Structure-based design, synthesis and antidepressant-like activity of phenylthiazolyl-1H,2H,3H,4H-naphthalene derivatives

Article abstract of DOI:10.14233/ajchem.2015.18457

In recent years, a bacterial homologue of SERT (LeuT) target protein was solved in complex with sertraline and offers promising pathway for the hit identification. Herein, we cover advanced computational methodology for hybrid class 1,2,3,4-tetrahydronaphalene and phenylthiazole derivatives using three two modules. First, these drug-like candidates were filtered by molecular properties from a training set of library. Second, compounds were prioritized according to previously optimized CDocker docking methodology. Finally, synthesized in silico actives were demonstrated enhanced antidepressant-like activity with reasonable non-toxicity using standard mice model (s).

Full text of DOI:10.14233/ajchem.2015.18457

Asian Journal of Chemistry; Vol. 27, No. 1 (2015), 379-384
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2015.18457
Structure-Based Design, Synthesis and Antidepressant-Like
Activity of Phenylthiazolyl-1H,2H,3H,4H-naphthalene Derivatives
1
1
ARCHANA UPPAL , ANITA SINGH2,* and PREETI KOTHIYAL
1Shri Guru Ram Rai Institute of Technology and Science, Patel Nagar, Dehradun-248 001, India
2Department of Pharmacy, Kumaon University, Bhimtal Campus, Bhimtal-263 136, India
*Corresponding author: Fax: +91 135 2721762; E-mail: asingh25661@gmail.com
Received: 17 July 2014;
Accepted: 30 August 2014;
Published online: 26 December 2014;
AJC-16577
In recent years, a bacterial homologue of SERT (LeuT) target protein was solved in complex with sertraline and offers promising pathway
for the hit identification. Herein, we cover advanced computational methodology for hybrid class 1,2,3,4-tetrahydronaphalene and
phenylthiazole derivatives using three two modules. First, these drug-like candidates were filtered by molecular properties from a training
set of library. Second, compounds were prioritized according to previously optimized CDocker docking methodology. Finally, synthesized
in silico actives were demonstrated enhanced antidepressant-like activity with reasonable non-toxicity using standard mice model (s).
Keywords: 1,2,3,4-Tetrahydronaphthalene, Phenylthiazole, Molecular properties, Docking.
energy and experimental data were obtained by using
INTRODUCTION
Discovery Studio Package. Further in an order to improve the
efficiency of drug discovery, we decided herein to pre-screen
compounds via structure variation of AU-11. Each compound
was constructed manually by incorporating distinguished
Target structure-based drug design (TSBDD) has become
increasingly important in the context of drug discovery1,2. In
practice, identifying potential leads using TSBDD rather than
via other approaches is faster, more economical and being
alkenyl/alkyl/aryl/hetero alkyl-aryl functionalities. Library
easier to setup3. For this reason, many drugs developed in part
of these putative compounds were filtered by molecular
by TSBDD are in late-stage clinical trials or have now reached
properties calculation and ranked according to docking based
the market, for example tyrosine kinase inhibitors, Canertinib4;
approach (Table-1).
topoisomerase II inhibitors,Amsacrine5; nitrogen mustard pre-
Subsequently, chemical synthesis of these rank-ordered
prodrug, PR-1046; VEGFR2 inhibitors, DMXAA7, etc.
compounds and their antidepressant-like effects were carried
Depressive disorders are one of the most prevalent mental
out using standard Porsolt's behavioral despair on albino mice,
illness worldwide with considerable social impact and eco-
tail suspension and open field tests.
nomic consequences8. In last two decades, the inhibition of
serotonin-transporter (SERT) is anticipated to provide an effec-
EXPERIMENTAL
tive treatment of depressive disorders, for instance a selective
Designing of compounds: A library comprising of more
than ten thousand compounds were constructed manually by
incorporating distinguished alkenyl/alkyl/aryl/hetero alkyl-aryl
substituents. Ligands were prepared by Marvin Sketch Tool14
and finally exported for docking calculations. The calculation
of important molecular properties like log P (milog P), topolo-
gical polar surface area (TPSA), hydrogen bond acceptors-
donors, bioactivity score and molecular toxicity was calculated
by Molinspiration15. Osiris16, an Java based library layer provides
ADMET and reusable cheminformatics functionality. Docking
calculation was carried out on HP workstation, NVIDIA Quadro
2000, windows 7 ultimate 64 bit. Docking experiments were
inhibitor from 1H,2H,3H,4H-naphthalene. Sertraline is prima-
rily prescribed in both adults and children9-11. Recent crystallo-
graphic studies have solved a 3D structure of bacterial homo-
logue of SERT viz. leucine transporter (LeuT) in complex with
Sertraline (3GWU.pdb) at 2.14 Å resolution12. This model
explores great opportunities for molecular docking using novel
1H,2H,3H,4H-naphthalene ligands.
Recent synthetic drug design work in our laboratories has
led to design, synthesis and characterization of a novel anti-
depressant hit, AU-11 from substituted phenylthiazolyl-
1H,2H,3H,4H-naphthalene class13. This work also emphasized
that the best correlation R2 0.77 between CDocker interaction

380 Uppal et al.
Asian J. Chem.
TABLE-1
DOCKING RESULT OF TETRAHYDRONAPTHALENE DERIVATIVES
R2
3
4
5
6
7
R1
2
1
8
OH
O
OH
5'
NH
6'
1'
2'
N
NH
N
4'
3'
HN
R3
S
S
AU-11
Compounds
AAP1
AAP2
AAP3
AAP4
AAP5
AAP6
AAP7
AAP8
AAP9
R1
6-OCH3
6-OCH3
6-OCH3
H
6-OCH3
H
6-OCH3
H
R2
R3
Highest cavity (-CDocker energy)
H
H
H
4-CH3
H
4-CH3
H
4-CH3
H
4’-NHCOCH3
3’-NO2
4’-CH3
3’,4’-diCl
4’-Br
48.39
48.39
47.58
46.56
46.45
46.38
46.15
45.60
45.52
3’-NO2
4’-NO2
4’-CH3
6-Cl
4’-NHCOCH3
done in compliance with previously validated docking
experiments using DS package supplied byAccelrys Software
Inc., San Diego USA in CHARMm based CDocker program
and highest cavity (x, y, z and Radius 24.7597, 27.4531,
22.7581 and 10 Å) as a binding site. The Cdocker Interaction
Energy of each ligand was calculated for ranking.
Synthesis of compounds: Synthesis of 1,2-epoxy-1,2,3,4-
tetrahydronaphthalene was done as per previously described
methodology17. The synthesized 1,2-epoxy-1,2,3,4-tetrahydro-
naphthalene (0.1 mol) and different substituted phenyl-2-amino
thiazole (0.1 mol) were refluxed under acetone (5 mL) at 70 °C
for 5-6 h. The reaction mixture was washed with hexane (5 mL)
to furnish semisolid matter and again with ethyl acetate (2 mL).
Finally, the mixture was re-crystallized with hexane to afford
nine compounds (AAP 1-9).
Melting points were uncorrected. Thin-layer chromato-
graphy was performed using silica gel-G (0.5 mm thickness,
Hexane and ethyl acetate solvent system) and spots were
visualized under iodine chamber. FTIR spectra were recorded
on Fourier transform infrared spectrometer-Spectrum 2 (Perkin
Elmer, USA). Spectra were recorded in KBr and expressed in
cm-1. The 1H and 13C NMR spectra were recorded on Bruker
Avance II 400 and 100 NMR spectrometers (Bruker, USA) in
CDCl3 and chemical shifts (δ) are reported in parts per million
(ppm) relative to tetramethylsilane. The mass spectra were
recorded on a Micromass Q-Tof spectrometer. Elemental
analysis was carried out on a Vario EL III elemental analyzer
(Elementar Analysensysteme, GmbH, Germany).
162.4 (C-S thiazole); 121.6, 128.5, 139.2, 127.4, 121.6, 148.4
(phenylthiazole); 112.4, 112.3, 129.5, 135.9, 155.9 (naphthalene);
164.7 (CO-CH3); FTIR (KBr, νmax, cm-1): 1611 (C=0), 1663
(N-H bending), 875 and 995 (C-H bending), 1364 (C-N), 2842
(aliphatic C-H), 1542 (C=C aromatic), 3446 (Sec. N-H); MS
m/z 409.2; Anal. Calcd for C22H23N3O3S: C 64.53, H 5.66, N
10.26; found C 64.43, H 5.60, N 10.12.
6-Methoxy-1-[4-(3-nitrophenyl)thiazol-2-ylamino]-
1,2,3,4-tetrahydronaphthalen-2-ol (AAP 2): Physical state
yellow crystals;Yield 76 %; m.p. 284-286 °C; Rf value 0.5914
(hexane: ethyl acetate 95:5); 1H NMR (CDCl3, 400 MHz) δ:
0.63-0.65 (m, 1H, 3-CH2 naphthalene), 0.66-0.69 (m, 1H, 3-
CH2 naphthalene), 1.64 (t, 1H, 4-CH2 naphthalene), 2.19 (t,
1H, 4-CH2 naphthalene), 2.46 (t, 1H, 2-OH naphthalene), 2.94
(m, 3H, 6-methoxy), 3.79 (m, 1H, 2-CH naphthalene), 4.17
(d, 1H, NH-thiazole), 4.19 (d, 1H, 1-CH naphthalene, J =
7.16 Hz), 6.47 (s, 1H, 4-CH thiazole), 6.96 (d, 4H, 5,6,7&8-
CH-naphthalene), 7.50 (d, 2H, 3, 5-CH phenyl), 7.79 (d, 2H,
2, 6-CH phenyl); 13C NMR (100 MHz) δ: 20.2, 22.2 (CH2-
naphthalene); 53.5 (CH3-O); 59.2 (C-NH); 78.7 (C-OH); 98.0,
162.4 (C-S thiazole); 126.5, 133.9, 126.5, 137.2, 146.4 (phenyl-
thiazole); 110.4, 111.3, 119.6, 119.6, 155.8 (naphthalene);
FTIR (KBr, νmax, cm-1): 1651 (N-H bending); 1536 (N-O stretch);
1368 (C-N); 2841 (aliphatic C-H); 781 (C-H aromatic
bending); 3435 (Sec. N-H); Mass (70 ev m/z): 397.0; Anal.
Calcd for C20H19N3O4S: C 60.44, H 4.82, N 10.57; found: C
60.56, H 4.76, N 10.45.
6-Methoxy-1-[4-(4-methylphenyl)thiazol-2-ylamino]-
1,2,3,4-tetrahydronaphthalen-2-ol (AAP 3): Physical state
white crystals;Yield 83 %; m.p. 266-268 °C; Rf value 0.7214
(hexane: ethyl acetate 95:5); 1H NMR (CDCl3, 400 MHz) δ:
1.24-1.26 (m, 2H, 3-CH2 naphthalene), 2.23-2.31 (s, 3H, 4-
CH3 phenyl), 2.40 (t, 2H, 4-CH2-naphthalene), 3.64 (m,1H, 2-
CH naphthalene), 3.67-3.73 (m, 3H, 6-methoxy) 3.76 (d, 1H,
2-OH naphthalene), 4.05 (d, 1H, 1-CH naphthalene), 4.33 (d,
1H, NH-thiazole), 6.55-6.63 (d, 3 × 1H, 5,7&8-CH naphtha-
lene), 7.12 (s, 1H, 4-CH thiazole), 7.23-7.4 (t, 2H, 3, 5-CH
phenyl), 7.85-7.96 (d, 2H, 2,6-CH phenyl); 13C NMR (100
MHz) δ: 24.5 (CH3); 21.6, 25.4 (CH2 naphthalene); 54.7 (CH3-
O); 60.2 (C-NH); 79.6 (C-OH); 99.4, 163.4 (C-S thiazole);
120.7, 127.5, 138.2, 127.4, 120.7, 147.4 (phenylthiazole);
111.4, 112.4, 129.6, 134.9, 156.9 (naphthalene); FTIR (KBr,
6-Methoxy-1-[4-(4-acetamidophenyl)thiazol-2-yl-
amino]-1,2,3,4-tetrahydronaphthalen-2-ol (AAP 1): Physical
state white crystals; Yield 54 %; m.p. 235-237 °C; Rf value
1
0.6415 (hexane: ethylacetate 95:5); H NMR (CDCl3, 400
MHz) δ: 1.29 (s, 3H, acetamido) 2.07-2.13 (m, 2H, 3-CH2
naphthalene), 2.90-2.93 (t, 2H, 4-CH2 naphthalene), 3.34 (m,
1H, 2-CH naphthalene), 3.69 (d, 1H, 2-OH naphthalene), 3.71-
3.77 (s, 3H, CH3-O phenyl), 3.84-3.86 (t, 1H, 1-CH naphtha-
lene), 4.11 (d, 1H, NH-thiazole), 4.13 (d, 1H, 1-CH naphtha-
lene, J = 7.16 Hz), 6.67-6.81 (m, 3H, 5,7&8-CH-naphthalene),
7.26 (s, 1H, NH-acetamido), 7.36 (s, 1H, 4-CH thiazole), 7.76
(d, 2H, 3, 5-CH phenyl), 7.99-8.03 (d, 2H, 2,6-CH phenyl);
13C NMR (100 MHz) δ: 20.2 (CH3-CO); 22.4, 26.5 (CH2
naphthalene); 55.4 (CH3-O); 61.3 (C-NH); 80.6 (C-OH); 100.2,

Vol. 27, No. 1 (2015)
Synthesis and Antidepressant-Like Activity of Phenylthiazolyl-1H,2H,3H,4H-naphthalene Derivatives 381
νmax, cm-1): 1637 (N-H bending); 794 (C-H bending); 1309
(C-N); 2853 (aliphatic C-H); 1543 (C=C aromatic); 3447 (sec.
N-H); Mass (70 ev m/z): 366.1; Anal. Calcd for C21H22N2O2S:
C 68.82, H 6.05, N 7.64; found: C 68.96, H 6.26, N 7.55.
4-Methyl-1-(3,4-dichlorophenylthiazol-2-ylamino)-
1,2,3,4-tetrahydronaphthalen-2-ol (AAP 4): Physical state
brownish yellow crystals; Yield 75 %; m.p. 291-293 °C; Rf
value 0.7322 (hexane: ethyl acetate 95:5); 1H NMR (CDCl3,
400 MHz) δ: 1.28-1.32 (d, 3H, 4-methyl), 1.34 (m, 2H, 3-CH2
naphthalene), 2.5 (t, 1H, 4-CH2 naphthalene), 3.56 (m, 1H, 2-
CH naphthalene), 3.15 (d, 1H, J = 7.2, 2-OH naphthalene),
4.2 (d, 1H, NH thiazole), 4.3 (d, 1H, 1-CH naphthalene, J =
7.15 Hz) 7.05-7.17 (d, 4 × 1H, 5,6,7&8-CH-naphthalene), 7.20
(s, 1H, 4-CH thiazole), 7.20 (t, 1H, 5-CH phenyl), 7.31 (d,
1H, 6-CH phenyl), 7.57 (d, 1H, 2-CH phenyl); 13C NMR (100
MHz) δ: 21.8 (CH3); 28.2, 30.0 (CH2-naphthalene); 60.8
(C-NH); 80.4 (C-OH); 100.5, 164.2 (C-S thiazole); 130.5,
133.1, 133.1, 132.4, 129.4, 148.2 (phenylthiazole); 128.6,
125.4, 125.4, 128.6 (naphthalene); FTIR (KBr, νmax, cm-1): 1607
(N-H bending), 771 (C-Cl), 1234 (C-N), 2816 (aliphatic C-H),
3436 (sec. N-H); Mass (70 ev m/z): 404.4; Anal. Calcd for
C20H18N2OSCl2: C 59.26, H 4.48, N 6.91; found: C 59.32, H
4.59, N 6.67.
C-H); 780, 828 (C-H aromatic bending); 3445 (sec. N-H); Mass
(70 ev m/z): 381.6; Anal. Calcd for C20H19N3O3S: C 62.97, H
5.02, N 11.02; found: C 62.86, H 5.15, N 11.05.
6-Methoxy-1-[4-(4-nitrophenyl)thiazol-2-ylamino]-
1,2,3,4-tetrahydronaphthalen-2-ol (AAP 7): Physical state
light yellow crystals; Yield 65 %; m.p. 287-289 °C; Rf value
1
0.8772 (hexane: ethyl acetate 95:5); H NMR (CDCl3, 400
MHz) δ: 0.62-0.64 (m, 1H, 3-CH2 naphthalene), 0.66-0.68
(m, 1H, 3-CH2 naphthalene), 1.64 (t, 1H, 4-CH2 naphthalene),
2.19 (t, 1H, 4-CH2 naphthalene), 2.45 (t, 1H, 2-OH naphthalene),
2.93 (m, 3H, 6-methoxy), 3.78 (m, 1H, 2-CH naphthalene),
4.21 (d, 1H, NH-thiazole), 6.47 (s, 1H, 4-CH thiazole), 6.95
(d, 4H, 5,6,7&8-CH-naphthalene), 7.50 (d, 2H, 3,5-CH
phenyl), 7.78 (d, 2H, 2,6-CH phenyl); 13C NMR (100 MHz):
25.7, 26.4 (CH2 naphthalene); 55.8 (CH3-O); 60.9 (C-NH);
80.5 (C-OH); 100.5, 164.7 (C-S thiazole); 121.7, 128.6, 137.3,
128.6, 121.7, 148.6 (phenylthiazole); 112.4, 113.3, 130.5,
136.6, 157.5 (naphthalene); FTIR (KBr, νmax, cm-1): 1641 (N-
H bending); 1542 (N-O stretch); 1108, 1338 (C-N); 2842
(aliphatic C-H); 3160 (C-H aromatic stretching); 3446 (sec.
N-H); 3400 (-OH); Mass (70 ev m/z): 397.1; Anal. Calcd for
C20H19N3O4S: C 60.44, H 4.82, N 10.57; Found: C 60.19, H
4.98, N 10.46.
6-Methoxy-1-[4-(4-bromophenyl)thiazol-2-ylamino]-
1,2,3,4-tetrahydronaphthalen-2-ol (AAP 5): Physical state
pale white crystals; Yield 79 %; m.p. 297-299 °C; Rf value
4-Methyl-1-(4-methylphenylthiazol-2-ylamino)-
1,2,3,4-tetrahydronaphthalen-2-ol (AAP 8): Physical state
white crystals;Yield 62 %; m.p. 250-252 °C; Rf value 0.5449
(hexane: ethyl acetate 95:5); 1H NMR (CDCl3, 400 MHz) δ:
1.25-1.26 (d, 2H, 4-CH3 naphthalene), 2.32-2.34 (m, 2H, 3-
CH2), 2.35 (s, 3H, 4-CH3 phenyl), 2.36-2.39 (t, 1H, 4-CH2
naphthalene), 3, 54-3.56 (m, 1H, 2-CH naphthalene), 3.57-
3.62 (m, 3H, 6-methoxy), 3.63-3.65 (m, 1H, 2-OH naphthalene),
4.05 (d, 1H, NH-thiazole), 4.33 (d, 1H, 1-CH naphthalene, J
= 7.16 Hz), 6.67 (d, 4 × 1H, 5,6,7&8-CH naphthalene), 7.26
(s, 1H, 4-CH thiazole), 7.51-7.53 (t, 2H, 3,5-CH phenyl), 8.01-
8.02 (d, 2H, 2,6-CH phenyl); 13C NMR (100MHz) δ: 21.7
(CH3); 24.3 (CH3 phenyl), 28.3, 30.2 (CH2 naphthalene); 60.6
(C-NH); 80.2 (C-OH); 100.1, 164.7 (C-S thiazole); 129.6,
127.4, 129.6, 127.4, 130.5, 138.4, 148.9, (phenylthiazole);
125.8, 128.9, 125.8, 128.9, 156.4 (naphthalene); FTIR ((KBr,
νmax, cm-1): 1641 (N-H bending); 830 (C-H bending); 1365
(C-N); 2850 (aliphatic C-H); 3160 (C-H aromatic stretching);
3231 (-OH); 3445 (sec. N-H); Mass (70 ev m/z): 350.1; Anal.
Calcd for C21H22N2OS: C 71.97, H 6.33, N 7.99; found: C
71.85, H 6.25, N 7.91.
6-Chloro-1-[4-(4-acetamidophenyl)thiazol-2-ylamino]-
1,2,3,4-tetrahydronaphthalen-2-ol (AAP 9): Physical state
white crystals;Yield 81 %; m.p. 272-275 °C; Rf value 0.8545
(hexane: ethyl acetate 95:5); 1H NMR (CDCl3, 400 MHz) δ:
1.25 (s, 3H, acetamido), 2.09-2.12 (m, 2H, 3-CH2 naphthalene),
2.90-2.92 (t, 2H, 4-CH2 naphthalene), 3.31-3.33 (m, 1H, 2-
CH naphthalene), 3.63 (d, 1H, 2-OH naphthalene), 3.67-3.68
(t, 1H, 1-CH naphthalene), 4.11 (d, 1H, NH-thiazole), 4.13
(d, 1H, 1-CH naphthalene, J = 7.16 Hz), 6.78-6.81 (m, 3H,
5,7&8-CH-naphthalene), 7.26 (s, 1H, 4-CH thiazole), 7.55 (d,
2H, 3, 5-CH phenyl), 7.99-8.02 (d, 2H, 2, 6-CHphenyl), 10.02
(s, 1H, NH-acetamido); 13C NMR (100 MHz) δ: 22.8 (CH3-
CO); 22.5, 26.9 (CH2 naphthalene); 60.8 (C-NH); 80.9 (C-
OH); 100.9, 162.3 (C-S thiazole); 127.6, 128.9, 139.8, 127.6,
122.7, 149.1 (phenylthiazole); 125.9, 127.6, 129.5, 135.9,
1
0.4615 (hexane: ethyl acetate 95:5); H NMR (CDCl3, 400
MHz) δ: 1.26 (m, 1H, 3-CH2 naphthalene), 1.67 (m, 1H, 3-
CH2 naphthalene), 2.54 (t, 1H, 4-CH2 naphthalene), 2.71 (t,
1H, 4-CH2 naphthalene), 3.31 (t, 1H, 2-OH naphthalene), 3.70
(m, 3H, 6-methoxy), 3.86 (m, 1H, 2-CH naphthalene), 4.11
(d, 1H, NH-thiazole), 4.13 (d, 1H, 1-CH naphthalene, J =
7.16 Hz), 6.67-6.89 (d, 4H, 5,6,7 & 8-CH-naphthalene), 6.81
(s, 1H, 4-CH thiazole), 7.53-7.55 (d, 2H, 3,5-CH phenyl), 8.01-
8.02 (d, 2H, 2,6-CH phenyl); 13C NMR (100 MHz) δ: 20.4,
24.4 (CH2 naphthalene); 53.5 (CH3-O); 59.2 (C-NH); 78.7 (C-
OH); 98.0, 162.4 (C-S thiazole); 119.6, 126.5, 137.2, 126.5,
119.6, 146.4 (phenylthiazole); 110.4, 111.3, 128.6, 134.9,
155.8 (naphthalene ); FTIR (KBr, νmax, cm-1): 560 (C-Br), 1638
(N-H bending), 753 (C-H bending), 1243 (C-N), 2842
(aliphatic C-H), 1542 (C=C aromatic), 3445 (sec. N-H); Mass
(70 ev m/z): 432.0; Anal. Calcd for C20H19N2O2SBr: C 55.69,
H 4.44, N 6.49; found: C 55.46, H 4.52, N 6.62.
4-Methyl-1-(3-nitrophenylthiazol-2-ylamino)-1,2,3,4-
tetrahydronaphthalen-2-ol (AAP 6): Physical state yellow
crystals;Yield 68 %; m.p. 262-265 °C; Rf value 0.6213 (hexane:
ethylacetate 95:5); 1H NMR (CDCl3, 400 MHz) δ: 1.29-1.30
(d, 3H, 4-CH3 napthalene) 1.99-2.04 (m, 2H, 3-CH2 naphtha-
lene), 3.01 (t, 2H, 4-CH2 naphthalene), 3.16-3.20 (m, 1H, 2-
CH naphthalene), 3.62 (d, 1H, J = 7.3, 2-OH naphthalene),
4.27 (d, 1H, NH-thiazole), 4.30 (d, 1H, 1-CH naphthalene,
J = 7.14 Hz), 7.08-7.14 (m, 4 × 1H, 5,6,7&8-CH-naphthalene),
7.24-7.26 (s, 1H, 4-CH thiazole), 7.35-7.38 (m, 2H, 5,6-CH
phenyl), 7.53 (s, 1H, 2-CH phenyl); 13C NMR (100 MHz) δ:
21.8 (CH3); 24.6, 25.3 (CH2 naphthalene); 60.8 (C-NH); 80.4
(C-OH); 100.5, 164.7 (C-S thiazole); 121.8, 128.6, 139.7,
128.6, 121.8, 148.9 (phenylthiazole); 130.2, 133.2, 129.4,
135.7, 156.4 (naphthalene); FTIR (KBr, νmax, cm-1): 1608 (N-
H bending); 1542 (N-O stretch); 1164 (C-N); 2841 (aliphatic

382 Uppal et al.
Asian J. Chem.
156.5 (naphthalene); 131.7 (C-Cl); 164.3 (CO-CH3); FTIR
(KBr, νmax, cm-1): 1591 (N-H bending); 675 (C-Cl); 829 (C-H
aromatic bending); 1333 (C-N); 1635 (C=O); 2968 (aliphatic
C-H); 3139 (C-H aromatic stretching); 3436 (sec. N-H); Mass
(70 ev m/z): 413.2; Anal. Calcd for C21H20N3O2SCl: C 60.94,
H 4.87, N 10.15; Found: C 60.88, H 4.78, N 10.22.
analysis of the pose explained that 5 resides Gly-24, Asn-27,
Ser-355, Gly-408, Asp-404 forms hydrogen bonding with
AAP 1 (Table-2).
These residues snugly fitted ligand inside the receptor
molecular surface. In addition, we found π-π stacking inter-
actions between ligand AAP 1 and protein residues, Arg-30
and Try-108 (Fig. 1). The common feature of these ligands is
connectivity Tween tetrahydronaphthalene and phenylthiazole
ring through NH bridge. The synthetic strategy used for cons-
truction of these in silico actives was described previously13
and is shown in Scheme-I.
Structure of these title ligands was confirmed on behalf
of their spectrometric and CHN data analysis.All synthesized
compounds were evaluated for antidepressant-like activity in
mice and two activesAAP 1 andAAP 2 have shown the highest
biological activity in both computational and in vivo procedures
(Table-3).
Biological activity: Five Swiss albino mice (20-25 g) of
either sex, aged 6-8 weeks were housed in groups of eleven.
All experiments using animals were conducted in accordance
with the CPCSEA Guideline for the Care and Use of Labora-
tory Animals and approved by the InstitutionalAnimal Ethics
Committee of Shri Guru Ram Rai Institute of Science and
Technology (RS/IAEC/01/2011/EEC-4). Mice were supplied
with test compounds (AAP1-9) 30 mg/kg orally to first 9 groups
and remaining groups were assigned for Sertraline at dose 15
mg/kg and control, respectively. The standard Porsolt forced
swimming test (FST)18, Tail suspension test (TST)19, Open field
test (OFT)20 were used to evaluate the antidepressant-like
effect. The results are presented as means, standard error of
means (SEM). Differences between data sets were considered
as significant when p value was less than 0.05.
Acute toxicity: Healthy female mice (6-7 weeks old),
weighed between 25 and 30 g, 3 animals in one cage was used
to determine LD50 cut off values of two key hits from starting
dose 50 mg/kg according to the Organisation for Economic
Co-operation and Development (OECD) 423 guideline21 and
animals were observed after dosing at least once during 0.5,
24 and 36 h.
RESULTS AND DISCUSSION
A straightforward approach was applied to the filter out
drug like candidates using Molinspiration and Osiris online
services from a large set of ten thousand compounds. Each
compound having distinguished alkenyl/alkyl/aryl/hetero
alkyl-aryl substituent demonstrated different physico-chemical
properties. Ninety five analogues that were in accordance with
minimum violations using lipinske rule of five, are selected
for docking studies.
In this present study the molecular interactions of SERT
inhibitors were based upon CDocker docking and CDocker
interaction energy calculations. The results from in silico assays
conformationally defined 9 compounds with un-substituted
or methoxy, chloro substituent in tetrahydronaphthalene at
position 6 and unsubstituted or methyl at position 4 (Table-1).
This compute-intensive method revealed that ligands AAP1
and 2 have exhibited the highest CDocker energy 48.39. Visual
Fig. 1. Predicted AAP 1 contact
TABLE-2
KEY INTERACTION IN SEROTONIN RECEPTOR WITH LIGAND AAP 1
Hydrogen bond interaction
A:GLY24:HN-AAP1:O28
A:ASN27:HN-AAP1:O28
A:SER355:HG-AAP1:O27
AAP1:H35-A: GLY408:O
AAP1:H36-A:ASP404:OD2
Distance (Å)
3.0725
3.7259
2.0327
1.9417
Angle DHA
113
Angle HAY
128
133
122
151
134
153
153
119
119
3.0655
Pi interaction
PiPi monitor
AAP1-A:ARG30:NE
AAP1-A:TYR108
4.2480
4.9862
Pi Cation monitor

Vol. 27, No. 1 (2015)
Synthesis and Antidepressant-Like Activity of Phenylthiazolyl-1H,2H,3H,4H-naphthalene Derivatives 383
TABLE-3
ANTIDEPRESSANT-LIKE ACTIVITY OF COMPOUNDS
Compounds
AAP 1
FST Duration of immobility# (s)
TST Duration of immobility# (s)
OFT no. of crossings in the square
102.0 3.34
39.6 3.73
48.2 2.67
AAP 2
37.8 3.59
50.0 2.81
96.0 2.29
AAP 3
AAP 4
AAP 5
AAP 6
61.6 2.13
64.8 1.65
63.2 1.01
65.2 2.84
105.2 3.39
148.4 3.16
103.0 3.35
105.8 2.35
96.0 2.78
117.2 2.57
107.6 2.07
112.8 1.92
113.6 2.91
AAP 7
69.4 2.47
107.8 2.25
AAP 8
74.0 2.33
95.2 2.02
116.2 2.47
AAP 9
Sertraline
Control
77.4 2.14
58.2 1.47
117.2 1.15
114.4 2.76
87.6 2.34
140.8 1.98
108.4 2.75
80.1 2.83
107.6 3.88
#Values represent the mean S.E.M., *Significantly compared to control (Dunnet’s test; p < 0.05)
R
R
2
2
R
2
R
R
1
R
1
1
a
b
O
OH
c
4
R
2
5
3
2
6
7
NH
2
R
N
1
1
8
R
2
R
OH
3
S
R
1
5'
NH
6'
1'
N
4'
2'
O
R
3
S
R : 6-OCH , H, Cl;
1
2
3
R : 4-CH , H;
3
R : 4'-NHCOCH , 3'-NO , 4'-CH , 3',4'-diCl, 4'-Br,
3
3
2
3
3'-NO , 4'-NO , 4'-CH
2
2
3
Scheme-I: Reaction and conditions (a) NaBH4/MeOH, (b) KHSO4, (c) m-chloro perbenzoic acid/dichloro methane
160
in vivo Test utilizes the established phenomenon of
receptor mediated inhibition, therefore a marked biological
140
120
effect was exhibited by these ligands. Literature clearly predicts
100
that tetrahydronaphthalene nucleus is required for antidepre-
ssant activity22,23. The results indicated that identified com-
80
pounds AAP 1 and AAP 2 elicited mean immobility time in
60
mice 39.6 and 37.8 sec, respectively at a dose 30 mg/kg body
40
FST
TST
weight in FST model. The mean immobility times were signi-
ficantly different from the control animals, better than all the
other compounds tested and comparable to standard sertraline
at a dose 15 mg/kg. Further substitution at 6th position with
electron withdrawing methoxy group augmented biological
activity and introduction of acetamido group at para position
to the phenylthiazole ring caused a increase in the antidepre-
ssant-like activity as reflected by AAP 1. The addition of 4-
methyl (AAP 3), 4-bromo(AAP 5) and 4-nitro (AAP 7) groups
in phenyl ring failed to elicit the reduction in the immobility
time. This was different from the standard Sertraline indicate
that the methyl, bromo and nitro groups are causing a loss in
the antidepressant-like activity. The introduction of 6-chloro
group of tetrahydronapthalene nucleus (AAP 9) abolishes the
antidepressant-like activity (Fig. 2).
20
0
AAP1 AAP2 AAP3 AAP4 AAP5 AAP6 AAP7 AAP8 AAP9SertralineControl
Fig. 2. Mice behavioral model (FST and TST)
and 95.2 sec, respectively of mean immobility time, but this is
non-significantly different from the standard Sertraline 87.6
sec in TST model, indicate that the methyl group at 4 position
of tetrahydronapthalene is causing a loss in the antidepressant-
like activity. Further, 6-methoxy showed the optimal activity
in mice behavior model using TST from its ability to cause
SERT inhibition. The derivatives comprised of phenylthiazole
functionalized, 4-acetamido and 3-nitro substituents have
shown prominent biological effects. OFT results addressed
that these compounds were practically non-stimulatory and
showing no significant effect on locomotion at a dose 30 mg/kg
in comparison to Sertraline.As listed inTable-3, there was about
three fold improvement in bioactivity from AAP 11 in mice
The presence of electron donating 4-methyl group in
tetrahydronapthalene nucleus along with 3-nitro and 4-methyl
substituted phenylthiazole (AAP 6 andAAP 8) displayed 105.8

384 Uppal et al.
Asian J. Chem.
3. B.S.P. Romano T. Kroemer, Curr. Protein Pept. Sci., 8, 312 (2007).
4. E. Varkondi, F. Pinter, K. Robert, R. Schwab, N. Breza, L. Orfi, G.
Keri and I. Petak, J. Recept. Signal Transduct. Res., 28, 295 (2008).
5. C. Ketron, W.A. Denny, D.E. Graves and N. Osheroff, Biochemistry,
51, 1730 (2012).
6. Q.Z. Zheng, F. Zhang, K. Cheng,Y.Yang,Y. Chen,Y. Qian, H.J. Zhang,
H.Q. Li, C.F. Zhou, S.Q.An, Q.C. Jiao and H.L. Zhu, Bioorg. Med. Chem.,
18, 880 (2010).
behavior model. Therefore, it is obvious that molecular docking
dictates not only the orientation of ligand but also prescreens
compounds for the finest pharmacological activity.
Table-4 summarizes results for oral toxicity study of two
active compounds (AAP 1 and AAP 2) in accordance with
OECD guidelines. LD50 cut off value was found to be 1000
mg/kg body weight as compared to standard (ibuprofen) value
500 mg/kg. Thus these two compounds were found to be non
toxic.
7. M. Buchanan, J.H. Shih, J.W. Astin, G.W. Rewcastle, J.U. Flanagan,
P.S. Crosier and P.R. Shepherd, Clin. Sci., 122, 449 (2012).
8. G.E. Simon, Biol. Psychiatry, 54, 208 (2003).
9. R. Lanzenberger, G.S. Kranz, D. Haeusler, E.Akimova, M. Savli,A. Hahn,
M. Mitterhauser, C. Spindelegger, C. Philippe, M. Fink, W. Wadsak,
G. Karanikas and S. Kasper, Neuroimage, 63, 874 (2012).
10. L.L. Brunton, D.K. Blumenthal, N. Murri, R.H. Dandan and B.C.
Knollmann, Goodman & Gilman's The Pharmacological Basis of Thera-
peutics. edn. 12, McGraw-Hill, New York, ISBN 978-0-07-162442-8
(2011).
11. J.M. Grohol, Top 25 Psychiatric Medication Prescriptions for 2011
Psych Central (2012);Available from: http://psychcentral.com/lib/2012/
top-25-psyciatric-medication-prescriptions-for-2011.
12. Z. Zhou, J. Zhen, N.K. Karpowich, C.J. Law, M.E.A. Reith and D.N.
Wang, Nat. Struct. Mol. Biol., 16, 652 (2009).
13. A. Uppal, P. Kothiyal and A. Singh, J. Heterocycl. Chem.; doi 10.1002/
jhet.2203.
14. http://www.chemaxon.com/marvin/sketch/index.php Retrieved 1 Janu-
ary (2013).
15. Calculated based on the methodology available from: http://
www.molinspiration.com/cgi-bin/properties Retrieved 9 January
(2013).
TABLE-4
ACUTE TOXICITY OF COMPOUNDS
Compound
AAP 1
AAP 2
LD50 cut off value mg/kg body weight
1000
1000
500
Ibuprofen (standard)
Conclusion
In this paper, we have demonstrated the use of CHARMm
docking based design for 1,2,3,4-tetrahydro-naphalene class.
These putative ligands were involved in optimal in silico
activity towards the SERT transporter. Synthesis of 9 actives
was achieved in simple and efficient manner. Interestingly,
the antidepressant-like effect in mice behavior model identified
two hitsAAP1 andAAP2, with reasonable non-toxicity using
standard OECD guideline.
16. Calculated based on the methodology available from: http://
www.organic-chemistry.org/prog/peo/Retrieved 15 January (2013).
17. K. Bhandari, V.L. Sharma, C.M. Singh, G. Shanker and H.K. Singh, J.
Indian Chem., 39B, 468 (2000).
ACKNOWLEDGEMENTS
18. R.D. Porsolt, M. Le Pichon and M. Jalfre, Nature, 266, 730 (1977).
19. L. Steru, R. Chermat, B. Thierry and P. Simon, Psychopharmacology,
85, 367 (1985).
20. C.S. Hall and E. L. Ballachey, Univ. Calif. Publ. Psych, 6, 1 (1932).
21. Test No. 423: Acute Oral Toxicity-Acute Toxic Class Method; OECD
Guidelines for the Testing of Chemicals, pp. 1-14(14) (2010).
22. Z. Rogoz, G. Skuza andA. Kodzinska, Pol. J. Pharmacol., 56, 519 (2004).
23. Y. Kitamura, H. Araki, K. Shibata, Y. Gomita and Y. Tanizaki, Eur. J.
Pharmacol., 481, 75 (2003).
The authors thank Maharaj Devendra Dasji and Uttara-
khand Technical University for the logistic support. The authors
also appreciate the help of S.A.I.F., Punjab University and
S.A.I.F., North Eastern Hill University, Shillong, India for
carrying out spectral analysis of reported compounds
REFERENCES
1. C.L.M.L.J. Verlinde and W.G.J. Hol, Structure, 2, 577 (1994).
2. D. Kuntz, Science, 257, 1078 (1992).