Synthesis, analgesic and anti-inflammatory activities of novel 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles

Article abstract of DOI:10.1016/j.ejmech.2008.05.022

A series of 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles (7a-7n) were synthesized and screened for analgesic and in vivo anti-inflammatory activities using acetic acid writhing in mice model and carrageenan-induced paw oedema method in mice, respectively. The analgesic activity of compounds 7i and 7m is superior while that of 7d, 7c, 7f and 7j is equal to the reference standard, diclofenac sodium. The anti-inflammatory activity of compounds 6, 7c, 7e, 7f, 7i, 7l, 7m and 7n is found to be superior than that of diclofenac sodium which is used as a reference, while compounds 7d and 7g are found to be equipotent with the reference compound.

Full text of DOI:10.1016/j.ejmech.2008.05.022

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 44 (2009) 794e799
http://www.elsevier.com/locate/ejmech
Original article
Synthesis, analgesic and anti-inflammatory activities of novel
3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles
c
Mazahar Farooqui a, , Rajesh Bora , C.R. Patil
a,b
*
a Department of Chemistry, Aurangabad College for Women, Navkhanda, Aurangabad 431001, India
b Wockhardt Research Centre, Chikalthana, Aurangabad 431 210, India
c R.C. Patel College of Pharmacy, Shirpur 425 405, India
Received 27 January 2008; received in revised form 17 May 2008; accepted 22 May 2008
Available online 14 July 2008
Abstract
A series of 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles (7ae7n) were synthesized and screened for analgesic and in vivo anti-
inflammatory activities using acetic acid writhing in mice model and carrageenan-induced paw oedema method in mice, respectively. The
analgesic activity of compounds 7i and 7m is superior while that of 7d, 7c, 7f and 7j is equal to the reference standard, diclofenac sodium.
The anti-inflammatory activity of compounds 6, 7c, 7e, 7f, 7i, 7l, 7m and 7n is found to be superior than that of diclofenac sodium which
is used as a reference, while compounds 7d and 7g are found to be equipotent with the reference compound.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Hydroxycarbamidoylmethyl; 1,2,4-Oxadiazoles; Anti-inflammatory activity; Analgesic activity; Diclofenac sodium
1. Introduction
of anti-inflammatory effects from GI toxicity is suggested by
recent discovery that COX exists in two isoforms, COX-1
and COX-2, which are encoded by two distinct genes. COX-
1 is thought to provide cytoprotection; COX-2 inhibitor might
have selective anti-inflammatory properties and lack of GI side
effects [5].
Inflammation is a complex phenomenon involving interre-
lationships of humoral and cellular reactions through a number
of inflammatory mediators. It is a usual symptom covering dif-
ferent pathologies, and there are still many questions to be an-
swered in order to understand the inflammatory process as
well as a need for better-tolerated and more efficient nonste-
roidal anti-inflammatory drugs [1]. Nonsteroidal anti-inflam-
matory drugs (NSAIDs) are important therapeutic agents for
the treatment of pain and inflammation. However, their thera-
peutic use is often limited by the common side effects, such as
gastrointestinal (GI) haemorrhage and ulceration and also af-
fects the functioning of platelets [2]. NSAIDs work by inhib-
iting the cyclooxygenase (COX), a key enzyme [3,4] so
preventing the formation of inflammatory prostaglandins
from metabolism of arachidonic acid. Since prostaglandins
have dual functions, mediation of inflammation and cytopro-
tection in the stomach and intestine, and possible dissociation
1,2,4-Oxadiazoles are well known compounds which ex-
hibit diversified biological activities [6e9]. Oxadiazoles
have often been described as bio-isosteres for amides and es-
ters [10]. Due to increased hydrolytic [11] and metabolic sta-
bilities of the oxadiazole ring, improved pharmacokinetic and
in vivo performance is often observed, which make these het-
erocycles an important structural motif for the pharmaceutical
industry. As a consequence of these characteristics, oxadia-
zoles have impacted numerous drug discovery programs in-
cluding muscarinic agonists [12], benzodiazepine receptor
partial agonists [13], dopamine transporters [14], anti-rhinovi-
rals [15], growth hormone secretogogues [16], 5-HT agonists
[17], antispasmodics [18], nematocidal, fungicidal and micro-
bicides [19], analgesics [20], anti-inflammatory agents [21],
Fab I inhibitors as antibacterial agents [22], immunosuppres-
sants [23], and also antiplatelet and antithrombotic agents
* Corresponding author.
E-mail address: mazahar_64@rediffmail.com (M. Farooqui).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.05.022

M. Farooqui et al. / European Journal of Medicinal Chemistry 44 (2009) 794e799
795
CN
NO
[24]. 3-Aryl-5-substituted 1,2,4-oxadiazoles have also shown
CN
CN
the activity against kinetoplastid parasites [25] and interleu-
kin-8 (IL-8) receptor antagonists and thereby leading to
unique anti-inflammatory agents [26].
2
i
+
NO
2
1
2a
2b
2. Chemistry
ii
OH
NH
N
Based on these understandings we have undertaken the syn-
thesis of 3,5-disubstituted [1,2,4]-oxadiazoles with amide
functionality at C05 terminal as novel compounds as a part
of our research programme. These are then screened for anal-
gesic and anti-inflammatory activities in different animal
models.
CN
CN
2
iii
iv
v
NHAC
5
NHAC
4
NH
3
2
Many synthetic methodologies are known in the literature
for the synthesis of 3,5-disubstituted-[1,2,4]-oxadiazoles.
Herein we have synthesized from N-[4-(N-hydroxycarbami-
doylmethyl)-phenyl]-acetamide (5) intermediate, which was
prepared as per the procedure reported in our earlier publica-
tion [27].
O
O
R
OH
N
H
O
O
N
N
N
N
vi
When compound 5 was reacted with succinic anhydride
[28] in high boiling solvents such as xylene it afforded 3-[3-
(4-acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
(6). This step is thermal cyclization in which open chain ami-
doxime undergoes in situ cyclodehydration yielding
substituted oxadiazole compound with free carboxylic acid
group. This substituted acid amidoxime when reacted with
substituted aromatic amines afforded 3,5-disubstituted oxadia-
zole amide derivatives. The amide bond formation was carried
out by using N-ethyl-N0-(3-dimethylaminopropyl)-carbodii-
mide hydrochloride [WSC, EDCI] and 1-hydroxy benzotria-
zole as a coupling reagent in solvent such as THF. All the
compounds were synthesized in good to excellent yield
(Scheme 1).
6
7(a-n)
NHAC
NHAC
Scheme 1. Conditions and reagents: (i) conc. HNO3/H2SO4, 0 ꢁC; (ii) Pd/C,
H2/rt, THF; (iii) acetyl chloride/Et3N/THF, 0 ꢁC; (iv) NH2OH$HCl/
NaHCO3/MeOH/reflux; (v) succinic anhydride/xylene/120 ꢁC; (vi) substituted
amine/EDC$HCl/DIEA/THF, rt.
with the vehicle control group. The results are summarized
in Table 1.
3.2. Analgesic activity [30]
For this test, male C57BL/6 mice were used. The drug
treatment was same as stated above. The treatments were ad-
ministered 1 h prior to acetic acid injection. For induction of
pain, 0.25 ml of 0.6% v/v acetic acid was injected i.p. Total
number of writhings were counted along the period of
30 min following acetic acid injection.
3. Biology
3.1. In vivo anti-inflammatory activity
Carrageenan footpad edema [29]. The acute anti-inflamma-
tory activity of the synthesized compounds was determined
following the carrageenan-induced paw oedema method in
mice. Carrageenan solution (1% w/v) was prepared by dissolv-
ing 100 mg of carrageenan (Marine Colloidal Div., Spring-
field, NJ) in 10 ml of sterile saline (0.9%) solution. Male
C57BL/6 mice were orally dosed with compound (at dose of
100 mg/kg p.o. as a suspension in 5% carboxymethylcellulose)
1 h before carrageenan challenge. Diclofenac sodium given at
100 mg/kg p.o. was used as a standard drug. Foot paw oedema
was induced by injecting 0.05 ml of the carrageenan solution
subcutaneously into the planter portion of the right hind paw
of each mice under light anesthesia. Initial foot paw volume
was measured immediately by digital plethysmometry (Ugo
Basile Digital Plethysmometer, Model-7140, Italy) following
carrageenan challenge. Oedema was measured 4 h after carra-
geenan administration. The swelling in each test group of an-
imals was used to calculate the percent inhibition ꢀ SEM of
edema achieved by the compound at the test dose compared
Average numbers of writhings in the control group were
used to calculate percentage inhibition of writhings in other
groups. The results are summarized in Table 1.
4. Results and discussion
Acute anti-inflammatory activity. Compounds 7d and 7g
showed activity equipotent to that of reference standard, diclo-
fenac, while compounds 6, 7c, 7e, 7i, 7l, 7m, and 7n are more
potent than diclofenac sodium in inhibiting the inflammation
induced by carrageenan.
The structureeanti-inflammatory activity relationship of
the synthesized compounds revealed that the activity is depen-
dant on the basic molecular skeleton. Compound 6 is one of
the most potent compounds. But having one or more lipophilic
substituents on the aromatic ring further enhances the activity.
This may be due to better partitioning of the molecule in the
lipid bilayer of the cell membrane. Compound 7i is the most

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M. Farooqui et al. / European Journal of Medicinal Chemistry 44 (2009) 794e799
Table 1
The anti-inflammatory and analgesic activities of 3,5-disubstituted-[1,2,4]-oxadiazoles
O
O
N
N
R
AcHN
S. no.
Entry
R
% Rise
in paw volume
% Inhibition of inflammation
% Decrease in writhing
1
6
eOH
eAniline
18 ꢀ 2
48 ꢀ 3
47 ꢀ 3
9 ꢀ 1
75.34 ꢀ 3.4
34.24 ꢀ 4.7
35.61 ꢀ 4.5
87.67 ꢀ 1.6
49.31 ꢀ 4.2
67.12 ꢀ 7.3
64.38 ꢀ 5
46.43 ꢀ 1.39
ꢂ13.10 ꢀ 1.94
ꢂ7.14 ꢀ 2.35
73.81 ꢀ 0.49
67.26 ꢀ 1.20
ꢂ23.21 ꢀ 1.40
67.86 ꢀ 1.07
ꢂ0.60 ꢀ 0.91
36.90 ꢀ 3.17
80.36 ꢀ 0.43
67.26 ꢀ 1.01
31.55 ꢀ 4.32
61.31 ꢀ 0.79
80.95 ꢀ 0.42
ꢂ0.60 ꢀ 1.58
ꢂ2.38 ꢀ 1.33
77.38 ꢀ 0.49
2
7a
7b
7c
3
-m-Anisidine
eo-Anisidine
ep-Anisidine
2-Fluoroaniline
4-Fluoroaniline
2,4-Fluoroaniline
4
5
7d
7e
37 ꢀ 3
24 ꢀ 5
26 ꢀ 4
34 ꢀ 4
29 ꢀ 5
3 ꢀ 1
6
7
7f
8
7g
7h
7i
52.05 ꢀ 6.7
60.27 ꢀ 7.3
95.89 ꢀ 1.9
16.43 ꢀ 1.9
36.98 ꢀ 5.7
84.93 ꢀ 1.6
87.67 ꢀ 1.9
76.71 ꢀ 6.2
0
9
3-F-4-methoxy-aniline
3,4-D-Methoxy-aniline
m-Toludine
10
11
12
13
14
15
16
17
7j
61 ꢀ 1
46 ꢀ 4
11 ꢀ 1
9 ꢀ 1
7k
7l
4-Trifluomethylaniline
3-Ethynyl aniline
Pyridine
7m
7n
Control
Std
Benzylamine
Control
Diclofenac
17 ꢀ 5
73 ꢀ 7
36 ꢀ 7
50.68 ꢀ 9
potent being two methoxy groups are present at ortho and para
compared to one methoxy substituent present in compound 7c
revealing the importance of electron-donating group like me-
thoxy substituents at ortho and para positions in the aromatic
ring.
All the raw materials, reagents and solvents used were of com-
mercial grade only.
5.1. Synthesis of 3-[3-(4-acetylamino-benzyl)-
[1,2,4]oxadiazol-5-yl]-propionic acid (6)
4.1. Analgesic activity
To a stirred solution of N-[4-(N-hydroxycarbamidoyl-
methyl)-phenyl]-acetamide 5 (10.0 g; 0.048 M) in xylene
(60 ml) was added succinic anhydride (4.8 g; 0.048 M). The
resulting reaction mixture was then heated at 120 ꢁC for 2 h
and then cooled to room temperature. Xylene was then dec-
anted and sticky brown solid left in the flask was triturated
in ice-cold water to afford free solid. The resulting solid was
filtered and triturated in diethyl ether to afford cream-colored
solid 6 (11.0 g, 80%).
Compounds 7i and 7m are more potent analgesic than di-
clofenac sodium, while compounds 7d, 7c, 7f, and 7j are equi-
potent as analgesic with respect to the reference standard.
Presence of two methoxy groups in aromatic ring at ortho
and para positions is highly effective for the analgesic and
anti-inflammatory activities. It may be speculated that hydro-
philicity of two amide groups is balanced by methoxy groups
and therefore its pharmacokinetic behaviour is better than rest
of the compounds. Hence compound 7i is found to be the most
active compound among the series in both the animal models.
Therefore, compound 7i can be considered as lead molecule
for further development.
M.p. 162e163 ꢁC. IR (cmꢂ1, KBr): 3400, 3312, 3100,
1
1716, 1659, 1601 and 1542. H NMR (DMSO-d6): d 2.1 (s,
3H, CH3), 2.7 and 3.1 (each t, each 2H, each eCH2e), 4.0
(s, 2H, eCH2Ph), 7.15 and 7.45 (each 2 d, each 2H, each
AreH), 9.95 (s, 1H, NH), 12.4 (broad s, 1H, eCOOH).
Mass (m/z): 290 (Mþ1). Anal. Found: C, 58.50; H, 5.63; N,
14.90. Calcd for C14H15N3O4: C, 58.13; H, 5.23; N, 14.53%.
5. Experimental
Melting points were taken on a Precision melting point ap-
paratus (DBK Instruments) and are uncorrected. IR spectra
were obtained in potassium bromide (KBr) disks on a Bruker
5.2. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-
N-phenyl-propionamide (7a)
1
IR spectrophotometer, and H NMR spectra were obtained on
To a stirred solution of 3-[3-(4-acetylamino-benzyl)-
[1,2,4]oxadiazol-5-yl]-propionic acid 6 (0.10 g, 0.35 mmol)
and aniline (0.035 ml, 0.35 mmol, 1.0 equiv) in THF were
added EDC$HCl (0.085 g, 0.42 mmol, 1.2 equiv), 1-hydroxy
benzotriazole (0.012 mg, 0.09 mmol, 0.25 equiv) and ethyl
N,N-diisopropylamine (0.075 ml, 0.42 mmol, 1.2 equiv).
deuteriochloroform (CDCl3) and or DMSO-d6 solution on
a Varian 400 MHz spectrophotometer. Elemental analyses
were performed on Fissons micro CHN analyzer. Mass spectra
were recorded on a MicroMass spectrometer by Waters. The
yields unless otherwise mentioned are for the pure product.

M. Farooqui et al. / European Journal of Medicinal Chemistry 44 (2009) 794e799
797
Reaction mixture was then stirred at room temperature for 2 h.
On completion of reaction organic solvent was evaporated un-
der vacuum to afford crude sticky mass. On triturating in 10%
NaHCO3 solution yellow solid separated was then filtered un-
der vacuum. It was then recrystallized from 95% ethanol to af-
ford pale yellow solid (0.1 g, 90%).
2H, Ar-H), 7.15 (d, 2H, Ar-H), 7.45 (d, 2H, Ar-H), 7.9 (broad
d, 1H, Ar-H), 9.24 (s, 1H, eNH), 9.87 (s, 1H, eNH). Mass m/
z: 395 (Mþ1). Anal. Found: C, 64.315; H, 5.97; N, 14.55.
Calcd for C21H22N4O4: C, 63.95; H, 5.62; N, 14.20%.
M.p. 179e180 ꢁC. IR (cmꢂ1, KBr): 3283, 3123, 1685,
1
5.6. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-
N-(2,4-dimethoxy-phenyl)-propionamide (7i)
1645, 1614 and 1578. H NMR (DMSO-d6): d 2.0 (s, 3H,
CH3), 2.95 and 3.25 (each t, each 2H, each eCH2e), 4.0 (s,
3H, eCH2Ph), 7.2 and 7.4 (each 2 d, each 2H, each Ar-H),
9.95 (broad s, 1H, eNH), 12.4 (broad s, 1H, eCOOH).
Mass (m/z): 365 (Mþ1). Anal. Found: C, 66.35; H, 5.91; N,
15.75. Calcd for C20H20N4O3: C, 65.92; H, 5.53; N, 15.37%.
Prepared from 2,4-dimethoxyaniline (0.10 g, 0.35 mmol)
and compound 6 (0.10 g, 0.35 mmol) by using the same pro-
cedure mentioned as in 7a to afford 7i as pale yellow solid
(115 mg, 78%).
M.p. 168e169 ꢁC. IR (cmꢂ1, KBr): 3235, 3085, 1649,
5.3. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-
N-(3-methoxy-phenyl)-propionamide (7b)
1
1624, 1587 and 1569. H NMR (DMSO-d6): d 2.0 (s, 3H,
CH3), 2.9 and 3.15 (each t, each 2H, each eCH2e), 3.9 (s,
3H, eOCH3), 4.0 (s, 2H, CH2-Ph), 4.1 (s, 3H, OCH3), 6.85
(d, 1H, Ar-H), 7.05 (m, 1H, Ar-H), 7.25 (m, 1H, Ar-H), 7.2
and 7.4 (each 2 d, each 2H, each Ar-H), 9.9 (s, 1H, eNH),
10.1(s, 1H, eNH). Mass (m/z): 425 (Mþ1). Anal. Found: C,
62.60; H, 6.05; N, 13.60. Calcd for C22H24N4O5: C, 62.25;
H, 5.70; N, 13.20%.
Prepared from m-anisidine (0.10 g, 0.35 mmol) and com-
pound 6 (0.10 g, 0.35 mmol) by using the same procedure as
mentioned in 7a to afford 7b as off-white solid (110 mg, 81%).
M.p. 137e138 ꢁC. IR (cmꢂ1, KBr): 3263, 3118, 1670,
1
1614, 1595 and 1577. H NMR (DMSO-d6): d 2.0 (s, 3H,
CH3), 2.85 and 3.25 (each t, each 2H, each eCH2e), 3.7 (s,
3H, eOCH3), 4.0 (s, 2H, eCH2Ph), 6.6 and 7.05 (each d,
each 1H, each Ar-H), 7.15 (s, 1H, eAr), 7.2 and 7.45 (each
2 d, each 2H, each Ar-H), 7.22 (m, 2H, Ar-H), 9.9 (s, 1H,
eNH), 10 (s, 1H, eNH). Mass (m/z): 395 (Mþ1). Anal. Found:
C, 64.30; H, 5.99; N, 14.55. Calcd for C21H22N4O4: C, 63.95;
H, 5.62; N, 14.20%.
5.7. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-
N-(3-fluoro-4-methoxy-phenyl)-propionamide (7h)
Prepared from 3-fluoro-4-dimethoxyaniline (0.10 g,
0.35 mmol) and compound 6 (0.10 g, 0.35 mmol) by using
the same procedure mentioned in 7a to obtain 7h as pale yel-
low solid (100 mg, 68.5%).
5.4. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-
N-(4-methoxy-phenyl)-propionamide (7d)
M.p. 197e198 ꢁC. IR (cmꢂ1, KBr): 3235, 3110, 1675,
1
1620, 1589 and 1570. H NMR (DMSO-d6): d 2.0 (s, 3H,
Prepared from p-anisidine (0.10 g, 0.35 mmol) and com-
pound 6 (0.10 g, 0.35 mmol) by using the same procedure
as mentioned in 7a to afford 7d as yellow solid (105 mg,
78%).
CH3), 2.8 and 3.2 (each t, each 2H, each eCH2e), 3.8 (s,
3H, eOCH3), 4.0 (s, 3H, OCH3), 7.05 (t, 2H, Ar-H), 7.15
(m, 2H, A), 9.9 (s, 1H, eNH), (10.1 (s, 1H, eNH). Mass
(m/z): 425 (Mþ1). Anal. Found: C, 61.52; H, 5.52; N, 13.95.
Calcd for C21H24 FN4O4: C, 61.16; H, 5.13; N, 13.58%.
M.p. 188e190 ꢁC. IR (cmꢂ1, KBr): 3256, 3108, 1677,
1
1624, 1590 and 1567. H NMR (DMSO-d6): d 2.0 (s, 3H,
CH3), 2.8 and 3.1 (each t, each 2H, each eCH2e), 3.75 (s, 3H,
eOCH3), 3.95 (s, 2H, eCH2Ph), 6.8 (d, 2H, Ar-H), 7.16 (d,
2H, Ar-H), 7.41 and 7.46 (each 2 d, each 2H, each Ar-H),
9.86 (s, 1H, eNH). Mass (m/z): 395 (Mþ1). Anal. Found: C,
64.35; H, 6.00; N, 14.60. Calcd for C21H22N4O4: C, 63.95;
H, 5.62; N, 14.20%.
5.8. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-
N-(4-fluoro-phenyl)-propionamide (7f)
Prepared from 4-fluoroaniline (0.10 g, 0.35 mmol) and
compound 6 (0.10 g, 0.35 mmol) by using the same procedure
mentioned in 7a to afford 7f as pale yellow solid (105 mg,
80%).
5.5. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-
N-(2-methoxy-phenyl)-propionamide (7c)
Prepared from o-anisidine (0.10 g, 0.35 mmol) and com-
pound 6 (0.10 g, 0.35 mmol) by using the same procedure
mentioned in 7a to obtain 7c as pale yellow solid (90 mg,
66%).
M.p. 193e194 ꢁC. IR (cmꢂ1, KBr): 3244, 3095, 1659,
1604, 1597 and 1577. 1H NMR (DMSO-d6): d 2 (s, 3H,
CH3), 2.9 and 3.1 (each t, each 2H, each eCH2e), 3.8 (s,
3H, eOCH3), 4 (s, 2H, CH2-Ph), 6.85 (d, 1H, Ar-H), 7 (m,
M.p. 196e197 ꢁC. IR (cmꢂ1, KBr): 3245, 3105, 1665,
1
1610, 1595 and 1560. H NMR (DMSO-d6): d 2.0 (s, 3H,
CH3), 2.81 and 3.13 (each t, each 2H, each eCH2e), 3.95
(s, 2H, eCH2ePh), 7.0 (t, 2H, Ar-H), 7.15 (d, 2H, Ar-H),
7.45 (d, 2H, Ar-H), 7.52 (m, 2H, Ar-H), 9.87 (broad s, 1H,
eNH), 10.08 (s, 1H, eNH). Mass (m/z): 383 (Mþ1). Anal.
Found: C, 63.18; H, 5.35; N, 15.00. Calcd for C21H19FN4O4:
C, 62.82; H, 5.01; N, 14.65%.

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M. Farooqui et al. / European Journal of Medicinal Chemistry 44 (2009) 794e799
5.9. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-yl]-
N-(2-fluoro-phenyl)-propionamide (7e)
2H, each eCH2e), 3.95 (s, 2H, eCH2ePh), 6.8 (d, 1H, Ar-
H), 7.3e7.17 (m, 3H, Ar-H), 7.29 (d, 1H, Ar-H), 7.35 (s,
1H, Ar-H), 7.46 (d, 2H, Ar-H), 9.8 (s, 1H, eNH), 9.93 (s,
1H, eNH). Mass (m/z): 379 (Mþ1). Anal. Found: C, 67.05;
H, 6.26; N, 15.20. Calcd for C22H22N4O3: C, 66.65; H, 5.86;
N, 14.80%.
Prepared from 2-fluoroaniline (0.10 g, 0.35 mmol) and
compound 6 (0.10 g, 0.35 mmol) by using the same procedure
mentioned in 7a to afford 7e as cream-colored solid (95 mg,
72%).
M.p. 147e148 ꢁC. IR (cmꢂ1, KBr): 3265, 3095, 1662,
1
1605, 1599 and 1575. H NMR (DMSO-d6): d 2.0 (s, 3H,
5.13. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-
CH3), 2.95 and 3.13 (each t, each 2H, each eCH2e), 3.95
(s, 2H, eCH2ePh), 7.10 (m, 2H, Ar-H), 7.16 (d, 2H, Ar-H
d), 7.21 (m, 1H, Ar-H), 7.46 (d, 2H, Ar-H), 7.78 (1H, broad
s, Ar-H), 9.82 (s, 1H, eNH) and 9.86 (s, 1H, eNH). Mass
(m/z): 383 (Mþ1). Anal. Found: 63.20; H, 5.39; N, 15.03.
Calcd for C21H19FN4O4: C, 62.82; H, 5.01; N, 14.65%.
yl]-N-(3-ethynyl-phenyl)-propionamide (7l)
Prepared from 3-ethynylaniline (0.10 g, 0.35 mmol) and
compound 6 (0.10 g, 0.35 mmol) by using the same procedure
mentioned in 7a to obtain 7l as pale yellow solid (105 mg,
78.4%).
M.p. 194e195 ꢁC. IR (cmꢂ1, KBr): 3257, 3111, 1666,
1
1607, 1586 and 1544. H NMR (DMSO-d6): d 2.0 (s, 3H,
5.10. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-
yl]-N-(2,4-difluoro-phenyl)-propionamide (7g)
CH3), 2.85 (t, 2H, CH2e), 4.15 (s, 1H, acetylene), 3.25 (t,
2H, CH2e), 4.0 (s, 2H, eCH2eAr), 7.15 (m, 3H, Ar-H),
7.2e7.25 (m, 1H, Ar-H), 7.4e7.50 (m, 3H, Ar-H), 7.7 (s,
1H, Ar-H) 9.86, 10.13 (each s, each 1H, each eNH protons).
Mass (m/z): 389 (Mþ1). Anal. Found: C, 68.33; H, 5.49; N,
14.72. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42%
Prepared from 2,4-difluoroaniline (0.10 g, 0.35 mmol) and
compound 6 (0.10 g, 0.35 mmol) by using the same procedure
mentioned in 7a to obtain 7g as pale yellow solid (110 mg,
80.3%).
M.p. 147e148 ꢁC. IR (cmꢂ1, KBr): 3260, 3100, 1672, 1600,
1589 and 1555. 1H NMR (DMSO-d6): d 2.0 (s, 3H, CH3), 2.85
and 3.15 (each t, each 2H, each eCH2e), 4.0 (s, 2H, eCH2ePh),
7 (t, 1H, Ar-H), 7.16 (d, 2H, Ar-H), 7.23e7.29 (m, 1H, Ar-H),
7.4 (d, 2H, Ar-H), 7.7 (m, 1H, Ar-H), 9.82 (m, 1H, N-H), 9.87 (s,
1H, eNH) Mass (m/z): 400 (Mþ1). Anal. Found: C, 63.22; H,
5.41; N, 15.05. Calcd for C21H18 F2N4O3: C, 62.82; H, 5.01;
N, 14.65%.
5.14. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-
yl]-N-pyridin-3-yl-propionamide (7m)
Procedure. Prepared from 3-aminopyridine (0.10 g,
0.35 mmol) and compound 6 (0.10 g, 0.35 mmol) by using
the same procedure mentioned in 7a to obtain 7m as cream-
colored solid (100 mg, 79.4%).
5.11. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-
yl]-N-(4-trifluoromethyl-phenyl)-propionamide (7k)
M.p. 189e190 ꢁC. IR (cmꢂ1, KBr): 3288, 3070, 1666,
1
1607, 1586 and 1544. H NMR (DMSO-d6) d 2.0 (s, 3H,
CH3), 2.85 and 3.15 (each t, each 2H, each eCH2e), 4.0 (s,
2H, eCH2eAr), 7.2e7.25 (d, 2H, Ar-H), 7.4 (d, 2H, Ar-H),
7.45 (m, 1H, Py-H), 8.4 (m, 1H, Py-H), 8.75 (dd, 1H, Py-H),
8.95 (d, 1H, Py-H), 9.8 (s, 1H, eNH) and 9.98 (s, 1H,
eNH). Mass (m/z): 366 (Mþ1). Anal. Found: C, 62.80; H,
5.60; N, 19.52. Calcd for C19H19N5O3: C, 62.46; H, 5.24; N,
19.17%.
Prepared from 4-trifluoromethylaniline (0.10 g, 0.35 mmol)
and compound 6 (0.10 g, 0.35 mmol) by using the same pro-
cedure mentioned in 7a to obtain 7k as pale yellow solid
(110 mg, 73.3%).
M.p. 201e202 ꢁC. IR (cmꢂ1, KBr): 3267, 3090, 1677,
1
1625, 1589 and 1567. H NMR (DMSO-d6): d 2.2 (s, 3H,
CH3), 2.95 and 3.2 (each t, each 2H, each eCH2e), 4.0 (s,
2H, eCH2ePh), 7.15 (d, 2H, eNH), 7.45 (d, 2H, Ar-H),
7.63 and 7.72 (each d, each 2H, Ar-H), 9.86 and 10.39 (each
s, each 1H, each eNH). Mass (m/z): 433 (Mþ1). Anal. Found:
C, 58.75; H, 4.80; N, 13.33. Calcd for C21H19F3N4O3: C,
58.33; H, 4.43; N, 12.96%.
5.15. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-
yl]-N-benzyl-propionamide (7n)
Prepared from benzyl amine (0.10 g, 0.35 mmol) and 6
(0.10 g, 0.35 mmol) by using the same procedure mentioned
in 7a to obtain 7n as white solid (120 mg, 92.3%).
5.12. 3-[3-(4-Acetylamino-benzyl)-[1,2,4]oxadiazol-5-
yl]-N-m-tolyl-propionamide (7j)
M.p. 163e164 ꢁC. IR (cmꢂ1, KBr): 3257, 3111, 1666,
1
1607, 1586 and 1544. H NMR (DMSO-d6): d 2.0 (s, 3H,
Prepared from m-toludine (0.10 g, 0.35 mmol) and com-
pound 6 (0.10 g, 0.35 mmol) by using the same procedure
mentioned in 7a to obtain 7j as white solid (115 mg, 88.5%).
M.p. 152e153 ꢁC. IR (cmꢂ1, KBr): 3240, 3120, 1680,
1615, 1599 and 1570. H NMR (DMSO-d6): d 2.0 (s, 3H,
CH3), 2.23 (s, 3H, AreCH3), 2.81 and 3.12 (each t, each
CH3), 2.65 (t, 2H, CH2e), 3.15 (t, 2H, CH2e), 3.95 (s, 2H,
eCH2eAr), 4.23 (s, 2H, Ar-CH2) 7.15e7.22 (m, 5H, Ar-H),
7.25 (m, 2H, Ar-H), 7.47e7.49 (d, 2H, Ar-H), 8.4 (s, 1H,
eNH) 9.88(s, 1H, -NH). Mass (m/z): 379 (Mþ1). Anal. Found:
C, 66.96; H, 6.24; N, 15.17. Calcd for C21H22N4O3: C, 66.65;
H, 5.86; N, 14.80%.
1

M. Farooqui et al. / European Journal of Medicinal Chemistry 44 (2009) 794e799
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