Facile and efficient preparation of hybrid phenylthiazolyl-1,3,5-triazines and their antidepressant-like effect in mice

Article abstract of DOI:10.1016/j.tetlet.2014.04.014

High safety, robust efficacy, and rapid onset of action remain the key challenges for improving antidepressant drug discovery. We report a facile and efficient synthetic strategy to structurally encompass mono-, di-, or tri-substituted derivatives using cyanuric chloride and various substituted phenylthiazole-2-amines. The predicted physicochemical property precisely state their specificity as CNS acting agent and antidepressant-like effect of the most promising compound 10 after oral administration significantly reduced immobility in mice behavior models, especially TST from 63 s. In addition, good safety features of 10 highlight its ability to modulate hallmarks for antidepressant discovery. These insights are useful in generalization and systematization of CRF₁antagonist design to develop future biological end points.

Full text of DOI:10.1016/j.tetlet.2014.04.014

Accepted Manuscript
Facile and efficient preparation of hybrid phenylthiazolyl-1,3,5-triazines and
their antidepressant-like effect in mice
Archana Gahtori, Abhay Kumar, Preeti Kothiyal, Prashant Gahtori
PII:
S0040-4039(14)00611-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.014
TETL 44476
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
23 February 2014
3 April 2014
4 April 2014
Please cite this article as: Gahtori, A., Kumar, A., Kothiyal, P., Gahtori, P., Facile and efficient preparation of hybrid
phenylthiazolyl-1,3,5-triazines and their antidepressant-like effect in mice, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.04.014
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Tetrahedron Letters
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Facile and efficient preparation of hybrid phenylthiazolyl-1,3,5-triazines and their
antidepressant-like effect in mice
Archana Gahtoria, Abhay Kumara, Preeti Kothiyala, Prashant Gahtorib, ∗
a Department of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology & Science, Patel Nagar, Dehradun 248001, India
b Faculty of Pharmacy, Uttarakhand Technical University, Dehradun, Uttarakhand 248007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
High safety, robust efficacy and rapid onset of action remain the key challenges for improving
antidepressant drug discovery. We report a facile and efficient synthetic strategy to structurally
encompass mono-, di-, or tri-substituted derivatives using cyanuric chloride and various
substituted phenylthiazole-2-amines. The predicted physicochemical property precisely state their
specificity as CNS acting agent and antidepressant-like effect of the most promising compound
10 after oral administration significantly reduced immobility in mice behavior models, especially
TST from 63 sec. In addition, good safety features of 10 highlights its ability to modulate
hallmarks for antidepressant discovery. These insights are useful in generalization and
systematization of CRF1 antagonist design to develop future biological end points.
Available online
Keywords:
Depression
1,3,5-triazine
CRF1 antagonist
Mice behavior model
Brine-shrimp bioassay
2009 Elsevier Ltd. All rights reserved.
Depression affects more than 350 million people worldwide
and impacts individuals regardless of their age, gender or socio-
economic conditions.1,2 Latest official figures reveal that by 2030
depression will be the leading cause of disease burden globally.3
Nonetheless, despite impressive advances in the variety of
therapeutics currently available, the major unmet clinical needs
for antidepressant are (i) high safety, (ii) robust efficacy and (iii)
rapid onset of action.4,5 The above mentioned reasons have
created a critical need to reinforce the discovery and development
of novel antidepressant agents.6
period of time of 6 hours (Scheme 1). Triple molar quantity of
diverse substituted phenylthiazoles as compared to cyanuric
chloride was used. The spectroscopic approach and elemental
analysis were applied to construct the structure of final
compounds.
Antidepressant-like screening in a group of six mice
(Albino, Swiss) of either sex, weighing 20–25 g, aged 6 to 8
weeks were conducted in accordance with the Institutional
Animal Ethics Committee (SGRR/CPCSEA/2011/264) and fully
complying with the CPCSEA guidelines. The behavioural Forced
swimming test (FST)16, Tail suspension test (TST)17, and Open
field test (OFT)18 were investigated by acute oral administration
at a dose 15 mg/kg and normal saline was used as a control.
Brine shrimp lethality bioassay19 was carried out to investigate
the cytotoxicity of key compound 10. The experimental data
were expressed as mean along with standard error of mean
(SEM) and evaluated by one-way analysis of variance (ANOVA)
followed by Dunnet’s test as post hoc. Differences between data
sets were considered as significant when p value was less than
0.05.
In recent years, hybrid class pyrazole and 1,3,5-triazine
derivatives are being studied as a next generation of CRF1
antagonist for targeting depression.7,8 In particular, a significant
concern is that systemic administration of these 1,3,5-triazines
leads to antidepressant effects in rodents.9 Recent evidence also
indicates that CRF1 receptor antagonists may be identified by
antidepressant-like activity in mice using tail suspension assay.10
Unfortunately, in the face of impressive efforts no subsequent
CRF1 antagonist has successfully completed a definitive Phase III
clinical trial.11
In our continued attempts to develop new, cost-effective and
innovative entities from hybrid phenylthiazolyl-1,3,5-triazine
derivatives12-14, we herein report that oral administration of these
agents exhibits significant antidepressant-like activity.
Additionally, the assessment of toxicity using brine-shrimp
methodology also ensures a good safety characteristic.
The reaction was found to be facile and efficient for the
preparation of various mono-, di-, or tri-substituted
phenylthiazolyl-1,3,5-triazine derivatives (1-12). The reaction
scheme involves nucleophillic substitution of chlorine atoms
from cyanuric chloride by different substituted phenylthiazole-2-
amines. As a matter of fact, electron-withdrawing groups20 of
phenylthiazole, for example nitro, bromo or chloro diminished
electron density on triazine core and tends to slow down
Cyanuric chloride was reacted with various substituted
phenylthiazoles15 under similar set of conditions for constant
———
∗ Corresponding author. Tel.: +91-73518-11300; fax: +91-135-2770119; e-mail: praniori@gmail.com

2
Tetrahedron Letters
replacement of other chlorine atoms of triazine to afford merely
Hence, it was quite ambiguous that title compounds were devoid
of violations except in case of logP, which already triggers key
step during CNS drug development.
mono-substituted triazines. On the other hand, optimal mobility
was investigated in case of un-substituted phenylthiazole and
strongly activating hydroxyl groups to report a simplistic
synthetic pathway to tri-substituted triazines (1, 2). In the next
instance, we might have observed that moderately activating
groups like dimethylamino, acetoxy, butoxy, methoxy and
weakly activating group like methyl releases electrons and tends
to intensify the negative charge and accordingly, destabilize the
carbanion to afford di- (3-7) and mono-substituted triazines (8-
12) respectively. Notably, a moderate to weak activating
characteristic of electron donating groups in substituted-
phenylthiazole-triazine did not facilitate nucleophillic
substitution and discouraged the formation of tri-substituted
derivatives. Whereas deactivating nitro, carboxy, chloro and
bromo groups by virtue of their delocalization by resonance
release electrons and stabilize the carbanion to compensate
merely mono substituted triazines. This clearly assigned that
reactivity of cyanuric chloride follows –H, -OH> (CH3)2NH-,
CH3CO-, -OC4H9, -OCH3> -CH3> Br> Cl> NO2 sequence
substitution pattern on phenylthiazole.
Encouraged by Molinspiration methodology, the
synthesized compounds (1-12) were screened for antidepressant-
like activity using forced swim test (FST), tail suspension test
(TST) and locomotor activity by open field tests (OFT). It was
quite apparent from Table 1 that 6, 10 and 12 have demonstrated
significant FST results in comparison to reference drug
Imipramine. We were surprised to see that minor structural
variation brought in by hybrid compounds were able to induce
marked influence on biological activity. The structure activity
relationship emphasized that 2,4-dichloro substitution pattern
(10) was a requisite for optimal biological activity. The mean
immobility time in case of 10 and control were 68 and 122 sec
respectively. The administration of 10 significantly decreased
immobility time by 54 sec in mice at 15 mg/kg doses tested.
Similar dose of Imipramine administered under the same
conditions clearly decreased the duration of immobility in
comparison with control.
In next counterpart, disubstituted 4-methoxy (6) and
mono-substituted, 4-bromo (12) also focus on escalating
antidepressant activity. However, 8 and 11 with 4-methyl and 3-
bromo substitutions respectively, were not well tolerated and
have shown no activity even in comparison with control.
Notably, two-fold amplified activity was disclosed by derivative
12, with structural variation 4-bromo and 3-bromo by keeping all
other fragments rigid. It was clearly evident that most active
compound possess 2,4-dichloro groups, phenylthiazole and
triazine functionalities. Hence, it seems that presence of the bulky
halo groups at position 4 endowed with intermolecular bonds to
establish good biological activity.
The FTIR spectral interval 3835-3946 cm-1 mainly
corresponds to the N-H stretching vibrations, in which the
highest range of frequency was recorded in case of 2.20 The
spectral interval 1542- 1783 cm-1 was formed by the bending
vibrations of NH groups and in this range C=C, C-N groups
vibration were also recorded. It was also seen from the spectra
that absorption bands lower than 1000 cm-1 correspond to the
bending vibrations of C-H. The assignment of structures was also
elucidated by their proton nuclear spectrum. The singlet signal at
δ 3.22- 3.90 ppm was a typical peak of bridged NH for these
compounds, among them the most shielded protons were
recorded in case of 2, with 4-hydroxy substituent. Also, tri-
substituted triazine (1) at δ 3.62 ppm exhibited broad singlet to
state presence of three identical protons. The proton spectrum
consists of all signals belonging to the thiazole hydrogen
exhibited a singlet at δ 6.64-7.66 ppm and due to effect of 2,4-
dichloro substitution, a hydrogen of later one was at maximum
downfield shift. The aromaticity assignments of the protons to 2,
3 and 4 orientations were based on their coupling constant (J)
values that range from 6.52- 8.72 Hz in case of ortho-
On inspection of data in Table 1, it was easy to analyze
that 6, 10 and 12 possess more potent intrinsic activity in TST
than Imipramine with mean immobility time 74, 70 and 79 sec
respectively. Once again, oral administration of 10 significantly
decreased duration of immobility by 63 sec in comparison with
control at 15 mg/kg dose tested. Therefore, once again it was of
interest that appropriate placement of 2,4-dicholoro/4-methoxy or
4-bromo group on aromatic ring were significant for biological
activity. Further, the biological effect of 4-substitutent followed
that pattern as 2,4-di-Cl> 4-OMe> 4-Br. Nevertheless, one
compound 10 was found almost equipotent to Imipramine in TST
and this identified hit may have CRF1 antagonistic activity.
substitutions and 1.45-1.72 Hz for meta-substitutions.
A
comparison of chemical shift of aromatic protons of nitro, bromo,
chloro, methoxy, hydroxy, methyl substituents with un-
substituted compound was a clear illustration of formation of
these compounds. All electron-withdrawing groups in phenyl
rings induce a deshielding of the protons, whereas electron
donating hydroxyl, dimethy amino, acetoxy, butoxy, methoxy
and methyl groups cause a shielding of the aromatic protons.
Finally, carbon, hydrogen, and nitrogen concentrations were
found within 0.4%. These values were in good agreement with
the proposed structures.
In support of the above mentioned studies, OFT model
also investigated the optimal pharmacological behavior as
expressed by 10 in mice anxiety model. This compound reduces
exit latency at a lower effective dose of 15 mg/kg. This suggests
that 2,4-dicholoro substitution pattern, was important for
suppression of locomotion effect. However, 4-methoxy/ 4-bromo
substitutions have shown a greater shift to modify motor
behaviour in comparison to Imipramine. Accordingly, structure
activity relationship for these title analogs, summarizes that
position of 2,4-dicholoro atoms was only the main determinant
for escalation and generation of bio-activity. In the next
counterpart, presence of 4-methoxy and 4-bromo would have its
unique role, in regard of biological activity.
The Molinspiration study clearly depicts that calculated
values of topological polar surface area (TPSA), total number of
atoms(natoms), molecular weight(MW), number of hydrogen
bond acceptors (nON) and donors (nOHNH) and number of
rotatable bonds(nrotb) were in accord to Lipinski21, lead
likeness22 and bioavailability rules23 of oral bioavailability.
Among them, the lowest degree of lipophilicity (log P 4.30 and
4.79) was exhibited by mono substituted compound 9 and 8 with
polar, 4-nitro and short chain, 4-methyl functionalities
respectively. All compounds excluding 2, having TPSA values
less than 140 Å2 claims for good oral absorption. Most of them
with mono substitution revealed minimal TPSA value at 63.60
and utmost permitted was achieved in case of 7. The number of
rotatable bonds count for these molecules were fewer than ten
except for 5 and deemed to have satisfactory oral bioavailability.
Additionally, hydrogen bond donors and acceptors count were
found to be important predictors of good oral bioavailability.
The brine shrimp lethality bioassay was considered as a
useful tool for rapid and preliminary assessment of toxicity of the
compounds. The hit compound 10 was analyzed for toxicity
results and LC50 was calculated 1559.5µg/ml. This assay has
exhibited overall a good safety profile of 10 (Table 2). The data
from earlier study indicated that a total blood volume of a mouse
was about 77-80 ml/kg.24 This amounts to a maximum blood
concentration 194.8- 187.5µg/ml in mice for 10 at a dose
15mg/kg. In particular, for 10 the difference between lethal

concentration and effective concentration has a high magnitude
that is unprecedented in drug discovery.
phenylthiazole-2-amines. These insights illustrate effectiveness
of hybrid analogue 10 as a novel antidepressant agent and
provide a molecular level insight that these identified entities
may be a CRF1 antagonist. Fortunately, the present work offers a
guidance of future antidepressant lead building and prospective
screens.
In summary, we report a simple, rapid and efficient
synthesis strategy for preparation of mono-, di-, or tri-substituted
phenylthiazolyl-1,3,5-triazine derivatives and offer well studied
reactivity of cyanuric chloride with various substituted
COCH3
S
R
SO2Cl2
S
H2N
Thiourea
NH2
R
Substituted
Acetophenone
NH2
N
Substitted 2-Amino-4-Phenylthiazole (X)
Cl
N
Cl
N
N
Cl
Cyanuryl chloride
Y
Compound
X
R
Y
-NH-phenylthiazole
-NH-4-hydroxyphenylthiazole
1
2
3
4
4-H
-NH-phenylthiazole
6
N1
N
-NH-4-hydroxyphenylthiazole
4-OH
2
4
4-N(CH3)2
4-COCH3
-Cl
-Cl
-NH-4-dimethylaminophenylthiazole
-NH-4-acetoxyphenylthiazole
HN
N
X
-Cl
-Cl
-Cl
-Cl
-Cl
5
6
7
8
9
4-OC4H9
4-OCH3
3-CN
-NH-4-butoxyphenylthiazole
-NH-4-methoxyphenylthiazole
-NH-3-cynophenylthiazole
-Cl
-Cl
S
N
4-CH3
4-NO2
-Cl
-Cl
-Cl
-Cl
-Cl
-Cl
10
11
12
2,4-Cl,Cl
3-Br
4-Br
R
Hybrid class substituted phenylthiazole 1,3,5-triazine
Scheme 1. Synthesis of substituted phenylthiazolyl-1,3,5-triazine derivatives. Reagents and conditions: (i) step 1: Acetophenone,
thiourea, sulfuryl chloride 105 °C for 3-5hrs; (ii) step 2: 4-Substituted phenylthiazole-2-amine, NaHCO3, dioxane 90°C for 6hrs.
Table 1. Antidepressant activity of compounds using FST, TST and OFT model
Compounds
FST
Duration of immobility#
(sec)
TST
Duration of immobility#
(sec)
OFT
Number of crossings in the
square
1
93 25
137 18
131 36
2
111 08
149 16
119 17
3
105 12
155 22
125 18
4
108 17
99 14
132 22
5
94 05
105 17
145 16
6
88 08*
74 12*
187 09*
7
99 18
109 19
136 21
8
136 22
175 39
53 26
9
10
102 15
68 03*
138 19
75 06*
61 12*
122 20
108 19
70 06*
99 10
79 07*
85 09*
133 10
162 26
136 05*
149 33
129 03*
128 02*
104 31
11
12
Imipramine
Control§
#Values represent the mean S.E.M. *Significant compared to control (Dunnet’s test; p < 0.05). §Normal saline
Table 2. Brine-shrimp bioassay for hit compound 10.
Concentration
(µg/ml)
Mortality#
1000.00
Control
LC50
3
1
1539.5 µg/ml
Toxicity
Non-toxic
#Ten larvae (Artemia salina) for each test concentration
Acknowledgments
References and notes
The authors express their deep sense of gratitude to Maharaj
Devendra Dasji and the Uttarakhand Technical University for
providing necessary facilities. The authors are also thankful to
the S.A.I.F. (Punjab University and NEHU Shillong) for
physicochemical characterization of compounds.
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4
Tetrahedron
3.
Ferrari, A. J.; Charlson, F. J.; Norman, R. E.; Patten, S. B.;
amine, 1470 methylene bending, 1654 C=C(ar-H), 1783 N-H
bending, 2920 methylene stret., 3885 broad N-H (sec. amine); 1H-
NMR (Bruker Avance II 400 MHz CDC13 δ ppm): 1.06(s, 6H, -
CH3), 1.42(s, 4H, -CH2), 1.96(s, 4H, -CH2), 3.71(s, 2H, bridge
NH), 3.98(s, 4H, -OCH2), 6.92(s, 2H, thiazole), 6.69(d, 4H, J =
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16.12 Found C: 57.01, H: 4.64, N: 15.88. 6: Physical state:
yellowish orange solid; % Yield: 40; Melting Range: 148-150°C;
Rf Value: (Benzene. ethylacetate. 0.1M alcoholic KOH= 3:3:4):
0.5778; FTIR (IRPrestige-21 KBr, cm-1): 781 C-H bending, 1368
C-N amine, 1651 C=C(ar-H), 1741 N-H bending, 3835 broad N-H
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δ
ppm): 3.62(s, 6H, -OCH3), 3.79(s, 2H, bridge NH), 6.99(s, 2H,
thiazole), 6.92(d, 4H, J = 8.44 Hz, Ar-H), 7.68(d, 4H, J = 8.32 Hz,
Ar-H); Anal. Calc. (Vario EL III) for C23H18ClN7O2S2: Calculated
C: 52.72, H: 3.46, N: 18.71 Found C: 52.72, H: 3.46, N: 18.71. 7:
Physical state: red orange oil; % Yield: 65; Boiling Range: 256-
258°C; Rf Value: (Benzene. ethylacetate. 0.1M alcoholic KOH=
3:3:4): 0.4885; FTIR (IRPrestige-21 KBr, cm-1): 575 C- Cl, 805
C-H bending, 1325 C-N amine, 1538 C=C ar., 1644 N-H bending,
2232 Ar C≡N, 3939 broad N-H(sec. amine); 1H-NMR (Bruker
Avance II 400 MHz CDC13 δ ppm): 3.76(s, 2H, bridge NH),
6.87(s, 2H, thiazole), 7.48(m, 2H, J = 7.52 & 1.49 Hz, ar-H),
7.50(d, 2H, J = 7.75 Hz, ar-H), 7.74(m, 2H, J = 1.61 Hz, ar-H),
7.78(m, 2H, J = 8.13, 1.58 & 1.62 Hz, ar-H); Anal. Calc. (Vario
EL III) for C23H12ClN9S2: Calculated C: 53.75, H: 2.35, N: 24.53
Found C: 53.49, H: 2.75, N: 24.86. 8: Physical state: yellow solid;
% Yield: 78; Melting Range: 135-136°C; Rf Value: (Benzene.
ethylacetate. 0.1M alcoholic KOH= 3:3:4): 0.3113; FTIR
(IRPrestige-21 KBr, cm-1): 564 C- Cl, 794 C-H bending, 1309 C-
N amine, 1513 C=C ar., 1637 N-H bending, 2870 sym. methyl
stret., 2955 asym. methyl stret., 3447 broad N-H(sec. amine); 1H-
NMR (Bruker Avance II 400 MHz CDC13 δ ppm): 2.36(s, 3H, -
CH3), 3.81(s, 1H, bridge NH), 7.10(s, 1H, thiazole), 7.20(d, 2H, J
= 7.04 Hz, ar-H), 7.67(d, 2H, J = 8.12 Hz, ar-H); Anal. Calc.
(Vario EL III) for C13H9Cl2N5S: Calculated C: 46.17, H: 2.68, N:
20.71 Found C: 45.87, H: 2.42, N: 20.50. 9: Physical state: purple
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20. Spectra data for 1: Physical state: yellowish green solid; % Yield:
89; Melting Range: 141-142°C; Rf Value: (Benzene. ethylacetate.
0.1M alcoholic KOH= 3:3:4): 0.4214; FTIR (IRPrestige-21 KBr,
cm-1): 780 C-H bending, 991 ar C-H bending, 1366 C-N amine,
1413 ar C=C, 1608 N-H bending, 3445 broad N-H (sec. amine);
1H-NMR (Bruker Avance II 400 MHz CDC13 δ ppm): 3.62(s, 3H,
bridge NH), 6.70(s, 3H, thiazole), 7.22(m, 3H, J = 7.36 & 1.46 Hz,
ar-H), 7.33(m, 6H, J = 7.68 & 1.45 Hz, ar-H), 7.91(d, 6H, J = 7.32
Hz, ar-H); Anal. Calc. (Vario EL III) for C30H21N9S3: Calculated
C: 59.68, H: 3.51, N: 20.88% Found C: 59.37, H: 3.14, N:
20.65%. 2: Physical state: orange solid; % Yield: 75; Melting
Range: 138-139°C; Rf Value: (Benzene. ethylacetate. 0.1M
alcoholic KOH= 3:3:4): 0.5234; FTIR (IRPrestige-21 KBr, cm-1):
875 C-H bending, 995 C-H ar bending, 1364 C-H amine, 1663
N-H bending, 3946 NH (sec. amine); 1H-NMR (Bruker Avance II
400 MHz CDC13 δ ppm): 3.22(s, 3H, bridge NH), 6.64(s, 3H,
thiazole), 7.34(s, 3H, ar-OH), 8.02(d, 6H, J = 8.22 Hz, ar-H),
8.11(d, 6H, J = 8.14 Hz, ar-H); Anal. Calc. (Vario EL III) for
C30H21N9O3S3: Calculated C: 55.29, H: 3.25, N: 19.34 Found C:
55.67, H: 3.55, N: 19.64. 3: Physical state: red purple solid; %
Yield: 82; Melting Range: 151-153°C; Rf Value: (Benzene.
ethylacetate. 0.1M alcoholic KOH= 3:3:4): 0.6541; FTIR
(IRPrestige-21 KBr, cm-1): 869 C-H bending, 989 C-H ar
bending, 1360 C-H amine, 1382 dimethylamino, 1659 N-H
bending, 3940 NH (sec. amine); 1H-NMR (Bruker Avance II 400
MHz CDC13 δ ppm): 2.84(s, 12H, -CH3), 3.34(s, 2H, bridge NH),
6.76(s, 2H, thiazole), 8.10(d, 4H, J = 8.15 Hz, ar-H), 8.19(d, 4H, J
= 8.19 Hz, ar-H); Anal. Calc. (Vario EL III) for C25H24ClN9S2:
Calculated C: 54.58, H: 4.40, N: 22.92 Found C: 54.64, H: 4.68,
N: 22.64. 4: Physical state: reddish purple oil; % Yield: 69;
Boiling Range: 286-288°C; Rf Value: (Benzene. ethylacetate.
0.1M alcoholic KOH= 3:3:4): 0.6275; FTIR (IRPrestige-21 KBr,
cm-1): 858 C-H bending, 987 C-H ar bending, 1355 C-H amine,
1650 N-H bending, 3934 NH (sec. amine); 1H-NMR (Bruker
Avance II 400 MHz CDC13 δ ppm): 2.07(s, 6H, -CH3), 3.42(s, 2H,
bridge NH), 6.85(s, 2H, thiazole), 7.11(d, 4H, J = 8.13 Hz, ar-H),
7.18(m, 4H, J = 8.14 Hz, ar-H); Anal. Calc. (Vario EL III) for
C25H18ClN7O4S2: Calculated C: 51.77, H: 3.13, N: 16.90 Found C:
51.45, H: 3.05, N: 16.58. 5: Physical state: orange solid; % Yield:
59; Melting Range: 187-189°C; Rf Value: (Benzene. ethylacetate.
0.1M alcoholic KOH= 3:3:4): 0.5814; FTIR (IRPrestige-21 KBr,
cm-1): 728 methylene rocking, 821 C-H bending, 1389 C-N
solid;
% Yield: 89; Melting Range: 261-263°C; Rf Value:
(Benzene. ethylacetate. 0.1M alcoholic KOH= 3:3:4): 0.6995;
FTIR (IRPrestige-21 KBr, cm-1): 719 C-Cl, 1108 C-N amine,
1342 C-N amine, 1641 C=N, 1741 N-H bending, 3400 broad N-H
(sec. amine); 1H-NMR (Bruker Avance II 400 MHz CDC13
δ
ppm): 3.90(s, 1H, bridge NH), 7.08(s, 1H, thiazole), 8.13(d, 2H, J
= 8.56 Hz, ar-H), 8.23(d, 2H, J = 8.72 Hz, ar-H); Anal. Calc.
(Vario EL III) for C21H13ClN8O4S2: Calculated C: 46.63, H: 2.42,
N: 20.71 Found C: 46.87, H: 2.49, N: 20.89. 10: Physical state:
yellow solid; % Yield: 47; Melting Range: 120-121°C; Rf Value:
(Benzene. ethylacetate. 0.1M alcoholic KOH= 3:3:4): 0.4771;
FTIR (IRPrestige-21 KBr, cm-1): 771 C-Cl, 1234 C-N amine,
1365 C=C(ar-H), 1542 N-H bending, 3436 broad N-H (sec.
amine); 1H-NMR (Bruker Avance II 400 MHz CDC13 δ ppm):
3.59(s, 1H, bridge NH), 7.51(m, 1H, J = 7.52 Hz, ar-H), 7.66(s,
1H, thiazole), 7.84(m, 1H, J = 8.40 & 1.72 Hz, ar-H), 8.12(d, 1H,
J = 1.56 Hz, ar-H); Anal. Calc. (Vario EL III) for C12H5Cl4N5S:
Calculated C: 36.67, H: 1.28, N: 17.82 Found C: 36.45, H: 1.04,
N: 17.68. 11: Physical state: yellow solid; % Yield: 80; Melting
Range: 141-143°C; Rf Value: (Benzene. ethylacetate. 0.1M
alcoholic KOH= 3:3:4): 0.5345; FTIR (IRPrestige-21 KBr, cm-1):
629 C-Cl, 830 C-H bending, 1365 C-N amine, 1542 C=C ar, 1601
N-H bending, 3442 broad N-H (sec. amine); 1H-NMR (Bruker
Avance II 400 MHz CDC13 δ ppm): 3.62(s, 1H, bridge NH),
7.31(s, 1H, thiazole), 7.49(m, 1H, J = 8.48 & 1.68 Hz, ar-H), 7.55
(d, 1H, J = 8.24 Hz, ar-H), 7.85(m, 1H, J = 1.61 Hz, ar-H),
7.91(m, 2H, J = 8.13, 1.62 & 1.65 Hz, ar-H); Anal. Calc. (Vario
EL III) for C12H6BrCl2N5S: Calculated C: 35.76, H: 1.50, N: 17.37
Found C: 35.87, H: 1.41, N: 17.43. 12: Physical state: orange
solid;
% Yield: 69; Melting Range: 145-146°C; Rf Value:
(Benzene. ethylacetate. 0.1M alcoholic KOH= 3:3:4): 0.6116;
FTIR (IRPrestige-21 KBr, cm-1): 779 C-Cl, 1243 C-N(Amine),
1367 C-N amine, 1364 C-H amine, 1638 C=N, 1708 N-H
bending, 3449 broad N-H (sec. amine); 1H-NMR (Bruker Avance
II 400 MHz CDC13 δ ppm): 3.68(s, 1H, bridge NH), 7.37(s, 1H,
thiazole), 7.50(d, 2H, J = 6.92 Hz, ar-H), 7.86(d, 2H, J = 8.00 Hz,
ar-H); Anal. Calc. (Vario EL III) for C12H6BrCl2N5S: Calculated
C: 35.76, H: 1.50, N: 17.37 Found C: 35.44, H: 1.42, N: 17.21.
21. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv.
Drug Delivery Rev. 1997, 23, 4-25.

22. Schneider, G.; Clement-Chomienne, O.; Hilfiger, L.; Schneider,
P.; Kirsch, S.; Bohm, H. J.; Neihart, W. Angew. Chem. Int. Ed.
2000, 39, 4130-4133.
23. Verber, D. F.; Johnson, S. R.; Chang, H. Y.; Smith, B. R.; Ward,
K. M.; Koppel, K. D. J. Med. Chem. 2002, 45, 2615-2623.
24. Harkness, J. E.; Wagner, J. E. Biology and husbandry. In:
Harkness, J. E.; Wagner, J. E. editors. The biology and medicine of
rabbits and rodents, third ed.; Lea & Febiger: Philadelphia, 1995;
pp 372-375.

6
Tetrahedron
Graphical Abstract
Leave this area blank for abstract info.
Facile and efficient preparation of hybrid
phenylthiazolyl-1,3,5-triazines and their
antidepressant-like effect in mice.
Archana Gahtori, Abhay Kumar, Preeti Kothiyal, Prashant Gahtori