyderabad for
providing 1H 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.
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interests.
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