Non-carboxylic analogues of arylpropionic acids: Synthesis, anti-inflammatory activity and ulcerogenic potential

Article abstract of DOI:10.1016/j.ejmech.2006.09.001

Two series of 1,2,4-triazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles derived from three selected arylpropionic acids namely, ibuprofen, flurbiprofen and naproxen, were synthesized and evaluated for anti-inflammatory activity and ulcerogenic potentia

Full text of DOI:10.1016/j.ejmech.2006.09.001

European Journal of Medicinal Chemistry 42 (2007) 152e160
http://www.elsevier.com/locate/ejmech
Original article
Non-carboxylic analogues of arylpropionic acids: Synthesis,
anti-inflammatory activity and ulcerogenic potential
a,*
a
Kamel A. Metwally , Shada H. Yaseen , El-Sayed M. Lashine ,
a
b
Hassan M. El-Fayomi , Mohamed E. El-Sadek
a
a
Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
b
Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
Received 28 March 2006; received in revised form 19 August 2006; accepted 4 September 2006
Available online 17 October 2006
Abstract
Two series of 1,2,4-triazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles derived from three selected arylpropionic acids namely, ibuprofen,
flurbiprofen and naproxen, were synthesized and evaluated for anti-inflammatory activity and ulcerogenic potential. All the tested compounds
exhibited anti-inflammatory activity comparable to that of hydrocortisone. Compared to ibuprofen, however, all the tested compounds dis-
played more potent anti-inflammatory activity. Compounds tested for ulcerogenicity showed no or minimal ulcerogenic effect compared
to indomethacin.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: Arylpropionic acids; Anti-inflammatory; Ulcerogenicity
1
. Introduction
COX-2 inhibitors is instrumental for combating inflammation
without the harmful side effects of the presently available
NSAIDs.
In the early 1990s, it was discovered that the cyclooxyge-
nase enzyme (COX) which is the key enzyme in the biosynthe-
sis of prostaglandins from arachidonic acid, exists as two
isoforms, one constitutive (COX-1) and the other inducible
The discovery of COX-2 provided the rationale for the de-
sign of drugs devoid of GI disorders while retaining clinical
efficacy as anti-inflammatory agents. Understanding the rela-
tionship between chemical structure and enzyme activity is
crucial in the design of new COX-2 selective inhibitors.
COX-1 and COX-2 have similar structures yet a few differ-
ences do exist. Of particular importance, substitution at posi-
tion 523 between isoleucine (in COX-1) and the relatively
smaller valine (in COX-2) creates extra space in the active
site of COX-2 recognized as the COX-2 side pocket at which
celecoxib, rofecoxib and related drugs appear to act. Addi-
tional exchange of valine/isoleucine at position 434 further in-
creases the effective size of the active site channel by
enhancing the mobility of side chains within the side pocket.
The final result of these differences is about 20% increase in
the active site of COX-2 compared to COX-1. In the light of these
findings, it could be speculated that arylpropionic acids act
non-selectively probably because of their relatively small
(
COX-2) [1]. COX-1 is constitutively expressed and provides
cytoprotection in the GIT while COX-2 is inducible and medi-
ates inflammation [2e4]. The traditional NSAIDs in current
use non-selectively inhibit COX-1 and COX-2. In fact, most
NSAIDs show greater selectivity for COX-1 than COX-2
[
5]. Consequently, long-term therapy with non-selective
NSAIDs may cause appreciable GI irritation, bleeding and ul-
ceration [6]. These clinical shortcomings comprise a major
challenge confronting medicinal chemists to develop safer
agents that spare COX-1 and subsequently its gastric cytopro-
tective role. In other words, the development of selective
*
Corresponding author. Tel.: þ20 5523 08021; fax: þ20 5523 03266.
E-mail address: kametwally@hotmail.com (K.A. Metwally).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.09.001

K.A. Metwally et al. / European Journal of Medicinal Chemistry 42 (2007) 152e160
153
size tolerated by both COX-1 and COX-2. It appears that bulk-
ier structures are more likely to confer selectivity to COX-2
due to its wider active site [7e9].
It has been reported that modification of the carboxyl func-
tion of representative NSAIDs results in retained anti-inflam-
matory activity with reduced ulcerogenic potential [10e14].
In addition, 1,2,4-triazoles [15e23] particularly 1,2,4-tria-
zole-5-thiols and their condensed heterocyclic derivatives
revealed the presence of two downfield D O-exchangeable
2
singlets characteristic of the two NH groups. The arylamino
NH group showed absorption in the range of d 8.75e9.38
whereas the absorption peak of the triazole NH group ap-
peared more downfield in the range of d 12.81e13.10 consis-
1
tent with H NMR spectra of similar triazoles reported in the
literature [36]. Furthermore, mass fragmentation pattern of
compound (6a) was consistent with that reported for similar
5-arylamino-1,2,4-triazoles [36].
[
24e28] particularly 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles
have been reported to possess anti-inflammatory activity. In
the present investigation, we were interested in replacing the
carboxyl function of three well-known arylpropionic acids,
namely ibuprofen, flurbiprofen and naproxen, by selected
bulkier moieties with the aim of improving the safety profile
of these agents while retaining anti-inflammatory activity.
The synthetically accessible 4-amino-5-mercapto-3-
substituted s-triazoles (8aec) were utilized as key intermedi-
ates for the synthesis of the target 1,2,4-triazolo[3,4-b]-1,3,
4-thiadiazoles (9aec) and (10aef). The Reid and Heindel pro-
cedure [37] was adopted to prepare these intermediates. The
acid hydrazides (5aec) were allowed to react with carbon di-
sulphide in the presence of KOH at room temperature to afford
the corresponding aroyldithiocarbazates as the potassium salts
2
. Chemistry
(7aec) which were subsequently converted to the required 4-
Following reported procedures [29e32], heating ammo-
nium thiocyanate and benzoyl chloride in dry acetone afforded
benzoylisothiocyanate which was treated with substituted ani-
amino-5-mercapto-s-triazoles (8aec) through direct hydrazi-
nolysis with hydrazine hydrate in ethanol as outlined in
Scheme 3. Physical constants of (8aec) are shown in Table 2.
The structure of the synthesized 4-amino-5-mercapto-1,2,4-
0
lines in dry acetone to give N-benzoyl-N -arylthioureas (1aeh)
0
1
as illustrated in Scheme 1. The resulting N-benzoyl-N -arylth-
triazoles (8aec) was confirmed by H NMR spectral data and
O-
1
microanalysis. H NMR spectra showed a downfield D
ioureas were cleaved by means of aqueous NaOH to yield the
corresponding arylthioureas (2aeh) which were subsequently
methylated using methyl iodide in methanol or acetone to af-
ford the requisite aryl-S-methylisothiouronium iodides (3aeh)
in good yields.
On the other hand, the required hydrazides were prepared
according to reported procedures [33e35]. The arylpropionic
acid was esterified with ethanol in the presence of sulphuric acid
to give the corresponding esters (4aec). Reaction of the result-
ing esters with hydrazine hydrate in ethanol produced the
corresponding acid hydrazides (5aec) which were refluxed
with aryl-S-methylisothiouronium iodides (3aeh) in dry pyri-
dine to afford the target 6-arylamino-4H-1,2,4-triazoles (6ae
x) as shown in Scheme 2. Physical constants of (6aex) are
given in Table 1.
2
exchangeable singlet at d 13.53 attributed to the thiol group
while the amino group appeared at d 5.39 as a singlet that
was also exchangeable by D O. Reaction of the intermediate
2
4-amino-5-mercapto-1,2,4-triazoles (8aec) with carbon disul-
phide in ethanolic KOH under reflux conditions afforded the
target 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole-6-thiols (9aec)
1
in good yields (Table 3). H NMR spectral data of compound
(9b) showed a characteristic D O-exchangeable singlet at
2
d 13.61 corresponding to the 6-thiol group.
Finally, the target 6-aryl-1,2,4-triazolo[3,4-b]-1,3,4-thiadia-
zoles (10aef) were obtained in low yields through treatment
of 4-amino-5-mercapto-1,2,4-triazoles (8a,b) with benzoyl
chloride or p-substituted derivatives in phosphorous oxychlor-
ide as illustrated in Scheme 3. Our attempts to improve the
yield as well as attempts to obtain these particular products
The chemical structure of the target triazoles was confirmed
1
by IR, H NMR and mass spectral data and microanalysis. IR
1
from naproxen hydrazide were unsuccessful. H NMR spectra
revealed the absence of D O-exchangeable protons and all the
2
spectra showed the appearance of characteristic absorption
ꢀ
1
bands at w 3200 and w 3300 cm corresponding to the tria-
zole NH groups. H NMR spectra of selected triazoles
target compounds were microanalyzed satisfactorily. In addi-
tion, mass fragmentation pattern of compound (10d) was
1
S
R
NH
O
(
a)
(
b)
COCl
CONCS
NH
(
1a-h)
(
c)
H CS
S
3
I
R
NH2
R
NH2
(d)
NH
3a-h)
NH
(
(2a-h)
4 3
Scheme 1. Reagents and conditions: (a) NH SCN, acetone, reflux. (b) Substituted anilines, acetone, reflux. (c) Aqueous NaOH, reflux. (d) CH I, acetone or meth-
anol, room temperature.

154
K.A. Metwally et al. / European Journal of Medicinal Chemistry 42 (2007) 152e160
5. Experimental protocols
(
a)
(b)
Ar
Ar
Ar
COOH
CONHNH2
(5a-c)
COOEt
4a-c)
5.1. Chemistry
(
(
c)
Melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. IR spectra were recorded
1
on a Bruker FT-IR spectrophotometer using KBr pellets. H
R
N
N
Ar
N
H
N
H
NMR spectra were recorded on a Varian-Gemini 200 MHz
spectrometer in DMSO-d . Chemical shifts were expressed
6
(
6a-x)
in parts per million with tetramethylsilane (TMS) as an inter-
nal standard. MS spectra were measured with Shimadzu GC
MS-QP instrument. Elemental analyses (C, H, N) were per-
formed at the National Research Centre, Cairo, Egypt. Com-
pounds (1aeh) [29,31,32], (2aeh) [29], (3aeh) [30], (4aec)
[33e35] and (5aec) [33e35] were synthesized according to
literature procedures.
Scheme 2. Reagents and conditions: (a) EtOH, H
NH NH $H O, EtOH, reflux. (c) (3aeh), pyridine, reflux.
2
4
SO ,
reflux. (b)
2
2
2
consistent with that reported for similar 6-aryl-1,2,4-tria-
zolo[3,4-b]-1,3,4-thiadiazoles [38]. Physical constants of
(
10aef) are summarized in Table 4.
5
1
.1.1. 3-Arylamino-5-[1-(4-isobutylphenyl)ethyl]-(4H )-
,2,4-triazoles (6aeh)
A mixture of the appropriate aryl-S-methylisothiouronium
3
. Results and discussion
The anti-inflammatory activity of the target compounds
6c), (6d), (6k), (6l), (6s), (6t), (9a) and (10f) was evaluated
iodide (3aeh; 10 mmol) and 2-methyl-2-(4-isobutylphenyl)
acetic acid hydrazide (5a; 10 mmol) in pyridine (10 mL)
was heated at reflux for 2 h. The cooled mixture was poured
into crushed ice and extracted with CH Cl (2 ꢁ 50 mL). The
(
by applying the carrageenan-induced rat paw edema bioassay
in rats following the method of Winter et al. [39]. Ibuprofen
was used as a reference substance in the assay. For comparison
purposes, hydrocortisone was additionally used as a second
reference standard representing steroidal anti-inflammatory
agents. The obtained pharmacological results revealed that
the 1,2,4-triazoles (6c), (6d), (6k), (6l), (6s) and (6t) are
more active than the 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles
represented by (9a) and (10f) as shown in Table 5. All the
tested compounds, however, were found more potent than ibu-
profen. In comparison to hydrocortisone, all the test com-
pounds showed comparable anti-inflammatory activity (Figs.
2
2
organic extract was washed with 5% NaHCO , brine and wa-
3
ter, dried with anhydrous Na SO and evaporated under re-
2
duced pressure. The crude products were purified by
recrystallization from DMF/H O. IR of compound (6a)
4
2
ꢀ1
1
KBr, cm ): 3296, 3199 (NH). H NMR of compound
(
(
(
6a) (DMSO-d ) d: 0.82 (d, 6H, J ¼ 6.6 Hz, 2CH ), 1.56
6
3
d, 3H, J ¼ 7.2 Hz, CH ), 1.74e1.83 (m, 1H, CH), 2.38 (d,
3
2
6
7
H, J ¼ 7.2 Hz, CH ), 4.16 (q, 1H, J ¼ 7.2 Hz, CH), 6.74e
2
.77 (m, 1H, AreH), 7.07 (d, 2H, J ¼ 7.8 Hz, AreH),
.15e7.25 (m, 4H, AreH), 7.47 (d, 2H, J ¼ 7.5 Hz, Are
1
e4). The triazole (6s) displayed the highest anti-inflamma-
H), 9.02 (s, 1H, NH), 12.92 (s, 1H, NH). MS of compound
tory activity among the set of compounds tested in the present
study.
Test compounds that exhibited the most potent anti-inflam-
matory activity namely, the triazoles (6d), (6k), (6l) and (6s)
were further evaluated for their ulcerogenic potential in rats
[40]. In general, the tested compounds showed a better GI
safety profile (0e33.3% ulceration) compared to indomethacin
as illustrated in Table 6.
þ
1
6a): (m/z) 320 (M , base peak). H NMR of compound
(
(
(
6b) (DMSO-d ) d: 0.82 (d, 6H, J ¼ 6.6 Hz, 2CH ), 1.57
6
3
d, 3H, J ¼ 7.2 Hz, CH ), 1.82e1.86 (m, 1H, CH), 2.38 (d,
3
2
H, J ¼ 7.2 Hz, CH ), 4.15 (q, 1H, CH), 7.08 (d, 2H,
2
J ¼ 7.8 Hz, AreH), 7.19e7.23 (m, 4H, AreH), 7.50 (d,
2
H, J ¼ 9.0 Hz, AreH), 9.25 (s, 1H, NH, D O exchange-
2
1
able), 12.98 (s, 1H, NH, D O exchangeable). H NMR of
2
compound (6f) (DMSO-d ) d: 0.83 (d, 6H, J ¼ 6.6 Hz,
6
2
CH ), 1.57 (d, 3H, J ¼ 6.9 Hz, CH ), 1.76e1.81 (m, 1H,
3
3
CH), 2.38 (d, 2H, J ¼ 7.2 Hz, CH ), 4.16 (q, 1H, CH),
2
4
. Conclusion
6.99e7.10 (m, 4H, AreH), 7.19 (d, 2H, J ¼ 8.1 Hz, Are
H), 7.47e7.52 (m, 2H, AreH), 9.06 (s, 1H, NH, D O ex-
2
1
It could be concluded that replacement of the carboxyl
changeable), 12.91 (s, 1H, NH, D O exchangeable). H
NMR of compound (6g) (DMSO-d ) d: 0.82 (d, 6H,
2
function of arylalkanoic acids by certain bulkier moieties gen-
erally improves their pharmacological profile. It was interest-
ing to note that all the non-carboxylic test compounds were
found to have anti-inflammatory activity greater than that of
ibuprofen. More interestingly, some of the test compounds
were more potent than hydrocortisone. In addition, compounds
tested for ulcerogenicity showed no or minimal ulcerogenic ef-
fects in rats.
6
J ¼ 6.6 Hz, 2CH ), 1.56 (d, 3H, J ¼ 7.2 Hz, CH ), 1.77e
3
3
1.82 (m, 1H, CH), 2.19 (s, 3H, CH ), 2.38 (d, 2H,
3
J ¼ 6.9 Hz, CH ), 4.18 (q, 1H, J ¼ 7.2 Hz, CH), 6.96 (d,
2
2H, J ¼ 8.4 Hz, AreH), 7.07 (d, 2H, J ¼ 8.1 Hz, AreH),
7.19 (d, 2H, J ¼ 7.8 Hz, AreH), 7.37 (d, 2H, J ¼ 8.4 Hz,
1
3
AreH), 8.86 (s, 1H, NH), 12.85 (s, 1H, NH). C NMR
(DMSO-d ) d: 20.00, 20.25, 21.94 (2C), 29.30, 36.81,
6

K.A. Metwally et al. / European Journal of Medicinal Chemistry 42 (2007) 152e160
155
Table 1
Physical constants of 3-arylamino-5-(1-substituted-ethyl)-4H-1,2,4-triazoles (6aex)
R
N
N
Ar
N
N
H
H
ꢂ
Compound
R
H
Ar
Yield (%)
75
M.P. ( C)
Formula
Analysis (%)
Calcd
Found
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
4-Isobutylphenyl
162e165
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
20
H
20
H
20
H
20
H
20
H
20
H
21
H
21
H
22
H
22
H
22
H
22
H
22
H
22
H
23
H
23
H
21
H
21
H
24
N
4
C ¼ 74.97
H ¼ 7.55
N ¼ 17.48
C ¼ 67.69
H ¼ 6.53
N ¼ 15.79
C ¼ 67.69
H ¼ 6.53
N ¼ 15.79
C ¼ 60.16
H ¼ 5.81
N ¼ 14.03
C ¼ 60.16
H ¼ 5.81
N ¼ 14.03
C ¼ 70.98
H ¼ 6.85
N ¼ 16.56
C ¼ 75.41
H ¼ 7.84
N ¼ 16.75
C ¼ 71.97
H ¼ 7.48
N ¼ 15.99
C ¼ 73.72
H ¼ 5.34
N ¼ 15.63
C ¼ 67.26
H ¼ 4.62
N ¼ 14.26
C ¼ 67.26
H ¼ 4.62
N ¼ 14.26
C ¼ 60.42
H ¼ 4.15
N ¼ 12.81
C ¼ 60.42
H ¼ 4.15
N ¼ 12.81
C ¼ 70.20
H ¼ 4.82
N ¼ 14.88
C ¼ 74.17
H ¼ 5.68
N ¼ 15.04
C ¼ 71.12
H ¼ 5.45
N ¼ 14.42
C ¼ 73.23
H ¼ 5.85
N ¼ 16.27
C ¼ 66.58
H ¼ 5.05
N ¼ 14.79
75.29
8.05
17.27
67.32
6.88
4-Cl
3-Cl
4-Br
3-Br
4-F
4-Isobutylphenyl
4-Isobutylphenyl
4-Isobutylphenyl
4-Isobutylphenyl
4-Isobutylphenyl
4-Isobutylphenyl
4-Isobutylphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
6-Methoxynaphthyl
6-Methoxynaphthyl
71
72
68
70
67
73
72
75
71
72
68
70
67
73
72
75
71
182e184
152e153
186e188
137e138
169e171
186e188
180e182
201e202
219e220
138e140
222e224
156e157
183e184
177e179
167e169
213e215
217e218
23ClN
4
4
15.54
68.02
6.55
23ClN
16.03
60.15
5.92
23BrN
4
4
14.03
60.06
5.81
23BrN
14.23
70.56
7.06
23FN
4
16.09
75.65
8.13
g
h
i
4-CH
3
26
N
N
4
4
16.59
71.55
7.70
4-OCH
3
26
O
15.60
73.78
5.18
H
19FN
4
15.28
67.17
4.59
j
4-Cl
3-Cl
4-Br
3-Br
4-F
18ClFN
4
4
14.15
67.06
4.64
k
l
18ClFN
14.42
60.62
4.35
18BrFN
4
4
13.00
60.43
4.68
m
n
o
p
q
r
18BrFN
12.76
69.87
4.65
18 2 4
F N
15.18
74.04
5.96
4-CH
3
21FN
4
4
14.54
71.00
5.61
4-OCH
3
21FN
O
14.02
73.50
5.71
H
20 4
N O
16.03
66.71
5.15
4-Cl
4
19ClN O
14.74
(continued on next page)

156
K.A. Metwally et al. / European Journal of Medicinal Chemistry 42 (2007) 152e160
Table 1 (continued)
ꢂ
Compound
R
Ar
Yield (%)
72
M.P. ( C)
Formula
Analysis (%)
Calcd
Found
6
6
6
6
6
6
s
3-Cl
6-Methoxynaphthyl
194e195
C
C
C
C
C
C
21
H
21
H
21
H
21
H
22
H
22
H
19ClN
4
O
C ¼ 66.58
H ¼ 5.05
N ¼ 14.79
C ¼ 59.59
H ¼ 4.52
N ¼ 13.24
C ¼ 59.59
H ¼ 4.52
N ¼ 13.24
C ¼ 69.60
H ¼ 5.28
N ¼ 15.46
C ¼ 73.72
H ¼ 6.19
N ¼ 15.63
C ¼ 70.57
H ¼ 5.92
N ¼ 14.96
66.41
5.41
14.77
59.69
4.12
t
4-Br
3-Br
4-F
6-Methoxynaphthyl
6-Methoxynaphthyl
6-Methoxynaphthyl
6-Methoxynaphthyl
6-Methoxynaphthyl
68
70
67
73
72
229e230
139e140
180e182
190e191
217e218
19BrN
4
O
O
13.04
59.90
4.94
u
v
w
x
19BrN
4
13.24
70.00
5.57
4
19FN O
15.58
73.85
6.63
4-CH
3
22
N
N
4
O
O
15.19
70.37
6.26
4-OCH
3
22
4
2
15.46
4
1
4.06, 115.60 (2C), 115.70, 120.44, 126.66 (2C), 127.20,
1
CH ), 4.25 (q, 1H, CH), 6.78e6.90 (m, 3H, AreH), 7.22e7.53
3
(complex m, 9H, AreH), 9.38 (s, 1H, NH, D O exchangeable),
2
28.70 (2C), 128.72 (2C), 139.05, 139.55, 140.50.
H
NMR of compound (6h) (DMSO-d ) d: 0.83 (d, 6H,
6
12.95 (s, 1H, NH, D O exchangeable).
2
J ¼ 6.6 Hz, 2CH ), 1.55 (d, 3H, J ¼ 7.2 Hz, CH ), 1.74e
3
3
1
3
.81 (m, 1H, CH), 2.38 (d, 2H, J ¼ 7.2 Hz, CH ), 3.74 (s,
2
5
.1.3. 3-Arylamino-5-[1-(6-methoxy-2-naphthyl)ethyl]-
H, OCH ), 4.14 (q, 1H, J ¼ 7.2 Hz, CH), 6.78 (d, 2H,
3
(4H )-1,2,4-triazoles (6qex)
A mixture of the appropriate aryl-S-methylisothiouronium
J ¼ 9.0 Hz, AreH), 7.07 (d, 2H, J ¼ 7.8 Hz, AreH), 7.19
(
H), 8.75 (s, 1H, NH), 12.81 (s, 1H, NH).
d, 2H, J ¼ 8.1 Hz, AreH), 7.39 (d, 2H, J ¼ 8.7 Hz, Are
iodide (3aeh; 10 mmol) and 2-methyl-2-(6-methoxy-2-naph-
thyl) acetic acid hydrazide (5c; 10 mmol) in pyridine
(10 mL) was heated at reflux for 3 h. The reaction mixture
5
1
.1.2. 3-Arylamino-5-[1-(2-fluorobiphenyl)ethyl]-(4H )-
,2,4-triazoles (6iep)
A mixture of the appropriate aryl-S-methylisothiouronium
was cooled to room temperature, poured into crushed ice
and the resulting precipitate was filtered, washed with 50%
cold aqueous MeOH and dried. The crude product was puri-
iodide (3aeh; 11 mmol) and 2-methyl-2-(2-fluorobiphenyl)
acetic acid hydrazide (5b; 10 mmol) in pyridine (10 mL) was
heated at reflux for 2 h. The cooled mixture was poured into
crushed ice and the resulting precipitate was collected by filtra-
tion. The crude product was purified by recrystallization from
fied by silica gel column chromatography using CH
MeOH (95:5) as an eluent followed by recrystallization from
Cl /
2 2
ꢀ
1
DMF/EtOH. IR of compound (6s) (KBr, cm ): 3313, 3194
1
(NH). H NMR of compound (6q) (DMSO-d
), 3.85 (s, 3H, OCH ), 4.33 (q, 1H,
) d: 1.66 (d,
6
3H, J ¼ 6.9 Hz, CH
3
3
ꢀ1
ethanol. IR of compound (6j) (KBr, cm ): 3315, 3194 (NH).
1
H NMR of compound (6i) (DMSO-d ) d: 1.63 (d, 3H,
6
J ¼ 6.6 Hz, CH), 6.74e6.77 (m, 1H, AreH), 7.12e7.20 (m,
3H, AreH), 7.26 (s, 1H, AreH), 7.41 (d, 1H, J ¼ 8.4 Hz,
J ¼ 7.2 Hz, CH ), 4.30 (q, 1H, J ¼ 7.2 Hz, CH), 6.75 (m, 1H,
3
AreH), 7.18e7.27 (m, 4H, AreH), 7.40e7.50 (complex m,
8
1
H, AreH), 8.98 (s, 1H, NH), 12.98 (s, 1H, NH). H NMR
(a)
CONHNH2
Ar
S
C
Ar
CONHNH
7a-c)
SK
of compound (6j) (DMSO-d ) d: 1.63 (d, 3H, J ¼ 7.2 Hz,
6
(5a-c)
(
CH ), 4.30 (q, 1H, J ¼ 6.9 Hz, CH), 7.22e7.43 (m, 4H, Are
3
(b)
H), 7.46e7.54 (complex m, 8H, AreH), 9.24 (s, 1H, NH),
1
N
N
N N
1
1
7
3.06 (s, 1H, NH). H NMR of compound (6l) (DMSO-d ) d:
6
N
N
Ar
Ar
(d)
Ar
(
c)
.64 (d, 3H, J ¼ 6.9 Hz, CH ), 4.31 (q, 1H, J ¼ 6.6 Hz, CH),
N
S
N
S
3
N
SH
.22e7.53 (complex m, 12H, AreH), 9.31 (s, 1H, NH, D O ex-
2
N
N
1
SH
NH2
changeable), 13.10 (s, 1H, NH, D O exchangeable). H NMR
2
(9a-c)
(10a-f)
(
8a-c)
of compound (6n) (DMSO-d ) d: 1.63 (d, 3H, J ¼ 7.2 Hz,
6
CH ), 4.30 (q, 1H, J ¼ 7.2 Hz, CH), 7.00e7.06 (m, 2H, Are
R
3
H), 7.22e7.28 (m, 2H, AreH), 7.38e7.53 (complex m, 8H,
Scheme 3. Reagents and conditions: (a) CS
b) NH NH $H O, reflux. (c) Benzoyl chloride or 4-substituted derivatives,
POCl , reflux. (d) CS , KOH, EtOH, reflux.
2
, KOH, EtOH, room temperature.
1
AreH), 9.09 (s, 1H, NH), 13.02 (s, 1H). H NMR of compound
(
2
2
2
(
6p) (DMSO-d ) d: 1.62 (d, 3H, J ¼ 6.6 Hz, CH ), 3.77 (s, 3H,
3
2
6
3

K.A. Metwally et al. / European Journal of Medicinal Chemistry 42 (2007) 152e160
157
Table 2
Physical constants of the 5-(1-substituted-ethyl)-4-amino-4H-1,2,4-triazole-3-thiols (8aec)
N
N
Ar
N
SH
NH2
ꢂ
Compound
Ar
Yield (%)
M.P. ( C)
Formula
Analysis (%)
Calcd
Found
8a
8b
8c
4-Isobutylphenyl
78
80
75
146e148
C
14
C
16
C
15
H
H
H
20
N
4
S
C ¼ 60.84
H ¼ 7.29
N ¼ 20.27
C ¼ 61.13
H ¼ 4.81
N ¼ 17.82
C ¼ 59.98
H ¼ 5.37
N ¼ 18.65
60.75
7.33
19.89
61.44
4.67
2-Fluorobiphenyl
169e170
150e152
4
15FN S
17.55
60.25
5.90
6-Methoxynaphthyl
16 4
N OS
18.33
1
12.90 (s, 1H, NH, D O exchangeable). H NMR of compound
AreH), 7.47 (d, 2H, J ¼ 7.8 Hz, AreH), 7.71 (s, 1H, AreH),
2
7
H), 9.03 (s, 1H, NH), 12.97 (s, 1H, NH). H NMR of com-
.75 (d, 1H, J ¼ 2.1 Hz, AreH), 7.78 (d, 1H, J ¼ 2.7 Hz, Are
(6x) (DMSO-d ) d: 1.66 (d, 3H, J ¼ 6.9 Hz, CH ), 3.67 (s, 3H,
6
3
1
CH ), 3.84 (s, 3H, CH ), 4.32 (q, 1H, J ¼ 7.2 Hz, CH), 6.78 (d,
3
3
pound (6s) (DMSO-d ) d: 1.67 (d, 3H, J ¼ 7.2 Hz, CH ),
2H, J ¼ 9.0 Hz, AreH), 7.12e7.16 (d, 1H, J ¼ 8.7 Hz, Are
H), 7.27 (s, 1H, AreH), 7.42 (d, 3H, J ¼ 8.7 Hz, AreH),
6
3
3
1
1
7
.85 (s, 3H, CH ), 4.36 (q, 1H, J ¼ 7.2 Hz, CH), 6.76 (d,
3
H, J ¼ 7.5 Hz, AreH), 7.12e7.17 (m, 2H, AreH), 7.19 (d,
H, J ¼ 2.4 Hz, AreH), 7.35 (d, 1H, J ¼ 7.8 Hz, AreH),
.41 (d, 1H, J ¼ 8.4 Hz, AreH), 7.68 (d, 1H, J ¼ 8.4 Hz,
7.71e7.79 (m, 3H, AreH), 8.78 (s, 1H, NH, D O exchange-
2
able), 12.87 (s, 1H, NH, D O exchangeable).
2
AreH), 7.76 (s, 1H, AreH), 7.78 (d, 2H, J ¼ 2.1 Hz, Are
5.1.4. 4-Amino-5-(1-substituted-ethyl)-4H-1,2,4-triazole-3-
thiols (8aec)
1
H), 9.37 (s, 1H, NH), 13.09 (s, 1H, NH). H NMR of com-
pound (6w) (DMSO-d ) d: 1.66 (d, 3H, J ¼ 6.6 Hz, CH ),
To an ice-cooled mixture of the appropriate acid hydrazide
(5aec; 10 mmol) and potassium hydroxide (0.84 g; 15 mmol)
in absolute ethanol (20 mL), carbon disulphide (12 mL;
198 mmol) was added in a dropwise manner. After the addi-
tion was complete, absolute ethanol (15 mL) was added and
6
3
2
.19 (s, 3H, CH ), 3.85 (s, 3H, CH ), 4.35 (q, 1H, CH), 6.97
3 3
(
d, 2H, J ¼ 7.50 Hz, AreH), 7.14 (d, 1H, J ¼ 7.8 Hz, Are
H), 7.25 (s, 1H, AreH), 7.38e7.40 (m, 3H, AreH), 7.70e
.77 (m, 3H, AreH), 8.89 (s, 1H, NH, D O exchangeable),
7
2
Table 3
Physical constants of the 3-(1-substituted-ethyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole-6-thiols (9aec)
N
N
Ar
N
S
N
SH
ꢂ
Compound
Ar
Yield (%)
70
M.P. ( C)
Formula
Analysis (%)
Calcd
Found
9a
9b
9c
4-Isobutylphenyl
198e199
C
15
C
17
C
16
H
H
H
18
N
4
S
2
C ¼ 56.57
H ¼ 5.70
N ¼ 17.59
C ¼ 57.29
H ¼ 3.68
N ¼ 15.72
C ¼ 56.12
H ¼ 4.12
N ¼ 16.36
56.77
5.74
18.13
57.37
3.77
2-Fluorobiphenyl
72
68
201e202
212e213
13FN
4
S
2
16.01
56.16
3.98
6-Methoxynaphthyl
14 4 2
N OS
16.25

158
K.A. Metwally et al. / European Journal of Medicinal Chemistry 42 (2007) 152e160
Table 4
Physical constants of the 6-aryl-3-(1-substituted-ethyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (10aef)
N
N
Ar
N
S
N
R
ꢂ
Compound
R
H
Ar
Yield (%)
M.P. ( C)
Formula
Analysis (%)
Calcd
Found
10a
10b
10c
10d
10e
10f
4-Isobutylphenyl
31
28
37
29
23
18
144e145
C
C
C
C
C
C
21
H
21
H
22
H
23
H
23
H
24
H
22
N
4
S
C ¼ 69.58
H ¼ 6.12
N ¼ 15.46
C ¼ 63.54
H ¼ 5.33
N ¼ 14.11
C ¼ 70.18
H ¼ 6.42
N ¼ 14.88
C ¼ 68.98
H ¼ 4.28
N ¼ 13.99
C ¼ 63.52
H ¼ 3.71
N ¼ 12.88
C ¼ 69.55
H ¼ 4.62
N ¼ 13.52
69.17
6.65
15.77
63.56
5.47
Cl
4-Isobutylphenyl
4-Isobutylphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
2-Fluorobiphenyl
168e170
140e142
209e210
179e180
194e196
4
21ClN S
14.20
69.89
6.20
CH
H
3
24 4
N S
14.52
68.72
3.99
4
17FN S
14.00
63.16
3.71
Cl
4
16ClFN S
12.88
69.24
4.88
CH
3
4
19FN S
13.33
the reaction mixture was allowed to stir at room temperature
for 16 h. After addition of dry ether (50 mL), the obtained
product was treated with hydrazine hydrate (99%; 20 mmol)
and water (4 mL) and heated at reflux for 30 min. The reaction
mixture was then diluted with water (10 mL) and neutralized
to litmus with concentrated hydrochloric acid. The separated
hydrochloric acid and the separated solid was filtered, washed
1
with water and recrystallized from aqueous ethanol. H NMR
of compound (9b) (DMSO-d ) d: 1.57 (d, 3H, J ¼ 7.2 Hz,
6
CH ), 4.45 (q, 1H, J ¼ 7.5 Hz, CH), 7.17e7.53 (complex m,
3
8H, AreH), 13.61 (s, 1H, SH, D O exchangeable).
2
solid was filtered, washed with cold water and recrystallized
1
from ethanol. H NMR of compound (8a) (DMSO-d ) d:
5.1.6. 6-Aryl-3-(1-substituted-ethyl)-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazoles (10aef)
Benzoyl chloride (0.28 g, 2 mmol) was added to a solution of
the appropriate 3-(1-substituted-ethyl)-4-amino-4H-1,2,4-tria-
zole-5-thiol (8a,b) in phosphorous oxychloride (10 mL) and
the mixture was heated at reflux for 4e7 h. The excess of
6
0
.83 (d, 6H, J ¼ 6.6 Hz, 2CH ), 1.61 (d, 3H, J ¼ 7.2 Hz,
3
CH ), 1.75e1.82 (m, 1H, CH), 2.38 (d, 2H, J ¼ 7.2 Hz,
3
CH ), 4.30 (q, 1H, J ¼ 6.9 Hz, CH), 5.39 (s, 2H, NH , D O ex-
2
2
2
changeable), 7.07 (d, 2H, J ¼ 8.1 Hz, AreH), 7.15 (d, 2H,
J ¼ 8.1 Hz, AreH), 13.53 (s, 1H, SH, D O exchangeable).
2
The crude products were used without further characterization
in the synthesis of the next compounds.
9
8
5.1.5. 3-(1-Substituted-ethyl)-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazole-6-thiols (9aec)
Control
Ibuprofen
7
Hydrocortisone
The appropriate 3-(1-substituted-ethyl)-4-amino-4H-1,2,4-
triazole (8aec; 10 mmol) was dissolved in a solution of potas-
sium hydroxide (0.56 g; 10 mmol) in absolute ethanol
(
6c)
6
5
4
(6d)
(
25 mL). Carbon disulphide (15 mL; 248 mmol) was then
added and the mixture was heated at reflux for 18 h. The reac-
tion mixture was evaporated under reduced pressure and the
residue was dissolved in 10% potassium hydroxide solution
and filtered. The cold filtrate was acidified with concentrated
0
1
2
3
4
Time (h)
5
6
7
8
9
Fig. 1. Anti-inflammatory activity of test compounds (6c) and (6d).

K.A. Metwally et al. / European Journal of Medicinal Chemistry 42 (2007) 152e160
159
9
8
7
6
5
4
9
8
Control
Control
Ibuprofen
Ibuprofen
7
Hydrocortisone
Hydrocortisone
9a)
(10f)
(
6k)
6l)
(
(
6
5
4
0
1
2
3
4
Time (h)
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
Fig. 2. Anti-inflammatory activity of test compounds (6k) and (6l).
Time (h)
Fig. 4. Anti-inflammatory activity of test compounds (9a) and (10f).
phosphorous oxychloride was removed under reduced pressure,
ice water was added and the precipitate was filtered, washed
with 20% NaHCO solution and water. The crude product was
The animals were randomly divided into 11 groups, six rats
each. Inflammation was induced in the right hind paw of rats
by injection of 0.05 mL of 1% carrageenan solution, dissolved
in normal saline, into the sub-plantar region of the hind paw
3
1
recrystallized from ethanol to give a white solid. H NMR of
compound (10b) (DMSO-d ) d: 0.78 (d, 6H, J ¼ 6.6 Hz,
6
2
CH ), 1.73 (d, 4H, J ¼ 7.2 Hz, CH, CH ), 2.34 (d, 2H,
3
3
[39]. Ibuprofen and the test compounds were dissolved in
J ¼ 7.2 Hz, CH ), 4.64 (q, 1H, J ¼ 7.5 Hz, CH), 7.07 (d, 2H,
2
DMSO and were injected subcutaneously in a dose of 30 mg/kg
body weight. Hydrocortisone was used in a dose of 200 mg/kg
body weight as subcutaneous injection. Control rats received
subcutaneous injection of DMSO. The hind paw volume was
measured for each rat before, and 0.5, 1.5, 2, 3, 6 and 8 h after
the carrageenan injection. The mean of the induced paw thick-
ness was calculated together with the standard error of the
mean. The total area under the curve (AUC), representing the
thickness of the edema, and the time in hours, were calculated
by the trapezoidal method.
J ¼ 8.1 Hz, AreH), 7.25 (d, 2H, J ¼ 8.1 Hz, AreH), 7.61 (d,
1
2
NMR of compound (10d) (DMSO-d ) d: 1.82 (d, 3H,
H, J ¼ 8.4 Hz, AreH), 7.86 (d, 2H, J ¼ 8.7 Hz, AreH). H
6
J ¼ 6.9 Hz, CH ), 4.81 (q, 1H, J ¼ 7.2 Hz, CH), 7.31e7.50
3
(
(
complex m, 8H, AreH), 7.60e7.66 (m, 3H, AreH), 7.90
dd, 2H, J ¼ 1.8, 1.5 Hz, AreH). MS of compound (10d): (m/
þ
1
z) 400 (M , 62.1%), 121 (base peak). H NMR of compound
(
3
10f) (DMSO-d ) d: 1.81 (d, 3H, J ¼ 6.9 Hz, CH ), 2.38 (s,
6
3
H, CH ), 4.90 (q, 1H, J ¼ 6.6 Hz, CH), 7.30e7.52 (complex
3
m, 10H, AreH), 7.79 (d, 2H, J ¼ 7.5 Hz, AreH).
5.3. Ulcerogenicity
5
.2. Anti-inflammatory activity
Male albino rats weighing 150e200 g were fasted for 12 h
Adult male albino rats weighing 150e200 g were used in
prior to the administration of the compounds. Water was given
ad libitum. The animals were divided into groups, each of six
animals. Control group received 1% gum acacia orally. Other
this study. Rats were obtained from the animal house of the
National Research Centre, Dokky, Cairo. The animals were
kept for one week in the animal house of the Faculty of Phar-
macy, Zagazig University under 12 h day and night cycle, for
accommodation with free access to food and water ad libitum.
Table 5
The anti-inflammatory activity of the test compounds
Compound
AUC (% h)
9
Mean ꢃ S.E.
% Effect
% Change
Control
Hydrocortisone
Ibuprofen
59.95 ꢃ 2.21
100.00
73.39
86.07
70.86
69.52
69.65
68.36
66.08
69.67
72.10
75.00
0.00
ꢀ26.61
ꢀ13.93
ꢀ29.14
ꢀ30.48
ꢀ30.35
ꢀ31.64
ꢀ33.16
ꢀ30.33
ꢀ27.90
ꢀ25.00
8
44 ꢃ 0.72*
Control
ꢄ,
51.6 ꢃ 0.94
*
*
Ibuprofen
7
ꢄ,
6
c
42.48 ꢃ 0.61
Hydrocortisone
,ꢄ,
,ꢄ,
,ꢄ,
,
ꢄ,
(6s)
6d
6k
41.68 ꢃ 0.63**
41.76 ꢃ 0.45**
40.98 ꢃ 0.91**
40.07 ꢃ 0.79**
*
*
*
*
6
5
4
(6t)
6
6
6
9
1
l
s
ꢄ,
t
41.77 ꢃ 0.99
43.23 ꢃ 1.2
44.97 ꢃ 1.81
*
ꢄ,
a
0f
*
ꢄ,*
0
1
2
3
4 5
Time (h)
6
7
8
9
*
Significantly different from control group at P < 0.05.
ꢄ
Significantly different from ibuprofen group at P < 0.05.
Fig. 3. Anti-inflammatory activity of test compounds (6s) and (6t).
**Significantly different from hydrocortisone group at P < 0.05.

1
60
K.A. Metwally et al. / European Journal of Medicinal Chemistry 42 (2007) 152e160
[12] A. Kalgutkar, A. Marnett, B. Crews, R. Remmel, L. Marnett, J. Med.
Table 6
Ulcerogenic effects of the test compounds
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13] M. Duflos, M. Nourrisson, J. Brelet, J. Courant, G. Le Baut, N. Grimaud,
[
[
[
[
[
Compound
Ulceration
Control
0.0
Indomethacin
100
6d
6k
6l
6s
J. Petit, Eur. J. Med. Chem. 36 (2001) 545e553.
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33.3
0.0
0.0
0.0
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sive days. Animals were sacrificed by diethyl ether 6 h after
the last dose and the stomach was separated. An opening at
the greater curvature was made and the stomach was washed
with cooled saline and inspected with a 3ꢁ magnifying lens
for any evidence of hyperemia, haemorrhage or ulcer [40].
The percentage ulceration for each group was calculated as
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(
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[
[
numberof animalsbearingulcerinagroup
%
Ulceration¼
ꢁ100
totalnumberof animalsinthesamegroup
[
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The authors are grateful to the government of Yemen for
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Shada H. Yaseen.
[
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