Synthesis of new 1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol derivatives and evaluation of their antidepressant-like effects

Article abstract of DOI:10.1007/s12272-013-0119-1

In this study, we synthesized eight novel 1-phenyl-2-(4-substituted- piperazin-1-yl)-propanol derivatives and evaluated their antidepressant-like activities. The chemical structures of the synthesised compounds were elucidated by spectroscopy and elemental analyses. Potential antidepressant-like effects of the test compounds (20 mg kg^-1) were investigated using the tail-suspension test and modified forced swimming test (MFST) in mice. Additionally, the spontaneous locomotor activity of the mice was assessed using the activity cage apparatus. Both the reference drug fluoxetine (20 mg kg ^-1) and the test compounds 3a-3e and 3g significantly shortened the immobility time of the mice in both the behavioural tests. These test compounds also increased the swimming time in MFST without any change in the climbing duration. Compounds 3c-3e and 3g were significantly more potent in inducing these effects than 3a and 3b. None of the compounds changed the locomotor activities of the animals, thus antidepressant-like effects of test compounds were specific. The findings support those of previous studies that reported antidepressant-like activities of aryl alkanol piperazine derivatives.

Full text of DOI:10.1007/s12272-013-0119-1

Arch. Pharm. Res. (2013) 36:802–811
DOI 10.1007/s12272-013-0119-1
RESEARCH ARTICLE
Synthesis of new 1-phenyl-2-(4-substituted-piperazin-1-yl)-
propanol derivatives and evaluation of their antidepressant-like
effects
¨
Umide Demir Ozkay Leyla Yurttas¸
¨
•
•
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¨
˙
¨
•
•
•
Yusuf Ozkay Umut Irfan Uc¸el Ozgu¨r Devrim Can
¨
Yusuf Oztu¨rk
Published online: 18 April 2013
Ó The Pharmaceutical Society of Korea 2013
Abstract In this study, we synthesized eight novel
1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol deriva-
tives and evaluated their antidepressant-like activities. The
chemical structures of the synthesised compounds were
elucidated by spectroscopy and elemental analyses.
Potential antidepressant-like effects of the test compounds
(20 mg kg-1) were investigated using the tail-suspension
test and modified forced swimming test (MFST) in mice.
Additionally, the spontaneous locomotor activity of the
mice was assessed using the activity cage apparatus. Both
the reference drug fluoxetine (20 mg kg-1) and the test
compounds 3a–3e and 3g significantly shortened the
immobility time of the mice in both the behavioural tests.
These test compounds also increased the swimming time in
MFST without any change in the climbing duration.
Compounds 3c–3e and 3g were significantly more potent in
inducing these effects than 3a and 3b. None of the com-
pounds changed the locomotor activities of the animals,
thus antidepressant-like effects of test compounds were
specific. The findings support those of previous studies that
reported antidepressant-like activities of aryl alkanol
piperazine derivatives.
Introduction
Depression is a potentially life-threatening disorder that
affects people worldwide. The lifetime prevalence of this
disease is estimated to be as high as 21 % of the general
population in some developed countries. Depression can
occur at any age from childhood to late life and has a
tremendous cost to society as it causes severe distress and
disruption of life and, if left untreated, can be fatal (Brigitta
2002; Cryan et al. 2002).
Drugs that increase the levels of monoamines in the
synaptic clefts of the central nervous system have been
used for the treatment of depression for many years. In the
early years, depression was treated with tricyclic antide-
pressants and monoamine oxidase inhibitors (Rosenzweig-
Lipson et al. 2007). However, the clinical applications of
these drugs were limited due to their many side effects
(Millan 2004). After the discovery of selective serotonin
reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine,
and citalopram (Fig. 1), and selective noradrenaline reup-
take inhibitors, such as reboxetine (Fig. 1), an important
shift occurred in depression therapy. Drugs in these groups
were found to be as effective as the traditional antide-
pressants but with fewer side effects because of their more
specific mechanisms of action. Afterwards, dual serotonin-
noradrenaline reuptake inhibitors (SNRIs), including ven-
lafaxine, desvenlafaxine, and duloxetine (Fig. 1), which
also have fewer side effects than traditional antidepres-
sants, were discovered (Richelson 1994; Andrews et al.
1996; Lieberman 2003; Capriotti 2006; Rosenzweig-Lipson
et al. 2007). Consequently, newer antidepressants, which
inhibit the reuptake of serotonin, noradrenaline or both
neurotransmitters, became the preferred drugs in psychiatry
clinics because of their pharmacological advantages over
the older drugs (Shelton 2003).
Keywords Aryl alkanol piperazine Á Tail-suspension test Á
Modified forced swimming test Á Activity cage test Á
Fluoxetine
¨
¨
˙
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U. Demir Ozkay (&) Á U. I. Uc¸el Á O. D. Can Á Y. Oztu¨rk
Department of Pharmacology, Faculty of Pharmacy,
Anadolu University, 26470 Eskisehir, Turkey
e-mail: udemir@anadolu.edu.tr
¨
L. Yurttas¸ Á Y. Ozkay
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Anadolu University, 26470 Eskisehir, Turkey
123

Synthesis of new 1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol derivatives
803
The remarkable antidepressant activity of compounds
inhibiting serotonin and/or noradrenaline reuptake has direc-
ted researchers to develop a new series of chemicals acting as
selectiveordualinhibitors.Thedesignofcompoundscarrying
an aryloxy or alkoxy alkylamine substructure is a rational
strategy for the synthesis of new antidepressants because, as
seen in Fig. 1, all known antidepressants contain this common
structural feature. Aryl alkanol piperazine derivatives fit this
key structure well and, thus, are suitable compounds for
evaluation of novel antidepressant drugs. Furthermore, sev-
eral compounds in the aryl alkanol piperazine group were
shown to inhibit the reuptake of serotonin and/or noradrena-
line in previous studies (Li et al. 2006; Chen et al. 2009; Jianqi
et al. 2010; Weng and Li 2010; Avram et al. 2012).
Chemical companies. All melting points (M.p.) were
determined by Electrothermal 9100 digital melting point
apparatus and were uncorrected. 1H NMR data was
recorded by Bruker 500 MHz spectrometer. MS-ES,
VG Quattro Mass spectrometer and Elemental analyses
were performed on a Perkin Elmer EAL 240 elemental
analyzer.
Synthesis of 2-bromopropiophenone (1)
Propiophenone (150 mmol, 19.8 mL) and HBr (1 mL)
were dissolved in 100 mL of chloroform and then bromine
(165 mmol, 8.5 mL) in chloroform (20 mL) was added
dropwise at room temperature. After completion of drop-
ping, reaction mixture was stirred for an additional 2 h and
then 100 mL of water was added. Chloroform phase was
separated and the solvent was evaporated to give 2-bro-
mopropiophenone as a liquid product. Yield; 93 %. M.p.
In the present study, prompted by the structural features and
potential antidepressant-like activity of the aryl alkanol piper-
azines, we synthesised some novel 1-phenyl-2-(4-substituted-
piperazin-1-yl)-propanol derivatives and evaluated their
antidepressant-like profiles in animal models of depression.
not determined. IR (KBr)
m
max(cm-1): 3072–3028
(aromatic C–H), 2969–2924 (aliphatic C–H), 1698 (C=O),
1
1494–1443 (C=C), 1319–1094 (C–N and C–O). H NMR
Materials and methods
(500 MHz, DMSO-d6): 1.92 (d, 3H, CH3, J = 6.60 Hz),
5.31 (q, 1H, CH, J = 6.60 Hz), 7.42–7.58 (m, 3H, Ar–H),
8.02 (d, 2H, Ar–H, J = 7.29 Hz). MS-ES [M ? 1]?: m/z
214.1. For C9H9BrO calculated: 50.73 % C, 4.26 % H,
7.51 % N; found: 50.59 % C, 4.24 % H, 7.53 % N.
Chemistry
All chemicals were purchased from Merck (Darmstadt,
Germany) or Sigma-Aldrich (St. Louis, MO, USA)
Fig. 1 Chemical structures of
some antidepressant drugs and
synthesized compounds that
carry aryloxy or alkoxy
alkylamine main structure
H
N
F
H
H
O
N
O
O
O
H
N
CF3
O
NC
Fluoxetine
Citalopram
Paroxetine
F
S
OH
H
H
N
N
O
N
O
H
O
O
H
O
Reboxetine
Duloxetine
Venlafaxine
OH
CH3
N
HO
N
N
R
OH
Desvenlafaxine
1-Phenyl-2-(4-substituted-piperazin-1-yl)propanol derivatives
123

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U. Demir Ozkay et al.
804
General synthesis of 1-phenyl-2-(4-substituted-
1-Phenyl-2-[4-(4-fluoro-phenyl)piperazin-1-yl]propanone
piperazin-1-yl)propanone derivatives (2a–2h)
(2d)
2-Bromopropiophenone (10 mmol, 2.13 g), appropriate
N-substituted piperazine derivative (10 mmol), and K2CO3
(10 mmol, 1.38 g) were dissolved in acetone and refluxed
for 6 h. After evaporation of solvent, the residue was
washed with water, dried, and recrystallized from ethanol if
it was obtained in solid form. Otherwise, the oily residue
was extracted with ethyl acetate dried on anhydrous
sodium sulfate and used in next step after evaporation of
the solvent.
Yield; 85 %. M.p. 172 °C. IR (KBr) mmax(cm-1): 3075–
3039 (aromatic C–H), 2968–2919 (aliphatic C–H), 1701
(C=O), 1484–1433 (C=C), 1332–1091 (C–N and C–O).
1H NMR (500 MHz, DMSO-d6): 0.83 (d, 3H, CH3,
J = 7.01 Hz), 2.56–3.24 (m, 8H, piperazine), 4,31 (q, H,
CH, J = 7.09 Hz), 6.94 (2H, d, Ar–H, J = 8.21 Hz), 7.02
(2H, d, Ar–H, J = 8.22 Hz), 7.41–7.56 (m, 3H, Ar–H),
8.01 (2H, d, Ar–H, J = 7.66 Hz). MS-ES [M ? 1]?: m/z
313.2. For C19H21FN2O calculated: 73.05 % C, 6.78 % H,
8.97 % N; found: 72.99 % C, 6.80 % H, 8.92 % N.
1-Phenyl-2-(4-phenyl-piperazin-1-yl)propanone (2a)
1-Phenyl-2-[4-(4-nitro-phenyl)piperazin-1-yl]propanone
Yield; 84 %. M.p. 104 °C. IR (KBr) mmax(cm-1): 3069–
3031 (aromatic C–H), 2974–2926 (aliphatic C–H), 1703
(C=O), 1483–1435 (C=C), 1324–1086 (C–N and C–O).
1H NMR (500 MHz, DMSO-d6): 0.83 (d, 3H, CH3,
J = 6.96 Hz), 2.58–3.23 (m, 8H, piperazine), 4,34 (q, H,
CH, J = 6.94 Hz), 7.03–7.15 (m, 5H, Ar–H), 7.43–7.57
(m, 3H, Ar–H), 8.03 (2H, d, Ar–H, J = 7.88 Hz). MS-ES
[M ? 1]?: m/z 295.6. For C19H22N2O calculated: 77.52 %
C, 7.53 % H, 9.52 % N; found: 77.46 % C, 7.49 % H,
9.50 % N.
(2e)
Yield; 87 %. M.p. 164 °C. IR (KBr) mmax(cm-1): 3071–
3028 (aromatic C–H), 2977–2934 (aliphatic C–H), 1701
(C=O), 1479–1431 (C=C), 1319–1094 (C–N and C–O).
1H NMR (500 MHz, DMSO-d6): 0.85 (d, 3H, CH3,
J = 7.11 Hz), 2.63–3.29 (m, 8H, piperazine), 4.30 (q, H,
CH, J = 7.17 Hz), 7.41–7.56 (m, 3H, Ar–H), 7.86 (2H, d,
Ar–H, J = 8.42 Hz), 8.02–8.11 (4H, m, Ar–H). MS-ES
[M ? 1]?: m/z 340.2. For C19H21N3O3 calculated:
67.24 % C, 6.24 % H, 12.38 % N; found: 67.36 % C,
6.25 % H, 12.41 % N.
1-Phenyl-2-[4-(4-methyl-phenyl)piperazin-1-yl]propanone
(2b)
1-Phenyl-2-(4-cyclohexyl-piperazin-1-yl)propanone (2f)
Yield; 79 %. M.p. 109 °C. 3074–3036 (aromatic C–H),
2968–2923 (aliphatic C–H), 1700 (C=O), 1478–1427
Yield; 77 %. M.p. 106 °C. IR (KBr) mmax(cm-1): 3068–
3034 (aromatic C–H), 2971–2927 (aliphatic C–H), 1701
(C=O), 1483–1435 (C=C), 1321–1083 (C–N and C–O).
1H NMR (500 MHz, DMSO-d6): 0.81 (d, 3H, CH3,
J = 7.05 Hz), 1.09–1.27 (m, 6H, cyclohexyl), 1.64–1.97
(m, 4H, cyclohexyl), 2.18–2.27 (m, H, cyclohexyl),
2.49–2.83 (m, 8H, piperazine), 4.36 (q, H, CH,
J = 7.06 Hz), 7.41–7.56 (m, 3H, Ar–H), 8.01 (2H, d,
Ar–H, J = 7.93 Hz). MS-ES [M ? 1]?: m/z 301.4. For
C19H28N2O calculated: 75.96 % C, 9.39 % H, 9.32 % N;
found: 75.88 % C, 9.36 % H, 9.30 % N.
1
(C=C), 1341–1093 (C–N and C–O). H NMR (500 MHz,
DMSO-d6): 0.85 (d, 3H, CH3, J = 6.97 Hz), 2.58–3.23 (m,
8H, piperazine), 4,32 (q, H, CH, J = 6.96 Hz), 6.88 (2H, d,
Ar–H, J = 8.24 Hz), 7.01 (2H, d, Ar–H, J = 8.26 Hz),
7.40–7.57 (m, 3H, Ar–H), 8.01 (2H, d, Ar–H, J =
7.69 Hz). MS-ES [M ? 1]?: m/z 309.2. For C20H24N2O
calculated: 77.89 % C, 7.84 % H, 9.08 % N; found:
78.02 % C, 7.79 % H, 9.02 % N.
1-Phenyl-2-[4-(4-chloro-phenyl)piperazin-1-yl]propanone
(2c)
1-Phenyl-2-[4-(2-hydroxy-ethyl)piperazin-1-yl]propanone
Yield; 81 %. M.p. 169 °C. IR (KBr) mmax(cm-1): 3064–
3038 (aromatic C–H), 2977–2923 (aliphatic C–H), 1702
(C=O), 1484–1432 (C=C), 1327–1081 (C–N and C–O). 1H
NMR (500 MHz, DMSO-d6): 0.83 (d, 3H, CH3,
J = 7.06 Hz), 2.59–3.21 (m, 8H, piperazine), 4,31 (q, H,
CH, J = 7.04 Hz), 6.94 (2H, d, Ar–H, J = 8.32 Hz), 7.03
(2H, d, Ar–H, J = 8.32 Hz), 7.41–7.56 (m, 3H, Ar–H),
8.00 (2H, d, Ar–H, J = 7.83 Hz). MS-ES [M ? 1]?: m/z
329.8. For C19H21ClN2O calculated: 69.40 % C, 6.44 % H,
8.52 % N; found: 69.23 % C, 6.46 % H, 8.55 % N.
(2g)
Yield; 74 %. M.p. not determined. IR (KBr) mmax(cm-1):
3294 (O–H), 3073–3036 (aromatic C–H), 2971–2937 (ali-
phatic C–H), 1700 (C=O), 1486–1428 (C=C), 1325–1088
(C–N and C–O). 1H NMR (500 MHz, DMSO-d6): 0.81 (d,
3H, CH3, J = 7.02 Hz), 2.44–2.81 (m, 10H, CH2 and
piperazine), 3.66 (t, 2H, J = 7.16 Hz), 4.00–4.08 (b, H,
O–H), 4.35 (q, H, CH, J = 7.04 Hz), 7.40–7.56 (m, 3H,
Ar–H), 8.01 (2H, d, Ar–H, J = 7.88 Hz). MS-ES
123

Synthesis of new 1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol derivatives
805
[M ? 1]?: m/z 263.2. For C15H22N2O2 calculated:
68.67 % C, 8.45 % H, 10.68 % N; found: 68.56 % C,
8.43 % H, 10.64 % N.
Ar–H, J = 8.34 Hz), 7.25–7.39 (m, 5H, Ar–H). MS-ES
[M ? 1]?: m/z 311.4. For C20H26N2O calculated: 77.38 %
C, 8.44 % H, 9.02 % N; found: 77.73 % C, 8.43 % H,
9.07 % N.
1-Phenyl-2-[4-(2-dimethylamino-ethyl)piperazin-1-
yl]propanone (2h)
1-Phenyl-2-[4-(4-chloro-phenyl)piperazin-1-yl]propanol
(3c)
Yield; 76 %. M.p. not determined. IR (KBr) mmax(cm-1):
3075–3033 (aromatic C–H), 2976–2929 (aliphatic C–H),
1703 (C=O), 1481–1426 (C=C), 1332–1093 (C–N and
Yield; 74 %. M.p. 186 °C. IR (KBr) mmax(cm-1): 3236
(O–H), 3056–3031 (aromatic C–H), 2976–2934 (aliphatic
1
C–H), 1452–1433 (C=C), 1318–1086 (C–N and C–O). H
1
C–O). H NMR (500 MHz, DMSO-d6): 0.83 (d, 3H, CH3,
J = 6.97 Hz), 2.15 (s, 6H, 2xCH3), 2.34–2.37 (m, 4H,
CH2CH2), 2.47–2.82 (m, 8H, piperazine), 4.33 (q, H, CH,
J = 7.02 Hz), 7.41–7.55 (m, 3H, Ar–H), 8.00 (2H, d,
Ar–H, J = 7.84 Hz). MS-ES [M ? 1]?: m/z 290.3. For
C17H27N3O calculated: 70.55 % C, 9.40 % H, 14.52 % N;
found: 70.39 % C, 9.37 % H, 14.56 % N.
NMR (500 MHz, DMSO-d6): 0.83 (d, 3H, CH3,
J = 7.15 Hz), 2.60–3.28 (m, 9H, CH and piperazine), 4.30
(d, H, CH, J = 8.26 Hz), 5.02–5.11 (b, H, –OH), 6.93 (m,
2H, Ar–H, J = 8.37 Hz), 6.99 (2H, d, Ar–H, J = 8.35),
7.26–7.42 (m, 5H, Ar–H). MS-ES [M ? 1]?: m/z 331.8.
For C19H23ClN2O calculated: 68.97 % C, 7.01 % H,
8.47 % N; found: 68.74 % C, 7.02 % H, 8.42 % N.
General synthesis of 1-phenyl-2-(4-substituted-
piperazin-1-yl)propanol derivatives (3a–3h)
1-Phenyl-2-[4-(4-fluoro-phenyl)piperazin-1-yl]propanol
(3d)
The intermediates 2a–2h (5 mmol) were dissolved in
methanol and NaBH4 (10 mmol) was added in several
portions. Reaction was monitored by TLC until the starting
material disappeared. After evaporation of solvent, the
residue was washed with water, dried, and recrystallized
from ethanol to give 3a–3g. Compound 3h was obtained as
an oily residue and its purification was performed by
extracting in ethyl acetate.
Yield; 63 %. M.p. 144 °C. IR (KBr) mmax(cm-1): 3241
(O–H), 3053–3027 (aromatic C–H), 2962–2924 (aliphatic
1
C–H), 1453–1417 (C=C), 1328–1096 (C–N and C–O). H
NMR (500 MHz, DMSO-d6): 0.83 (d, 3H, CH3,
J = 7.12 Hz), 2.61–3.31(m, 9H, CH and piperazine), 4.31
(d, H, CH, J = 8.24 Hz), 4.99–5.11 (b, H, –OH), 6.92
(m, 2H, Ar–H, J = 8.26 Hz), 6.98 (2H, d, Ar–H,
J = 8.28 Hz), 7.25–7.41 (m, 5H, Ar–H). MS-ES
[M ? 1]?: m/z 315.4. For C19H23FN2O calculated: 72.58 %
C, 5.57 % H, 8.91 % N; found: 72.44 % C, 5.56 % H,
8.89 % N.
1-Phenyl-2-(4-phenyl-piperazin-1-yl)propanol (3a)
Yield; 69 %. M.p. 127 °C. IR (KBr) mmax(cm-1): 3246
(O–H), 3042–3024 (aromatic C–H), 2978–2921 (aliphatic
1
C–H), 1456–1432 (C=C), 1321–1083 (C–N and C–O). H
1-Phenyl-2-[4-(4-nitro-phenyl)piperazin-1-yl]propanol
NMR (500 MHz, DMSO-d6): 0.84 (d, 3H, CH3,
J = 7.16 Hz), 2.59–3.22 (m, 9H, CH and piperazine), 4,32
(d, H, CH, J = 8.31 Hz) 5.08–5.14 (b, H, –OH), 7.01–7.14
(m, 5H, Ar–H), 7.26–7.41 (m, 5H, Ar–H). MS-ES
[M ? 1]?: m/z 297.5. For C19H24N2O calculated: 76.99 %
C, 8.16 % H, 9.45 % N; found: 77.16 % C, 8.18 % H,
9.38 % N.
(3e)
Yield; 81 %. M.p. 182 °C. IR (KBr) mmax(cm-1): 3248
(O–H), 3047–3018 (aromatic C–H), 2974–2931 (aliphatic
1
C–H), 1458–1411 (C=C), 1336–1070 (C–N and C–O). H
NMR (500 MHz, DMSO-d6): 0.85 (d, 3H, CH3,
J = 7.16 Hz), 2.63–3.29 (m, 9H, CH and piperazine), 4.30
(d, H, CH, J = 8.17 Hz), 5.02–5.09 (b, H, –OH), 7.25–7.41
(m, 5H, Ar–H), 7.86 (2H, d, Ar–H, J = 8.42 Hz), 8.09
(2H, d, Ar–H, J = 8.48 Hz). MS-ES [M ? 1]?: m/z 342.4.
For C19H23N3O3 calculated: 66.84 % C, 6.79 % H,
12.31 % N; found: 66.76 % C, 6.77 % H, 12.36 % N.
1-Phenyl-2-[4-(4-methyl-phenyl)piperazin-1-yl]propanol
(3b)
Yield; 72 %. M.p. 112 °C. IR (KBr) mmax(cm-1): 3242
(O–H), 3044–3027 (aromatic C–H), 2970–2927 (aliphatic
C–H), 1458–1433 (C=C), 1321–1086 (C–N and C–O).
1H NMR (500 MHz, DMSO-d6): 0.83 (d, 3H, CH3,
J = 7.18 Hz), 2.32 (s, 2H, CH3), 2.62–3.24 (m, 9H, CH
and piperazine), 4.30 (d, H, CH, J = 8.27 Hz) 5.07–5.13
(b, H, –OH), 6.86 (2H, d, Ar–H, J = 8.32 Hz), 6.98 (2H, d,
1-Phenyl-2-(4-cyclohexyl-piperazin-1-yl)propanol (3f)
Yield; 66 %. M.p. 101 °C. IR (KBr) mmax(cm-1): 3216
(O–H), 3051–3024 (aromatic C–H), 2972–2938 (aliphatic
C–H), 1454–1416 (C=C), 1329–1077 (C–N and C–O).
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U. Demir Ozkay et al.
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1H NMR (500 MHz, DMSO-d6): 0.79 (d, 3H, CH3,
J = 7.25 Hz), 1.07–1.29 (m, 6H, cyclohexyl), 1.61–1.92
(m, 4H, cyclohexyl), 2.18–2.30 (m, H, cyclohexyl),
2.48–2.82 (m, 9H, CH and piperazine), 4.24 (d, H, CH,
J = 8.26 Hz), 5.11–5.26 (b, H, –OH), 7.25–7.37 (m, 5H,
Ar–H). MS-ES [M ? 1]?: m/z 303.5. For C19H30N2O
calculated: 75.45 % C, 10.00 % H, 9.26 % N; found:
75.81 % C, 9.98 % H, 9.31 % N.
the Local Ethical Committee on Animal Experimentation
of Anadolu University, Eskis¸ehir, Turkey.
Administration of compounds
The mice were assigned randomly into following treatment
groups: a control group, a reference drug-treated group, and
eight test compounds-treated groups. All of the groups
consisted of seven animals. The reference drug fluoxetine
(20 mg kg-1, Sigma-Aldrich Chemical Company, St.
Louis, MO, USA), control solution (sunflower oil), and the
test compounds (20 mg kg-1) were given orally three times
24, 5, and 1 h before the behavioural tests (Sanmukhani
et al. 2011).
1-Phenyl-2-[4-(2-hydroxy-ethyl)piperazin-1-yl]propanol
(3g)
Yield; 69 %. M.p. 109 °C. IR (KBr) mmax(cm-1): 3292 (O–H),
3198 (O–H), 3062–3033 (aromatic C–H), 2981–2914
(aliphatic C–H), 1462–1418 (C=C), 1338–1082 (C–N and
C–O). 1H NMR (500 MHz, DMSO-d6): 0.78 (d, 3H,
CH3, J = 7.21 Hz), 2.47–2.83 (m, 11H, CH2, CH and
piperazine), 3.64 (t, 2H, J = 7.16 Hz), 3.98–4.06 (b, H,
O–H), 4.25 (d, H, CH, J = 8.14 Hz), 5.06–5.18 (b, H,
–OH), 7.26–7.37 (m, 5H, Ar–H). MS-ES [M ? 1]?: m/z
265.4. For C15H24N2O2 calculated: 68.15 % C, 9.15 % N,
10.60 % N; found: 68.26 % C, 9.13 % H, 10.53 % N.
Behavioural tests
Tail-suspension test (TST)
To assess the antidepressant-like activities of the test
compounds, the tail-suspension test (TST) was conducted
according to the method described previously (Steru et al.
1985). Each mouse was individually suspended 30 cm
above the floor using adhesive tape placed approximately
1 cm from the tip of its tail. Mice were considered
immobile only when they hung passively and were com-
pletely motionless. The total duration of immobility was
measured with a stopwatch during the last 4 min of a 6-min
test period (Can et al. 2012).
1-Phenyl-2-[4-(2-dimethylamino-ethyl)piperazin-1-
yl]propanol (3h)
Yield; 71 %. M.p. not determined. IR (KBr) mmax(cm-1):
3226 (O–H), 3042–3017 (aromatic C–H), 2970–2941 (ali-
phatic C–H), 1459–1413 (C=C), 1341–1083 (C–N and
1
C–O). H NMR (500 MHz, DMSO-d6): 0.79 (d, 3H, CH3,
J = 7.29 Hz), 2.14 (s, 6H, 2xCH3), 2.33–2.38 (m, 4H,
CH2CH2), 2.47–2.80 (m, 9H, CH and piperazine), 4.24 (d,
H, CH, J = 8.19 Hz), 5.09–5.18 (b, H, –OH), 7.25–7.37
(m, 5H, Ar–H). MS-ES [M ? 1]?: m/z 292.5. For
C17H29N3O calculated: 70.06 % C, 10.03 % H, 14.24 % N;
found: 70.09 % C, 10.03 % H, 14.40 % N.
Modified forced swimming test (MFST)
The modified forced swimming test (MFST) was per-
formed as described elsewhere (Tanaka and Telegdy, 2008;
Cryan et al. 2002; Can et al. 2011). The mice were forced
to swim individually in a glass cylinder (diameter, 12 cm;
height, 30 cm) containing 20 cm of water at 25 1 °C.
One day prior to the test, mice were exposed to a pre-test
for 15 min with no behavioural observation. Twenty-four
hours after the pre-test, the mice were tested under the
same conditions for 5 min (test session). During the test
session, the times spent swimming (horizontal movement
on the surface of the water and crossing into another
quadrant), climbing (upward-directed movements of the
forepaws along the side of the swim chamber) and
immobility (the movement required just to keep the head
above the water) in 5-s intervals were recorded by a
stopwatch.
Pharmacology
Animals
Adult BALB/c mice, weighing approximately 30–35 g,
were used for the experiments. All animals were kept under
a 12-h light/12-h dark cycle (lights on at 8:00 a.m.) at a
constant temperature of 25 1 °C. These temperature,
sound, and light conditions were maintained during the
experiments. To ensure adaptation to the new environment,
mice were housed in the laboratory for at least 48 h before
the experimental session. Food was withdrawn 12 h before
the experiments in order to avoid any possible interference
of the food with the absorption of the test substances.
Water was allowed ad libitum. All experimental procedures
were performed in accordance with protocols approved by
Activity cage test
The spontaneous locomotor activities of the mice were
evaluated using an activity cage apparatus (Ugo Basile,
123

Synthesis of new 1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol derivatives
807
No.7420, Varese, Italy) containing 2 pairs of 16 photocells
under a transparent cover. Interruptions in light beams to
the photocells during horizontal and vertical movements of
the animals were recorded automatically for 4 min (Votava
et al. 2005).
2a–2h were reduced by NaBH4 in methanol to produce
1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol deriva-
tives (compounds 3a–3h). Due to the presence of two
chiral carbons in their structures, the target compounds
were obtained as diastereomers. The structures of the
compounds were assigned on the basis of spectroscopic and
analytical data. The infrared (IR) spectra were very infor-
mative about the structures of the target compounds. The
disappearance of the characteristic stretching absorptions
for ketone carbonyl group (C=O) at approximately
1700 cm-1 and the appearance of stretching bands for O–H
bonds at approximately 3216–3292 cm-1 indicated the
successful reduction of ketone to alcohol. Stretching
absorption at approximately 1077–1341 cm-1 was recor-
Statistical analyses
Statistical analyses of the experimental data were per-
formed using GraphPad Prism 3.0 software (GraphPad
Software, San Diego, CA, USA). The data used in the
statistical analyses were obtained from seven animals for
each of the groups. The effects of the test compounds on
the behavioural parameters of the animals were analysed
by one-way analysis of variance (ANOVA) followed by
Tukey’s post hoc test. The data are presented as the
mean standard error of the mean (SEM). Differences
between groups were considered statistically significant at
a level of p \ 0.05.
1
ded for C–N and C–O bonds. In the H nuclear magnetic
resonance (NMR) spectra, the methyl group appeared at
0.78–0.84 ppm as a doublet. Protons of piperazine and
C–H gave a peak together at approximately 2.47–3.31 ppm
as multiplets. C–H protons, which are bonded to O–H
groups, were observed at 4.25–4.32 ppm as doublets.
Protons of the O–H were observed at 5.02–5.26 ppm as
broad peaks. The other peaks, belonging to aromatic and
aliphatic protons of variable side chains, were observed at
the estimated areas. In the mass spectra, the observed
M ? 1 peaks agreed with the calculated molecular weights
of the synthesised compounds. The results of elemental
analyses for C, H, and N were within the calculated values
for the compounds.
Results and discussion
Chemistry
In this study, we synthesised new 1-phenyl-2-(4-sub-
stituted-piperazin-1-yl)-propanol derivatives and investi-
gated their antidepressant-like activities. The target
compounds were synthesised in three steps (Scheme 1).
Firstly, propiophenone was brominated in chloroform to
give 2-bromopropiophenone (compound 1), which was
then reacted with corresponding-N-substituted piperazines
to produce 1-phenyl-2-(4-substituted-piperazin-1-yl)-prop-
anone derivatives (compounds 2a–2h). Finally, compounds
Pharmacology
The potential antidepressant-like activities of the new
phenyl alkanol piperazine derivatives were next evaluated,
using TST and MFST. Furthermore, the effects of the
Scheme 1 Synthesis of
O
O
HN
N R
1-phenyl-2-(4-substituted-
piperazin-1-yl)-propanol
derivatives (3a–3h)
Br
Br2
K2CO3 / Acetone
CHCl3
CH3
93%
CH3
1
R
OH
N
R
O
N
NaBH4
MeOH
N
N
CH3
CH3
63-81%
74-87%
3a-3h
2a-2h
R: 3a;
CH3
Cl
3b;
3f;
3c;
F
3d;
3e;
NO2
3g;
-CH2CH2N(CH3)2
3h;
-CH2CH2OH
123

¨
¨
U. Demir Ozkay et al.
808
3g may be related to serotonergic rather than noradrenergic
mechanisms in the central nervous system (Detke and
Lucki 1996; Cryan et al. 2002; Can et al. 2012). However,
the involvement of the serotonergic system in the exhibited
antidepressant-like activity must be confirmed with further
detailed studies.
In addition, drugs that increase locomotor activity may
give a ‘false positive’ result in TST and MFST, whereas
drugs that decrease locomotion may give a ‘false negative’
result (Borsini and Meli 1988; Brocardo et al. 2008).
Therefore, the activity cage test was performed in order to
rule out these probabilities. As illustrated in Fig. 4, the test
compounds had no effect on the total number of horizontal
or vertical locomotor activities of the mice. Thus, antide-
pressant-like effects of test compouds were specific.
The structure–activity relationship (SAR) study revealed
that the antidepressant-like activity of compounds 3a–3h
was sensitive to the nature of the substituents at the fourth
position of the piperazine ring. The significant antide-
pressant-like activity of compounds 3a–3e, which carry
phenyl or 4-substituted phenyl groups on their piperazine
ring, indicated the impact of the compound’s lipophilicity
on its pharmacological activity because these compounds
have a greater lipophilicity than the inactive compounds 3f
and 3h, which contain cyclohexane and dimethylamino-
ethyl side chains, respectively. Lipophilicity is a key
property of a drug that influences its ability to reach its
target by transmembrane diffusion and therefore influences
its biological activity (Testa et al. 2000; Patil et al. 2010).
The importance of this property increases for drugs tar-
geting the central nervous system because they need to
have sufficient lipophilicity to allow them to cross the
blood–brain barrier and, therefore, display pharmacological
activity (Alavijeh et al. 2005). In addition to lipophilicity,
the electron characteristics of the substituents in com-
pounds 3a–3e influenced their pharmacological activity.
The antidepressant-like effects of compounds 3c–3e that
had electron withdrawing substituents such as chloro, flu-
oro, and nitro seemed to be significantly stronger than those
of the unsubstituted compound 3a and compound 3b with
an electron donating methyl group substituent. This is an
interesting finding suggesting that the electron density on
the piperazine ring is very important for a compound’s
pharmacological activity. Thus, it may be declared that
electron-withdrawing substituents decrease the electron
density on the piperazine ring and increase the antide-
pressant-like activity. Another interesting observation was
the significant antidepressant-like activity of compound 3g.
This compound carried a 2-hydroxyethyl group instead of a
phenyl substituent at the fourth position of the piperazine
ring. According to the above explanations, including the
relationships between antidepressant-like activity and
physicochemical features such as lipophilicity and electron
Fig. 2 Effects of the test compounds on immobility time of mice in
the TSTs. Values are given as mean SEM. Significance against
control values, *p \ 0.05, **p \ 0.01, ***p \ 0.001; significance
against compound 3a treated group, ap \ 0.05, bp \ 0.01; signifi-
cance against compound 3b treated group, &p \ 0.05, &&p \ 0.01.
One-way ANOVA, post hoc Tukey test, n = 7
compounds on spontaneous locomotor activities were
evaluated using the activity cage apparatus.
The TST and MFST tests are widely accepted behav-
ioural models for the screening of antidepressant-like
activity. These tests are sensitive to antidepressant drugs
and treatment with antidepressants decreases the immo-
bility time of the animals in both the tests (Porsolt et al.
1977; Steru et al. 1985; Brocardo et al. 2008; Girish et al.
2012). Moreover, MFST provides additional information
about the possible mechanisms of antidepressant action
(Detke and Lucki 1996; Cryan et al. 2002; Akhtar et al.
2005; Aksoz et al. 2008; Nakatomi et al. 2008; Can et al.
2011). In MFST, evaluation of the active behaviours of
animals (climbing and swimming) contributes to an esti-
mation of the probable neurotransmitters involved in the
antidepressant-like action. Antidepressant drugs that
mainly activate the noradrenergic system reduce immo-
bility and increase climbing behaviour, whereas drugs that
mainly stimulate the serotonergic system decrease immo-
bility and increase swimming behaviour (Detke and Lucki
1996; Cryan et al. 2002). In the present study, compounds
3a, 3b, 3c, 3d, 3e, and 3g and the reference drug fluoxetine
significantly decreased the immobility time of the animals
in TST (Fig. 2). Compounds 3c, 3d, 3e, and 3g were sig-
nificantly more effective than compounds 3a and 3b in
terms of this antidepressant-like activity. The antidepres-
sant-like activities of these compounds observed in TST
were confirmed by the results of MFST (Fig. 3). Moreover,
the observed decrease in the immobility time and increase
in the swimming time of the mice without any change in
the climbing duration in MFST indicated that the antide-
pressant-like effects of compounds 3a, 3b, 3c, 3d, 3e, and
123

Synthesis of new 1-phenyl-2-(4-substituted-piperazin-1-yl)-propanol derivatives
809
Fig. 3 Effects of the test compounds on immobility (a), swimming
(b) and climbing (c) times of mice in the MFSTs. Significance against
control values, *p \ 0.05, **p \ 0.01, ***p \ 0.001; significance
against compound 3a treated group, ap \ 0.05, bp \ 0.01; signifi-
cance against compound 3b treated group, &p \ 0.05, &&p \ 0.01.
One-way ANOVA, post hoc Tukey test, n = 7
Fig. 4 Effects of the test compounds on spontaneous locomotor activity parameters of mice in the activity cage tests. Values are given as
mean SEM. One-way ANOVA, post hoc Tukey’s test, n = 7
density, compound 3g was not expected to possess notable
pharmacological activity. Thus, additional physicochemi-
cal properties of this compound should be described. The
distinctive feature of compounds 3g in the series was its
second free hydroxyl group, which enabled easier inter-
action with biomolecules via hydrogen bonds. Hence, it
123

¨
¨
U. Demir Ozkay et al.
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be proposed for the pharmacologically active compounds
3c–3e, which bear chloro, fluoro, and nitro substituents and
are able to form hydrogen bonds with biomolecules.
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Conclusion
In the present study, eight novel compounds that are
members of the aryl alkanol piperazine group were syn-
thesised and their antidepressant-like activities were
investigated. Previously reported similar compounds have
been suggested to have serotonergic and/or noradrenergic
mechanisms of action (Li et al. 2006; Chen et al. 2009;
Jianqi et al. 2010; Weng and Li, 2010; Avram et al.
2012). In this study, in vivo pharmacological studies
indicated that most of the synthesised compounds pos-
sessed significant antidepressant-like activity, which
seemed to be related to a serotonergic mechanism of
action. An SAR study revealed that compounds 3c–3e and
3g, which had 4-chloro phenyl, 4-fluoro phenyl, 4-nitro
phenyl and or 2-hydroxyethyl groups on the nitrogen of
their piperazine ring, displayed the strongest antidepres-
sant-like activity. These results supported previously
reported antidepressant-like activities of aryl alkanol
piperazine derivatives and confirmed the antidepressant-
like activity of these types of compounds once more
(Li et al. 2006; Chen et al. 2009; Jianqi et al. 2010;
Weng and Li 2010; Avram et al. 2012).
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