Reaction of methyl 5(6)-(4-aminophenylthio)-2-benzimidazolylcarbamate with carboxylic acid chlorides

Article abstract of DOI:10.1023/B:RUGC.0000015999.23658.b5

Methyl 5(6)-(4-aminophenylthio)-2-benzimidazolylcarbamate was reacted with carboxylic acid chlorides to obtain mono- and disubstitution products. The formation of the former involves the aniline nitrogen and of the latter, both the aniline and benzimidazole nitrogens. Biological properties of the products are studied.

Full text of DOI:10.1023/B:RUGC.0000015999.23658.b5

Russian Journal of General Chemistry, Vol. 73, No. 9, 2003, pp. 1457 1462. Translated from Zhurnal Obshchei Khimii, Vol. 73, No. 9, 2003,
pp. 1541 1547.
Original Russian Text Copyright
2003 by Pilyugin, Mikhailyuk, Kosareva, Chikisheva, Klimakova, Vorob’eva.
Reaction of Methyl
5(6)-(4-Aminophenylthio)-2-benzimidazolylcarbamate
with Carboxylic Acid Chlorides
V. S. Pilyugin, A. N. Mikhailyuk, V. M. Kosareva,
G. E. Chikisheva, E. V. Klimakova, and T. P. Vorob’eva
Research Technological Institute of Gerbicides and Growth Regulators,
Academy of Sciences of Bashkortostan, Ufa, Bashkortostan, Russia
Received August 20, 2001
Abstract Methyl 5(6)-(4-aminophenylthio)-2-benzimidazolylcarbamate was reacted with carboxylic acid
chlorides to obtain mono- and disubstitution products. The formation of the former involves the aniline nitro-
gen and of the latter, both the aniline and benzimidazole nitrogens. Biological properties of the products are
studied.
Helminthiasis is widespread and causes a severe
economical damage to cattle breeding, producing
cattle plague, declining production, and retarding
growth and development of young animals [1].
nucleophiles, i.e. act as mild acylating agents. This
property is also of great biological significance, since
N-acetylimidazoles effect enzymatic transacylation
reactions [15].
Traditional technologies of cattle breeding and
poultry farming make use of chemical agents. This,
however, involves some disadvantages, since prepara-
tions should be constantly changed because of adapta-
tion and side effect problems.
Consequently, the condensation of aminobenzim-
idazole I with acid chlorides will involve both nucleo-
philic centers only if an excess of the acid chloride
will be used. With equimolar reactant amounts, deri-
vatives by the aniline nitrogen atom will be formed.
Aminobenzimidazole I derivatives bearing substi-
tuents in the aniline moiety were prepared in thorough-
ly purified pyridine with equimolar reagent amounts
at room temperature for 16 18 h in yields of 56
100% [scheme (1), Table 1].
At present a great number of methyl 2-benzimida-
zolylcarbamate derivatives exhibiting a high antihel-
minthic activity [2 11] but simultaneously causing
some side effects (embriotoxicity, etc.) have been
synthesized. Nevertheless, search for new nontoxic
altihelminthic preparations in this class of compounds
still remains an actual task.
Diacyl derivatives III were prepared in thoroughly
dried DMSO with double the molar amount of acid
chloride at 60 70 C for 3 h [scheme (2), Table 1].
It is known [12] that methyl 5(6)-(4-aminophenyl-
thio)-2-benzimidazolylcarbamate (I) acts a potent
antihelminthic but simultaneously possesses embrio-
toxicity and general toxicity. In view of the present
notion of the mechanism of the side effect of this
compound [13] one can suggest that substitution in
nucleophilic centers of methyl 2-benzimidazolylcar-
bamate will attenuate or eliminate side effects.
We also obtained a series of compounds on the
basis of monoacyl derivatived II and phenyl iso-
cyanate and 4-chlorophenyl isocyanate, in which the
carbamoyl substituents are attached to the benz-
imidazole nitrogen atom [scheme (3), Table 1].
Compounds IV were synthesized in a thoroughly
dried DMSO with a molar amount of isocyanate at
60 70 C for 3 h.
The presence of two nucleophilic centers in methyl
5(6)-(4-aminophenylthio)-2-benzimidazolylcarbamate
(I): aniline and benzimidazole nitrogens, makes
possible its reactions with carboxylic acid chlorides,
involving one or both nucleophilic centers. However,
N-substituted benzimidazoles are known to readily
transfer their substituents like acyl groups onto other
The physicochemical characteristics of the com-
pounds obtained by the above procedures are listed
in Table 1.
All the products were tested for antihelminthic
activity and toxicity. The resulting data are presented
1070-3632/03/7309-1457$25.00 2003 MAIK Nauka/Interperiodica

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PILYUGIN et al.
N
N
C NHCO2Me
C NHCO2Me
(1)
+ RCOCl
RCONH
N
H
S
N
H
H 2 N
S
I
IIa IIy
R = CH3(CH2)2 (a), cyclo-C6H11 (b), CH3(CH2)6 (c), CH3(CH2)14 (d), ClCH2 (e), C6H5CH2 (f), C6H5OCH2 (g), C6H5 (h),
2-CH3OC6H4 (i), 4-CH3OC6H4 (j), 2-BrC6H4 (k), 2-ClC6H4 (l), 4-ClC6H4 (m), 2-NO2C6H4 (n), 4-NO2C6H4 (o), 5-Cl-2-
HOC6H3 (p), 2-Br-3-NO2C6H3 (q), 2,4-(NO2)2C6H3 (r), 2-Cl-3,5-(NO2)2C6H2 (s), 4-C6H4CO2H (t), 4-C6Cl4CO2H (u),
2-C5H4N (v), 3-C5H4N (w), 4-C5H4N (x), C(CH3)3 (y).
N
N
C NHCO2CH3
C NHCO2CH3
(2)
RCONH
N
+ 2RCOCl
S
N
H
H 2 N
S
COR
I
IIIa IIIg
R = CH3(CH2)2 (a), cyclo-C6H11 (b), CH3(CH2)6 (c), CH3(CH2)14 (d), ClCH2 (e), C6H5CH2 (f), C6H5OCH2 (g).
N
C NHCO2CH3
+ R
RCONH
NCO
N
H
S
II
RCONH
N
C NHCO2CH3
N
S
(3)
R
CONH
IVa IVg
R = 2-BrC6H4 (a, f), 2-ClC6H4 (b, g), C3H7 (c), C6H5OCH2 (d), C6H5 (e); R = C6H4NCO (a), C6H4NCO (b),
4-ClC6H4NCO (c g).
in Table 2. Toxicity tests were performed with mice,
and antihelminthic activity tests, with rats experi-
mentally infected with nippostrongilus larvae.
transformations in animals and are fairly rapidly ex-
creted. Their biotransformation products exhibit no
antihelminthic activity, and, consequently, the useful
properties of the parent compounds are limited by
their rapid metabolic deactivation.
The antihelminthic, antifungoid, and other activity
of compounds of this chemical group derives not only
from any one common universal biological effect; in
each case, a combination of effects takes place, with
one or another prevailing.
As shown in [19 22], the antihelminthic effect of
benzimidazole derivatives depends on their contact
time with helminthes. Naturally, the rapidly absorbed,
metabolized, and excreted thiabendazol should be a
less potent antihelminthic than benzimidazoles whose
biodegradation is slow, which depends on the
properties of substituents in 2-aminobenzimidazole.
The features of biotransformations and pharmaco-
kinetics of benzimidazole derivatives are determined
by substitution in the 5 position of the benzene ring.
According to [16 18], the adduct of methyl 2-benz-
imidazolylcarbamate and butyl isocyanate by N1
(benomil) mainly metabolizes by cleavage of the side
chain and 5-hydroxylation of the benzene ring to form
Benzimidazole antihelmintics strongly metabolize
in the organism of animals when orally introduced.
Starting compounds are rarely preserved unchanged.
conjugates. Similar data were obtained in biotrans- In blood, liver, tissues, and urine, metabolites prevail
formational studies on 2-(4-thiazolyl)benzimidazole
(thiabendazol). These compounds undergo similar
over starting compounds. These free metabolites are
formed by oxidative and hydrolytic processes, and
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REACTION OF METHYL 5(6)-(4-AMINOPHENYLTHIO)-2-BENZIMIDAZOLYLCARBAMATE
1459
Hlg
Table 1. Monoacyl derivatives IIa IIy of aminobenzimidazole I
Found, %
N
Calculated, %
Comp.
no.
mp,
C
Yield,
%
Formula
C
H
S
Hlg
C
H
N
S
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
165 167 93.3 59.15 5.11 14.29 8.00
245 247 87.2 62.01 5.48 13.01 7.07
183 185 95.4 62.47 6.20 12.59 7.00
C19H20N4O3S
C22H24N4O3S
C23H32N4O3S
C31H44N4O3S
59.36 5.24 14.57 8.34
62.24 5.70 13.19 7.55
62.70 6.41 12.72 7.28
67.35 8.02 10.14 5.80
52.24 3.87 14.34 8.20
63.87 4.66 12.95 7.41
61.87 4.06 12.56 7.18
63.14 4.34 13.39 7.66
61.59 4.49 12.49 7.15
61.59 4.49 12.49 7.15
243 245 88.6 67.12 7.85
9.96 5.43
202 204 56.4 52.07 3.65 14.13 7.85
165 167 93.0 63.56 4.47 12.62 7.05
175 177 97.7 61.62 3.88 12.38 7.00
212 214 95.6 62.87 4.23 13.19 7.35
176 178 82.0 61.32 4.28 12.21 6.85
256 258 87.3 61.37 4.35 12.28 6.87
8.97 C17H15ClN4O3S
C23H20N4O3S
9.07
C23H20N4O4S
C22H18N4O3S
C23H20N4O4S
C23H20N4O4S
IIj
IIk
IIl
181 183 92.8 52.97 3.19 11.05 6.17 16.62 C22H17BrN4O3S
53.12 3.44 11.27 6.45 16.06
178 180 97.7 58.13 3.62 12.13
7.64 C22H17ClN4O3S
7.68 C22H17ClN4O3S
C22H17N5O5S
58.34 3.78 12.37 7.08
58.34 3.78 12.37 7.08
57.01 3.70 15.11 6.92
57.01 3.70 15.11 6.92
56.47 3.45 11.96 6.75
7.83
7.83
IIm 253 255 97.7 58.21 3.58 12.14 6.85
IIn
IIo
IIp
IIq
IIr
IIs
IIt
177 179 79.7 56.92 3.50 14.88 6.52
232 234 83.3 56.87 3.44 14.83 6.63
163 165 98.5 56.21 3.36 11.77 6.32
C22H17N5O5S
C22H16ClN4O4S
195 197 93.7 48.51 2.86 12.68 5.78 18.27 C22H16BrN4O5S
48.71 2.97 12.91 5.91 18.44
51.96 3.17 16.53 6.31
48.67 2.78 15.48 5.91
60.14 3.98 14.77 8.45
175 177 92.0 51.68 3.01 16.46 5.98
196 198 88.3 48.45 2.56 15.21 5.49
224 226 93.9 59.95 3.75 14.56 8.15
C22H16N6O7S
C22H15ClN6O7S
C38H30N8O6S2
IIu
IIv
>300
90.3 51.12
12.65 6.80
C38H26Cl4N8O6S2 50.90
12.50 7.15
173 175 76.0 59.92 3.96 16.48 7.29
C20H17N5O3S
C20H17N5O3S
C20H17N5O3S
C20H22N4O3S
60.13 4.08 16.70 7.64
60.13 4.08 16.70 7.64
60.13 4.08 16.70 7.64
60.28 5.56 14.06 8.04
IIw 178 180 86.0 59.88 3.95 16.47 7.45
IIx
IIy
180 182 81.0 59.95 3.98 16.45 7.39
213 215 92.3 59.95 5.40 13.86 7.95
they are usually more soluble than the starting com-
pounds and readily excreted from the organism [23].
from each other by two orders of magnitude, whereas
the dissociation constant of o-methoxybenzoic acid
(pKa 4.09) compares with that of benzoic acid. At
the same time, the antihelminthic activity of the o-
methoxybenzoic acid derivative is almost 4 times
lower (compounds IIh and IIn).
As seen from Table 2, there is no correlation
between the antihelminthic activity and the acidity of
the carboxylic acids whose residues enter in the
composition of monoacyl derivatives II of aminobenz-
imidazole I and are responsible for its hydrolytic sta-
bility. For example, the dissociation constants of
butyric (pKa 4.87), cyclohexanecarboxylic (pKa
4.90), caprylic (pKa 4.89), and trimethylacetic (pKa
5.05) acids are quite close to each other, and the
dissociation constant of monochloroacetic acid (pKa
2.85) [24] differs from them by two orders of
magnitude, whereas the derivatives of butyric, tri-
methylacetic, and monochloroacetic acids (compounds
IIa, IIe, and IIg) far suprass in antihelminthic activity
the derivatives of caprylic and cyclohexanecarboxylic
acids (compounds IIb and IIc).
The derivatives of aminobenzimidazole and aro-
matic acids having electronegative substituents, such
as Cl, Br, and NO2, in the para or meta positions of
the aromatic ring of the acid chloride (compounds IIm,
IIo, IIq IIs) sharply reduce the antihelminthic acti-
vity, whereas the same substituents in the ortho posi-
tion have no effect (compounds IIg, IIn, and IIk).
This effect is apparently associated with the interac-
tion of lone electron pairs of the heteroatoms with the
adjacent aromatic ring, as well as with the steric
hindrance the ortho substituent creates to hydrolytic
cleavage of the amide bond involving this substituent.
The same relates to the derivatives of aromatic
acids. Thus, the dissociation constants of benzoic (Ka
4.17) and o-nitrobenzoic (pKa 2.17) acids differ
Nitro substituents in the aromatic acid residues
enhance toxicity of the corresponding derivatives
(compounds IIn, IIp, and IIr). This negative effect is
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 9 2003

1460
PILYUGIN et al.
Table 2. Biological properties of derivatives of methyl 5(6)-(4-aminophenylthio)-2-benzimidazolylcarbamates and
carboxylic acid chlorides and isocyanates
Toxicity
Antihelminthic activity
Toxicity
animal
Antihelminthic activity
quantity of effective-
Comp.
no.
Comp.
no.
animal
deaths,
%
quantity of effective-
dose
dose,
dose,
dose,
nematodes
per heada
ness,
%
deaths,
%
nematodes
ness,
%
mg/kg
mg/kg
mg/kg
mg/kg
per heada
I
40
100
1000
500
500
50
100
30
0
40
30
50
50
0
0
0
0
0
0
0
40
50
0
20
25
25
100
100
25
25
25
25
25
25
25
25
25
25
25
100
25
6.1
0
20.1
23.1
15.1
1.1
7.1
2.2
3.0
27.5
37.8
1.3
4.6
35.1
1.3
39.7
25.2
26.0
85.11
100
IIr
IIs
IIt
IIu
IIv
IIw
IIx
100
100
1000
1000
50
100
100
100
40
0
0
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
100
100
26.0
37.8
14.3
8.0
5.0
22.3
1.7
0
21.0
0.8
16.0
8.0
0
38.0
10.0
65.9
80.0
88.0
47.0
94.0
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
IIm
IIn
IIo
IIp
IIq
52.0
45.0
60.0
97.6
83.0
94.0
92.8
24.4
10.0
97.0
89.0
16.4
97.0
5.4
0
60
30
0
40
0
100
500
IIy
100
1000
1000
1000
1000
1000
1000
500
500
1000
500
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IVa
IVb
IVc
1000
1000
100
50.0
98.0
60.0
80.0
0
30
50
0
0
0
50
0
0
500
1000
1000
1000
50
1000
1000
100
19.3
13.9
3.3
76.7
78.4
54.0
67.0
96.0
7.0
40.0
38.0
0
5.0
a
Nematodes per head in the control group 40.2.
fully eliminated when ortho-chlorine or ortho-
bromine is present (compounds IIq and IIs).
IIk, IIl, IIt, IIu, IIIa, IIId, and IIIg were tested for
embriotropic activity. Only one of them, compound
IIu, exhibited embriotoxicity nor in therapeutic doses
nor in a dose of 100 mg/kg [Eq. (4)].
Of pyridinecarboxylic acids (compounds IIv IIx)
the least toxic and the most active against helminthes
is the isonicotinic acid derivative (compound IIx).
The anomalous trend in embriotoxicity compared
with general toxicity which is probably associated
with faster cleavage (hydrolysis) of derivatives II with
liberation of aminobenzimidazole I in embrions com-
pared with adult animals can be explained by the fact
that compound IIu is the only where there are suf-
ficient steric hindrances to hydrolytic clevage of
amide bonds, since all ortho positions in the tere-
phthalic residue are substituted by chlorine atoms
which are bulkier than hydrogens.
Diacyl derivatives IIIa IIIg compare in anti-
helminthic properties with monoacyl derivatives II.
Moreover, all the products were tested for cestocide
activity, and the terephthalic and tetrachloroterephtha-
lic acid derivatives (compounds IIt and IIu) were
found to be the most active.
The most active and the least toxic derivatives IIh,
N
Cl
Cl
C NHCO2CH3
(4)
HO2C
CONH
N
S
H
Cl Cl
Compound IIu was tested for antihelminthic ac-
tivity in farm animals, but, unfortunately, it proved
less effective than some known benzimidazoles.
The above findings show that substituents at the
aniline nitrogen in methyl 5(6)-(4-aminophenylthio)-
2-benzimidazolylcarbamates, such as carboxylic acid
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REACTION OF METHYL 5(6)-(4-AMINOPHENYLTHIO)-2-BENZIMIDAZOLYLCARBAMATE
1461
residues, should not cleave fast in animals and
embrions, forming the parent methyl 5(6)-(4-amino-
phenylthio)-2-benzimidazolylcarbamate which is a
toxic compound. Aromatic acids with sufficiently
bulky substituents in both ortho positions, coplanar
to the carbonyl group, and capable of creating hin-
drances to attack of nucleophiles, such as hydroxyl,
on the carbonyl carbon meet this condition.
tives will form salts which are insufficiently lipophilic
to be absorbed in intestines until hydrolytic cleavage
of the amide bond occurs, ensuring prolonged uniform
delivery of the active substance to the organism.
The above reasoning explains why the derivatives
of methyl 5(6)-(4-aminophenylthio)-2-benzimidazolyl-
carbamate and substituted phthalic anhydrides are
ineffective antihelminthics: They form in intestines
the same salts, and the latter, possessing increased
hydrolytic stability, cannot cleave to give the parent
methyl 5(6)-(4-aminophenylthio)-2-benzimidazolyl-
carbamate.
Phthalic, tetrachlorophthalic, and tetrabromo-
phthalic anhydrides are accessible representatives of
this group of compounds. However, the reaction of
phthalic anhydride with methyl 5(6)-(4-aminophenyl-
thio)-2-benzimidazolylcarbamate gives a derivative
bearing only one ortho substituent and expectedly
insufficiently resistant to hydrolysis in animals and
embrions. Tetrachloro- and tetrabromophathalic acid
derivatives Vb and Vc bearing substituents in both
ortho positions with respect to the carbanilide moiety
should be much more resistant to hydrolysis.
The derivative of phthalic anhydride IVa behaved
like known drugs of prolonged action and, therefore,
it proved to be a potent antihelminthic and a strong
toxicant.
It is known that the lipophilicity of salts is much
enhanced by phase-transfer catalysis [27]. We sug-
gested that if we impart enhanced lipophilicity to the
synthesized derivatives of aminobenzimidazole I and
substituted phthalic anhydrides, then they, preserving
their positive properties (lack of toxic and embrio-
tropic action), would exhibit antihelminthic activity.
N
R1
O
C NHCO2CH3
R2
R3
C NH
N
H
S
C OH
O
R4
We prepared mixtures of methyl 5(6)-[4-(tetra-
chlorophthalimino)phenylthio]- and methyl 5(6)-[4-
(tetrabromophthalimino)phenylthio]-2-benzimidazo-
lylcarbamates and a phase-transfer catalyst (a mixture
of PEG-400 and Katamin AB), which showed a high
antihelminthic activity (effectiveness higher than
85%), and the mixture with the latter methyl ester
exhibited a 100% effectiveness against strogylatosis
of gastrointestinal tract in sheeps in doses of 10 and
15 mg/kg.
Va Vc
R1 = R2 = R3 = R4 = H (a), Br (b), Cl (c).
By reacting methyl 5(6)-(4-aminophenylthio)-2-
benzimidazolylcarbamate (I) with tetrachloro- and
tetrabromophthalic anhydrides in acetic acid in the
presence of sodium acetate at 40 45 C we obtained
in high yields sodium salts of the corresponding
phthalic acid derivatives in high yields. The same
reactions in DMSO at 35 40 C gave in high yields
the corresponding derivatives as free acids.
Thus, we prepared a series of derivatives of methyl
5(6)-(4-aminophenylthio)-2-benzimidazolylcarbamate
and substituted phthalic anhydrides, which proved to
be potent antihelminthics comparing in effectiveness
with methyl 5(6)-(4-phenylthio)-2-benzimidazolylcar-
bamate (known antihelminthic preparations Fenbe-
ndazol and Panakur), but exhibiting no undesirable
side effects.
As we expected, the derivatives of methyl 5(6)-(4-
aminophenylthio)-2-benzimidazolylcarbamate with
substituted phthalic anhydrides proved to be nontoxic,
but exhibited no antihelminthic activity. At the same
time, the derivative of phthalic anhydride (compound
IVa) proved to be a potent antihelminthic, but was
fairly toxic. The derivatives of tetrachloro- and
tetbromophthalic anhydrides exhibited no embrio-
tropic activity in critical days of pregnancy at a dose
of 100 mg/kg.
EXPERIMENTAL
Analysis of technical products for methyl 5(6)-(4-
aminophenylthio)-2-benzimidazolylcarbamate (I) and
for reaction products of carboxylic acid chlorides with
aminobenzimidazole (I) involved HPLC on Altex-330
chromatograph on an Ultraspher-ODS column in the
systems (vol% are given): 70% of acetonitrile and
30% of water plus 5% of DMF; and 67.5% of me-
thanol, 29.0% of water, and 3.5% of DMF plus 4 ml/l
It is known that phthalic anhydride derivatives are
used in designing drugs of prolonged action [25, 26].
The prolonged action of such drugs can be explained
by the fact that they are primarily absorbed in intes-
tines, where the medium is alkaline. In such a medium,
the drugs on the basis of phthalic anhydride deriva-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 9 2003

1462
PILYUGIN et al.
of tetrabutylammonium phosphate (0.5 g per 20 ml
of water).
Chukina, S.I., Novik, T.S., Berezkina, S.V., Volko-
va, G.N., Pilyugin, V.S., and Valitov, R.B., USSR
Inventor’s Certificate no. 1573817, Byull. Isobret.,
1990, no. 23.
The chromatograms were registered with a UV
detector at 254 nm and treated by internal normaliza-
tion of peak areas.
11. US Patent 3935209, Izobreteniya za rubezhom, 1976,
nos. 18 24.
Mono derivatives IIa IIu of aminobenzimida-
zole I and carboxylic acid chlorides. Acid chloride,
0.055 mol, was added to 0.05 mol of aminobenzimi-
daze I in 60 ml of pyridine, and the mixture was
stirred at room temperature for 16 18 h and then
poured into water. The precipitate was filtered off,
washed with water, 50% acetic acid, and water,
and dried.
12. Kosareva, V.M., Cand. Sci. (Khim.) Dissertation, Ufa,
1988.
13. Chukina, S.I., Cand. Sci. (Biol.) Dissertation, Moscow,
1990.
14. Paquette, L.A., Principles of Modern Heterocyclic
Chemistry, New York: Benjamin, 1968. Translated
under the title Osnovy sovremennoi khimii geterotsik-
licheskikh soedinenii, Moscow: Mir, 1971, p. 191.
Toxicity tests were performed with mice 18 20 g
in weight. Samples as suspensions were introduced
orally in one portion in doses of 100 to 1000 mg/kg.
The animals were observed over the course of 5 days,
keeping a record of deaths.
15. Ivanskii, V.I., Khimiya geterotsiklicheskikh soedine-
nii (Chemistry of Heterocyclic Compounds), Moscow:
Vysshaya Shkola, 1978, p. 154.
16. Douche, P.G.C., Xenobiotica, 1973, vol. 3, no. 6,
p. 367.
Nematocide activity tests were performed with rats
50 60 g in weight experimentally infected with
nippostrongilus larvae (300 350 per head). Samples
as suspensions were introduced orally in doses of
10 do 100 mg/kg eight days after infection. For each
dose, five infected and five control rats were used.
After 5-day exposure the animals were killed. The
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