Synthesis, anti-inflammatory and antimicrobial activities of new 1,2,4-oxadiazoles peptidomimetics

Article abstract of DOI:10.1016/S0014-827X(00)00099-9

A new series of 1,2,4-oxadizoles 6a-g have been synthesised in good yields using the peptide synthesis strategy. The prepared compounds were tested for anti-inflammatory and antimicrobial activities. The anti-inflammatory activities were determined in the

Full text of DOI:10.1016/S0014-827X(00)00099-9

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 719–724
Synthesis, anti-inflammatory and antimicrobial activities of new
1
,2,4-oxadiazoles peptidomimetics
a,
a
a
Ana Cristina L. Leite *, Renata F. Vieira , Antonio R. de Faria ,
b
b
c
Almir G. Wanderley , Parviz Afiatpour , Eul a´ lia Camelo P.A. Ximenes ,
Rajendra M. Srivastava , Claudia F. de Oliveira , M.V. Medeiros , Edson Antunes ,
d
e
e
e
a
Dalci J. Brondani
a
Laborat o´ rio de Planejamento, A6alia c¸ a˜ o e S ´ı ntese de F a´ rmacos, LABSINFA, Departamento de Ci eˆ ncias Farmac eˆ uticas,
Rua Prof. Artur S a´ s/n, Cidade Uni6ersit a´ ria, Uni6ersidade Federal de Pernambuco, Recife-PE, Brazil, CEP: 50740-520
Departamento de Fisiologia e Farmacologia, Rua Prof. Artur S a´ s/n, Cidade Uni6ersit a´ ria, Uni6ersidade Federal de Pernambuco,
b
Recife-PE, Brazil, CEP: 50740-520
Departamento de Antibi o´ ticos, Rua Prof. Artur S a´ s/n, Cidade Uni6ersit a´ ria, Uni6ersidade Federal de Pernambuco, Recife-PE, Brazil,
c
CEP: 50740-520
d
Departamento de Qu ´ı mica Fundamental, Rua Prof. Artur S a´ s/n, Cidade Uni6ersit a´ ria, Uni6ersidade Federal de Pernambuco,
Recife-PE, Brazil, CEP: 50740-520
Departamento de Farmacologia, Uni6ersidade Estadual de Campinas, Cidade Uni6ersit a´ ria, Zeferino Vaz s/n, Bar a˜ o Geraldo, Campinas,
e
S a˜ o Paulo, Brazil, CEP: 13.081-970 Caixa postal 6111
Received 25 March 2000; accepted 12 September 2000
Abstract
A new series of 1,2,4-oxadizoles 6a–g have been synthesised in good yields using the peptide synthesis strategy. The prepared
compounds were tested for anti-inflammatory and antimicrobial activities. The anti-inflammatory activities were determined in the
rat paw oedema induced by carrageenin. Compounds 6a, c, f and g (i.v.) significantly inhibited the rat paw oedema induced by
carrageenin depending upon the dose employed. The compounds were also evaluated for their in vitro antimicrobial activity.
Some compounds were found to have significant activity against Gram positive and Gram negative microorganisms. © 2000
Elsevier Science S.A. All rights reserved.
Keywords: Anti-inflammatory activity; Potential antimicrobial agents; 1,2,4-Oxadiazoles; Peptidomimetics; Peptide synthesis
been reported [8,9]. It has been shown that therapeuti-
1. Introduction
cally active agents with small peptides or amino acid
residues, exhibit reduced toxicity and enhance their
therapeutic effect [10–12]. It is supposed that an amino
acid transport system in the cell can be exploited to
deliver the oxadiazole nucleus to target cells for the
drug activity.
Considering the potential of these 1,2,4-oxadiazoles,
we undertook the synthesis of 1,2,4-oxadiazoles 6a–g
employing the classical strategy of peptide synthesis
1
,2,4-Oxadiazoles in general have attracted wide-
spread attention due to their important biological activ-
ities such as antiviral [1], fungicide [2], herbicide [3],
analgesic and anti-inflammatory [4]. Some of these ex-
hibited pronounced b-adrenoreceptor blocking activity
and moderate a-adrenoreceptor blocking properties [5].
Oxadiazoles are often considered as ester and amide
bioisosteres in drug research, and they have also been
used as dipeptidomimetics [6,7]. The optimum condi-
tions for the synthesis of 1,2,4-oxadiazole have already
[13]. This paper reports the synthesis of little com-
pounds for the first time and the verification of their
structures by spectroscopic means and elemental analy-
sis. The anti-inflammatory study was carried out ac-
cording to Winter et al. [14]. The antibacterial
properties of these compounds were tested as well.
*
Corresponding author.
E-mail address: aclb@npd.ufpe.br (A.C.L. Leite).
0
014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00099-9

7
20
A.C.L. Leite et al. / Il Farmaco 55 (2000) 719–724
2. Chemistry
the chiral carbon. Two singlets for NH group show
2
non-equivalence of these protons. For the NH function
1
,2,4-Oxadiazoles [15–17] are most commonly syn-
a characteristic doublet due to coupling with proton of
chiral carbon (J=8.0 Hz) appeared at l=4 ppm.
Different chemical shifts for the groups next to chiral
center are observed. This phenomenon is more pro-
nounced with bulky substituents. The IR spectra
showed characteristic group absorptions for wNH (3300
thesised from amidoximes and acetylating agents such
as carboxylic acid chlorides or anhydrides [18]. In this
study, the benzamidoxime was obtained as previously
reported, by reaction with hydroxylamine and benzoni-
trile [19]. A suitable treatment of 1 with succinic anhy-
dride gave 3 [8].
The pseudopeptide heterocyclic derivatives were syn-
thesised from Boc-protected amino acids. The synthetic
routes to afford the pseudopeptide derivatives were
applied on appropriately protected lipophilic (phenyl-
−1
−1
cm ), for wCꢀO, amide I band (1670 cm ), and CꢀN
−1
ring stretching (1573 cm ). The analytical data and
proton chemical shifts of the compounds are shown in
Tables 1–3.
alanine
D and L, valine, leucine and isoleucine) and
acidic (aspartic and glutamic) amino acids. The car-
boxylic acid function of 4 was treated with isobutyl
chloroformate in the presence of triethylamine and
ammonium hydroxide to obtain the desired amide in
good yield. In our strategy, we have chosen using the
aspartic and glutamic amino acids whose side chain’s
carboxylic acid function is protected by a benzyl ester.
The expected pseudopeptides derivatives 6a–g have
been synthesised by condensation of 3-[3-(phenyl)-1,2,4-
oxadiazol-5-yl] propionic acid 3 with 5a–g using benzo-
triazolyloxy-tris-(dimethylamino) phosphonium hexa-
fluorophosphate (BOP) to activate the carboxylic acid
function by generation of a highly reactive 1-hydroxy-
benzotriazole ester of the carboxyl component [20,21].
The 1,2,4-oxadiazol derivatives were obtained in a 40–
90% yield (Scheme 1).
3. Results
3.1. Chemistry
1
All compounds present characteristic H NMR sig-
nals for NH and NH moiety and the proton linked to
2
Scheme 1.
Table 1
Analytical data of 1,2,4-oxadiazoles derivatives
20 b
Rf c
Comp.
M.p. (°C) a
Yield (%)
(h)D
Molecular formula
C20H20N O
Calc. (%)
C
Found (%)
H
N
C
H
N
6
6
6
6
6
6
6
a
b
c
d
e
f
226–8
235–7
237–9
181–2
230–2
101–3
134–6
55
86
99
72
90
56
66
+21.3
−25.2
+30.1
−39.0
+20.5
−62.9
+30.1
0.69
0.52
0.34
0.40
0.45
0.56
0.69
65.92
65.92
60.74
61.80
61.80
62.55
63.29
5.53
5.53
6.37
6.71
6.71
5.24
5.54
15.37
15.37
17.70
16.96
17.70
13.26
12.83
65.87
65.90
60.81
61.81
61.72
62.63
63.50
5.50
5.52
6.39
6.70
6.7
15.4
4
3
3
3
3
3
5
5
C20H20N O
15.38
17.72
17.01
17.01
13.3
4
C16H20N O
4
C17H22N O
4
C17H22N O
4
C22H22N O
5.24
5.51
4
g
C23H24N O
12.75
4
a
b
c
Crystallized from ethyl acetate/ether/hexane.
Solvent: dimethylsulfoxyde; [ ]=4 mg/ml.
Solvent system: Ethyl acetate.

A.C.L. Leite et al. / Il Farmaco 55 (2000) 719–724
721
Table 2
IR spectral data of compounds
−
1
Comp.
IR cm
(KBr)
Assym. (NꢁH)(NH2)
Sym. (NꢁH)(NH2)
w(NꢁH)(NH2)
(CꢀOamide1a
)
(CꢀOamide2a
)
(CꢀC)
(CꢀN)
(CꢁN)
6
6
6
6
6
6
6
a
b
c
d
e
f
3363.7
3363.6
3357.8
3371.1
3358
3286.2
3286.7
3283
3281.1
3287
3199.9
3199.7
3200.5
3203.6
3199.5
3211.8
3206.4
1674.5
1674.7
1674.3
1673.4
1673.8
1667.7
1672.3
1642
1594.6
1573.3
1595.2
1547.2
1424.4
1570.1
1573.4
1573.2
1545.4
1573.1
1574
1545.8
1550.6
1539.7
1346.5
1346.5
1345.0
1346.8
1374.3
1366.9
1346.8
1642.4
1641.5
1641.7
1638
1667.7
1643.7
3414.1
3374.7
3302.9
3284.5
g
Table 3
NMR spectral data of compounds
1
Comp H NMR l ppm (DMSO-d )
6
.
6
6
6
6
a
b
c
2.68(t, J=7.29, 2H); 2.71(dd, J=13.35, 4.95, 1H, CH ); 2.99(dd, J=13.35, 4.49, 1H, CH ); 3.06(t, J=7.19, 2H); 4.30–4.45
2 2
(
m, 1H); 7.06(s (NH ), 1H); 7.10–7.30(m, 5H); 7.45(s (NH ), 1H); 7.50–7.62(m, 3H); 7.88–8.02(m, 2H); 8.23(d (NH), J=8.09 Hz, 1H)
2
2
2.70(t, J=7.29, 2H); 2.77(dd, J=13.94, 4.49, 1H, CH ); 3.0(dd, J=13.94, 4.79, 1H, CH ); 3.08(t, J=7.29, 2H); 4.36–4.48
2
2
(
m, 1H); 7.07(s (NH ), 1H); 7.2–7.28(m, 5H); 7.44(s (NH ), 1H); 7.53–7.62(m, 3H); 7.95–8.02(m, 2H); 8.25(d (NH), J=8.09 Hz, 1H)
2
2
1.23(d, J=5.99, 6H), 2.3–2.45(m, 1H), 3.20(t, J=6.89, 2H), 3.6(t, J=6.90, 2H); 4.52(dd, J=8.39, 7.49, 1H), 7.44(s (NH ), 1H),
2
7
.82(s (NH ), 1H); 7.9–8.1(m, 3H); 8.3–8.5(m, 2H); 8.41(d (NH), J=8.39 Hz, 1H)
2
d
0.74(d, J=6.29, 3H); 0.82(d, J=6.29, 3H); 1.41(2ddd, J=7.49, 7.19, 6.89, 2H); 1.48–1.61(m, 1H); 2.74(t, J=6.89, 2H), 3.18
(
t, J=7.19, 2H); 4.2(ddd, J=8.09, 7.34, 6.59, 1H); 6.97(s (NH ), 1H); 7.34(s (NH ), 1H); 7.53–7.62(m, 3H); 7.96–8.02 (m, 2H);
2
2
8
.13(d (NH), J=8.39 Hz, 1H)
6
e
0.75 (dd, J=7.49, 7.19, 3H); 0.78(d, J=6.59, 3H); 0.98–1.12(m (CH ), 1H); 1.37–1.45(m (CH ), 1H); 1.62–1.8(m, 1H); 2.79(t,
2
2
J=7.49, 2H); 3.18(t, J=7.49, 2H); 4.10(dd, J=8.09, 7.79, 1H); 7.02(s (NH ), 1H); 7.47(s (NH ), 1H); 7.52–7.6(m, 3H);
2
2
7
.94–8.02(m, 2H); 8.16(d (NH), J=8.99 Hz, 1H);
2.55(2 dd, J=12.89, 5.69, 2H); 2.75(t, J=7.19, 2H); 3.16(t, J=7.19, 2H); 4.63(ddd, J=13.79, 7.19, 6.89, 1H); 5.07(s, 2H); 6.96
s (NH ), 1H); 7.28–7.38(m, 5H); 7.41(s (NH ), 1H); 7.52–7.62(m, 3H); 7.96–8.02 (m, 2H); 8.49(d (NH), J=7.79 Hz, 1H)
6
f
(
2
2
6
g
1.79–1.82(m (CH ), 1H); 1.92–2.04(m (CH ), 1H); 2.36(dd, J=8.09, 7.79, 2H); 2.76(t, J=6.89, 2H); 3.17(t, J=6.89, 2H);
2
2
4
.21(ddd, J=8.99, 8.09, 5.69, 1H); 5.04(s, 2H); 7.09(s (NH ), 1H); 7.29–7.37(m, 5H); 7.38(s (NH ), 1H); 7.52–7.59(m, 3H),
2
2
7
.95–8.01(m, 2H); 8.19(d (NH), J=8.09 Hz, 1H)
3
3
.2. Biological acti6ity
h of observation (n=6). Compound 6d significantly
potentiated the oedema at 1 h after administration
(76931 and 5399.7% potentiation for 3 and 10 mg/
kg, respectively) but had no significant effects there-
after. The compound 6e did not show any noticeable
inhibitory effect on the carrageenin-induced oedema at
3 mg/kg (not shown). Higher doses of 6e were not
studied since it evoked toxic effect in the animals
.2.1. Anti-inflammatory acti6ity
Table 4 shows that compounds 6a, c, f and g signifi-
cantly inhibited the rat paw oedema induced by car-
rageenin depending on the dose employed. At the doses
of 3 and 10 mg/kg, compounds 6a and c caused marked
inhibition (PB0.05) of the carrageenin-induced paw
oedema. At 3 mg/kg, compound 6f showed a discrete
and non-significant inhibition, but with a higher dose
accompanied by death in ca.
administration.
1
min after
(
10 mg/kg), it significantly inhibited the carrageenin-in-
duced oedema (Table 4). The compound 6g markedly
PB0.05) inhibited the carrageenin-induced oedema at
The oral administration of the compounds 6a, c and
g was totally ineffective in inhibiting the oedema in-
duced by carrageenin during all the observed periods of
time. As expected, the indomethacin produced signifi-
cant inhibition (between 30 and 45%) of the oedema
(not shown).
(
the dose of 3 mg/kg, but failed to affect the oedemato-
genic response at 10 mg/kg (Table 4).
The compound 6b potentiated the oedematogenic
activity by 20–40% at 3 mg/kg whereas at 10 mg/kg it
significantly inhibited (PB0.05) the oedema at 1 and 2
The pharmacological results presented here demon-
strate that compounds 6a, c and g when administered

7
22
A.C.L. Leite et al. / Il Farmaco 55 (2000) 719–724
Table 4
The inhibitory effects of compounds 6a,c,f,g (i.v.) on the carrageenin-induced rat oedema
Inhibition (%)
Comp.
1 h
2 h
3 h
4 h
5 h
3
6
6
6
6
mg/kg
a
c
f
37914.7 *
3399.3 *
0
5497 *
3597.8 *
2695.7 *
20913.0
5497.7 *
1999.5
2098
3899.4 *
25911.3
6397.4 *
3397.3 *
24911.0
30915.5 *
2296.7 *
20914.1
896.4
g
4495.5 *
1
6
6
6
6
0 mg/kg
a
c
f
57910.7 *
6894.5 *
2598.6
5796.9 *
17912.8
5594.6 *
3696.4 *
5296.8 *
1596.9
5194.6 *
3294.4 *
4399.4 *
1195.3
4896.8 *
3395.2 *
35911.6 *
9.997.1
0
0
0
g
*
PB0.05 compared with the controlled animals.
intravenously are anti-edematogenic. However, when
administered orally, these compounds did not modify
the carrageenin-induced oedema. We do not have infor-
mation on the action mechanism of these compounds,
but this report suggests their possible incapability of
absorption or destruction by the digestive enzymes.
mg/ml against P. mirabilis. Compound 6d presents an
interesting bacteriostatic activity, but this activity was
inferior to ciprofloxacin, the reference antibiotic whose
MIC was 2 and 4 mg/ml against E. coli and P. mirabilis,
respectively.
Concerning the relationships between structure and
activity, it can be noted that the compounds 6d, e and
f carrying a leucine, isoleucine, and aspartic acid moi-
eties, respectively, exhibited an antimicrobial potency,
generally superior to compounds 6a, b, c and g. These
compounds containing an amino acid residue in side
chain of 1,2,4-oxadiazoles showed a novel profile of
antimicrobial activity for this class of heterocyclic
compounds.
3.2.2. Antimicrobial acti6ity
The antimicrobial activity of seven synthesised com-
pounds was determined in vitro by the disc diffusion
method [22] against two strains of Staphylococcus au-
reus, Bacillus cereus, Escherichia coli, Klebsiella pneu-
moniae, Proteus mirabilis, Salmonella enteritidis,
Pseudomonas aeruginosa and two strains of Candida
albicans. The Mueller–Hinton, Sabouraud agar and
Mueller–Hinton broth have been used as a medium of
reference for antimicrobial activity tests and minimal
inhibitory concentration (MIC) determination, respec-
tively [23].
4
. Experimental
4.1. Chemistry
Compound 6d was found to be the most active of
them all. E. coli was the most sensitive and its inhibi-
tion zone was 22 mm. This compound showed to be
active also against P. mirabilis, S. enteritidis, and P.
aeruginosa. The inhibition zones were 17, 12, and 11
mm, respectively. Compound 6f was found to be active
against both strains of S. aureus and its inhibition zones
was equal to 11 mm. K. pneumoniae and B. cereus were
inhibited by 6e; inhibition zones were 13 and 10 mm,
respectively. The other compounds were either devoid
of activity or the inhibition zones were inferior to 10
mm for all considered strains.
The bacteriostatic activity of compound 6d was de-
termined in vitro against E. coli and P. mirabilis.
Ethyleneglicol was used as the solvent for the com-
pounds and a control without the test compound was
included for each tested microorganisms in the 1:10
dilution. Its MIC was 64 mg/ml against E. coli and 128
All melting points were determined with a Thomas
Hoover apparatus and are uncorrected. IR spectra were
obtained on FTIR spectrophotometer Brukker, model
1
IFS66 using KBr pellets. H NMR spectra were mea-
sured with a Varian UNITYplus 300 MHz NMR spec-
trophotometer using DMSO-d6 as solvent and
tetramethylsilane as an internal standard. Thin-layer
chromatography (TLC) was carried out on silica gel
coated plates having fluorescence indicator F254 (0.2
mm, E. Merck); the spots were visualised under UV
light, and by spraying with a 5% acetone solution of
ninhydrin or Charing reagent. Column chromatogra-
phy was carried out on using Kiesegel 60 (230–400
mesh, E. Merck). Protected amino acids (Boc and
Obzl), were purchased from Bachem (Switzerland) or
Propeptide (France), BOP reagent was purchased from
Propeptide. All reagents used in the present work were
of analytical grade.

A.C.L. Leite et al. / Il Farmaco 55 (2000) 719–724
723
4
.1.1. 3-[3-(Phenyl)-1,2,4-oxadiazol-5-yl] propionic
acid (3)
This compound was prepared according to the
method reported earlier [8].
kg (n=6). The Student t-test [24] was used to test for
statistical significance (PB0.05).
4.2.2. Antimicrobial acti6ity
The antimicrobial activity was determined in vitro by
disc diffusion method [22] against two strains of S.
aureus, B. cereus, E. coli, K. pneumoniae, P. mirabilis, S.
enteritidis, P. aeruginosa and two strains of C. albicans.
Overnight cultures were grown at 37°C in Mueller–
Hinton broth and diluted to obtain an opacity equiva-
lent to 0.5 on the McFarland scale. It was then
dispensed into Petri dishes to yield an uniform depth of
4 mm. The drugs are weighed and dissolved in
ethyleneglicol to give concentrations equal to 2 mg/ml.
The ciprofloxacin and cycloheximide were used to an-
timicrobial standard. The discs with a 6 mm diameter
were saturated to 20 ml drug solutions. The discs are
placed in the surface of culture medium after the com-
plete evaporation of ethyleneglicol. The plates are incu-
bated for 18 h at 37°C. Growth inhibition zones with
diameters equal to or greater than 10 mm were consid-
ered as positive results.
4
.1.2. General procedure for the protection of the
C-terminus moiety of the amino acids
To a cold (−10–0°C) solution of N-Boc-amino acid
(
3.5 mmol) in dimethylformamide, were successively
added isobutyl chloroformate (3.5 mmol) and ammo-
nium hydroxide (7.0 mmol) dropwise for 20 min. After-
wards, the mixture was stirred at room temperature for
2
h. Water was added and the pure product was
isolated by filtration followed by drying.
4
1
.1.3. General procedure for the synthesis of
,2,4-oxadiazoles containing pseudopeptide moiety
To the Boc-amino acylamide (3.0 mmol), trifl-
uoroacetic acid was added and left to stand at room
temperature for 1 h. Solvent evaporation in vacuo, and
trituration with diethyl ether–hexane gave a white pow-
der. The pure product was easily isolated by filtration
and dried. TFA–amino acylamide (2.6 mmol) was dis-
solved in DMF (10 ml) containing 3 (2.6 mmol), BOP
4.2.3. Bacteriostatic acti6ity
The bacteriostatic activity of compound 6d was de-
(
2.6 mmol) and TEA (0.7 ml) was added to it. The
termined in vitro against E. coli and P. mirabilis.
Overnight cultures were grown at 37°C in Mueller–
Hinton broth and afterwards, diluted to obtain an
opacity equivalent to 0.5 on the McFarland scale. The
compound is solubilized in ethyleneglicol and a serial
preparation was left to stand for 4 h at room tempera-
ture. Afterwards, ethyl acetate (50 ml) was added under
stirring. The organic layer was washed several times
with sodium bicarbonate (50 ml), water (50 ml), 1 M
citric acid (50 ml), water (50 ml), dried over sodium
sulfate and concentrated in vacuo. The residue was a
white powder after trituration with n-hexane.
2
-fold dilution of compound is prepared in water to
give concentrations 10-fold higher than the final one
desired. The concentration of 1280 mg/ml was used as
the starting one, providing a final concentration equal
to 128–0.5 mg/ml. The ciprofloxacin was used as refer-
ence antibiotic. It was verified that ethyleneglicol was
completely inactive against the tested microorganisms
in the 1:10 dilution.
4
4
.2. Anti-inflammatory acti6ity
.2.1. Measurement of paw oedema
Male Wistar rats (150–200 g) were used. Oedema
was induced by a single sub-plantar injection of car-
rageenin (1 mg/paw) into the left hind paw of the rat
under light ether anaesthesia. The total volume injected
was always 0.1 ml. The paw volume was measured
immediately before the injection and at hourly intervals
thereafter using a hydroplethysmometer (model 7150,
Ugo Basile, Italy). The results were expressed as the
increase in paw volume (ml) calculated by subtracting
the basal volume. The compounds 6a–g were intra-
venously administered (i.v.) at doses of 3 and 10 mg/kg
each (n=6 each) immediately before the subplantar
injection of carrageenin. Control animals (n=25) re-
ceived 0.5 ml of vehicle (60% DMSO). In another
experimental procedure, the compounds 6a, c and g
A series of tubes is prepared by mixing one part of
each dilution of compound with nine parts of the
Mueller–Hinton broth, previously inoculated and incu-
bated for 18 h at 37°C. The MIC is considered to be the
lowest drug concentration for which there is no micro-
bial growth [25].
Acknowledgements
The financial support from Conselho Nacional de
Desenvolvimento Cient ´ı fico e Tecnol o´ gico (CNPq),
Funda c¸ a˜ o de Amparo a` Ci eˆ ncia e Tecnologia de Per-
nambuco (FACEPE) is gratefully acknowledged. We
thank Dr Jean Martinez-LAPP (Laboratoire des
Amino acides, Peptides et Proteines–CNRS, Montpel-
lier, France) for having provided protected amino
acids. The authors also thank the technicians of Depar-
(
n=6 each) were administered by oral route (gavage) 1
h before at doses of 75 and 150 mg/kg. The control
animals (n=8) received 1.0 ml of the vehicle (60%
DMSO) and the group reference indomethacin 10 mg/

7
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A.C.L. Leite et al. / Il Farmaco 55 (2000) 719–724
[
[
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