Synthesis, characterization and evaluation of antibacterial activity of some thiazolo[3,2-b][1,2,4]triazole incorporating diphenylsulfone moieties

Article abstract of DOI:10.1016/j.ejmech.2009.06.021

A series of thiazolo[3,2-b][1,2,4]triazole incorporating diphenylsulfone moieties were synthesized starting from 5-[4-(4-X-phenylsulfonyl)phenyl]-4H-1,2,4-triazole-3-thioles 3a-c, X = H, Cl, Br. Thus, alkylation of 1,2,4-triazoles 3 with phenacyl bromide

Full text of DOI:10.1016/j.ejmech.2009.06.021

European Journal of Medicinal Chemistry 44 (2009) 4752–4757
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, characterization and evaluation of antibacterial activity of some
thiazolo[3,2-b][1,2,4]triazole incorporating diphenylsulfone moietiesq
,
a
a
b
Stefania-Felicia Barbuceanu a , Gabriela Laura Almajan , Ioana Saramet , Constantin Draghici ,
*
Ana Isabela Tarcomnicu c, Gabriela Bancescu d
a Organic Chemistry Department, Faculty of Pharmacy, Traian Vuia Street 6, 020956 Bucharest, Romania
b C.D. Nenitescu Institute of Organic Chemistry, Romanian Academy, Splaiul Independentei 202B, 060023 Bucharest, Romania
c Pharma Serv International, Sabinelor Street 52, 050853 Bucharest, Romania
d Microbiology Department, Faculty of Dentistry, Calea Plevnei Street 19, 050051 Bucharest, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
A
series of thiazolo[3,2-b][1,2,4]triazole incorporating diphenylsulfone moieties were synthesized
starting from 5-[4-(4-X-phenylsulfonyl)phenyl]-4H-1,2,4-triazole-3-thioles 3a–c, X ¼ H, Cl, Br. Thus,
alkylation of 1,2,4-triazoles with phenacyl bromide or 4-bromophenacyl bromide afforded
Received 20 January 2009
Received in revised form
2 June 2009
3
S-substituted 1,2,4-triazoles 4, 5. These new intermediates 4 and 5, in the presence of H2SO4 (c), were
cyclized to 2-[4-(4-X-phenylsulfonyl)phenyl]-6-(4-Y-phenyl)[1,3]thiazolo[3,2-b]-[1,2,4]-triazoles 6, 7 (I)
and not to isomeric thiazolo[2,3-c][1,2,4]-triazoles 6, 7 (II). The newly synthesized compounds were
characterized by IR, 1H, 13C NMR and elemental analysis. MS spectra confirmed the formation of thia-
zolo[3,2-b][1,2,4]triazole 6, 7 (forms I) in detriment of [2,3-c] isomeric compounds (forms II). The
potential antibacterial effects of the synthesized compounds were investigated using standard bacterial
strains: Acinetobacter baumannii ATCC 19606, Citrobacter freundii ATCC 8090, Escherichia coli ATCC 11775,
Pseudomonas aeruginosa ATCC 9027, Enterococcus faecalis ATCC 19433, Staphylococcus aureus ATCC 12600,
Staphylococcus epidermidis ATCC 14990, Bacillus cereus ATCC 14579.
Accepted 19 June 2009
Available online 26 June 2009
Keywords:
5-Substituted-1,2,4-triazole-3-thiole
Alkylation
Thiazolotriazole
(Phenylsulfonyl)phenyl moiety
Antibacterial activity
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
Further, diphenylsulfone derivatives were also found to possess
antibacterial activity [23,24]. The incorporation of diphenylsulfone
Literature survey revealed that many compounds bearing five-
membered rings such as triazoles and thiazoles show significant
biological activity. Compounds containing 1,2,4-triazole nucleus
exhibit antibacterial [1–3], antifungal [1,4,5], anti-tubercular [6], anti-
inflammatory [7,8], activities. The thiazole nucleus is also present in
various molecules with diverse pharmacological properties, such as
antimicrobial [9–11], anti-inflammatory [12], antitumoral [13].
The thiazolo-triazoles are those compounds which contain in
their structure two fused rings of thiazole and triazole. These
condensed heterocyclic compounds can exist in both the isomer
forms: thiazolo[3,2-b][1,2,4]triazole and thiazolo[2,3-c][1,2,4]tri-
azole. Thiazolo[3,2-b][1,2,4]-triazoles possess a broad spectrum of
biological activities: antimicrobial [14–16], analgesic, anti-inflam-
matory [17–20], antipyretic [20], anticancer [21], vasodilatory [22].
moiety into various heterocyclic systems was found to increase
their pharmacological activity.
Keeping this observation in view and in continuation of our
research on the synthesis of heterocyclic compounds containing
nitrogen, sulfur and bicyclic systems with expected biological
activity [25–27], this paper presents the synthesis of several new
heterocyclic condensed compounds with bridgehead nitrogen from
thiazolo[3,2-b][1,2,4]triazoles class which contain diphenylsulfone
moiety and the study of their antibacterial activity.
2. Chemistry
The reaction sequences employed for synthesis of title
compounds are shown in Scheme 1. The key intermediates, 5-[4-(4-
X-phenylsulfonyl)phenyl]-4H-1,2,4-triazole-3-thioles 3a–c (X ¼ H,
Cl, Br), were prepared starting from 4-(4-X-phenylsulfonyl)-ben-
zoic acid hydrazides 1a–c according to literature [28]. Hydrazides
1a–c were obtained according to the previously described method
[29].
q
This work was in part presented as a poster presentation at XX International
Symposium on Medicinal Chemistry, Vienna, Austria, August 31–September 4,
2008.
* Corresponding author. Tel.: þ40 722 763428.
E-mail address: stefaniafelicia_barbuceanu@yahoo.com (S.-F. Barbuceanu).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.06.021

S.-F. Barbuceanu et al. / European Journal of Medicinal Chemistry 44 (2009) 4752–4757
4753
O
KSCN, H+
HO-
X
SO2
C
O
NH NH
C
S
NH2
X
X
SO2
C
N
NH
NH2
1a-c
2a-c
CH2
Br
C
O
Y
N
N
NH
SH
SO2
X
SO2
N
H
N
X
DMSO
SH
3a-c
A
B
N
N
Y
X
SO2
S
CH2
C
Y
N
N
N
H
O
SO2
4,5a-c
4a-c
A
N
S
H2SO4 (c)
. X= H, Cl, Br; Y= H
5a-c. X= H, Cl, Br; Y= Br
6,7 (I)
X
N
NH
CH2
C
O
Y
X
SO2
S
N
Y
X
SO2
N
B
N
N
S
6,7 (II)
6,7a-c
6a-c
. X= H, Cl, Br; Y= H
7a-c. X= H, Cl, Br; Y= Br
Scheme 1.
The alkylation of 1,2,4-triazoles 3 with phenacyl bromide or 4-
bromophenacyl bromide, in the presence of dimethyl sulfoxide,
afforded a new series of 5-[4-(4-X-phenylsulfonyl)phenyl]-3-phe-
nacylthio-4H-1,2,4-triazole 4 and 5 with good yields (72–88.5%). By
reaction of these S-alkylated 1,2,4-triazole derivatives 4, 5 with
sulfuric acid were obtained the thiazolo[3,2-b]-[1,2,4]triazole 6, 7
(I) (with yields varying from 53% to 90%) and not thiazolo[2,3-
c][1,2,4]triazole isomers 6, 7 (II). Cyclization of S-substituted 1,2,4-
triazoles 4, 5 in acidic media may occur either at nitrogen N-2 (from
intermediate B) or N-4 atom (from intermediate A). The N-2 atom is
more likely involved in the cyclization reaction than N-4 atom
because of its greater basicity [30,31]. Thus, previous studies indi-
cate that if cyclization take place in acidic media (H2SO4, H3PO4,
HCl, CH3COOH) isomers [3,2-b] are obtained. However, if cycliza-
tion takes place in POCl3 media, N-4 would be more basic owing to
the formation of [2,3-c] isomers [15,19,20,30,31].
may be proceeded via the nucleophilic attack of nitrogen
N-2 atom from intermediate B0 to carbonyl carbon protonated at
oxygen atom with formation of intermediate C. By intramolecular
dehydration reaction of intermediate C were obtained heterocyclic
compounds from thiazolo[3,2-b][1,2,4]triazoles 6, 7 class (Scheme 2).
The structural assignments of the new compounds were based
on their elemental analysis and spectral (IR, 1H NMR, 13C NMR and
MS) data. The characterization data of all the new compounds are
summarized in Table 1.
The IR spectra of S-substituted 1,2,4-triazoles 4, 5a–c showed
a strong band at 1681–1684 cmꢀ1 characteristic for carbonyl group.
The absorption band due to –NH group appeared at 3265–3304 cmꢀ1
,
while the –SH peak (2540–2565 cmꢀ1) [28] disappeared.
In the 1H NMR spectra of the S-alkylated derivatives 4 and 5, the
signal corresponding to protons of the methylene group appeared
as singlet at 4.81–4.95 ppm.
The attributions of the signals 13C NMR of 4–7 resulted from the
2D-HETCOR spectra. In compounds 4 and 5, the C]O signal is
observed at w193 ppm and the –CH2– group resonated at
w39 ppm. The C(3) and C(5) heterocyclic carbon resonated at
w153 ppm and w152 ppm, respectively.
3. Biological activity
The synthesized compounds were tested for their in vitro
antibacterial activity against the following standard Gram-positive
and Gram-negative bacterial strains: Acinetobacter baumannii ATCC
19606; Citrobacter freundii ATCC 8090; Escherichia coli ATCC 11775;
Pseudomonas aeruginosa ATCC 9027; Enterococcus faecalis ATCC
19433; Staphylococcus aureus ATCC 12600; Staphylococcus epi-
dermidis ATCC 14990; Bacillus cereus ATCC 14579 using the paper
disc diffusion method [32] (for the qualitative determination) and
the serial dilutions in liquid broth method [33] for determination
of MIC. Tetracycline and ampicillin were used as control drugs.
Thiazolo[3,2-b][1,2,4]triazole 6, 7a–c show, in their IR spectra,
the disappearance of NH and C]O vibration bands. The absorption
band at 1600–1603 cmꢀ1 is due to the presence of –C]N– stretch
of the triazole and thiazole ring system.
In the 1H NMR spectra of thiazolotriazole, methyne proton
appears as a singlet at 7.96–8.06 ppm, in agreement with data
reported for analogous compounds [15,20,34], while the signal of
the methylene proton (4.81–4.95 ppm) from compounds 4, 5 dis-
appeared. The phenyl or p-phenylene protons from phenacyl or 4-
bromophenacyl groups were seen at the expected chemical shifts
and integral values (see Section 6).
4. Results and discussions
The 13C NMR spectrum of 6, 7 displayed no signals belonging to
C]O and –CH2 groups; instead, new signal corresponding to
methyne carbon (–S–CH]Co) was observed at 111.10–112.19 ppm.
Moreover, new signals observed at 130.09–131.72 ppm and 163.59–
164.11 ppm could be attributed to the heterocyclic carbon C(6) of
4.1. Chemistry
The proposed mechanism of formation of thiazolo-triazoles 6 and
7 (Scheme 2) from S-alkylated 1,2,4-triazoles 4 and 5, in acidic media,

4754
S.-F. Barbuceanu et al. / European Journal of Medicinal Chemistry 44 (2009) 4752–4757
OH
C
O
H
N
H
N
Y
N
C
Y
N
H
Ar
CH2
Ar
CH2
N
N
S
N
4,5a-c
S
B
B'
OH2
Y
Y
N
N
N
H2O
H
Ar
CH
Ar
C
H
N
6,7a-c (I)
S
N
S
C
H
Ar =
X
SO2
X = H, Cl, Br; Y = H, Br
Scheme 2.
the thiazole ring system and to heterocyclic carbon which belongs
to both triazole and thiazole ring nucleus, respectively.
4.2. Antibacterial activity
The IR and NMR spectral data being very similar in isomers [2,3-c]
and [3,2-b], the differentiation between them is not possible based
on these. Presence of [3,2-b] or [2,3-c] isomer can be explained by
mass spectra. Literature indicates that the presence of the signal
deriving from the loss of a N2 molecule [M ꢀ 28]þ is characteristic of
thiazolo[2,3-c][1,2,4]triazole [20,35,36]. In the mass spectra of these
new compounds the signal corresponding to N2 less is not present
which indicates the formation of thiazolo[3,2-b][1,2,4]triazole
isomers 6,7 (I). Molecular ion [M þ H]þ peak of condensed hetero-
cyclic compounds 6a–c and 7a–c was observed at different intensi-
ties in positive ionization mode and confirmed the molecular
weights. All the compounds which have a halogen atom in their
molecule show in their mass spectrum the characteristic peaks
corresponding to isotopic distribution (35Cl and 37Cl or 7Br and 81Br
isotopes).
The results of antibacterial screening of newly prepared
compounds 4a–c, 5a–c, 6a–c and 7a–c expressed as the MIC values,
compared with the starting triazoles 3a–c, and control (tetracycline
and ampicillin), are summarized in Table 2.
In the studied series, the tested 3-phenacylthio-triazoles 4, 5a–c
exhibited better activity against the used strains (MIC values: 64,
128, 256
mg/mL) compared to the ‘‘parent’’ triazole 3a–c (MIC
values: 256, 512, 1024
mg/mL). These results confirmed the data
collected from literature [20,37–39] and our expectations according
to which the presence of C]O group and another aromatic ring
increase the potency of triazole nuclei.
The transformation into thiazolo-triazoles 6, 7a,b almost
cancelled the results previously obtained, demonstrating that only
the presence of diphenylsulfone moiety are the most important
factor for their antibacterial activity and not the presence of
Table 1
Characterization data of compounds 4–7.
Compd.
X
Y
Molecular formula
Molecular mass
M.p. (ꢁC)
Yield (%)
Elemental analysis, found (calcd)
C
H
N
S
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
H
H
C22H17N3O3S2
435.52
469.96
514.42
514.42
548.86
593.31
417.51
451.95
496.40
496.40
530.84
575.30
209–211
156–158
140–142
205–207
99–101
79.5
84
60.73
(60.67)
56.30
(56.22)
51.27
(51.37)
51.46
(51.37)
48.07
(48.14)
44.65
(44.54)
63.36
(63.29)
58.50
(58.47)
53.11
(53.23)
53.29
(53.23)
49.83
(49.78)
46.03
3.86
(3.93)
3.50
(3.43)
3.06
(3.14)
3.20
(3.14)
2.71
(2.75)
2.46
(2.55)
3.56
(3.62)
3.17
(3.12)
2.76
(2.84)
2.77
(2.84)
2.41
(2.47)
2.37
9.61
(9.65)
8.88
(8.94)
8.26
(8.17)
8.10
(8.17)
7.61
(7.66)
7.15
(7.08)
10.00
(10.06)
9.25
(9.30)
8.40
14.70
(14.72)
13.61
(13.65)
12.41
(12.47)
12.52
(12.47)
11.64
(11.68)
10.75
(10.81)
15.31
(15.36)
14.15
(14.19)
12.99
(12.92)
12.89
(12.92)
12.04
(12.08)
11.06
Cl
Br
H
H
C22H16ClN3O3S2
H
C
22H16BrN3O3S2
78
Br
Br
Br
H
C22H16BrN3O3S2
C22H15BrClN3O3S2
C22H15Br2N3O3S2
88.5
77
Cl
Br
H
108–110
224–226
117–120
147–149
247–249
253–255
254–257
72
C
22H15N3O2S2
84
Cl
Br
H
H
C23H14ClN3O2S2
C22H14BrN3O2S2
C22H14BrN3O2S2
53
H
66
(8.46)
8.39
(8.46)
7.85
(7.92)
7.20
Br
Br
Br
87
Cl
Br
C
22H13BrClN3O2S2
90
C22H13Br2N3O2S2
88
(45.93)
(2.28)
(7.30)
(11.15)

S.-F. Barbuceanu et al. / European Journal of Medicinal Chemistry 44 (2009) 4752–4757
4755
Table 2
Antibacterial activities of compounds 3–7 as MIC values (
m
g/mL).
Compound
X
Y
Gram-negative bacteriaa
Gram-positive bacteriab
Ab
Cf
Ec
Pa
Ab
Cf
Pc
Ba
1024
128
512
512
128
3a
H
–
256
64
512
64
64
256
64
>1024
128
512
64
512
64
>1024
128
512
128
128
1024
64
>1024
256
512
64
512
128
128
>1024
64
4a
5a
6a
7a
3b
4b
5b
6b
7b
3c
4c
5c
6c
7c
H
H
H
H
H
Br
H
Br
–
H
Br
H
Br
–
512
128
128
512
512
256
512
64
64
64
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
>1024
128
1024
64
>1024
256
1024
64
1024
64
1024
64
64
128
64
64
256
64
64
64
512
128
64
64
64
64
64
1.5
>1024
>1024
128
128
128
128
128
1
2
1024
>1024
64
>1024
>1024
128
128
128
128
128
12
>1024
>1024
256
256
128
256
256
32
0.5
>1024
512
64
128
128
128
128
>1024
>1024
256
64
>1024
>1024
64
128
256
256
256
0.094
H
Br
H
Br
64
64
64
64
1.5
2
64
64
64
24
Control (TE)
Control (AM)
0.19
0.5
–
–
0.064
–
Control: TE ¼ tetracycline; AM ¼ ampicillin.
a
Ab (Acinetobacter baumannii ATCC 19606); Cf (Citrobacter freundii ATCC 8090); Ec (Escherichia coli ATCC 11775); Pa (Pseudomonas aeruginosa ATCC 9027).
Ef (Enterococcus faecalis ATCC 19433); Sa (Staphylococcus aureus ATCC 12600); Se (Staphylococcus epidermidis ATCC 14990); Bc (Bacillus cereus ATCC 14579).
b
heterocyclic condensed systems. These results are contrary to our
produced by Applied Biosystems/SCIEX. The instrument was
operated in positive ion mode, using an atmospheric pressure
pneumatically assisted electrospray ionization interface (ESI, AB
model Turboionspray). The voltage of the mass spectrometer (MS)
source was set at 5000 V. Molecular ions were detected in full scan
over an adequate mass range. Stock solutions were prepared at
expectations, but in concordance with other studies [15].
Moreover, similar MIC values obtained for 3c, 4c, 5c, 6c and 7c
demonstrated again that the presence of condensed systems is not
the main cause of appearance for antibacterial activity. This
behaviour could be attributed to the presence of bromine atom on
diphenylsulfone moiety.
The investigations of antibacterial screening data revealed that
all of the newly synthesized compounds exhibited poor activity
compared to that of the control drugs. Because the MIC values are
not spectacular, no statistical calculations were made.
1 mg/ml in DMSO. The sample solution (2
1/1, v/v) was introduced in the MS interface by direct infusion, at
a flow rate of 20 l/min, with the help of the built-in Harvard
mg/ml in water/methanol
m
syringe pump. The mass spectra of the compounds 6a, c and 7a, c
were registered with a triple quadrupole mass spectrometer Varian
1200L/MS/MS coupled with a high performance liquid chromato-
graph with Varian ProStar 240 pump and a Varian ProStar 410
automatic injector. An atmospheric pressure chemical ionization
interface (APCI) was used in order to obtain the ions. The liquid
chromatography was performed on a Hypersil Gold (Thermo)
column with pre-column, and the mobile phase was 30% water and
70% methanol.
5. Conclusions
This study reports the synthesis and characterization of new
heterocyclic condensed systems with bridgehead nitrogen from
thiazolo[3,2-b][1,2,4]triazole class bearing diphenylsulfone moiety.
The title compounds were synthesized as new compounds with
expected biological activity and their structures were confirmed
successfully by spectral and elemental analyses. The antibacterial
data given for the compounds presented in this paper allowed us to
state that the diphenylsulfone moiety and halogen atom are in
general the main cause for the appearance of their activity. The
antibacterial assay against other Gram-negative and Gram-positive
strains is in progress, because none of the presented compounds is
effective against the tested micro-organisms in comparison with
used drugs.
7. Experimental
7.1. Chemistry
7.1.1. 5-[4-(4-X-phenylsulfonyl)phenyl]-3-(4-Y-phenacylthio)-4H-
1,2,4-triazole 4, 5a–c
1,2,4-Triazole 3a–c (1 mmol) dissolved in dimethyl sulfoxide
(40 mL) was treated with a-halogeno ketone (1 mmol) and then
6. Experimental protocols
mixture was stirred at room temperature for 9 h. The reaction
mixture was then poured into ice water. The precipitate obtained
was filtered, washed with water and then with diethyl ether. The
compound was purified by crystallization from ethanol.
6.1. Chemistry
Melting points were determined with Boetius apparatus and are
uncorrected. The IR spectra (in KBr pellets) were recorded on the
FTS-135 BioRad spectrometer and the wave number were given in
cmꢀ1. The NMR spectra were registered on a Varian Gemini 300 BB
spectrometer working at 300 MHz for a 1H and 75 MHz for 13C in
Compound 4a: IR (KBr, n
, cmꢀ1): 3265 (NH), 3095, 3068
(aromatic C–H); 2980, 2920 (aliphatic C–H); 1681 (C]O), 1599,
1449 (C]N þ C]Caryl); 1322, 1290, 1158 (SO2); 1015 (N–N); 1H
NMR (DMSO-d6, d ppm): 7.95–8.17 (m, 8H; aromatic protons); 7.53–
7.72 (m; 3H; aromatic protons); 4.95 (ws; 2H; –S–CH2–CO); 13C
NMR (DMSO-d6, ppm): 192.81 (C]O); 153.50 (C3-triazolic ring);
DMSO-d6. All chemical shifts are reported in
d
(ppm) using TMS as
d
an internal standard. The mass spectra of compounds 6b and 7b
have been acquired with a hybrid quadrupole-time of flight
(QqTOF) high resolution mass spectrometer model API QStar Pulsar
152.85 (C5-triazolic ring); 141.40, 140.40, 135.40, 133.87, 133.68,
129.83, 128.82, 128.39, 127.39, 127.30, 126.92, 126.88 (aromatic
ring); 39.77 (–S–CH2–CO).

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S.-F. Barbuceanu et al. / European Journal of Medicinal Chemistry 44 (2009) 4752–4757
Compound 4b: IR (KBr,
n
, cmꢀ1): 3265 (NH); 3093 (aromatic C–
(dd, 2H, J ¼ 8.1; 1.4 Hz, aromatic protons): 8.10 (d, 2H, J ¼ 8.7 Hz,
H); 2987, 2921 (aliphatic C–H); 1681 (C]O); 1599, 1449
(C]N þ C]Caryl); 1324, 1287, 1158 (SO2); 1013 (N–N); 767 (C–Cl);
aromatic protons); 8.00 (m, 2H, aromatic protons); 7.97 (s, 1H, –S–
CH]Co); 7.48–7.75 (m, 6H, aromatic protons); 13C NMR (DMSO-d6,
d ppm): 163.93 (thiazolic and triazolic ring); 157.95 (C2-triazolic
1H NMR (DMSO-d6,
d
ppm): 7.96–8.16 (m, 10H, aromatic protons);
7.70 (wt; 2H; J ¼ 7.5 Hz, aromatic protons); 7.56 (tt; 1H; J ¼ 7.5 Hz,
ring); 141.74, 140.86, 135.43, 133.87, 129.84, 128.96, 127.38, 127.33,
126.33, 126.08 (aromatic ring); 131.58 (C6-thiazolic ring); 111.60
(–S–CH]Co); MS (APCI) m/z: 418 [M þ H]þ.
aromatic proton); 4.95 (ws; 2H; –S–CH2–CO); 13C NMR (DMSO-d6,
d
ppm): 193.01 (C]O); 153.43 (C3-triazolic ring); 152.10 (C5-tri-
azolic ring); 140.90, 139.95, 139.60, 135.52, 133.65, 129.95, 128.79,
128.36, 128.23, 128.15, 126.88 (aromatic ring); 39.75 (–S–CH2–CO).
Compound 6b: IR (KBr, n
, cmꢀ1): 3093 (aromatic C–H); 1603,
1464 (C]N þ C]Caryl); 1324,1280, 1159 (SO2); 1013 (N–N); 771 (C–
Compound 4c: IR (KBr,
n
, cmꢀ1): 3273 (NH); 3088 (aromatic C–
Cl); 1H NMR (DMSO-d6,
d
ppm): 8.35 (d, 2H, J ¼ 8.5 Hz, aromatic
H); 2991, 2922 (aliphatic C–H); 1681 (C]O); 1599, 1449
(C]N þ C]Caryl); 1323, 1288, 1158 (SO2); 1009 (N–N); 579 (C–Br);
protons); 8.24 (dd, 2H, J ¼ 8.6; 1.6 Hz, aromatic protons); 8.12 (d,
2H, J ¼ 8.5 Hz, aromatic protons); 8.02 (d, 2H, J ¼ 8.7 Hz, aromatic
protons); 7.99 (s, 1H, –S–CH]Co); 7.72 (d, 2H, J ¼ 8.7 Hz, aromatic
protons); 7.60 (t, 2H, J ¼ 8.6 Hz, aromatic protons); 7.56 (tt, 1H,
1H NMR (DMSO-d6,
d ppm): 7.82–8.12 (m, 10H, aromatic protons);
7.56 (wt; 2H; J ¼ 7.4 Hz, aromatic protons); 7.79 (wt; 1H; J ¼ 7.4 Hz,
aromatic proton); 4.83 (ws; 2H; –S–CH2–CO); 13C NMR (DMSO-d6,
J ¼ 8.6; 1.6 Hz, aromatic proton); 13C NMR (DMSO-d6,
d ppm):
d
ppm): 192.52 (C]O); 153.22 (C3-triazolic ring); 153.05 (C5-tri-
164.01 (thiazolic and triazolic ring); 157.96 (C2-triazolic ring);
141.35, 139.80, 138.91, 135.69, 129.85, 129.63, 129.25, 128.85, 128.10,
127.38, 126.34 (aromatic ring); 131.72 (C6-thiazolic ring); 111.35
(–S–CH]Co); MS (ESI-QqTOF) m/z: 452.0678 [M þ H]þ; m/z:
454.0649 [M þ H]þ.
azolic ring); 141.05, 140.10, 135.61, 133.65, 132.93, 129.41, 128.82,
128.38, 128.30, 127.79, 126.93, 126.75 (aromatic ring); 39.79 (–S–
CH2–CO).
Compound 5a: IR (KBr, n
, cmꢀ1): 3304 (NH), 3095 (aromatic C–
H); 2976, 2918 (aliphatic C–H); 1682 (C]O), 1584, 1548
(C]N þ C]Caryl); 1314, 1289, 1157 (SO2); 1017 (N–N); 572 (C–Br);
Compound 6c: IR (KBr, n
, cmꢀ1): 3090 (aromatic C–H); 1603,
1464 (C]N þ C]Caryl); 1324, 1279, 1159 (SO2); 1010 (N–N); 578 (C–
1H NMR (DMSO-d6,
d
ppm): 8.10 (d, 2H, J ¼ 8.7 Hz, aromatic
Br); 1H NMR (DMSO-d6,
d
ppm): 8.32 (d, 2H, J ¼ 8.6 Hz, aromatic
protons); 8.02 (d, 2H, J ¼ 8.7 Hz, aromatic protons); 7.96 (dd, 2H,
J ¼ 7.0; 1.3 Hz, aromatic protons); 7.93 (d, 2H, J ¼ 8.7 Hz, aromatic
protons); 7.74 (d, 2H, J ¼ 8.7 Hz, aromatic protons); 7.69 (tt, 1H,
J ¼ 7.0; 1.3 Hz, aromatic proton); 7.64 (t, 2H, J ¼ 7.0 Hz, aromatic
protons); 8.22 (dd, 2H, J ¼ 8.2; 1.6 Hz, aromatic protons); 8.10 (d,
2H, J ¼ 8.6 Hz, aromatic protons); 7.96 (s, 1H, –S–CH]Co); 7.92 (d,
2H, J ¼ 8.8 Hz, aromatic protons); 7.84 (d, 2H, J ¼ 8.8 Hz, aromatic
protons); 7.43–7.61 (m, 3H, aromatic protons); 13C NMR (DMSO-d6,
protons); 4.82 (s, 2H, –S–CH2–CO); 13C NMR (DMSO-d6,
d
ppm):
d ppm): 163.85 (thiazolic and triazolic ring); 157.94 (C2-triazolic
192.79 (C]O); 153.67 (C3-triazolic ring); 152.80 (C5-triazolic ring);
141.00, 140.87, 134.63, 133.33, 131.51, 129.97, 129.37, 127.80, 127.68,
127.27, 126.99, 126.62 (aromatic ring); 39.93 (–S–CH2–CO).
ring); 141.18, 140.10, 135.62, 132.92, 129.39, 128.92, 128.23, 127.36,
126.30, 126.09 (aromatic ring); 131.56 (C6-thiazolic ring); 111.59
(–S–CH]Co); MS (APCI) m/z: 496 [M þ H]þ; m/z: 498 [M þ H]þ.
Compound 5b: IR (KBr,
n
, cmꢀ1): 3281 (NH), 3091 (aromatic C–
Compound 7a: IR (KBr, n
, cmꢀ1): 3061 (aromatic C–H); 1603,
H); 2972, 2918 (aliphatic C–H); 1684 (C]O), 1584, 1448
(C]N þ C]Caryl); 1321, 1287, 1157 (SO2); 1012 (N–N); 767 (C–Cl);
1464 (C]N þ C]Caryl); 1321, 1280, 1158 (SO2); 1012 (N–N); 570 (C–
Br); 1H NMR (DMSO-d6,
d
ppm): 8.34 (d, 2H, J ¼ 8.5 Hz, aromatic
584 (C–Br); 1H NMR (DMSO-d6,
d
ppm): 8.08 (d, 2H, J ¼ 8.8 Hz,
protons); 8.20 (d, 2H, J ¼ 8.6 Hz, aromatic protons); 8.08 (d, 2H,
J ¼ 8.5 Hz, aromatic protons); 7.98 (s, 1H, –S–CH]Co); 7.82 (d, 2H,
J ¼ 8.6 Hz, aromatic protons); 7.68 (wt, 1H, J ¼ 8.2 Hz, aromatic
proton); 7.64 (t, 2H, J ¼ 8.2 Hz, aromatic protons); 7.18 (m, 2H,
aromatic protons); 7.98 (d, 2H, J ¼ 8.8 Hz, aromatic protons); 7.95
(d, 2H, J ¼ 8.5 Hz, aromatic protons); 7.85 (d, 2H, J ¼ 8.8 Hz,
aromatic protons); 7.76 (d, 2H, J ¼ 8.5 Hz, aromatic protons); 7.68
(d, 2H, J ¼ 8.8 Hz, aromatic protons); 4.86 (s, 2H, –S–CH2–CO); 13C
aromatic protons); 13C NMR (DMSO-d6,
d ppm): 163.59 (thiazolic
NMR (DMSO-d6,
d
ppm): 193.24 (C]O); 153.50 (C3-triazolic ring);
and triazolic ring); 157.37 (C2-triazolic ring); 141.39, 140.48, 134.83,
133.03, 131.11, 129.05, 127.38, 127.29, 126.74, 122.39 (aromatic ring);
130.09 (C6-thiazolic ring); 111.46 (–S–CH]Co); MS (APCI) m/z: 418
[M þ H]þ.
152.72 (C5-triazolic ring); 141.30, 139.84, 139.17, 134.84, 131.96,
130.43, 130.04, 128.23, 127.80, 127.11 (aromatic ring); 39.70 (–S–
CH2–CO).
Compound 5c: IR (KBr,
n
, cmꢀ1): 3265 (NH), 3088 (aromatic C–
Compound 7b: IR (KBr, n
, cmꢀ1): 3097 (aromatic C–H); 1600,
H); 2987, 2918 (aliphatic C–H); 1683 (C]O), 1582, 1449
(C]N þ C]Caryl); 1322, 1287, 1158 (SO2); 1017 (N–N); 579 (C–Br);
1464 (C]N þ C]Caryl); 1324, 1280, 1159 (SO2); 1013 (N–N); 773 (C–
Cl); 582 (C–Br); 1H NMR (DMSO-d6,
d
ppm): 8.34 (d, 2H, J ¼ 8.4 Hz,
1H NMR (DMSO-d6,
d
ppm): 8.11 (d, 2H, J ¼ 8.7 Hz, aromatic
aromatic protons); 8.21 (d, 2H, J ¼ 8.6 Hz, aromatic protons); 8.13
(d, 2H, J ¼ 8.4 Hz, aromatic protons); 8.06 (s, 1H, –S–CH]Co); 8.02
(d, 2H, J ¼ 8.7 Hz, aromatic protons); 7.79 (d, 2H, J ¼ 8.6 Hz,
aromatic protons); 7.75 (d, 2H, J ¼ 8.7 Hz, aromatic protons); 13C
protons); 8.06 (d, 2H, J ¼ 8.7 Hz, aromatic protons); 7.94 (d, 2H,
J ¼ 8, 7 Hz aromatic protons); 7.88 (d, 2H, J ¼ 8.8, aromatic proton);
7.82 (d, 2H, J ¼ 8.8 Hz, aromatic proton); 7.74 (d, 2H, J ¼ 8.7 Hz,
aromatic proton); 4.81 (s, 2H, –S–CH2–CO); 13C NMR (DMSO-d6,
NMR (DMSO-d6,
d ppm): 163.87 (thiazolic and triazolic ring);
d
ppm): 192.58 (C]O); 153.25 (C3-triazolic ring); 152.84 (C5-tri-
157.84 (C2-triazolic ring); 141.23, 139.60, 138.77, 135.43, 131.75,
129.73, 129.12, 128.09, 127.99, 127.24, 126.55, 122.83 (aromatic
ring); 130.45 (C6-thiazolic ring); 111.10 (–S–CH]Co); MS (ESI-
QqTOF) m/z: 529.9841 [M þ H]þ; m/z: 531.9817 [M þ H]þ.
azolic ring); 140.31, 139.89, 134.38, 132.61, 131.56, 130.06, 129.09,
127.88, 127.73, 127.43, 126.66 (aromatic ring); 39.65 (–S–CH2–CO).
7.1.2. 2-[4-(4-X-phenylsulfonyl)phenyl]-6-(4-Y-
Compound 7c: IR (KBr, n
, cmꢀ1): 3094 (aromatic C–H); 1602,
phenyl)[1,3]thiazolo[3,2-b][1,2,4]triazoles 6, 7a–c
1464 (C]N þ C]Caryl); 1323, 1279, 1158 (SO2); 1014 (N–N); 578
Compound 4, 5 (1 mmol) was stirred in 50 mL H2SO4 (c) at 0 ꢁC
for 3 h and then another 3 h at room temperature. The reaction
mixture was poured into ice water and the precipitate obtained was
filtered off, washed with water, and recrystallized from
C6H6:C2H5OH (2:1, v:v).
(C–Br); 1H NMR (DMSO-d6,
d
ppm): 8.34 (d, 2H, J ¼ 8.5 Hz,
aromatic protons); 8.18 (d, 2H, J ¼ 8.7 Hz, aromatic protons);
8.08 (d, 2H, J ¼ 8.5 Hz, aromatic protons); 7.96 (s, 1H, –S–
CH]Co); 7.90 (d, 2H, J ¼ 8.7 Hz, aromatic protons); 7.82 (d, 2H,
J ¼ 8.7 Hz, aromatic proton); 7.75 (d, 2H, J ¼ 8.7 Hz, aromatic
Compound 6a: IR (KBr,
n
, cmꢀ1): 3061 (aromatic C–H); 1603,
protons); 13C NMR (DMSO-d6,
d ppm): 164.11 (thiazolic and tri-
1466 (C]N þ C]Caryl); 1321,1283,1158 (SO2); 1013 (N–N); 1H NMR
azolic ring); 157.55 (C2-triazolic ring); 141.55, 140.31, 135.79,
132.99, 132.07, 129.44, 128.43, 128.20, 128.16, 127.63, 126.84,
(DMSO-d6,
d
ppm): 8.33 (d, 2H, J ¼ 8.7 Hz, aromatic protons); 8.24

S.-F. Barbuceanu et al. / European Journal of Medicinal Chemistry 44 (2009) 4752–4757
4757
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123.19 (aromatic ring); 130.91 (C6-thiazolic ring); 112.19 (–S–
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[M þ DMSO þ H]þ; m/z: 656 [M þ DMSO þ H]þ; m/z: 658
[M þ DMSO þ H]þ fragmentation by collision at 35 eV: m/z: 574
[M þ H]þ; m/z: 576 [M þ H]þ; m/z: 578 [M þ H]þ; m/z: 580
[M þ H]þ.
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Acknowledgements
This work is supported by project ID_226 no. 301/1.10.2007 from
the Exploratory Research Projects of the National University
Research Council (NURC-Romania).
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