Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance

Article abstract of DOI:10.1016/j.ejmech.2012.07.009

In an effort to establish new candidates with improved analgesic and anti-inflammatory activities and lower ulcerogenic risk, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives of ibuprofen were synthesized. All compounds were evaluated for their in vivo anti-inflammatory and analgesic activities in mice. Furthermore, the ulcerogenic risks of the compounds were determined. In general, none of the compounds represent a risk for developing stomach injury as much as observed in the reference drugs ibuprofen and indomethacin. The compounds carrying a 3-phenyl-2-propenylidene (1a), (biphenyl-4-yl)methylidene (1f) and (1-methylpyrrol-2-yl)methylidene (1n) at the 6th position of the fused ring have been evaluated as potential analgesic/anti-inflammatory agents without a gastrointestinal side effect. These new compounds, therefore, deserve further attention to develop new lead drugs.

Full text of DOI:10.1016/j.ejmech.2012.07.009

European Journal of Medicinal Chemistry xxx (2012) 1e9
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel
non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance
a
b
a
b
b
c
_
_
Ays¸e Uzgören-Baran , Banu Cahide Tel , Deniz Sarıgöl , Elif Inci Öztürk , Inci Kazkayası , Gürol Okay ,
Mevlüt Ertan d, Birsen Tozkoparan d
,
*
a Hacettepe University, Faculty of Science, Department of Chemistry, 06800 Ankara, Turkey
b Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, 06100 Ankara, Turkey
c Siirt University, Faculty of Arts and Sciences, Department of Chemistry, 56000 Siirt, Turkey
d Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Sihhiye, 06100 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to establish new candidates with improved analgesic and anti-inflammatory activities and
lower ulcerogenic risk, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives of ibuprofen were
synthesized. All compounds were evaluated for their in vivo anti-inflammatory and analgesic activities in
mice. Furthermore, the ulcerogenic risks of the compounds were determined. In general, none of the
compounds represent a risk for developing stomach injury as much as observed in the reference drugs
ibuprofen and indomethacin. The compounds carrying a 3-phenyl-2-propenylidene (1a), (biphenyl-4-yl)
methylidene (1f) and (1-methylpyrrol-2-yl)methylidene (1n) at the 6th position of the fused ring have
been evaluated as potential analgesic/anti-inflammatory agents without a gastrointestinal side effect.
These new compounds, therefore, deserve further attention to develop new lead drugs.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Received 26 April 2012
Received in revised form
18 June 2012
Accepted 5 July 2012
Available online xxx
Keywords:
Ibuprofen derivatives
Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one
Analgesic activity
Anti-inflammatory activity
Gastric risk
1. Introduction
generally attributed to two factors: local irritation by the carboxylic
acid moiety, common to most of NSAIDs (topical effect), and
Inflammation is a spontaneous biological response of vascular
tissues to harmful stimuli, such as pathogens, chemicals, thermal
and mechanical injuries. It is produced and controlled by the
interaction of a wide range of inflammatory mediators such as
histamine, 5-hydroxytryptamine, various chemotactic factors such
as bradykinin, leukotrienes, prostaglandins [1]. Therefore, a variety
of drugs that antagonize the chemical mediators of inflammation,
individually or in combination, could be effective to alleviate the
signs of it. However, prostaglandin synthesis inhibitors such as
non-steroidal anti-inflammatory drugs (NSAIDs) and steroidal anti-
inflammatory drugs (glucocorticoids) are extensively used in the
treatment of inflammation. The NSAIDs such as acetylsalicylic acid,
indomethacin and ibuprofen inhibit early steps in the biosynthesis
pathway of prostaglandins by the inhibition of cyclooxygenase
(COX) enzymes, and are the main drugs used to reduce the adverse
consequences of inflammation [1]. However, the side effects
including gastrointestinal (GI) perforation, ulceration, bleeding and
renal toxicity of currently available NSAIDs pose a major problem in
their clinical use. The gastrointestinal damage from NSAIDs is
decreased cytoprotective prostaglandin production [2e5]. The use
of steroidal drugs as anti-inflammatory agents is also becoming
highly controversial due to their multiple side effects [6]. Thus, in
spite of the tremendous advances in the last decade, the design and
development of a safe, effective and economical therapy for treat-
ing inflammatory conditions still presents a major challenge.
To develop novel compounds that are biologically effective but
devoid of side effects inherent in traditional NSAIDs, several strat-
egies have been reported on the modification of well-known
nonselective NSAIDs. Studies describe that the derivatization of
the carboxylate function of representative NSAIDs result in
increased anti-inflammatory activity with reduced ulcerogenic
potential [7e12]. Furthermore, certain compounds bearing 1,3,4-
oxadiazole/thiadiazole and 1,2,4-triazole nucleus have emerged as
a promising group of substances [13e19].
In view of the aforementioned reports, the decision was made to
synthesize new compounds by combining thiazolo[3,2-b]-1,2,4-
triazole ring with ibuprofen, (S)-naproxen and flurbiprofen, which
are members of the 2-arylpropionic acid (profen) family of NSAIDs,
in order to improve their safety profile while maintaining full anti-
inflammatory/analgesic activity. One of the most interesting char-
acteristics of these novel compounds is their non-acidic structure,
* Corresponding author. Tel.: þ90 312 305 30 20; fax: þ90 312 311 47 77.
E-mail address: tbirsen@hacettepe.edu.tr (B. Tozkoparan).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.07.009
Please cite this article in press as: A. Uzgören-Baran, et al., Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-
steroidal anti-inflammatory agents with favorable gastrointestinal tolerance, European Journal of Medicinal Chemistry (2012), http://
dx.doi.org/10.1016/j.ejmech.2012.07.009

2
A. Uzgören-Baran et al. / European Journal of Medicinal Chemistry xxx (2012) 1e9
which differentiates them from the classic acidic nonsteroidal anti-
inflammatory/analgesic agents. The preliminary screening test
results have revealed that the incorporation of the free carboxylic
acid group of NSAIDs into the thiazolo[3,2-b]-1,2,4-triazole ring is
often accompanied by decreased gastric toxicity in vivo [20e22].
Prompted by these promising results, and in continuation of the
efforts toward the development of new molecules exhibiting
analgesic/anti-inflammatory activity, it is worthwhile to carry on
further structural modification on these hybrid compounds. In this
study, new analogs of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one
carrying ibuprofen residue were synthesized by bioisosteric
replacement of substituted benzylidene at the 6th position of the
ring with various arylalkyls, a bulky ring (biphenyl and napthyl) or
a heterocyclic ring. The present report provides an extended study of
the chemistry and evaluation of analgesic/anti-inflammatory activ-
ities, as well as the gastric risk of a new series of these compounds.
that cyclocondensation proceeded regioselectively in the N1
nitrogen atom, and the phenyl ring was located in a cis (Z) config-
uration at the 6th position.
All new condensed compounds were characterized by their
melting points, elementary analysis, IR, 1H and APT 13C NMR and
mass spectra. The spectral data are in agreement with the proposed
structures (Tables 1e3). The structure of compounds 1ae1o was
confirmed by the presence of a band between 1762 and 1724 cmꢁ1
for C]O of the lactam group in their IR spectra. In the 1H NMR
spectra of the compounds, the methylidene proton has been
exhibited at
d 7.50e8.56 ppm as a singlet, and sometimes in the
aromatic region together with aromatic protons. All the other
protons were observed accordingly to the expected chemical shift
and integral values (Table 2). The APT 13C NMR spectra of the
compounds showed the characteristic lactam C]O carbon of the
condensed ring at approximately 176 ppm (Table 3). The mass
spectroscopic analysis of the compounds was studied under electron
spray ionization. Either quasimolecular ions [Mþ þ H] or [Mþ þ Na]
peaks confirmed the molecular weights of the examined compounds.
2. Chemistry
Over the last fifteen years, our research group has reported the
general synthesis of 3-substituted-1,2,4-triazole-5-thiones, which
are fascinating 1,3-dinucleophilic building blocks, and have
demonstrated their use in the preparations of a wide range of
heterocyclic compounds. In this study, the synthesis of desired
compounds, Scheme 1 was followed. The starting compound, (ꢀ)-3-
[1-(4-(2-methylpropyl) phenyl)ethyl]-1,2,4-triazole-5-thione (1)
was prepared via dicyclohexylcarbodiimide (DCC)-promoted amid
formation reaction starting from ibuprofen in three steps by
employing the previously reported procedure [20]. In brief,
ibuprofen reacted with N-hydroxysuccinimide in the presence of
DCC to obtain N-[2-(4-(2-methylpropyl)phenyl)propanoyloxy]suc-
cinimide. The resulting ester reacted with thiosemicarbazide to
yield 1-acylthiosemicarbazide. Cyclization of the intermediate thi-
osemicarbazide by heating with NaOH 10% under reflux, followed
by the acidification with concentrated hydrochloric acid, gave rise
to the desired (ꢀ)-3-[1-(4-(2-methylpropyl)phenyl)ethyl]-1,2,4-
triazole-5-thione (1). The melting point of the compound was in
accordance with the literature. Therefore, the next step of the
reaction was carried out without any further analysis [20].
3. Pharmacology
In pharmacological studies, anti-inflammatory and analgesic
activityas well as the ulcerogenic risk of the synthesized compounds
were investigated. In order to screen the anti-inflammatory profile,
the carrageenan-induced hind-paw edema model in mice was used
[25]. The analgesic activity of the compounds was studied using both
tail-flick assay and the hot plate test [26,27]. In the tail-flick test,
latency until the mouse flicked its tail away from the heat source was
measured. In the hot plate test, latency of forepaw licking or jump
response was evaluated for each animal as an index of nociception.
The evaluation of anti-inflammatory and analgesic activities was
carried out orally at two dose levels of 50 and 100 mg/kg. To observe
the maximum possible effect, the experiments began with a dose
level of 100 mg/kg. However, the dose was lowered by half to 50 mg/
kg in order to investigate the therapeutic effects of the compounds.
The gastric safety on acute administration was also conducted by
microscopic examination, and this test was carried out after the
carrageenan-induced hind-paw edema test. For the purpose of
comparison, two nonselective COX inhibitors, indomethacin (10 and
50 mg/kg) and ibuprofen (50 and 100 mg/kg), and an opioid anal-
gesic oxycodone (50 and 100 mg/kg), which acts on a different
mechanism than COX inhibition, were used as the positive control.
6-Substituted thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones (1ae1o)
were synthesized by the cyclization of the mercaptotriazole (1) with
chloroacetic acid and relevant aldehydes in the presence of acetic
acid, acetic anhydride and anhydrous sodium acetate in one step in
10e51% yields.
During the reaction of 1,2,4-triazole-5-thione with various die-
lectrophiles, two isomeric cyclization products, such as thiazolo
[3,2-b]-1,2,4-triazole or thiazolo[2,3-c]-1,2,4-triazole, can be
obtained. The mode of cyclization and the configuration around the
C]C double bond of similar compounds was assigned on the basis
of X-ray crystallographic analysis earlier [23,24], and it was proven
4. Results and discussion
4.1. Anti-inflammatory activity
Fig. 1 shows the results of the anti-edematous effect of orally
administered test compounds on carrageenan-induced paw edema
Scheme 1. The reaction leading to thiazolo[3,2-b]-1,2,4-triazole derivatives 1ae1o.
Please cite this article in press as: A. Uzgören-Baran, et al., Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-
steroidal anti-inflammatory agents with favorable gastrointestinal tolerance, European Journal of Medicinal Chemistry (2012), http://
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A. Uzgören-Baran et al. / European Journal of Medicinal Chemistry xxx (2012) 1e9
3
Table 1
Melting points, reaction yields and formulas of the compounds synthesized.
Compounds
R
Yield %
30
M.p. (ꢂC)
Formula (M.W. g/mol)
C25H25N3OS (415)
1a
203e205
1b
1c
14
46
148e150
123e125
C26H27N3OS (429)
C30H29N3O2S (495)
1d
1e
1f
41
35
23
22
180e182
140e142
160e162
195e196
C30H29N3O2S (495)
C25H25N3O3S (447)
C29H27N3OS (465)
C27H25N3OS (439)
1g
1h
1i
51
43
146e148
131e133
C21H21N3O2S (379)
C22H23N3O2S (393)
1j
45
185e187
C21H21N3OS2 (395)
1k
1l
41
26
198e200
178e180
C22H23N3OS2 (409)
C22H23N3OS2 (409)
(continued on next page)
Please cite this article in press as: A. Uzgören-Baran, et al., Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-
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4
A. Uzgören-Baran et al. / European Journal of Medicinal Chemistry xxx (2012) 1e9
Table 1 (continued )
Compounds
R
Yield %
49
M.p. (ꢂC)
Formula (M.W. g/mol)
C21H20BrN3OS2 (475)
1m
1n
1o
242e244
10
30
150 (dec.)
C22H24N4OS (392)
165e167
C27H26N4O2S (470)
in mice at 50 and 100 mg/kg doses. In the oral administration of
a 50 mg/kg dose, all compounds except 1, 1a and 1e showed
moderate to high anti-inflammatory activity, ranging from 30% to
56%, while ibuprofen, indomethacin and oxycodone references
showed 55%, 53% and 1% of anti-inflammatory activity, respectively.
Compounds 1b, 1c, 1d, 1g, 1j, 1n and 1o were found as potent as
ibuprofen and indomethacin (not statistically significant compared
to references). Compounds 1c, 1d and 1o have the highest anti-
inflammatory activity among all. The compounds, when adminis-
tered in a two-fold dose (100 mg/kg, p.o.), exhibited a higher
activity profile compared to the 50 mg/kg dose level (except 1, 1d,
1l, 1n and 1o). All derivatives except 1 and 1l showed noticeable
anti-inflammatory activity compared to ibuprofen at 100 mg/kg.
Especially compounds 1a, 1c, 1f and 1m showed the most
remarkable activity at this dose. In this test, oxycodone, which acts
on opioid receptors and has no COX inhibitory activity, exhibited no
anti-inflammatory activity in both doses as expected, whereas
ibuprofen and indomethacin (non-selective COX inhibitors)
showed the highest anti-inflammatory activity.
compounds, compounds 1j (41%) and 1n (44%) possessed the most
prominent and consistent activity compared to ibuprofen (46%) at
50 mg/kg. With an oral dose of 100 mg/kg, all synthesized derivatives
except compound 1 showed statistically significant analgesic activity
compared to vehicle control. However, derivatives 1d, 1f, 1h, 1j, 1l
and 1n were found as potent as ibuprofen. Interestingly, increasing
the dose to 100 mg/kg did not cause a dramatic increase in analgesic
activity (except 1d and 1h). Similar to the tail-flick test, none of the
compounds reached the analgesic activity of oxycodone (Fig. 3).
When compared to the results of the tail-flick and hot plate
tests, all test compounds (except compounds 1b and 1l at the
50 mg/kg dose; 1b and 1i at the 100 mg/kg dose) exhibited similar
analgesic activity profile in both tests. Some of the compounds with
notable anti-inflammatory properties coupled with a good anal-
gesic activity profile (such as 1j, 1n and 1o at the 50 mg/kg dose; 1a,
1d and 1f at the 100 mg/kg dose).
As a result, unlike oxycodone (the effect of which is mediated by
opioid receptors), all test compounds showed a similar activity
profile to ibuprofen with respect to tail-flick and hot plate tests, as
well as carrageenan-induced paw edema test. Therefore, it could be
concluded that the test compounds might act on the inhibition of
the prostaglandin production.
4.2. Analgesic activity
4.2.1. Tail-flick test
In analgesic activity experiments, most of the compounds
exhibited some degree of analgesic activity in both the hot plate
and tail-flick tests (Figs. 2 and 3). Oral administration of all
synthesized derivatives produced markedly increased latency of
the tail-flick response compared to vehicle control at the 50 mg/kg
dose level (except compounds 1, 1e, 1h and 1k). Especially
compounds 1f, 1l and 1n have attracted attention with higher or
almost equivalent activity to ibuprofen (50%) with percentage
activity values 53%, 46% and 47%, respectively, at the 50 mg/kg dose
level. When the administered dose was increased two-fold, some of
the compounds (compounds 1, 1a, 1b, 1d, 1h, 1i, 1j, 1l and 1n)
increased the latencies of the tail-flick response compared to
vehicle control. Compounds 1a, 1b, 1i, 1j, 1l and 1n exhibited
a similar activity profile with ibuprofen at this dose level. None of
the test compounds reached the analgesic activity of narcotic
analgesic oxycodone (Fig. 2).
4.3. Acute ulcerogenesis
The stomachs of mice were examined for lesions in gastric
mucosa by using a dissecting microscope. The quantification of
gastric mucosal lesions was scored according to their number and
size in a scale from 0 up to 7 points, as given in detail in the
methods section [28]. As seen in Fig. 4, in spite of the high gastric
ulcer incidence in reference compounds ibuprofen (50 and
100 mg/kg doses) and indomethacin (10 and 50 mg/kg doses), all
of the test compounds were generally found safe from the
viewpoint of ulcer induction at both 50 and 100 mg/kg dose
levels. Particularly the ulcerogenic effect of the compounds 1a, 1b,
1f, 1i, 1l, and 1n was appreciably lesser than ibuprofen (p < 0.01)
and indomethacin in both doses. Additionally, 1h at the 100 mg/
kg and 1j at 50 mg/kg doses were found safe as well (p < 0.01).
Furthermore, some of the aforementioned test compounds (1a, 1f,
1n) are also among the compounds that exhibited marked anal-
gesic and anti-inflammatory activity. The ulcerogenic score of
oxycodone was similar to the vehicle control. The analgesic
effects of traditional NSAIDs, such as ibuprofen and indometh-
acin, have been attributed to the inhibition of COX-2, while the GI
4.2.2. Hot plate test
All synthesized derivatives except 1, 1g, 1h and 1k produced
significant inhibition of the hot plate paw-licking response
compared to the vehicle control at a dose of 50 mg/kg. Among the
Please cite this article in press as: A. Uzgören-Baran, et al., Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-
steroidal anti-inflammatory agents with favorable gastrointestinal tolerance, European Journal of Medicinal Chemistry (2012), http://
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A. Uzgören-Baran et al. / European Journal of Medicinal Chemistry xxx (2012) 1e9
5
Table 2
IR and 1H NMR and mass spectroscopic data of the compounds 1ae1o.
Compounds
IR (KBr):
n
(1/cm)
1H NMR (DMSO-d6) (
d
(ppm); J in Hz)
Mass spectra (ESI)
1a
1742 (C]O);
1605 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.57 Hz), 1.68 (d, 3H, CH3, J ¼ 7.19 Hz), 1.73e1.82 (m, 1H,
CH), 2.36 (d, 2H, CH2, J ¼ 7.11 Hz), 4.25 (q, 1H, CH, J ¼ 7.20 Hz), 6.74e6.81 (dd,
1H, CH, J1 ¼ 11.58 Hz, J2 ¼ 15.17 Hz), 7.03 (d, 2H, ArH, J ¼ 8.05 Hz), 7.13 (d, 1H,
CH, J ¼ 15.17 Hz), 7.22 (d, 2H, ArH, J ¼ 8.05 Hz), 7.34e7.37 (m, 3H, ArH), 7.48
e7.51 (m, 2H, ArH), 7.83 (d, 1H, CH, J ¼ 11.54 Hz).
416 [Mþ þ H],
438 [Mþ þ Na]
1b
1c
1757 (C]O);
1607 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.60 Hz), 1.68 (d, 3H, CH3, J ¼ 7.21 Hz), 1.73e1.80 (m, 1H,
CH), 2.24 (d, 3H, CH3, J ¼ 0.94 Hz), 2.36 (d, 2H, CH2, J ¼ 7.14 Hz), 4.24 (q, 1H, CH,
J ¼ 7.20 Hz), 7.03 (d, 2H, ArH, J ¼ 8.05 Hz), 7.08 (s, 1H, CH), 7.19 (d, 2H, ArH,
J ¼ 8.05 Hz), 7.26e7.38 (m, 5H, ArH), 7.89 (d, 1H, CH, J ¼ 0.57 Hz).
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.61 Hz), 1.68 (d, 3H, CH3, J ¼ 7.22 Hz), 1.73e1.80 (m, 1H,
CH), 2.37 (d, 2H, CH2, J ¼ 7.14 Hz), 4.24 (q, 1H, CH, J ¼ 7.18 Hz), 5.06 (s, 2H, CH2),
7.02e7.06 (m, 4H, ArH), 7,11 (d, 1H, ArH, J ¼ 7.77 Hz), 7.22 (d, 2H, ArH,
J ¼ 8.05 Hz), 7.29 (d, 1H, ArH, J ¼ 6.79 Hz), 7.32e7.38 (m, 5H, ArH), 8.06 (s, 1H,
CH).
430 [Mþ þ H],
452 [Mþ þ Na]
1734 (C]O);
1602 (C]N)
496 [Mþ þ H],
518 [Mþ þ Na]
1d
1e
1f
1727 (C]O);
1587 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.61 Hz), 1.69 (d, 3H, CH3, J ¼ 7.22 Hz), 1.73e1.80 (m, 1H,
CH), 2.36 (d, 2H, CH2, J ¼ 7.15 Hz), 4.25 (q, 1H, CH, J ¼ 7.21 Hz), 5.08 (s, 2H, CH2),
7.02e7.04 (m, 4H, ArH), 7.22 (d, 2H, ArH, J ¼ 8.03 Hz), 7.29e7.37 (m, 5H, ArH),
7.48 (d, 2H, ArH, J ¼ 8.81 Hz), 8.07 (s, 1H, CH).
496 [Mþ þ H],
518 [Mþ þ Na]
1765 (C]O);
1731 (C]O);
1597 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.61 Hz), 1.69 (d, 3H, CH3, J ¼ 7.23 Hz), 1.73e1.80 (m, 1H,
CH), 2.27 (s, 3H, CH3), 2.37 (d, 2H, CH2, J ¼ 7.14 Hz), 4.25 (q, 1H, CH, J ¼ 7.34 Hz),
7.04 (d, 2H, ArH, J ¼ 8.03 Hz), 7.21e7.23 (m, 4H, ArH), 7.54 (d, 2H, ArH,
J ¼ 8.66 Hz), 8.10 (s, 1H, CH).
448 [Mþ þ H],
470 [Mþ þ Na]
1736 (C]O);
1595 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.61 Hz), 1.70 (d, 3H, CH3, J ¼ 7.21 Hz), 1.73e1.80 (m, 1H,
CH), 2.37 (d, 2H, CH2, J ¼ 7.16 Hz), 4.26 (q, 1H, CH, J ¼ 7.15 Hz), 7.04 (d, 2H, ArH,
J ¼ 8.03 Hz), 7.23 (d, 2H, ArH, J ¼ 8.03 Hz), 7.36 (d, 1H, ArH, J ¼ 7.28 Hz), 7.43 (t,
2H, ArH, J ¼ 7.73 Hz), 7.57 (d, 2H, ArH, J ¼ 10.33 Hz), 7.59 (d, 2H, ArH,
J ¼ 11.48 Hz), 7.69 (d, 2H, ArH, J ¼ 8.37 Hz), 8.16 (s, 1H, CH).
466 [Mþ þ H],
488 [Mþ þ Na]
1g
1h
1739 (C]O);
1601 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.61 Hz), 1.70 (d, 3H, CH3, J ¼ 7.23 Hz), 1.73e1.82 (m, 1H,
CH), 2.37 (d, 2H, CH3, J ¼ 7.13 Hz), 4.27 (q, 1H, CH, J ¼ 7.22 Hz), 7.04 (d, 2H, ArH,
J ¼ 8.11 Hz), 7.23 (d, 2H, ArH, J ¼ 8.10 Hz), 7.45e7.59 (m, 3H, ArH), 7.79e7.91(m,
3H, ArH), 8.03 (s, 1H, ArH), 8.29 (s, 1H, CH).
440 [Mþ þ H],
462 [Mþ þ Na]
1729 (C]O);
1620 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.58 Hz), 1.68 (d, 3H, CH3, J ¼ 7.14 Hz), 1.71e1.80 (m, 1H,
CH), 2.36 (d, 2H, CH2, J ¼ 7.11 Hz), 4.24 (q, 1H, CH, J ¼ 7.20 Hz), 6.56 (dd, 1H,
furan ring, J1 ¼ 1.56 Hz, J2 ¼ 3.30 Hz), 6.87 (d, 1H, furan ring, J ¼ 3.54 Hz), 7.03 (d,
2H, ArH, J ¼ 7.94 Hz), 7.17e7.22 (m, 2H, ArH), 7.69 (d, 1H, furan ring,
J ¼ 1.16 Hz), 7.83 (s, 1H, CH).
380 [Mþ þ H],
402 [Mþ þ Na]
1i
1734 (C]O);
1611 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.61 Hz), 1.68 (d, 3H, CH3, J ¼ 7.23 Hz), 1.73e1.80 (m, 1H,
CH), 2.36 (d, 2H, CH2, J ¼ 7.17 Hz), 2.39 (s, 3H, CH3), 4.24 (q, 1H, CH, J ¼ 7.17 Hz),
6.20 (d, 1H, furan ring, J ¼ 4.03 Hz), 6.80 (d, 1H, furan ring, J ¼ 3.47 Hz), 7.03 (d,
2H, ArH, J ¼ 8.06 Hz), 7.22 (d, 2H, ArH, J ¼ 8.06 Hz), 7.76 (s, 1H, CH).
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.60 Hz), 1.68 (d, 3H, CH3, J ¼ 7.20 Hz), 1.73e1.80 (m, 1H,
CH), 2.36 (d, 2H, CH2, J ¼ 7.14 Hz), 4.42 (q, 1H, CH, J ¼ 7.14 Hz), 7.03 (d, 2H, ArH,
J ¼ 7.98 Hz), 7.15e7.22 (m, 3H, 2xArH, thiophene ring), 7.44 (d, 1H, thiophene
ring, J ¼ 3.64 Hz), 7.68 (d, 1H, thiophene ring, J ¼ 4.76 Hz), 8.27 (s, 1H, CH).
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.61 Hz), 1.69 (d, 3H, CH3, J ¼ 7.20 Hz), 1.73e1.80 (m, 1H,
CH), 2.36 (d, 2H, CH2, J ¼ 7.15 Hz), 2.42 (s, 3H, CH3), 4.25 (q, 1H, CH, J ¼ 7.11 Hz),
6.98 (d, 1H, CH, J ¼ 5.00 Hz), 7.03 (d, 2H, ArH, J ¼ 8.00 Hz), 7.22 (d, 2H, ArH,
J ¼ 7.98 Hz), 7.60 (d, 1H, CH, J ¼ 4.94 Hz), 8.33 (s, 1H, CH).
394 [Mþ þ H],
416 [Mþ þ Na]
1j
1727 (C]O);
1603 (C]N)
418 [Mþ þ Na]
1k
1l
1725 (C]O);
1589 (C]N)
410 [Mþ þ H],
432 [Mþ þ Na]
1715 (C]O);
1592 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.60 Hz), 1.61 (d, 3H, CH3, J ¼ 7.26 Hz), 1.73e1.79 (m, 1H,
CH), 2.37 (d, 2H, CH2, J ¼ 7.15 Hz), 3.70 (s, 3H, CH3), 4.13 (q, 1H, CH, J ¼ 7.27 Hz),
6.70 (d, 1H, thiophene ring, J ¼ 3.64 Hz), 7.02 (d, 2H, ArH, J ¼ 8.06 Hz), 7.09 (d,
2H, ArH, J ¼ 8.07 Hz), 7.24 (d, 1H, thiophene ring, J ¼ 3.65 Hz), 8.24 (s, 1H, CH).
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.60 Hz), 1.68 (d, 3H, CH3, J ¼ 7.20 Hz), 1.73e1.80 (m, 1H,
CH), 2.37 (d, 2H, CH2, J ¼ 7.16 Hz), 4.24 (q, 1H, CH, J ¼ 7.15 Hz), 7.03 (d, 2H, ArH,
J ¼ 8.00 Hz), 7.21 (d, 2H, ArH, J ¼ 8.11 Hz), 7.32 (s, 1H, thiophene ring), 7.54 (s,
1H, thiophene ring), 8.14 (s, 1H, CH).
410 [Mþ þ H]
498 [Mþ þ Na]
415 [Mþ þ Na]
1m
1n
1722 (C]O);
1601 (C]N)
1722 (C]O);
1596 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.60 Hz), 1.68 (d, 3H, CH3, J ¼ 7.22 Hz), 1.73e1.79 (m, 1H,
CH), 2.36 (d, 2H, CH2, J ¼ 7.13 Hz), 3.74 (s, 3H, CH3), 4.25 (q, 1H, CH, J ¼ 7.19 Hz),
6.30e6.32 (dd, 1H, pyrrole ring, J1 ¼ 2.51 Hz, J2 ¼ 4.16 Hz), 6.73 (d, 1H, pyrrole
ring, J ¼ 4.14 Hz), 6.90 (d, 1H, pyrrole ring, J ¼ 1.18 Hz), 7.03 (d, 2H, ArH,
J ¼ 7.96 Hz), 7.23 (d, 2H, ArH, J ¼ 8.05 Hz), 7.97 (s, 1H, CH).
1o
1722 (C]O);
1598 (C]N)
0.82 (d, 6H, 2ꢃ CH3, J ¼ 6.61 Hz), 1.70 (d, 3H, CH3, J ¼ 7.21 Hz), 1.74e1.80 (m, 1H,
CH), 2.37 (d, 2H, CH2, J ¼ 7.15 Hz), 2.70 (s, 3H, CH3), 4.26 (q, 1H, CH, J ¼ 7.04 Hz),
7.04 (d, 2H, ArH, J ¼ 8.03 Hz), 7.23 (d, 2H, ArH, J ¼ 8.04 Hz), 7.36e7.44 (m, 2H,
indole ring), 7.74 (d, 1H, indole ring, J ¼ 7.14 Hz), 7.75 (s, 1H, indole ring), 8.34 (s,
1H, CH), 8.37 (d, 1H, indole ring, J ¼ 8.12 Hz).
493 [Mþ þ Na]
side effects are thought to result from the inhibition of COX-1.
COX-2-specific inhibition was expected to preserve effective
anti-inflammatory activity while causing little or no associated GI
toxicity. Therefore, test compounds showing a lower ulcerogenic
risk suggest the possibility of high selectivity on COX-2 enzyme
over COX-1.
It is well known that quantumechemical methods and molec-
ular modeling techniques enable the definition of a large number of
molecular and local quantities characterizing the reactivity, shape
and binding properties of a complete molecule, as well as of
molecular fragments and substituents. The electrophilicity index
(u) is one of the calculated quantum chemical descriptors and
Please cite this article in press as: A. Uzgören-Baran, et al., Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-
steroidal anti-inflammatory agents with favorable gastrointestinal tolerance, European Journal of Medicinal Chemistry (2012), http://
dx.doi.org/10.1016/j.ejmech.2012.07.009

6
A. Uzgören-Baran et al. / European Journal of Medicinal Chemistry xxx (2012) 1e9
Table 3
The APT 13C data of representative carbon atoms of the compounds 1ae1o.
Compounds
APT-NMR (CDCl3, d (ppm))
10
20
30
40
50
2
5
6
7a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
40.15
40.17
40.17
40.17
40.17
40.19
40.19
40.16
40.15
40.17
40.16
38.00
40.17
40.14
40.19
22.41
22.42
22.41
22.41
22.41
22.42
22.41
22.40
22.42
22.40
22.41
22.35
22.41
22.42
22.41
45.07
45.07
45.07
45.07
45.07
45.08
45.08
45.08
45.07
45.07
45.07
44.99
45.06
45.07
45.07
30.16
30.17
30.16
30.16
30.16
30.17
30.16
30.14
30.17
30.14
30.16
30.17
30.16
30.17
30.18
19.78
19.86
19.82
19.84
19.78
19.81
19.84
19.84
19.93
19.82
19.85
20.17
19.77
19.88
19.85
155.89
156.58
156.19
156.60
156.17
156.33
156.27
156.35
156.60
156.26
156.55
149.60
155.84
156.92
155.85
176.29
176.35
176,60
176.35
140.48
140.46
140.51
140.47
140.54
140.53
140.51
140.44
140.40
140.47
140.45
140.93
140.56
140.41
140.54
158.80
159.96
159.32
159.73
159.74
159.83
159.89
160.63
160.59
159.14
159.30
166.22
158.83
159.09
158.36
176.65
176.58
176.56
176.39
176.15
176.47
176.31
166.79
176.75
175.94
176.58
defines a quantitative classification of the global electrophilic
nature of a molecule within a relative scale [29]. According to the
electrophilicity index generated using the semiempirical PM3
method basis sets from the Gaussian 03 package, the compounds
1a, 1f and 1n displayed an enormous similarity to selective COX-2
inhibitors celecoxib and rofecoxib (Table 4). The possibility that
these compounds would be selective COX-2 inhibitors will be
investigated in future studies.
ibuprofen and/or the selective inhibition of the COX-2 enzyme.
Therefore, it was concluded that thiazolo[3,2-b]triazol derivatives
of ibuprofen might provide a safer alternative to ibuprofen for the
treatment of inflammatory disease and pain.
6. Experimental protocol
6.1. Chemistry
Ibuprofen was supplied by Atabay Pharmaceuticals (Istanbul,
Turkey). All chemicals were from Aldrich Chemical Co. (Steinheim,
Germany). Melting points were measured in sealed tubes using an
electrothermal digital melting point apparatus (Gallenkamp) and
are uncorrected (London, UK). IR spectra (KBr) were recorded on
a Perkin Elmer spectrumOne, Nicolet 520 FTIR spectrometer
(PerkineElmer, USA). APT 13C and 1H NMR spectra were obtained
by a Bruker instrument DPX-400, 400 MHz High Performance
Digital FTeNMR Spectrometer (Bruker, Fällanden, Switzerland)
4.4. Acute toxicity
In the acute toxicity study, mortality was not observed in either
the 50 mg/kg or 100 mg/kg doses. During the 14-day observation
period, animals showed no weight loss, no behavioral alteration or
toxicity signs at any of the dose levels tested. However, indo-
methacin at a 50 mg/kg dose caused mortality for six of seven mice
(86%) in the first 12 h of observation.
5. Conclusion
In conclusion, a series of 6-substituted thiazolo[3,2-b]-1,2,4-
triazole-5(6H)-one derivatives of ibuprofen were prepared with
the objective of developing better analgesic/anti-inflammatory
molecules with minimum ulcerogenic risk. Although it is not
possible to draw an exact conclusion according to the results of
in vivo experiments, which substituent at the 6th position is more
active, it could be claimed that the condensing of (ꢀ)-3-[1-(4-(2-
methylpropyl)phenyl)ethyl]-1,2,4-triazole-5-thione (1) with a thia-
zole ring provides a superior result in both analgesic and anti-
inflammatory activity. As a general consideration, in accordance
with previous results, the incorporation of the free carboxylic acid
group of ibuprofen into thiazolo[3,2-b]-1,2,4-triazole provides
a
simple strategy for generating much safer analgesic/anti-
Fig. 1. The anti-inflammatory activity results of the compounds 1e1o, ibuprofen (Ibu)
and oxycodone (Oxc) at 50 mg/kg (,) and 100 mg/kg (-); indomethacin (Indo) at
10 mg/kg ( ) and 50 mg/kg (,) doses. *p < 0.01 vs ibuprofen, xp < 0.05 vs ibuprofen;
data expressed as mean ꢀ SEM, one-way ANOVA followed by post hoc Dunnett’s test,
n ¼ 7 per group.
inflammatory compounds when compared with ibuprofen (50
and 100 mg/kg) and indomethacin (10 and 50 mg/kg). It is likely
that the marked reduction of gastrointestinal toxicity of the
molecules is due to the masking of the free carboxylic acid group of
Please cite this article in press as: A. Uzgören-Baran, et al., Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-
steroidal anti-inflammatory agents with favorable gastrointestinal tolerance, European Journal of Medicinal Chemistry (2012), http://
dx.doi.org/10.1016/j.ejmech.2012.07.009

A. Uzgören-Baran et al. / European Journal of Medicinal Chemistry xxx (2012) 1e9
7
Fig. 4. The ulcerogenic scores of the compounds 1e1o, ibuprofen (Ibu) and oxycodone
Fig. 2. The analgesic activity results of the tail-flick experiment for compounds 1e1o,
ibuprofen (Ibu) and oxycodone (Oxc) at 50 mg/kg (,) and 100 mg/kg (-) doses.
*p < 0.01 vs vehicle control group; xp < 0.05 vs vehicle control group; þp < 0.01 vs
ibuprofen; zp < 0.05 vs ibuprofen; data expressed as mean ꢀ SEM, one-way ANOVA
followed by post hoc Dunnett’s test, n ¼ 7 per group.
(Oxc) at 50 mg/kg (,) and 100 mg/kg (-) doses; indomethacin (Indo) at 10 mg/kg (
)
and 50 mg/kg (,). *p < 0.01 vs vehicle control; xp < 0.05 vs vehicle control; þp < 0.01
vs ibuprofen; data expressed as mean ꢀ SEM, KruskaleWallis test followed by post hoc
Dunn’s test, n ¼ 7 per group.
using DMSO-d6 and tetramethylsilane as an internal standard. All
consumption of the starting material. After completion of the
reaction, the reaction mixture was poured on ice, and the crude
precipitate was filtered and dissolved in dichloromethane and
washed with a sodium bicarbonate and saturated sodium chloride
solution, respectively. The organic layer was evaporated to dryness
and the crude product then recrystallized from methanol [20e22].
The characterization data of synthesized novel 6-substituted
thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones are given in Tables 1e3.
chemical shift values were recorded as
compounds was controlled by thin layer chromatography on silica
gel-coated aluminum sheets (Merck, 1.005554, silicagel HF254e361
d (ppm). The purity of the
,
Type 60, 0.25 mm, Darmstadt, Germany). Mass spectra were
obtained with the positive ion electrospray technique using
a Micromass ZQ MS Spektrometer and MassLynx 4.1 software
(Manchester, UK). The elementary analysis of the compounds was
performed on a Leco CHNS 932 analyzer (Philadelphia, USA) at the
Central Instrumental Analysis Laboratory of Ankara University,
Faculty of Pharmacy. Elementary analysis for C, H, N and S were
within ꢀ0.4% of theoretical values.
6.2. Computations
All structures were drawn and optimized using Gaussian 03
software with the semiempirical PM3 method to calculate elec-
trophilicity index (u).
6.1.1. General procedures
6.1.1.1. Synthesis of (ꢀ)-3-[1-(4-(2-methylpropyl)phenyl)ethyl]-1,2,4-
triazole-5-thione (1). The compound (1) was prepared to the
method reported earlier [20].
6.3. Pharmacology
6.3.1. Animals
6.1.1.2. Synthesis of 6-substituted thiazolo [3,2-b]-1,2,4-triazole-
Swiss albino mice of both sexes, weighing 20e35 g, were housed
at a room temperature of 22 ꢂC with a 12/12 h light/dark cycle. All
animal procedures were conducted in accordance with the insti-
tutional guidelines for care and use of laboratory animals, and were
approved by the Hacettepe University Animal Ethics Committee
(2008/21-5). Animals were kept for one week to acclimatize to
laboratory conditions before starting the experiment. Twelve hours
before experiments, animals received only water, in order to avoid
food interference with substance absorption. Animals were divided
into groups (n ¼ 7), and two doses of the test compounds in 0.5%
carboxymethyl cellulose (CMC) solution (50 and 100 mg/kg) were
intragastrically administered to the test groups. The control group
received the vehicle control (0.5% CMC solution only) and ibuprofen
(Ibu, 50 and 100 mg/kg, p.o.) as the reference drug, respectively.
Oxycodone (Oxc, 50 and 100 mg/kg, p.o.) was used in the analgesic
tests as an opioid reference drug. Also, indomethacin (Indo, 10 mg/
kg and 50 mg/kg) was used as an additional reference drug in
determining gastric side effects.
5(6H)-ones (1ae1o). The equimolar amounts of (ꢀ)-3-[1-(4-(2-
methylpropyl)phenyl)ethyl]-1,2,4-triazole-5-thione
(1),
the
corresponding aldehyde, chloroacetic acid and sodium acetate
were added to 6 ml of acetic acid and 8 ml of acetic anhydride.
Reaction time was determined by TLC-monitoring the
6.3.2. Carrageenan-induced paw edema test
The synthesized compounds were evaluated by carrageenan-
induced paw edema described by Winter et al. [25] with modifi-
cations. The synthesized compounds (50 and 100 mg/kg) were
compared with the vehicle control and reference ibuprofen (50 and
100 mg/kg). Edema was induced by injecting 0.01 ml of a 2%
carrageenan suspension into the subplantar region of the right
Fig. 3. The analgesic activity results of the hot plate experiment for the compounds
1e1o, ibuprofen (Ibu) and oxycodone (Oxc) at 50 mg/kg (,) and 100 mg/kg (-) doses.
*p < 0.01 vs vehicle control group; xp < 0.05 vs vehicle control group; þp < 0.01 vs
ibuprofen; zp < 0.05 vs ibuprofen; data expressed as mean ꢀ SEM, one-way ANOVA
followed by post hoc Dunnett’s test, n ¼ 7 per group.
Please cite this article in press as: A. Uzgören-Baran, et al., Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-
steroidal anti-inflammatory agents with favorable gastrointestinal tolerance, European Journal of Medicinal Chemistry (2012), http://
dx.doi.org/10.1016/j.ejmech.2012.07.009

8
A. Uzgören-Baran et al. / European Journal of Medicinal Chemistry xxx (2012) 1e9
Table 4
Calculated electrophilicity values (
u
) for compounds.
1f
1.926
Compounds
1a
1n
Ibuprofen
1.183
Indomethacin
1.368
Celecoxib
1.938
Rofecoxib
1.840
u
1.898
1.775
hind-paw of the mice with a Hamilton injector. The carregeenan
injection was applied 1 h after the gavage. The thickness of the
paws was measured by a dial thickness gauge (0.01e1 mm, Ozaki
Co., Japan) immediately before (T0) and 2 h (Tt) after the injection.
The edema was calculated as the increase in thickness (mm) of the
paw after treatment subtracted from the basal volume
scored according to their number and size in a scale from 0 up to 7
points, adapted from Magistretti et al. [28] as follows: (0) without
injury, (1) color modification, (2) few petechia/alterations of villous,
(3) 1e3 small injuries (ꢄ1 mm length), (4) 1e3 large injuries
(ꢄ1 mm length), (5) 1e3 large injuries (>1 mm), (6) more than
three small injuries, (7) more than three large injuries or massive
bleeding or digested blood in stomach.
(DT ¼ Tt ꢁ T0). For each animal, the anti-inflammatory effect of the
drugs was expressed as a percentage of edema inhibition [30].
Inhibition (%) ¼ [(Control
6.3.3. Tail-flick test
D
T ꢁ Test
D
T)/Control
D
T] ꢃ 100.
6.3.6. Acute toxicity study
Test compounds, vehicle control (CMC), reference drugs
(ibuprofen, oxycodone) in 50 mg/kg and 100 mg/kg doses, were
administered orally in 0.5% CMC. Indomethacin was tested at
a 50 mg/kg dose. However, indomethacin at a 50 mg/kg dose
caused high mortality in the first 12 h of observation, therefore, the
dose was lowered to 10 mg/kg. The animals were observed
continuously for 6 h after treatment, then intermittently for 72 h,
and thereafter for over a period of 14 days after administration [32]
for behavioral changes, signs of toxicity and/or death.
For the tail-flick test, an automated tail-flick apparatus (TF 0703,
8 V/50 W Tail-flick Commat Ltd.-Ankara) was used, which elicited
a response by applying radiant heat to the dorsal surface of the tail.
For the experiment, each mouse was gently held and an automatic
timer measured latency until the mouse flicked its tail away from
the source of the light. The heat stimulus was set to provide a pre-
drug tail-flick response time of 6e8 s. The cut-off time for the heat
stimulus was set at 15 s to avoid tissue damage [26,31]. After the
baseline readings (T0) were taken, the mice were treated with CMC
as a control, oxycodone or ibuprofen as reference drugs, or the test
compounds of 50 or 100 mg/kg doses. Response latencies (T1) were
measured 2 h after the application of drugs or vehicle. The analgesic
activity was calculated as the percentage maximum possible effect
(MPE) using the following formula:
6.3.7. Statistical analysis of data
All data are expressed as mean ꢀ SEM. Results of carrageenan-
induced paw edema experiments are also expressed as
a percentage of change from control (pre-drug) values. Differences
between vehicle control, reference drugs and treatment groups
were tested using a one-way analysis of variance (ANOVA) followed
by a post hoc Dunnett’s test. Ulcer scores were analyzed using the
KruskaleWallis test followed by a post hoc Dunn’s test.
%MPE ¼ (T1 ꢁ T0)/(T2 ꢁ T0) ꢃ 100, where the cut-off time (T2)
was 15 s.
6.3.4. Hot plate test
Conflict of interest
For determination of antinociceptive activity, a conventional hot
plate test was performed according to the method of Eddy and
Leimbach [27]. Mice (n ¼ 7) were placed individually on a hot plate
(9601 Analgesic Hot Plate Commat Ltd.-Ankara) set at 50 ꢀ 0.5 ꢂC
and a plexiglass cylinder (12 cm diameter, 20 cm height) was used
to confine the mouse on the heated surface of the plate. The time of
licking the forepaws or jump response (whichever appears first)
were recorded as an index of nociception. Only mice that showed
a nociceptive response within 25 s were used in the experiment.
Maximum cut-off time was chosen as 25 s to avoid tissue damage.
After the baseline readings (T0) were taken, the mice were treated
with CMC as a control, oxycodone or ibuprofen as reference drugs
or the test compounds of 50 or 100 mg/kg doses. Response latencies
(T1) were measured 2 h after the application of the drugs or vehicle.
The effects of the compounds on nociception were determined by
the percentage of maximal possible effect (%MPE) was calculated as
below:
Additionally, the authors have declared no conflict of interest.
Acknowledgments
This study is supported by a grant from Hacettepe University
Research Center (Project no: 04A601005). The authors gratefully
thank Allison Block (Nova Translation Ltd.) for her editing work,
Tugba Taskin-Tok for her computational study.
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Please cite this article in press as: A. Uzgören-Baran, et al., Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: Novel non-
steroidal anti-inflammatory agents with favorable gastrointestinal tolerance, European Journal of Medicinal Chemistry (2012), http://
dx.doi.org/10.1016/j.ejmech.2012.07.009