Synthesis of 3-aryl-5-decapentyl-1,2,4-oxadiazoles possessing antiinflammatory and antitumor properties

Article abstract of DOI:10.1016/j.farmac.2005.08.003

A simple, convenient and straightforward synthesis of 3-aryl-1,2,4- oxadiazoles 4a-f from arylamidoximes 1a-f and palmitic acid 2 is described. Compounds 4a-f are non-lethal in mice at four times the therapeutic dose (i.p., LD₅₀ > 1:g:kg^-1 of the animals' body weight). These heterocycles have been found to possess antiinflammatory property similar to aspirin and ibuprofen. Three compounds, viz., 4a, d, e have also been evaluated for antitumor activity, where 4d exhibited an excellent activity comparable to lapachol.

Full text of DOI:10.1016/j.farmac.2005.08.003

Il Farmaco 60 (2005) 955–960
http://france.elsevier.com/direct/FARMAC/
Original article
Synthesis of 3-aryl-5-decapentyl-1,2,4-oxadiazoles possessing
antiinflammatory and antitumor properties
Natércia M. Miranda Bezerra 1, Shalom P. De Oliveira,
Rajendra M. Srivastava *, Joel R. Da Silva
Departamento de Química Fundamental, Centro de Ciencias Exatas e de Natureza, Universidade Federal de Pernambuco,
CEP 50740-540 Recife, PE, Brazil
Received 28 January 2005; received in revised form 9 August 2005; accepted 10 August 2005
Abstract
A simple, convenient and straightforward synthesis of 3-aryl-1,2,4-oxadiazoles 4a–f from arylamidoximes 1a–f and palmitic acid 2 is
described. Compounds 4a–f are non-lethal in mice at four times the therapeutic dose (i.p., LD50 > 1 g kg–1 of the animals’ body weight).
These heterocycles have been found to possess antiinflammatory property similar to aspirin and ibuprofen. Three compounds, viz., 4a, d, e
have also been evaluated for antitumor activity, where 4d exhibited an excellent activity comparable to lapachol.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Arylamidoximes; 1,2,4-Oxadiazoles; Spectroscopy; Antiinflammatory activity; Antitumor property
1. Introduction
spring was explored with interesting findings [5]. PEA is gain-
ing more importance as evident in the following paragraphs.
In 2001, Ueda et al. [6] purified and characterized an acid
amide which selectively hydrolyzed N-palmitoyletha-
nolamine. These authors also cited the previous work related
to the antiinflammatory behavior of PEA [7–10]. They con-
cluded that the mechanism of action of PEA was not clear.
In another work, Petrocellis et al. [11] tried to explain the
mechanism of action of PEA and suggested that PEA might
act as a positive modulator of vaniloidVR receptors or inhibit
the degradation of anandamide (AEA) by inhibiting either
the activity or the expression of fatty acid amide hydrolase
(FAAH). Actually, PEA increases the biological activity of
AEA. Here also, the exact mechanism of action for inflam-
mation reduction was not dealt with. In the same year, Costa
et al. [12] described the therapeutic effect of palmitoyletha-
nolamide (PEA) and demonstrated its curative effect in acute
inflammation. They concluded that the inhibition of COX
activity and of NO and free-radical formation at the inflam-
mation sight might be responsible for the activity. Lambert et
al. [13], revising their work on PEA considered this com-
pound as a new class of antiinflammatory agent and thought
that PEA (an endogenous compound) is accumulated at the
inflammation site and helps to suppress it. Very recently,
A search of literature revealed that several 1,3,4-
oxadiazoles containing long hydrocarbon chains have been
synthesized [1]. These heterocyclic fatty acid derivatives were
prepared with a view to enlarge the variety of new fatty com-
pounds with possible biological activity. However, no bio-
logical activity tests of these fatty heterocyclic compounds
have been described. To the best of our awareness, 1,2,4-
oxadiazoles having long fatty acid chain at C-5 have not been
reported. Therefore, it appeared attractive to undertake the
synthesis of 1,2,4-oxadiazoles carrying a 15-carbon side-
chain at C-5. In fact, these new heterocycles may be consid-
ered as isosters of palmitic acid esters and amides which pos-
sess interesting pharmacological properties. For example,
N-(2-hydroxyethyl)palmitamide (PEA) helps to prevent acute
respiratory diseases (ARD) in men [2,3]. It has also been
shown that administration of PEA does not have any influ-
ence on the formation of antibodies [4]. The production of
palmitic acid ethyl ester (PAEE) in pregnant rat and its off-
* Corresponding author. Tel.: +55 81 2126 8440; fax: +55 81 2126 8442.
E-mail address: rms@ufpe.br (R.M. Srivastava).
1 Part of work was done while holding the undergraduate CNPq fel-
lowship and another part under the State Government fellowship (FACEPE).
0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2005.08.003

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N.M.M. Bezerra et al. / Il Farmaco 60 (2005) 955–960
Verme et al. [14] identified the nuclear receptor peroxisome
proliferator-activated receptor-a (PPAR) which secures the
fatty acid amide (PEA) and causes the inflammation reduc-
tion. A recent publication also reports the antiinflammatory
activity of triterpene-fatty acid esters and free fatty acids [15].
1,2,4-Oxadiazoles themselves are significant in terms of
their pharmacological properties. Several such activities have
been cited by Kaboudin and Navaee [16]. 1,2,4-Oxadiazoles
with propyl and isopropyl functions at C-5 have been found
to possess antiinflammatory activity [17,18]. The title com-
pounds 4a–f exhibited antiinflammatory activity closely
resembling to aspirin and ibuprofen. Further, compounds 4a,
d, e were tested for antitumor activity where 4d has demon-
strated the growth inhibition of carcinoma cells by 75%. Thus,
it is clear that the 1,2,4-oxadiazole nucleus is quite interest-
ing and might disclose more undiscovered biological activi-
ties. Therefore, this contribution reports for the first time a
simple and straightforward synthesis of six 1,2,4-oxadiazoles
having a long hydrocarbon chain attached at C-5 (Scheme 1)
possessing antiinflammatory and antitumor properties.
Scheme 1
.
2. Chemistry
ing Ltd., UK, and are uncorrected. Elemental analyses of all
compounds were carried out by Eliete de Fátima V. Barros of
our Department. Infrared spectra were recorded on a Bruker
spectrophotometer Model IF S66 using KBr pellets, and the
1H NMR spectra were measured with a 300 MHzVarian Unity
Plus Instrument in CDCl3 employing tetramethylsilane (TMS)
as an internal standard. Low resolution mass spectra of all
compounds were obtained on a Finnigan MATGCQ ion trap
instrument, having electron energy of 70 eV. Thin-layer chro-
matography (TLC) was done on plates coated with silica gel
g (Merck) containing fluorescent indicator (F254). The plates
were developed with chloroform/n-hexane (4:1) and the spots
were visualized under ultraviolet light. Commercially avail-
able solvents and reagents were used for the experiments
described in this paper.
The title 1,2,4-oxadiazoles 4a–f have been prepared by
reacting arylamidoximes 1a–f with palmitic acid 2 in the pres-
ence of dicyclohexylcarbodiimide. The formation of the inter-
mediates 3a–f were visualized on the thin-layer chromato-
gram. Filtration and work-up left crude 3a–f in almost
quantitative yield. No effort was made to purify them because
even slight heating causes some ring closure hence the prod-
uct remains as a mixture of 3a–f and 4a–f. These were heated
individually for about 6 h at 110 °C for complete cyclization.
The structures of 4a–f were verified by the spectroscopic data
period. The infrared spectra (KBr pellets) and the 1H NMR
chemical shift data agreed with the proposed structures.
Two of these compounds, 4b is a thick oil while 4c is a
paste, but the others could be recrystallized from chloroform/
n-hexane.
3.2. Synthesis
3.2.1. Benzamidoximes 1a–f
Benzamidoxime and ring substituted benzamidoximes
were synthesized by the method reported earlier [19,20].
3. Experimental
3.1. General
3.2.2. 3-Aryl-5-decapentyl-1,2,4-oxadiazoles 4a–f
Melting points were determined with a digital Melting
Point Apparatus, series 1A-9100, Electrothermal Engineer-
An appropriate arylamidoxime 1 (1.0 mmol), palmitic acid
2 (1.0 mmol) and dicyclohexylcarbodiimide (1.25 mmol) were

N.M.M. Bezerra et al. / Il Farmaco 60 (2005) 955–960
957
dissolved in dichloromethane (5.0 ml) and left under stirring
for 6 h at room temperature under nitrogen atmosphere. TLC
(cyclohexane/ethyl acetate, 9:1) confirmed the consumption
of all arylamidoxime. Filtration of dicyclohexylurea and
washing the solid with a little dichloromethane gave a trans-
parent solution which contained largely the intermediate
O-palmitoylbenzamidoxine 3a–f. Each intermediate was
heated individually at 110 °C for about 6 h for complete
cyclization. Further purification was achieved by passing the
crude 1,2,4-oxadiazole through a column containing silica
gel. The pure compound could be eluted with cyclohexane/
ethyl acetate (9.9:0.1). Thus, all oxadiazoles 4a–f have been
obtained in the pure form. The yields furnished below are of
chromatographically pure compounds. Oxadiazoles 4a, d–f
were crystallized and recrystallized from chloroform–n-
hexane. The details of each compound are given below:
Calcd. for C24H38N2O (370.5492): C, 77.79; H, 10.34; N,
7.56. Found: C, 77.59; H, 10.36; N, 7.59%.
3.2.2.4. 5-Decapentyl-3-(p-tolyl)-1,2,4-oxadiazole (4d). M.p.
57.1 °C (74.4%), Rf = 0.52; IR (KBr): 3063 (m C–H, aro-
matic), 2954 (m CH3), 2917 (mas CH2), 2848 (ms CH2), 1588
(m C=N) cm−1; 1H NMR (CDCl3): d 7.96 (d, 2H, J = 8.7 Hz,
Ar-H), 7.28 (d, 2H, J = 8.7 Hz,Ar-H), 2.93 (t, 2H, H-6, H-6′),
2.41 (s, 3H, Ar-CH3), 1.86 (p, 2H, H-7, H-7′), 1.18–1.48 (m,
24H, H-8, H-8′ to H-19, H-19′), 0.88 (t, 3H, CH3); 13C NMR
(CDCl3): d 179.9 (C-5), 168.2 (C-3), 141.3 (C-4′), 129.5 (C-3′
and C-5′), 127.3 (C-2′ and C-6′), 124.1 (C-1′), 31.9 (C-6),
29.6, 29.5, 29.3, 29.1, 29.0, 26.7, 22.7 (C-7 to C-19), 21.5
(Ar-CH3), 14.1 (C-20); MS (EI): m/z (M+, 370);Anal. Calcd.
for C24 H38N2O (370.5492): C, 77.79; H, 10.34; N, 7.56.
Found: C, 77.50; H, 10.36; N, 7.12%.
3.2.2.1. 5-Decapentyl-3-phenyl-1,2,4-oxadiazole (4a). M.p.
44.5–45.0 °C (86%), Rf = 0.50; IR (KBr): 3060 (m C–H, aro-
matic), 2947 (m CH3), 2920 (mas CH2), 2839 (ms CH2), 1598
(m C=N) cm−1; 1H NMR (CDCl3): d 8.05–8.09 (m, 2H,Ar-H),
7.45–7.51 (m, 3H, Ar-H), 2.94 (t, 2H, H-6, H-6′), 1.87 (p,
2H, H-7, H-7′), 1.18–1.45 (m, 24H, H-8, H-8′ to H-19, H-19′),
0.88 (t, 3H, CH3); 13C NMR (CDCl3): d 180.1 (C-5); 168.2
(C-3), 131.0 (C-4’), 128.8 (C-3′ and C-5′), 127.4 (C-2′ and
C-6′), 126.9 (C-1′), 31.9 (C-6), 29.66, 29.64, 29.61, 29.5, 29.4,
29.3, 29.1, 29.0, 26.7, 26.6, 22.7 (C-7 to C-19), 14.1 (C-20);
MS (EI): m/z (M+, 356); Anal. Calcd. for C23H36N2O
(356.5194): C, 77.47; H, 10.17; N, 7.85. Found: C, 77.61; H,
10.17; N, 8.16%.
3.2.2.5. 5-Decapentyl-3-(p-Chlorophenyl)-5-decapentyl-1,2,4-
oxadiazole (4e). M.p. 60.2 °C (85%), Rf = 0.56; IR (KBr):
2955 (m CH3), 2918 (mas CH2), 2847 (ms CH2), 1591 (m C=N)
1
cm−1; H NMR (CDCl3): d 8.01 (d, 2H, J = 9.0 Hz, Ar-H),
7.45 (d, 2H, J = 8.7 Hz, Ar-H), 2.93 (t, 2H, H-6, H-6′), 1.86
(p, 2H, H-7, H-7′), 1.18–1.48 (m, 24H, H-8, H-8′ to H-19,
H-19′), 0.87 (t, 3H, CH3); 13C NMR (CDCl3): d 180.3 (C-5),
167.4 (C-3), 137.1 (C-4′), 129.1 (C-3′ and C-5′), 128.7 (C-2′
and C-6′), 125.4 (C-1′), 29.64, 29.60, 29.5, 29.3, 29.1, 29.0,
26.6, 22.7 (C-7 to C-19), 31.9 (C-6), 14.1 (C-20); MS (EI):
m/z (M+, 390); Anal. Calcd. for C23H35N2OCl (390.9658):
C, 70.65; H, 9.02; N, 7.17. Found: C, 70.77; H, 8.80; N,
7.36%.
3.2.2.2. 5-Decapentyl-3-(o-tolyl)-1,2,4-oxadiazole (4b). Col-
orless oil (70.3%), Rf = 0.49; IR (KBr): 3063 (m C–H, aro-
matic), 2928 (mas CH2), 2853 (ms CH2), 1592 (m C=N) cm−1;
1H NMR (CDCl3): d 7.94–8.00 (dd, 1H, J = 7.5 Hz,
J = 1.8 Hz,Ar-H), 7.26–7.42 (m, 3H,Ar-H), 2.95 (t, 2H, H-6,
H-6′), 1.88 (p, 2H, H-7, H-7′), 1.19–1.50 (m, 24H, H-8, H-8′
to H-19, H-19′), 0.88 (t, 3H, CH3); 13C NMR (CDCl3): d 178.9
(C-5), 168.8 (C-3), 138.1 (C-2′), 131.3 (C-4′), 130.4 (C-6′),
129.9 (C-3′), 126.2 (C-1′), 125.9 (C-5′), 29.66, 29.64, 29.61,
29.5, 29.4, 29.3, 29.1, 29.0, 26.6, 26.5, 22.7 (C-7 to C-19),
14.1 (C-20); MS (EI): m/z (M+, 370); Anal. Calcd. for C24
H38N2O (370.5492): C, 77.79; H, 10.34; N, 7.56. Found: C,
77.97; H, 10.42; N, 7.87%.
3.2.2.6. 5-Decapentyl-3-(p-bromophenyl)-5-decapentyl-1,2,4-
oxadiazole (4f). M.p. 63.4 °C (81%), Rf = 0.57; IR (KBr):
3081 (m C–H aromatic), 2949 (m CH3), 2917 (masCH2), 2846
(msCH2), 1593 (m C=N) cm−1; 1H NMR (CDCl3): d 7.95 (d,
2H, J = 8.7 Hz, Ar-H), 7.61 (d, 2H, J = 8.7 Hz, Ar-H), 2.93
(t, 2H, H-6, H-6′), 1.86 (p, 2H, H-7, H-7′), 1.18–1.52 (m,
24H, H-8, H-8′ through H-19, H-19′), 0.88 (t, 3H, CH3); 13
C
NMR (CDCl3): d 180.3 (C-5), 167.5 (C-3), 132.1 (C-3′ and
C-5′), 128.9 (C-2′ and C-6′), 125.9 (C-4′), 125.6 (C-1′), 29.6,
29.5, 29.3, 29.1, 29.0, 26.6, 22.7 (C-7 to C-19), 31.9 (C-6),
14.1 (C-20); MS (EI): m/z (M+c, 434); Anal. Calcd. for
C23H35N2OBr (435.4198): C, 63.43; H, 8.10; N, 6.43. Found:
C, 63.79; H, 8.39; N, 6.18%.
3.2.2.3. 5-Decapentyl-3-(m-tolyl)-1,2,4-oxadiazole (4c). Paste
(70%), Rf = 0.54; IR (KBr): ~3050 (m C–H, aromatic), 2926
4. Biological evaluation of compounds 4a–f
1
(mas CH2), 2854 (ms CH2), 1576 (m C=N) cm−1; H NMR
4.1. Determination of acute antiinflammatory activity
(CDCl3): d 7.84–7.92 (m, 2H, Ar-H), 7.28–7.40 (m, 2H,
Ar-H), 2.94 (t, 2H, H-6, H-6′), 2.42 (s, 3H, Ar-CH3), 1.87 (p,
2H, H-7, H-7′), 1.20–1.48 (m, 24H, H-8, H-8′ to H-19, H-19′),
0.88 (t, 3H, CH3); 13C NMR (CDCl3): d 179.9 (C-5), 168.3
(C-3), 138.6,9 (C-3′), 131.8 (C-4′), 128.7 (C-5′), 127.9 (C-2′),
126.8 (C-1′), 124.5 (C-6′), 31.9 (C-6), 29.66, 29.64, 29.61,
29.5, 29.4, 29.3, 29.1, 29.0, 26.68, 26.64, 22.7 (C-7 to C-19),
21.3 (Ar-CH3), 14.1 (C-20); MS (EI): m/z (M+, 370); Anal.
Three-month-old Swiss white mice with 25–30 g body
weight were maintained with water and food (Labina-
Agribands of Brazil, Ltd.) ad libitum. Ten groups, each con-
taining 10 animals, were used separately for each experi-
ment. Saline solution (0.9%) was administered to the control
group. The drugs used for comparison purposes were aspirin

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N.M.M. Bezerra et al. / Il Farmaco 60 (2005) 955–960
Table 1
Acute antiinflammatory activity test results of compounds 4a–f
Compound Dose
(mg kg–1
Average paw weight
(g)
Edema
inhibition (%)
)
Control
Aspirin
Ibuprofen
CMC
4a
4b
4c
4d
4e
–
0.155
–
250
250
–
0.049***
0.042***
0.147*
68
73
5
250
250
250
250
250
250
0.109*
29
55
67
67
33
34
0.070**
0.051***
0.051***
0.103**
0.102**
4f
Significant differences: *P < 0.05 **P < 0.005 and ***P < 0.001.
Fig. 1. Dose–response for 4c (n), 4d (*) and ibuprofen (m). For introducing
inflammation, 1.0% of carrageenin in 0.9% aqueous NaCl solution was used.
and ibuprofen. All compounds were suspended in 1% car-
boxymethylcellulose (CMC) dissolved in water and a single
dose of 250 mg kg–1 was administered intraperitoneally in
the morning. Other animal group received 1% CMC only.
Two positive and one negative antiinflammatory tests were
done in three animal groups by intraperitoneal administra-
tion of 250 mg kg–1 of aspirin (standard for pharmacological
comparative tests [21] in the first group, 250 mg kg–1 of ibu-
profen (Brazilian Teuto Laboratory Ltd., Brazil) in the sec-
ond group and 0.9% of aqueous saline solution in the third
group, respectively. The antiinflammatory activity was deter-
mined by Levy and Kerley [22] method. A 0.1 ml of 1% car-
rageenin (Sigma, St. Louis, USA) in 0.9% aqueous NaCl solu-
tion was injected through the plantar tissue of the right hind
paw of each mouse to produce inflammation. The test com-
pounds were injected intraperitoneally 30 min later.After 4 h,
their paws were cut and weighed. The results were analyzed
according to the percentage of inflammation reduction as
described earlier [23]. Table 1 represents the results obtained.
4.4. Statistics
The antiinflammatory activity differences between the con-
trol and test groups of various drugs were analyzed by the
Student’s t-test for independent samples. P < 0.05 was used
as the criterion of statistical significance, which is the test
standard.
4.5. Determination of antitumor activity of 4a, d, e
Five groups of Swiss white mice (each containing six ani-
mals) were used for carrying out the tests. The Stock et al.’s
method [25] was used for pharmacological tests. The ani-
mals were disinfected, and anesthetized and subjected to a
surgical intervention with one incision in the axial region
where a tumor fragment was inserted subcutaneously. The
treatment was started 48 h after surgical intervention. The
compounds 4a, d, e were administered intraperitoneally for
8 days in only one dose of 200 mg kg–1 day–1. All com-
pounds were suspended in 1% CMC solution. After complet-
ing the treatment, the animals were weighed again to observe
the change in weight. The tumoral mass was removed and
put in the sterilized petridish, separated by the group and
finally weighed. The tumor inhibition percentage was deter-
mined by the equation: TWI = [C – T/C] × 100, where
TWI = percentage of tumor growth inhibition, C = average
tumor weight of control group and T = average tumor weight
of the treated group [26].
4.2. Determination of dose–response for antiinflammatory
activity
Compounds with the best antiinflammatory activity (4c
and 4d) and ibuprofen (obtained from Bristol-Myers Squibb,
Brazil) were administrated in single doses of 50, 150, 250 and
350 mg kg–1, in separate animal groups having inflammation
induced by carrageenan. The reduction of inflammation was
recorded after 4 h in each animal group (Fig. 1).
4.3. Determination of acute toxicity of 4a–f
5. Results and discussion
Graded doses (50–1000 mg kg–1) of the compounds were
administered intraperitoneally to various groups each con-
taining five mice [24]. On the first day, the animals were evalu-
ated every 10 min for 4 h followed by 24, 48 and 72 h for
changes in spontaneous motor activity, reactivity, gait, respi-
ration, appearance of writhing, piloerection, etc., plus mor-
tality. This shows that the compounds employed in these
experiments did not show any abnormal phenomenon.
5.1. Preliminary acute toxicity and antiinflammatory
activity test of 3-aryl-5-decapentyl-1,2,4-oxadiazoles 4a–f
All six compounds 4a–f are non-lethal in mice at four times
the therapeutic dose (i.p., LD50 > 1 g kg–1). Preliminary anti-
inflammatory activity tests for compounds 4a–f exhibited
positive results. Oxadiazoles 4a, 4e and 4f reduced
carrageenan-induced edema in mice by 29, 33 and 34%,

N.M.M. Bezerra et al. / Il Farmaco 60 (2005) 955–960
959
respectively. This result is significant (P < 0.05) (see Table 1)
compared to the control group treated with saline solution.
However, compounds 4b, 4c and 4d, which have a ortho-,
meta- and para-substituent in the phenyl ring did show a sig-
nificant decrease in edema (55, 67 and 67%; P < 0.001)
greater than the control animals treated with 0.9% saline or
1% CMC solution. Furthermore, the antiinflammatory effect
of compounds 4c and 4d were comparable with aspirin (68%)
and ibuprofen (73%). These results are compiled in Table 1.
Since compounds 4c and 4d gave the best acute antiinflam-
matory activity, its dose–response curve was compared with
ibuprofen (see Fig. 1), which clearly shows that administra-
tion of 250 mg of compound 4c per kg of animal’s body
weight reduces the inflammation by 67%. This is closer to
the value obtained by ibuprofen. Increasing the dose of 4c
and 4d to 350 mg kg–1 of the animal’s weight slightly
improves the performance of these heterocycles and brings
the activity very close to ibuprofen (70 and 73%, Fig. 1). A
comparison of the antiinflammatory activity of 3-(m-tolyl)-
Fig. 2
.
Effect of PEA on edema (10 mg kg–1 of the animal’s body weight)
[m], ibuprofen (250 mg kg–1) [*], 4c (250 mg kg–1) [♦ ], 4 d (250 mg kg–1
)
[n] and CMC (1% w/v in saline) [n], after 2, 4, 24 and 30 h injection of
carrageenan (1% w/v in saline solution). Each point represents the percen-
tage of edema reduction of five animals per group.
lished, it appears that both class of compounds presumably
have something in common when they approach the enzyme
site. Possibly PEA and oxadiazoles form hydrogen bonds with
one or more amino acid residues present in the enzyme cav-
ity.
5-decapentyl-3-(m-tolyl)-1,2,4-oxadiazole
4c
and
5.2. Preliminary antitumor activity test of 3-aryl-5-decap-
5-decapentyl-3-(p-tolyl)-1,2,4-oxadiazole 4d with oxadiaz-
oles containing isopropyl chain at C-5 clearly shows the bet-
ter performance of 4c and 4d, respectively [18]. We observed
that all compounds with decapentyl group at C-5 of 1,2,4-
oxadiazoles increased the antiinflammatory activity. This
observation might be explained by postulating that the com-
pounds with longer hydrocarbon chains are able to enter the
cells more quickly and leave the cells more slowly than those
with shorter chains due to their increased hydrophobicity, or
perhaps the shorter molecules are excreted more quickly.
In order to get more insight especially for compounds 4c
and 4d, we wished to compare these oxadiazoles with N-(2-
hydroxyethyl)palmitamide (PEA). For this purpose, we syn-
thesized PEA by the known procedure [27]. Its antiinflam-
matory property was determined and compared with
oxadiazoles 4c and 4d. Carrageenan-induced edema in a group
of five animals showed quite interesting results. Compound
4c reduced inflammation by 44% in 2 h whereas PEA behaved
somewhat similarly. After 4 h, the diminution was approxi-
mately 67% for 4c and 60% for PEA. This effect gradually
decreased and after 24 h, the observed decrease was only 56%
which means that the drug started losing its effect after some
time. However, both oxadiazole 4d and PEA kept on decreas-
ing the inflammation and after 30 h, a reduction of 74 and
80% were observed (Fig. 2). This clearly indicates that 4d
and PEA behave similarly.
entyl-1,2,4-oxadiazoles 4a–f
Tumors were created in the epithelial cells (see Section 4).
Compounds 4a, d, e showed the inhibition of 75, 55 and 23%,
respectively, in descending order 4d > 4a > 4e. These results
were compared with lapachol which inhibited Ehrlich’s car-
cinoma cells’ growth by 80%. According to the standard of
National Cancer Institute, a substance is considered active if
it inhibits the tumor growth by 50% [28]. The tumor appear-
ance of the control group gradually became intensely red with
normal growth which was not limited to the surface only but
started penetrating into the tissues. With the exception of 4e,
the other two compounds 4a, d exhibited significant reduc-
tion in red color and turning slowly to whitish color. No tis-
sue penetrating effects were observed. Although we tested
only three compounds for this activity, it is quite clear that
electron donating group at para position on the phenyl ring
have profound influence in reducing the tumor size whereas
the electron-withdrawing group diminishes such effect.
In conclusion, we have achieved the synthesis of six 3-aryl-
5-decapentyl-1,2,4-oxadiazoles 4a–f in an efficient manner.
Pharmacological evaluation of these compounds revealed
them to possess antiinflammatory and antitumor activities.
None of the tested compounds presented any toxicity in doses
ranging from 50 to 1000 mg kg–1 of the animals’ body-
weight.
As far as compounds 4c and 4d are concerned, we feel
that the 1,2,4-oxadiazole moiety gets attached at PPAR-a also
in a similar manner as PEA. This attachment should be
through the hydrogen bonding where the hydrogen donor is
from the receptor and acceptor is either PEA or 1,2,4-
oxadiazole part. Both molecules have some similarity. Shorter
chains due to their increased hydrophobicity, or perhaps the
shorter molecules are excreted more rapidly.
Acknowledgments
The authors express their gratitude to the Brazilian National
Research Council (CNPq) for financial help. One of us
(N.M.M.B.) is grateful to CNPq for an undergraduate fellow-
ship. We are thankful to Dr. Ivone Antônia de Souza, Antibi-
otics Department of this University, for her help in determin-
ing the antitumoral activity tests.
Although the mechanism of inflammation reduction either
by PEA or by 1,2,4-oxadiazole derivatives has not been estab-

960
N.M.M. Bezerra et al. / Il Farmaco 60 (2005) 955–960
[15] R.W. Li, D.N. Leach, S.P. Myers, G.J. Leach, G.D. Lin, D.J. Brushett,
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