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Synthesis and Molluscicidal Activity of New Cinnoline and Pyrano [23-c]pyrazole Derivatives.

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456
Arch. Pharm. Chem. Life Sci. 2006, 339, 456 – 460
Full Paper
Synthesis and Molluscicidal Activity of New Cinnoline and
Pyrano [2,3-c]pyrazole Derivatives
Fathy M. Abdelrazek1, 2 , Peter Metz1, Nadia H. Metwally2, Sherif F. El-Mahrouky3
1
Institut fr Organische Chemie, Technische Universitt Dresden, Dresden, Germany
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
3
Research Institute for Tropical Medicine, Cairo, Egypt
2
2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile 5 undergoes an azo coupling reaction
with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline4-carbonitriles 7. Upon reflux in acetic acid, these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a, b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a, b to afford the pyrano[2,3-c]pyrazole derivatives 13a – d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.
Keywords: Cinnolines / Molluscicidal activity / Pyrano[2,3-c]pyrazoles / Pyrazolones /
Received: January 2, 2006; accepted: March 27, 2006
DOI 10.1002/ardp.200600057
Introduction
In the past few years, we have been involved in a program
aiming to synthesize new heterocyclic compounds of biological interest that may find applications as biodegradable agrochemicals [1 – 3]. Schistosomiasis (bilharziasis) still
represents one of the major national health problems in
Egypt as well as in most of the Third World Countries
and great national and international efforts are made to
combat this disease. Although praziquantel has been successfully used as chemical therapeutic in Egypt and other
places the habits of the Egyptian farmers, however,
which necessitate their continuous and daily contact
with canal water during the irrigation process, especially
in the Nile Delta, where Nile water canals and streams
are widespread, and even the habits of the school pupils,
who dive and swim in these streams lead to repeated
infection. Therefore, snail control through molluscicides, is considered not only complementary but essential in schistosomal control. Copper sulfate and niclosa-
Correspondence: Fathy Mohamed Abdelrazek, Chemistry Department,
Faculty of Science, Cairo University, Giza, Egypt.
E-mail: prof_fmrazek@yahoo.com
Phone: +20 25 676-601
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 1. Chemical structure of chromene derivatives 1 and 2.
mide were used tentatively in Egypt within a program
developed by Bayer AG, however, due to their hazardous
environmental effects [4 – 6] the program was stopped.
Therefore, the search and need for synthetic or naturally
occurring molluscicides is still ongoing.
In the context of this program, we have previously
reported that some chromene derivatives derived from
dimedone (1, Fig. 1) showed moderate molluscicidal
activity towards Biomphalaria alexandrina snails, the
intermediate host of the infective phase of Schistosoma
mansoni in Egypt [7]. We have also recently reported [8]
that some pyrido[3,2-c]pyridazines (2, Fig. 1) showed moderate molluscicidal activity against these snails as well. It
seemed of interest to synthesize new classes of com-
Arch. Pharm. Chem. Life Sci. 2006, 339, 456 – 460
Bioactive Cinnolines and Pyrano[2,3-c]pyrazoles
457
Scheme 1. Synthesis route of cinnolines 7 and 9.
Scheme 2. Synthesis route of pyrano[2,3-c]pyrazoles 13.
pounds holding either the dimedone moiety fused to a
pyridazine ring, or a pyran ring bearing the 3-furanyl or
the 3-thienyl substituents fused to another heterocyclic
ring which may result in enhanced molluscicidal activity.
Dimedone 3 is reported to couple easily with diazotized aromatic amines to afford the azo/hydrazo derivatives 4 [9, 10] (Scheme 1). It has also been reported that 3
undergoes condensation with malononitrile to afford
the tautomer 5 [11]. The combination of the functionalities present in 4 and 5 within a single compound such as
6, which might be a good candidate to synthesize the cinnolines 8, has not yet been reported. Some arylazo derivatives of dimedone were reported to cyclize to cinnoline
derivatives upon reaction with phosphonium ylides [12].
On the other hand, the pyrazol-5-one derivatives 10a, b
(Scheme 2) are reported to undergo a cyclization with
arylidenemalononitriles to afford pyrano[2,3-c]pyrazole
derivatives [13]. Thus, the reaction of 10a, b with 3-furfurylidene or 3-thienylidene malononitriles 11a and 11b,
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
respectively, seemed promising for a facile synthesis of
the pyranopyrazoles 13a – d, which are hitherto
unknown in the literature.
Results and discussion
Synthesis of cinnolines 7 and 9
The azo derivatives 4, prepared from dimedone 3 according to literature methods [9, 10] were allowed to condense with malononitrile in order to obtain the combined azo/condensation derivatives 6 (Scheme 1). However, using this route, we could neither obtain any of the
derivatives 6 nor their cyclized derivatives 7 or 8. This can
probably be attributed to the acidity of the NH moiety in
4, which disfavors a nucleophilic attack on the carbonyl
groups. Therefore, an alternative route featuring a reversal of events was followed. To this end, dimedone 3 was
allowed to condense with malononitrile according to a
known method [11]. Spectroscopic data showed that the
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458
F. M. Abdelrazek et al.
product exists as enol form 5, which is in agreement with
the literature report [11]. To our delight, compound 5
couples easily with diazotized aromatic amines to afford
products in high yields, which at first were thought to be
the hydrazo derivatives 6 or a tautomeric azo form of 6.
Whereas the elemental analysis data of the products
were in complete agreement with these structures, the
spectroscopic data did not fit this suggestion. The IR spectra of all products show a carbonyl absorption band.
However, the 1H-NMR spectra of all products display a
two-proton singlet at d = 6.3 – 6.6 ppm that disappears
upon addition of D2O. Moreover, the 1H-NMR and 13CNMR spectra show the presence of only one methylene
group and of an olefinic C=CH moiety, which rules out a
cyclized structure 8 as well. These data led us to assign
the isomeric cyclized cinnoline structure 7 for the products obtained. Upon reflux in acetic acid, all compounds 7a – c were converted to the cinnoline derivatives
9a – c, in which the imino group is acetylated. Elemental
analyses and spectroscopic data are in complete agreement with the depicted structures.
Synthesis of pyrano[2,3-c]pyrazoles 13
The pyrazolones 10a and 10b were allowed to react with
3-furfurylidene and 3-thienylidene malononitrile derivatives 11a and 11b [7] in refluxing ethanol in the presence
of piperidine catalyst to afford 1:1 white to pale-yellow
adducts. Elemental analyses and spectroscopic data of
these products fully support the depicted structures
13a – d (Scheme 2). The formation of compounds 13a – d
is assumed to proceed via Michael addition of the active
methylene groups in 10 to the activated double bond in
11 to give the acyclic adduct intermediates 12, which in
turn undergo cyclization through addition of the
hydroxy group of the enol tautomer of 12 to one of the
adjacent cyano groups to afford the desired heterocycles
13.
Molluscicidal activity
The toxicity of compounds 7a – c, 9a – c, and 13a – d
toward Biomphalaria alexandrina snails was evaluated.
The tenth, quarter, half, and sublethal doses (LC10, LC25,
LC50, and LC90 in ppm/nM) for each compound were determined and are shown in Table 1.
An insight inspection of the results listed in Table 1
shows that all compounds have moderate to low effects
on the snails, and they all showed very weak activity
below 5 ppm. The most effective of them are 13a, 7c, and
9c (LC90 = a 7, 9, and 9 ppm, respectively). The activity of
7c and 9c may be attributed mainly to the presence of the
4-chlorophenyl residue. At the same concentration, compounds 7a – c display activities similar to their isomer-
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2006, 339, 456 – 460
Table 1. Molluscicidal activity of compounds 7a – c, 9a – c, and
13a – d expressed as LC10, LC25, LC50, and LC90 in ppm (nM).
No
LC10
ppm (nM)
7a
7b
7c
9a
9b
9c
13a
13b
13c
13d
3 (10.26)
6 (20.52)
3 (09.79)
6 (19.58)
a 3 (a 9.18)
4 (12.24)
A 3 (A 8.97)
6 (17.94)
3 (8.61)
6 (17.22)
3 (8.13)
4 (10.85)
3 (12.38)
4 (16.51)
A 3 (A 9.86)
7 (23.00)
A 3 (A 11.61) 8 (30.97)
A 3 (A 9.36) 11 (34.34)
LC25
ppm (nM)
LC50
ppm (nM)
LC90
ppm (nM)
8 (27.37)
11 (37.63)
7 (22.85)
15 (48.96)
7 (21.42)
9 (27.54)
8 (23.93)
13 (38.88)
9 (25.83) A 15 (A 43.05)
7 (18.98)
9 (24.40)
6 (24.79)
a 7 (a 28.90)
8 (26.29)
14 (46.01)
10 (38.71) A 15 (A 58.07)
A 15 (A 46.82) A 15 (A 46.82)
ized/acetylated derivatives 9a – c. Compound 13a showed
the highest activity (LC50 = 6 and LC90 = a 7 ppm) within
the pyrano[2,3-c]pyrazole series. The phenyl analog 13b is
far less active (LC90 = 14 ppm), while the 3-thienyl derivatives 13c, d are seldom active. These results confirm our
previous observations [7]. A comparison of the molluscicidal activity of the new compounds reported here with
the international standard 29,5-dichloro-4-nitrosalicylanilide (LC100 = 1 ppm) [4, 5] showed that our compounds are
still far inferior as molluscicidal agents. However, compounds 7c, 9c, and 13a look promising after further structural modification e. g., by using polyhalogenated anilines in the diazotization process for 7 and 9, which will
be considered in a future study.
We thank the Alexander von Humboldt Foundation (Germany) for granting a research fellowship to F. M. Abdelrazek
from July to September 2005; during this time, a considerable
synthetic part of this work has carried out.
Experimental
Melting points were measured on a digital Electrothermal 9100
apparatus (Electrothermal, Essex, UK) and are uncorrected. FT-IR
spectra (KBr) were obtained on a Nicolet 205 spectrophotometer
(Nicolet, Madison, WI, USA). 1H-NMR and 13C-NMR spectra were
obtained on a Bruker AC 300 P (1H: 300 MHz, 13C: 75.5 MHz) in
DMSO-d6 using TMS as internal reference (Bruker). Chemical
shifts are expressed in d values. 13C multiplicities were determined using DEPT pulse sequences. Mass spectra were recorded
with a Hewlett Packard Esquire-LC (LC/MS) and with an Agilent
GC 6890N coupled to an Agilent MSD 5973 (GC/MS) (Hewlett
Packard and Agilent, both: Palo Alto, CA, USA). Elemental analyses were carried out in the Microanalytical Laboratory of the
Institut fr Organische Chemie, Technische Universitt Dresden. Satisfactory elemental analysis results (l 0.35%) have been
obtained for all compounds. Molluscicidal activity tests were
conducted in the Research Institute for Tropical Medicine,
Cairo, Egypt. 2-Arylhydrazono-5,5-dimethylcyclohexane-1,3www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2006, 339, 456 – 460
diones 4 and 2-(3-hydroxy-5,5-dimethylcyclohex-2-enylidene)malononitrile 5 were prepared according to literature methods
[10, 11]. 3-Furfurylidene/thienylidene-malononitrile derivatives
11a and 11b were prepared according to the method reported in
our previous paper [7].
Azo coupling with 5, preparation of 7a – c
To a solution of the dicyanomethylidene derivative of dimedone
5 (1.88 g, 10 mmol) in glacial acetic acid a cold solution of the
diazotized aromatic amines (aniline, 4-toluidine, 4-chloroaniline, 10 mmol) was added drop-wise at 08C with stirring over a
period of approx. 20 min. The reaction mixture was kept at 0 –
58C for one additional hour with stirring and then diluted with
ice-cold water. The precipitated solids were collected by filtration and recrystallized from ethanol.
3-Amino-6,6-dimethyl-8-oxo-2-phenyl-2,6,7,8tetrahydrocinnoline-4-carbonitrile 7a
Fine, deep orange crystals, yield 80% (2.3 g); m.p. 2078C (EtOH);
C17H16N4O (M = 292.34); IR 2203 (C3N), 1703 (C=O) cm – 1; 1H-NMR
d 1.06 (s, 6H, 2 CH3), 2.54 (s, 2H, ring CH2), 4.92 (s, 1H, olefinic H),
6.45 (s, 2H, D2O exchangeable, NH2), 7.35 – 7.55 (m, 5H, arom. H);
13
C-NMR d 29.66 (q, intense), 34.53 (s), 53.27 (t), 63.58 (s), 115.31
(d), 117.11 (s), 121.47 (s), 127.18 (d, intense), 128.87 (d), 129.56 (d,
intense), 139.51 (s), 140.55 (s), 150.42 (s), 194.52 (s).
3-Amino-6,6-dimethyl-8-oxo-2-p-tolyl-2,6,7,8tetrahydrocinnoline-4-carbonitrile 7b
Deep orange powder, yield 70% (2.1 g); m.p. 195 – 1968C (EtOH);
C18H18N4O (M = 306.36); IR 2193 (C3N), 1702 (C=O) cm – 1; 1H-NMR
d 1.05 (s, 6H, 2 CH3), 2.35 (s, 3H, tolyl CH3), 2.53 (s, 2H, ring CH2),
4.90 (s, 1H, olefinic H), 6.38 (s, 2H, D2O exchangeable, NH2),
7.25 – 7.35 (m, 4H, arom. H); 13C-NMR d 20.64 (q), 29.70 (q,
intense), 34.55 (s), 53.32 (t), 63.54 (s), 115.17 (d), 117.16 (s), 121.52
(s), 127.04 (d, intense), 130.07 (d, intense), 136.99 (s), 138.56 (s),
140.54 (s), 150.56 (s), 194.60 (s).
3-Amino-2-(4-chlorophenyl)-6,6-dimethyl-8-oxo-2,6,7,8tetrahydrocinnoline-4-carbonitrile 7c
Orange crystals, yield 82% (2.7 g); m.p. 1568C (EtOH); C17H15ClN4O
(M = 326.78); IR 3286, 2227 (C3N), 1698 (C=O) cm – 1; 1H-NMR d
1.06 (s, 6H, 2 CH3), 2.54 (s, 2H, ring CH2), 4.94 (s, 1H, olefinic H),
6.58 (s, 2H, D2O exchangeable, NH2), 7.38 – 7.62 (m, 4H, arom. H);
13
C-NMR d 29.65 (q, intense), 34.55 (s), 53.26 (t), 63.54 (s), 115.69
(d), 117.04 (s), 121.41 (s), 129.14 (d, intense), 129.53 (d, intense),
133.27 (s), 138.47 (s), 140.66 (s), 150.38 (s), 194.43 (s).
N-(4-Cyano-6,6-dimethyl-8-oxo-2-aryl-5,6,7,8tetrahydro-2H-cinnolin-3-ylidene)-acetamide
derivatives 9a – c
Each of the compounds 7a – c (10 mmol) was refluxed in glacial
acetic acid (15 mL) for 2 h, after which the mixture was allowed
to cool to room temperature. The reaction mixture was then
poured on crushed ice (10 g) and neutralized cautiously with
ammonia. The precipitated solids were collected by filtration
and recrystallized from ethanol.
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Bioactive Cinnolines and Pyrano[2,3-c]pyrazoles
459
N-(4-Cyano-6,6-dimethyl-8-oxo-2-phenyl-5,6,7,8tetrahydro-2H-cinnolin-3-yliden)acetamide 9a
Yellow crystals, yield 75% (2.5 g); m.p. 252-2538C (EtOH);
C19H18N4O2 (M = 334.37); MS (LC/MS) m/z (%) 291 (95) [M-CH3CO]; IR
2193 (C3N), 1703 (CO), 1667 (C=O) cm – 1; 1H-NMR d 1.09 (s, 6H, 2
CH3), 1.91 (s, 3H, COCH3), 2.67 (s, 2H, ring CH2), 3.07 (s, 2H, ring
CH2), 7.50 – 7.65 (m, 5H, arom. H); 13C-NMR d 21.00 (q), 27.42 (q,
intense), 32.00 (s), 40.63 (t), 51.56 (t), 111.79 (s), 112.85 (s), 125.62
(d, intense), 128.78 (d, intense), 129.23 (d), 136.81 (s), 140.31 (s),
153.09 (s), 156.23 (s), 191.22 (s), 191.70 (s).
N-(4-Cyano-6,6-dimethyl-8-oxo-2-p-tolyl-5,6,7,8tetrahydro-2H-cinnolin-3-ylidene)acetamide 9b
Dark yellow fine crystals, yield 68% (2.4 g); m.p. 1408C (EtOH);
C20H20N4O2 (M = 348.40); IR 2237 (C3N), 1709 (CO), 1666 (C=O)
cm – 1; 1H-NMR d 1.08 (s, 6H, 2 CH3), 1.90 (s, 3H, COCH3), 2.38 (s,
3H, tolyl CH3), 2.65 (s, 2H, ring CH2), 3.05 (s, 2H, ring CH2), 7.20 –
7.50 (m, 4H, arom. H); 13C-NMR d 20.63 (q), 20.93 (q), 27.46 (q,
intense), 32.03 (s), 40.65 (t), 51.59 (t), 111.68 (s), 112.93 (s), 125.38
(d, intense), 129.19 (d, intense), 136.78 (s), 137.93 (s), 138.99 (s),
153.00 (s), 156.31 (s), 191.28 (s), 191.74 (s).
N-(4-Cyano-6,6-dimethyl-8-oxo-2-p-chlorophenyl5,6,7,8-tetrahydro-2H-cinnolin-3-ylidene)acetamide 9c
Yellowish orange crystals, yield 77% (2.8 g); m.p. 210 – 2128C
(EtOH); C19H17ClN4O2 (M = 368.82); MS (LC/MS) m/z (%) 325.8 (98)
[M-CH3CO], 369 (15) [M + H+]; IR 2234 (C3N), 1714 (C=O), 1674
(CO) cm-1; 1H-NMR d 1.09 (s, 6H, 2 CH3), 2.08 (s, 3H, COCH3), 2.67 (s,
2H, ring CH2), 3.06 (s, 2H, ring CH2), 7.60 – 7.70 (m, 4H, arom. H);
13
C-NMR d 27.41 (q, intense), 30.51 (q), 32.01 (s), 40.65 (t), 51.56 (t),
111.93 (s), 112.78 (s), 127.48 (d, intense), 128.85 (d, intense),
133.73 (s), 136.96 (s), 139.04 (s), 153.19 (s), 156.18 (s), 191.18 (s),
206.33 (s).
6-Amino-3-methyl/phenyl-4-(3-furyl/3-thienyl)-1,4dihydropyrano[2,3-c]pyrazole-5-carbonitriles 13a – d
To a solution of 3-methylpyrazolin-5-one 10a or 3-phenylpyrazolin-5-one 10b (10 mmol) in ethanol (20 mL) was added an equimolar amount of the arylidene derivative 11a or 11b (10 mmol)
followed by five drops of piperidine, and the reaction mixture
was heated under reflux for 30 min. The solvent was evaporated
in vacuo to one third of its original volume, and the reaction mixture was then left to cool to room temperature. The solid products so obtained were filtered off, dried, and recrystallized
from ethanol to give 13a – d.
6-Amino-3-methyl-4-(furan-3-yl)-1,4-dihydropyrano[2,3c]pyrazole-5-carbonitrile 13a
Yellowish white powder, yield 76% (1.8 g); m.p. 2128C (EtOH);
C12H10N4O2 (M = 242.23); MS (LC/MS) m/z (%) 243 (90) [M + H+]; IR
3411, 3318, 3173 (NH), 2192 (C3N) cm – 1; 1H-NMR d 1.92 (s, 3H,
CH3), 4.59 (s, 1H, pyran 4-H), 6.21 (s, 1H, furan 2-H), 6.83 (s, 2H,
D2O exchangeable, NH2), 7.54 – 7.60 (m, 2H, furan 4-H, 5-H), 12.10
(s, 1H, D2O exchangeable, NH); 13C-NMR d 9.55 (q), 26.32 (d), 56.24
(s), 96.33 (s), 109.39 (d), 120.71 (s), 128.11 (s), 135.60 (s), 139.08 (d),
143.64 (d), 154.56 (s), 160.80 (s).
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F. M. Abdelrazek et al.
6-Amino-3-phenyl-4-(furan-3-yl)-1,4-dihydropyrano[2,3c]pyrazole-5-carbonitrile 13b
Pale yellowish powder, yield 75% (2.3 g); m.p. 2158C (EtOH);
C17H12N4O2 (M = 304.30); IR 3483, 3169, 3107 (NH), 2201 (C3N)
cm-1; 1H-NMR d 5.00 (s, 1H, pyran 4-H), 6.08 (apparent t, J = 1.2 Hz,
1H, Furan H), 6.93 (s, 2H, D2O exchangeable, NH2), 7.30 – 7.43 (m,
5H, phenyl), 7.53 – 7.58 (m, 2H, furan H), 12.88 (s, 1H, D2O
exchangeable, NH); 13C-NMR d 27.27 (d), 56.86 (s), 96.52 (s), 109.27
(d), 120.62 (s), 126.23 (d, intense), 128.06 (s), 128.24 (d), 128.50 (d,
intense), 128.60 (s), 137.94 (s), 138.99 (d), 143.37 (d), 155.47 (s),
160.35 (s).
6-Amino-3-methyl-4-(thien-3-yl)-1,4-dihydropyrano[2,3c]pyrazole-5-carbonitrile 13c
White crystalline solid, yield 82% (2.1 g); m.p. 227 – 2288C
(EtOH); C12H10N4OS (M = 258.30); MS (LC/MS) m/z (%) 259 (54) [M +
H+]; IR 3363, 3310, 3176 (NH), 2190 (C3N) cm – 1; 1H-NMR d 1.83 (s,
3H, CH3), 4.70 (s, 1H, pyran 4-H), 6.80 – 6.90 (m, 3H; after D2O
exchange of embedded NH2: d, J = 4.9 Hz, 1H, thiophene 4-H),
7.20 – 7.23 (m, 1H, thiophene H), 7.39 (dd, J = 3.1 Hz, J = 4.9 Hz,
1H, thiphene 5-H), 12.10 (s, 1H, D2O exchangeable, NH); 13C-NMR
d 9.54 (q), 31.11 (d), 56.65 (s), 97.06 (s), 120.73 (s), 121.05 (d),
126.47 (d), 126.67 (d), 135.57 (s), 145.15 (s), 154.45 (s), 160.68 (s).
6-Amino-3-phenyl-4-(thien-3-yl)-1,4-dihydropyrano[2,3c]pyrazole-5-carbonitrile 13d
Yellowish white powder, yield 80% (2.5 g); m.p. 237 – 2388C
(EtOH); C17H12N4OS (M = 320.37); MS (LC/MS) m/z (%) 321 (55) [M +
H+]; IR 3474 – 3107 (NH), 2205 (C3N) cm – 1; 1H-NMR d 5.10 (s, 1H,
pyran 4-H), 6.73 (dd, J = 1.2 Hz, J = 5.0 Hz, 1H, thiophene H), 6.93
(s, 2H, D2O exchangeable, NH2), 7.17 (dd, J = 1.2 Hz, J = 2.9 Hz, 1H,
thiophene H), 7.25 – 7.40 (m, 4H, phenyl), 7.46 – 7.52 (m, 2H, phenyl H + thiophene H), 12.88 (s, 1H, D2O exchangeable, NH). 13CNMR d 31.90 (d), 57.47 (s), 97.21 (s), 120.64 (s), 121.09 (d), 126.11
(d, intense), 126.35 (d), 126.50 (d), 128.21 (d), 128.49 (d, intense),
128.59 (s), 137.86 (s), 145.14 (s), 155.53 (s), 160.19 (s).
Molluscicidal activity tests
The molluscicidal activity tests were carried out by determination of the tenth, quarter, half, and sublethal doses LC10, LC25,
LC50, and LC90 of each compound under investigation. Biomphalaria alexandrina snails (ca. 7 mm shell diameter) were collected
from the field (water canals), maintained under laboratory conditions for a period of 21 days before the test, and fed daily by
lettuce leaves. Then, the snails were examined to ensure that
they were free from parasitic infection. Seven concentrations of
each compound under investigation were prepared ranging
from 3 ppm to 15 ppm. The required amount of the compound
under investigation was mixed thoroughly with a few drops of
Tween 20 and 2 mL of DMSO to render the compounds completely soluble, followed by addition of the appropriate volume of
untreated raw water (taken directly from the Nile River or its
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2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2006, 339, 456 – 460
subsidiary branches/canals) to get a homogeneous suspension
(turbid) with the requisite concentration and placed in glass jar
vessels, 15625620 cm in dimensions, fitted with air bubblers.
Ten snails having the same size and diameter (ca. 7 mm) were
used in each experiment and maintained in the test solution
under laboratory conditions at 258C for 24 h. Each experiment
was repeated three times, and the mean number of killed snails
was taken for each concentration. A control group was taken by
placing ten snails in water containing few drops of Tween 20
and 2 mL of DMSO. These bioassays are in accordance with the
WHO guidelines [14 – 16], slightly modified by using two mixed
solvents to dissolve the compounds.
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