Synthesis and molluscicidal activity of some new thiophene, thiadiazole and pyrazole derivatives

Article abstract of DOI:10.1016/j.ejmech.2008.09.006

The base-catalyzed reaction of benzoyl acetone 1 with phenyl isothiocyanate yields the non-isolable intermediate 2. Treatment of 2 with dilute HCl afforded the corresponding thiocarbamoyl derivative 3. Reaction of the intermediate 2 with phenacyl bromide,

Full text of DOI:10.1016/j.ejmech.2008.09.006

European Journal of Medicinal Chemistry 44 (2009) 1250–1256
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and molluscicidal activity of some new thiophene, thiadiazole
and pyrazole derivatives
*
Ahmed A. Fadda , E. Abdel-Latif, Rasha E. El-Mekawy
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2008
Received in revised form 22 July 2008
Accepted 1 September 2008
Available online 16 September 2008
The base-catalyzed reaction of benzoyl acetone 1 with phenyl isothiocyanate yields the non-isolable
intermediate 2. Treatment of 2 with dilute HCl afforded the corresponding thiocarbamoyl derivative 3.
Reaction of the intermediate 2 with phenacyl bromide, ethyl bromoacetate, chloroacetonitrile, chlor-
oacetyl chloride, bromodiethyl malonate and chloroacetone afforded the corresponding thiophene
derivatives 5, 8, 15 and 17. The thiocarbamoyl derivative 3 reacts with arylazophenacyl bromide and/or
hydrazine hydrate to afford the corresponding thiadiazole and pyrazole derivatives 20a–c and 22,
respectively. These new synthesized compounds show generally a moderate molluscicidal activity to
Biomphalaria alexandrina snails.
Keywords:
Thiocarbamoyl
Molluscicidal activity
Thiophene
Ó 2008 Elsevier Masson SAS. All rights reserved.
Thiadiazole
Pyrazole
1. Introduction
pyrazole derivatives seemed promising for molluscicidal evalua-
tion. In spite of the fact that, the synthetic compounds in this paper
Schistosomiasis is an endomic disease in tropical and subtrop-
ical regions that affects over 200 million humans worldwide.
Control of snail intermediate hosts is an effective means of reducing
the disease transmission. The early use of molluscicides in schis-
tosomiasis control has been reviewed by Duncan et al. [1,2] and
Bayluscide [3], the ethanol amine salt of niclosamide is considered
the compound of choice in many parts of the world. A major
disadvantage of Bayluscide as a chemical molluscicide is related to
its toxicity to fish. Interests of medicinal chemists on this
compound continued and, as a result, other aryl [4,5] and hetero-
cycles [6–9] have been prepared and tested as molluscicides.
We have found it mandatory to participate in these efforts and
directed a part of our research towards the synthesis of heterocyclic
compounds that can be used as molluscicides [10,11]. Pyrazoles and
their fused derivatives are known to exhibit diverse biological
activities and important applications in pharmaceutical industries
[7,8]. Thiophene, in particular, has been investigated by Royer and
his co-workers [12]; they reported the effectiveness of some mono-
and polyhalogenated thiophene carboxanilides against Biomphalaria
glabrata. Other thiophene containing compounds have been also
evaluated [13]. In continuation of our search for some effective
synthetic molluscicides, phenylaminothiophene, thiadiazole and
may have more hazardous effect to the environment, however, we
are just making the so-called preliminary blind screening until we
find the suitable effective lead compounds, then we can study
modifying its properties and expand this study to evaluation of its
biodegradability/stability as well as its effect on other water-living
organisms.
2. Chemistry
2.1. Synthesis of some new thiophene derivatives
Previously, we investigated the reaction of phenyl iso-
thiocyanate with active methylene compounds in alkaline medium,
which has proved to be a convenient route for the synthesis of
thiazole, pyrazole, oxazine and pyrimidine ring systems [14–17].
Now, we have extended our synthetic program to the synthesis of
otherwise inaccessible heterocyclic ring system, utilizing phenyl
isothiocyanate as a key starting material. It is known that a great
variety of reactants bearing the N]C]S fragment undergo cycli-
zation on reaction with
a-halocarbonyl compounds to afford thia-
zoles, 2,3-dihydrothiazoles and thiazolidines [18], which have been
shown to exhibit antiprotozoal [19] and fungicidal properties [20].
In this paper, we describe a generally applicable extension of this
synthetic approach, first reported by Hantzch and Weber [21]. Thus,
the base-catalyzed reaction of the acidic methylene compound 1
with phenyl isothiocyanate in dry DMF at room temperature yields
* Corresponding author. Tel.: þ20 109338294; fax: þ20 502246781.
E-mail address: afadda2@yahoo.com (A.A. Fadda).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.09.006

A.A. Fadda et al. / European Journal of Medicinal Chemistry 44 (2009) 1250–1256
1251
the non-isolable intermediate 2. Treatment of 2 with dilute HCl
afforded the corresponding thiocarbamoyl derivative 3. Assign-
ment of the product 3 was based on elemental analysis, IR, and 1H
NMR spectral data. The IR spectrum showed absorption bands at
3229, 3125, 1595 and 1293 cmꢀ1 attributable to the enolic OH, NH,
C]O and C]S, functions, respectively. 1H NMR spectrum of 3
In a similar manner to the behaviour of ethyl bromoacetate
with the non-isolable intermediate 2, chloroacetonitrile reacted
with 2 under the same reaction conditions to yield the same
product 8.
However, the product obtained had molecular formula
C19H15NSO2 which did not correspond to those of the expected
product 10. We deduced that the compound was identical in all
respects with product 8 (m.p., mixed m.p., IR, 1H NMR).
The derivative 8 in this case is expected to be formed via an
initial elimination of KCl molecule with the formation of the
intermediate 9 that cyclizes into the product 10. It was found that,
the cyano group was hydrolyzed under the reaction conditions to
give the carboxylic acid group and yielded product 8. The structure
of 8 which obtained in this case was established by spectral data.
The IR spectrum showed no absorption band of cyano group around
the region 2150–2300 cmꢀ1 indicating that the cyano group was
disappeared during the reaction course. On the other hand, the IR
spectrum showed two bands at 1731 and 1639 cmꢀ1 due to the
carboxylic and ketonic carbonyl groups. Moreover, the 1H NMR
displayed multiplet signals at d 7.1–7.5 ppm for NH proton. Its mass
spectrum showed the molecular ion peak m/z ¼ 297 (Mþ, 14%) The
non-isolable potassium salt 2 was allowed to react with phenacyl
bromide in stirring dry DMF at room temperature to give thiophene
derivative 5. The structure 5 was inferred from its spectral data.
Thus, the IR spectrum showed absorption bands at
1626 cmꢀ1 corresponding to NH and carbonyl groups. Its 1H NMR
spectrum showed a broad singlet at 11.6 ppm, singlet at 1.7 ppm
n
3330 and
d
d
and multiplet signals integrated for (15H) centered at 7.4 (aromatic
protons). On shaking the compound with D2O, the broad band
signal at
d 11.6 ppm disappeared. Based on the foregoing data,
structure 5 was further confirmed by Indirect method. Thus, it was
found that, refluxing of 3 with phenacyl bromide in dry acetone and
dry potassium carbonate produced the acyclic intermediate 4.
Structure 4 was suggested for the reaction on the basis of both
elemental and spectral analyses. The IR spectrum showed the
spectrum revealed three singlet signals at d 1.8, 10.8 and 11.79 ppm
attributable to methyl, COOH and NH protons, respectively.
All attempts to prepare the intermediate 9 by stirring at room
temperature compound 2 with chloroacetonitriles in the presence
of different bases to subject it for cyclization to obtain 10 were
failed, and instead gave almost compound 8.
In a similar way, it has been found that reaction of chloroacetyl
chloride with 2 in the presence of DMF gave exclusively the
unexpected product 8 instead of compound 12 (Scheme 2).
In continuation of our work on the synthesis of biologically
interesting heterocyclic molecules containing thiophene moiety via
multicomponent one-flask reaction, we reported here in our results
for the synthesis of thiophene derivatives 15.
As an application, stirring equimolar amounts of bromodiethyl
malonate with the non-isolable intermediate 2 in the presence of
potassium hydroxide and DMF gave a solid product 15. The
formation of compound 15 can be explained according to the
following proposed mechanism (Scheme 3).
Bromodiethyl malonate reacted with the non-isolable interme-
diate potassium salt 2 to give the intermediate 13 which hydrolyzes
and decarboxylates one of the carbethoxy groups under the reac-
tion condition to give compound 14 which cyclized directly to give
2-carboethoxy-3-methyl-4-benzoyl-5-phenylaminothiophene 15.
The structure of 15 was established on the basis of both elemental
and spectral data. The IR spectrum showed absorption bands at
3448, 1710 and 1670 cmꢀ1 corresponding to NH and two carbonyl
presence of a carbonyl absorption bands at
respectively, while the NH appeared at 3422 cmꢀ1. The 1H NMR
spectrum of 4 revealed three singlet signals at 1.62, 6.15 and
11.6 ppm due to the protons of CH3, SCH2 and NH groups, besides
n
1741 and 1627 cmꢀ1
d
multiplet signals at
protons.
d 7.01–7.8 ppm attributable to the aromatic
Refluxing 4 in a mixture of DMF/EtOH containing catalytic
amounts of TEA led to the formation of a product identical in all
respects (m.p., mixed m.p., IR and 1H NMR) to 5 (Scheme 1).
In a similar manner, treatment of the non-isolable intermediate
2 with ethyl bromoacetate in situ gave a single product which
analyzed correctly for C19H15NSO3. The structure of 8 was inferred
from its spectral and elemental analyses. Thus, the infrared spec-
trum of 8 showed a band near 3421 cmꢀ1 corresponding to an NH
function, and two bands at 1727 and 1662 cmꢀ1 due to the two
carbonyl groups. The mass spectrum of 8 showed the molecular ion
peak at m/z ¼ 337 (9%) indicating that the reaction proceeds via the
proposed intermediates 6 and 7, in addition to the presence of
fragment at m/z ¼ 294 (63%) due to the loss of carbon dioxide from
the molecular ion.
All attempts to prepare the acyclic intermediate 6 under
different reaction conditions were failed and instead, in all cases,
the reaction always afforded the cyclic thiophene derivative 8.
O
O
O
O
O
O
CH3
Ph
CH3 dil. HCl
CH3
Ph
1) KOH / DMF
2) PhNCS
Ph
PhCOCH2COCH3
SH
PhHN
S
1
PhHN
K
S
PhHN
2
3
1) acetone/K2CO3
2) PhCOCH2Br
PhCOCH2Br
CH3
O
O
O
CH3
Ph
EtOH/DMF
TEA
COPh
Ph
PhHN
S
COPh
PhHN
S
5
4
Scheme 1.

1252
A.A. Fadda et al. / European Journal of Medicinal Chemistry 44 (2009) 1250–1256
O
O
O
CH3
CH3
Ph
Ph
H2O/OH
O
S
COOEt
PhHN
PhHN
COOH
S
2
6
7
DMF
-H2O
O
O
O
O
CH3
CN
CH3
Ph
ClCH2CN Ph
DMF
CH3
H2O/OH
Ph
2
S
CN
PhHN
PhHN
S
PhHN
COOH
S
9
10
8
H2O/OH
CH3
O
O
O
Ph
CH3
Ph
S
COCl
PhHN
PhHN
COCl
S
11
12
Scheme 2.
groups, respectively. Moreover, the mass spectrum showed the
molecular ion peak at m/z ¼ 365 (100%, as base peak). All attempts
to isolate the intermediates 13 and 14 were failed.
Thus, when 18a–c reacted with 3 in boiling ethanol containing
a catalytic amount of triethylamine afforded the final product 20.
The formation of 20 is assumed to proceed via first elimination of
HBr to give the open acyclic intermediate 19 which then cyclized by
loss of aniline moiety affording the final product 20 (Scheme 5).
This result finds parallelism with previously reported work [17].
Structures 20a–c was proposed for the reaction product based on IR
spectrum which revealed the absence of any absorption band for
the NH function group and showed bands at 1670, 1665 and
1660 cmꢀ1 due to the three carbonyl groups and C]N function
group, respectively.
We thought to extend this synthetic approach by allowing 2 to
react with chloroacetone under the same previous reaction
conditions. It was found that, the reaction yielded a single product
which analyzed correctly for C20H17NSO2. This product was
formulated as 2-acetyl-3-methyl-4-benzoyl-5-phenylamino thio-
phene 17.
The structure of 17 was proved by IR and 1H NMR spectra. Its 1H
NMR spectrum revealed three singlet signals at
d 2.2, 2.5 and
10.24 ppm due to the CH3, COCH3 and NH protons, in addition to
multiplet bands at 7.1–7.7 ppm for aromatic protons. Moreover, the
mass spectrum give an additional conformation for the correct
structure which showed the molecular ion peak m/z ¼ 335 (Mþ,
22%) (Scheme 4).
The mass spectroscopy measurements of 20a showed the
molecular ion peak at m/z ¼ 426 (Mþ, 12%).
2.3. Synthesis of new substituted pyrazole derivative
Finally, in continuation of our interest in pyrazole chemistry, and
with a view directed towards preparing biological active hetero-
cycles, we wish to broaden the scope of the reaction of hydrazine
with compound 3 as candidates for facile synthetic route of
heterocyclic pyrazoles. The work resulted in the formation of
unexpected pyrazole derivative. Thus, it has been found that
treatment of 3 with hydrazine hydrate in boiling ethanol containing
2.2. Synthesis of new thiadiazole derivatives
On the other hand, it has been found that the arylazophenacyl
bromides 18a–c behaved differently towards the non-isolable
intermediate 2 when compared with the reaction of phenacyl
bromide itself.
O
O
CH3
Ph
BrCH(COOC2H5)2
1) KOH / DMF
2) PhNCS
PhCOCH2COCH3
1
S K
PhHN
2
O
O
O
O
CH3
O
Ph
Ph
CH3
CH3
Ph
H2O
-CO2
PhHN
S
COOEt
SCH(COOEt)2
COOEt
S
PhHN
PhHN
13
15
14
Scheme 3.

A.A. Fadda et al. / European Journal of Medicinal Chemistry 44 (2009) 1250–1256
1253
O
O
ClCH2COCH3
Ph
1) KOH / DMF
2) PhNCS
CH3
S K
PhCOCH2COCH3
1
PhHN
2
O
O
O
CH3
Ph
Ph
CH3
PhHN
COCH3
S
S
COCH3
PhHN
16
17
Scheme 4.
a catalytic amount of triethylamine afforded 3-methyl-4-benzoyl-
thiophene carrying compound showed lower activity as observed
previously [8]. The available results indicate some important
points regarding structure–activity correlation. Variation in the
type of heterocyclic ring showed a marked difference in activity.
During the exposure period, it was noticed an effusion of the
gelatinous material from snails under the influence of the tested
compounds. This fact may reveal that the mode of their toxic
action is through a physical interference with cell membranes,
resulting in hindering their functions and leading to hemolysis and
subsequent death.
5-phenylaminopyrazole 22 and not the expected
phenylamino derivative 21.
b-hydrazino-b-
Structure 22 was proved by IR spectrum which showed
stretching frequencies at 3405 and 3286 cmꢀ1 for two (NH) func-
tion groups while the carbonyl group showed absorption band at
1665 cmꢀ1
.
Moreover, structure 22 was also proved by mass spectroscopy
which give molecular ion peak at m/z ¼ 277 (Mþ, 42%) (Scheme 6).
A comparison of the molluscicidal activity of our compounds
with an international standard, 2,5-dichloro-4-nitrosalicylanilide
which is reported to posses LC100 ¼ 1 ppm [22,23] showed that our
compounds are far inferior as molluscicidal agents. Compound 20b
seems promising after some modifications which will be consid-
ered in a future study.
3. Conclusion
We report a facile route for the formation of thiophene based on
benzoyl a-phenylthiocarbamoylacetone.
4. Biological evaluation
The B. alexandrina snails had been recently considered as one of
the most serious pests in Egypt. It increases year after one. There-
fore, control measures are necessary. The effectiveness of pesticides
on mollusca pests was studied by many investigators. These
synthetic chemical compounds are expensive and in addition, may
lead to problems of toxicity to non-target organisms and delete-
rious long term effect in the environment. Therefore, our interest
must be directed to evaluate some anti-snails which can be easily
synthesized, economic and are safe in use.
4.1. Molluscicidal activity
The toxicity of compounds (5, 8, 15, 17, 20a–c and 22) to Bio-
mphalaria alexandrina snails was evaluated as shown in Table 1.
The half lethal dose (LC50) and sublethal dose (LC90) in ppm for
each compound were determined and are shown in Table 2.
Compounds 20b and c exhibited the highest toxic action and were
nearly similar in their (LC50) values (5.5 and 6 ppm), respectively.
Compounds 20a and 22 were also active with (LC50) values of (8
and 13 ppm), respectively, where compounds (5, 8, 15 and 17) were
the least toxic (15–19 ppm) among the interesting compounds. The
thiadiazole derivatives (20a–c) are superior to the thiophene
derivatives (5, 8, 15 and 17) apparently due to the high basicity of
the thiadiazole ring. Compound 20b shows the highest activity
may be due to the presence of methyl substituent in the phenyl
group. It seems that the presence of methyl group in the phenyl
group activates the biological activity more than the methoxy or
the unsubstituted phenyl group itself. Also, the presence of methyl
group in the pyrazole ring showed moderate activity. The
5. Experimental
5.1. Chemistry
5.1.1. General methods
All melting points are uncorrected. FTIR spectra (KBr disk) were
recorded on a Nicolet Magna. IR model 550 spectrophotometers, 1H
NMR spectra in DMSO-d6, were determined on Brucker Wpsy 200
MHZ spectrometer with TMS as internal standard and the chemical
shifts are in
s ppm. Mass spectra were recorded at 70 eV with
O
O
O
O
O
O
CH3
Ph
ArN
CH3
+
Ph
CH3
Ph
PhCO CBr
N-NHAr
EtOH
TEA
S
S-CCOPh
N-NHAr
19
PhHN
SH
PhHN
N
COPh
3
18a-c
20a-c
Ar= Ph, p-CH3-C6H4, p-CH3O-C6H4
Scheme 5.

1254
A.A. Fadda et al. / European Journal of Medicinal Chemistry 44 (2009) 1250–1256
Table 2
O
O
O
O
Molluscicidal activity of compounds (5, 8, 15, 17, 20a–c and 22) expressed as LC50 and
LC90 in ppm
EtOH
TEA
Ph
CH3
NHNH2
21
CH3
Ph
NH2NH2
+
Compound number
LC50 (C.L.)a
LC90 (C.L.)a
PhHN
SH
5
8
15
15.6 [11–80]
19 [15–33]
18 [16–61]
16 [14–85]
8 [7–65]
5.5 [4–12]
6 [5–20]
13 [12–63]
20 [15–78]
23 [22–65]
20 [15–60]
22 [18–85]
10 [9–60]
9 [8–32]
PhHN
3
17
O
20a
20b
20c
22
CH3
Ph
11 [10–15]
18 [16–65]
N
PhHN
a
N
H
Confidence limit.
22
(1.62 g, 10 mmol) and followed by phenyl isothiocyanate (1.35 g,
10 mmol). The mixture was stirred overnight at room temperature
and treated with the phenacyl bromide (1.99 g, 10 mmol); stirring
was continued for 4 h. The reaction mixture was poured onto ice-
cold water. Acidification using dilute HCl until the medium
becomes acidic gave solid product 5 which was filtered off, washed
with water, dried and recrystallized from aqueous ethanol to give
compound 5.
Scheme 6.
a varian MAT 311. Microanalyses were performed at the micro-
analytical center of Cairo University.
5.1.2. Benzoyl a-phenyl thiocarbamoyl acetone (3)
A cold suspension of potassium hydroxide (1.4 g, 25 mmol), in
DMF (30 ml) was added the benzoyl acetone (4.05 g, 25 mmol),
followed by phenyl isothiocyanate (3.37 g, 25 mmol). The mixture
was stirred overnight at room temperature and then poured onto
ice-cold water. Acidification using dilute HCl until the medium
becomes acidic gave solid product 3 which was filtered off, washed
with water, dried and crystallized from aqueous ethanol to give
compound 3.
5.1.4.2. Pathway (2). Refluxing of acyclic intermediate 4 (4.07 g,
1 mmol) for 2 h in the presence of ethanol (10 ml)/DMF (10 ml) and
TEA (4 drops) the reaction mixture was left to cool, and collected
the solid product which dried well and recrystallized from ethanol
to give compound 5.
Yellow crystal (Yield 45%), m.p. 127 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3422
(NH), 1741 and 1627 for two (C]O); 1H NMR: (DMSO-d6),
d 1.62 (s,
Yellow crystal (Yield 55%), m.p. 140 ꢁC; IR (KBr):
3H, CH3), 7.1–7.5 (m, 15H, Ar), 11.59 (s, 1H, NH); Anal. Calcd for
C25H19NO2S (397): C, 75.54; H, 4.82; N, 3.52; Found: C, 75.20; H,
4.62; N, 3.29.
n
/cmꢀ1 ¼3229 (OH), 3125 (NH), 1595 (C]O), 1293 (C]S); 1H
NMR (DMSO-d6),
d 2.5 (s, 3H, CH3), 7.1–7.5 (m, 10H, Ar), 11.9 (s,
1H, NH); MS: (m/z) (%) 297 (Mþ, 14), 255 (17), 222 (25); Anal.
Calcd for C17H15NO2S (297): C, 68.69; H, 5.05; N, 4.71; Found: C,
68.33; H, 5,00; N, 4.40.
5.1.5. 4-Benzoyl-3-methyl-5-(phenylamino)thiophene-2-carboxylic
acid (8)
To a cold suspension of potassium hydroxide (0.56 g, 10 mmol)
in DMF (30 ml), benzoyl acetone was added (1.62 g, 10 mmol) and
followed by phenyl isothiocyanate (1.35 g, 10 mmol). The mixture
was stirred overnight at room temperature and treated with the
ethyl bromoacetate and/or chloroacetonitrile and/or chloroacetyl
chloride (10 mmol); stirring was continued for 4 h. The reaction
mixture was poured onto ice-cold water. Acidification using dilute
HCl until the medium becomes acidic gave solid product 8 which
was filtered off, washed with water, dried and recrystallized from
aqueous ethanol to give compound 8.
5.1.3. 2-((2-Oxo-2-phenylethylthio)(phenylamino)methyl)-1-
phenyl-butane-1,3-dione (4)
Equimolecular quantities of 3 (2.97 g, 10 mmol) in acetone
containing potassium carbonate (1.39 g, 10 mmol) and phenacyl
bromide (1.99 g, 10 mmol) were refluxed for 2 h, then left to stand
at the room temperature. The crude product was filtered off, dried
and recrystallized from ethanol to give 4.
Yellow crystal (Yield 55%), m.p. 175 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3422
(NH), 1741 and 1627 for two (C]O); 1H NMR: (DMSO-d6),
d 1.62 (s,
3H, CH3), 6.15 (s, 2H, CH2), 7.01–7.80 (m, 15H, Ar), 11.6 (s, 1H, NH);
Anal. Calcd for C25H21NO3S (415.5): C, 72.27; H, 5.09; N, 3.36;
Found: C, 72.20; H, 5.00; N, 3.10.
Yellow crystal (Yield 65%), m.p. 230 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3421
(NH), 1727 and 1662 for two (C]O); 1H NMR: (DMSO-d6),
d 1.8 (s,
3H, CH3), 7.1–7.5 (m, 10H, Ar), 10.8 (s, 1H, COOH), 11.79 (s, 1H, NH);
MS: m/z (%) 337 (Mþ, 9), 294 (62.95), 232 (27.78), 221 (33.99), 190
(32.78), 144 (13.15), 105 (100), 77 (98.80); Anal. Calcd for
C19H15NO3S (337): C, 67.65; H, 4.45; N, 4.15; Found: C, 67.35; H,
4.15; N, 3.85.
5.1.4. (3-Methyl-5-(phenylamino)thiophene-2,4-diyl)bis(phenyl-
methanone) (5)
5.1.4.1. Pathway (1). To a cold suspension of potassium hydroxide
(0.56 g, 10 mmol) in DMF (30 ml), benzoyl acetone was added
Table 1
The mean number of snails killed ꢂ1 after an exposure time of 24 h at concentrations in ppm
Compound number
4 (ppm)
6 (ppm)
8 (ppm)
10 (ppm)
12 (ppm)
14 (ppm)
16 (ppm)
5
8
1
1
0
1
2
2
1
1
4
2
1
3
2
3
3
3
5
3
1
5
4
5
4
4
6
5
2
8
6
8
7
8
9
6
2
8
9
10
10
9
10
8
4
10
10
10
10
10
10
10
10
10
10
10
10
10
15
17
20a
20b
20c
22

A.A. Fadda et al. / European Journal of Medicinal Chemistry 44 (2009) 1250–1256
1255
5.1.6. Ethyl-4-benzoyl-3-methyl-5-(phenylamino)thiophene-2-
carboxylate (15)
precipitated on hot then filtered off dried and recrystallized from
DMF:EtOH (1:1) to give compound 20c.
To a cold suspension of potassium hydroxide (0.56 g, 10 mmol)
in DMF (30 ml), benzoyl acetone was added (1.62 g, 10 mmol) and
followed by phenyl isothiocyanate (1.35 g, 10 mmol). The mixture
was stirred overnight at room temperature and treated with the
bromodiethyl malonate (2.39, 10 mmol), stirring was continued
for 4 h. The reaction mixture was poured onto ice-cold water.
Acidification using dilute HCl until the medium becomes acidic
gave solid product 15 which was filtered off, washed with water,
dried and recrystallized from aqueous ethanol to give compound
15.
Yellow crystal (Yield 35%), m.p. 210 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3060
and 3100 for two (CH3), 1670 and 1660–1670 for three (C]O); 1H
NMR: (DMSO-d6), d 2.3 (s, 3H, CH3), 4.0 (s, 3H, CH3), 7.1–7.8 (m, 14H,
Ar), 10.24 (s, 1H, NH); MS: m/z (%) 456 (Mþ, 85); Anal. Calcd for
C26H20N2O4S (456): C, 68.41; H, 4.42; N, 5.26; Found: C, 68.40; H,
4.42; N, 5.00.
5.1.11. (3-Methyl-5-(phenylamino)-1H-pyrazol-4-
yl)(phenyl)methanone (22)
A mixture of equimolecular amounts of 3 (2.97 g, 10 mmol) and
hydrazine hydrate (0.32 g, 10 mmol) was refluxed in ethanol
(20 ml) and TEA (4 drops) for 2 h. The reaction mixture was poured
onto ice-cold water, filtered off and recrystallized from ethanol to
give the corresponding pyrazole 22.
Yellow crystal (Yield 70%), m.p. 162 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3448
(NH), 1710 and 1670 for two (C]O); MS: m/z (%) 365 (Mþ, 100), 304
(20.54), 260 (10.69), 246 (12.32), 147 (11.70), 128 (6.79), 77 (31.43);
Anal. Calcd for C21H19NO3S (365): C, 69.02; H, 5.24; N, 3.83; Found:
C, 68.72; H, 4.94; N, 3.53.
Yellow crystal (Yield 76%), m.p. 160 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3405
and 3286 (two NH), 1665 (C]O); MS: m/z (%) 277 (Mþ, 42); Anal.
Calcd for C17H15N3O (277): C, 73.63; H, 5.45; N, 15.16; Found: C,
73.33; H, 5.15; N, 14.86.
5.1.7. 1-4-Benzoyl-3-methyl-5-(phenylamino)thiophene-2-
ethanone (17)
To a cold suspension of potassium hydroxide (0.56 g, 10 mmol)
in DMF (30 ml), benzoyl acetone was added (1.62 g, 10 mmol) and
followed by phenyl isothiocyanate (1.35 g, 10 mmol). The mixture
was stirred overnight at room temperature and treated with the
chloroacetone (0.925, 10 mmol), stirring was continued for 4 h. The
reaction mixture was poured onto ice-cold water. Acidification
using dilute HCl until the medium becomes acidic gave solid
product 17 which was filtered off, washed with water, dried and
recrystallized from aqueous ethanol to give compound 17.
5.2. Molluscicidal activity tests
The molluscicidal activity tests were carried out by determina-
tion of the half lethal dose LC50 and sublethal dose LC90 of each
compound under investigation. B. alexandrina snails were collected
from the field (water canals) and maintained under laboratory
conditions for a period of 45 days before the tested and fed daily
with lettuce leaves. Then, the snails were examined to ensure that
they were free from parasitic infection. A series of concentrations
(seven) ranging from 4 to 16 ppm of each compound under
investigation were prepared. The required amount of the
compound under investigation was mixed thoroughly with few
drops of Tween 20 followed by addition of the appropriate volume
of untreated raw water (taken directly from the River Nile) to get
a homogeneous suspension with the necessary concentration, it
was poured in glass jar vessels 15 ꢃ 25 ꢃ 20 cm 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 tested
solution under laboratory conditions at ambient temperature for
24 h. Each experiment was repeated three times and the mean
number of killed snails was taken for each concentration as shown
in Table 1. A control group was taken by placing 10 snails in water
containing few drops of Tween 20. These bioassays are in accor-
dance with the W.H.O. guidelines [24].
Yellow crystal (Yield 59%), m.p. 230 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3444
(NH), 1710 and 1665 for two (C]O); 1H NMR: (DMSO-d6),
d 2.2 (s,
3H, CH3), 2.5 (s, 3H, CH3), 7.1–7.7 (m, 10H, Ar), 10.24 (s, 1H, NH); MS:
m/z (%) 335 (Mþ, 22), 304 (20.54), 260 (10.69), 246 (12.32), 147(21);
Anal. Calcd for C20H17NO2S (335): C, 71.62; H, 5.11; N, 4.17; Found:
C, 71.321; H, 4.81; N, 3.77.
5.1.8. (Z)-1-Phenyl-2-(3-phenyl-1,3,4-thiadiazol-2-(3H)-
ylidene)butane-1,3-dione (20a)
A mixture of 3 (2.97 g, 10 mmol) and phenylazophenacyl
bromide (3.03 g, 10 mmol) in the presence of boiling ethanol
(20 ml) and TEA (4 drops) was heated for 2 h. The solid product that
separated while hot was precipitated on hot then filtered off, dried
and recrystallized from DMF:EtOH (1:1) to give compound 20a.
Yellow crystal (Yield 87%), m.p. 188 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3060
(CH3), 1670 and 1665–1660 for three (C]O); MS: m/z (%) 426 (Mþ,
12); Anal. Calcd for C25H18N2O3S (426): C, 70.40; H, 4.25; N, 5.63;
Found: C, 70.40; H, 4.00; N, 5.33.
Acknowledgments
5.1.9. (Z)-2-(3-(p-Tolyl)-1,3,4-thiadiazol-2-(3H)-ylidene)-1-
phenyl-butane-1,3-dione (20b)
The authors are grateful to Agricultural Research Center for
biological evaluation, Mansoura, Egypt.
A mixture of 3 (2.97 g, 10 mmol) and p-tolylazo phenacyl
bromide (3.17 g, 10 mmol) in the presence of boiling ethanol and
TEA (4 drops) was heated for 2 h. The reaction mixture precipitated
on hot then filtered off dried and recrystallized from DMF:EtOH
(1:1) to give compound 20b.
References
[1] F.S. Mecullough, P. Gayral, J. Duncan, J.D. Christie, Bull. World Health Organ. 58
(1980) 681–689.
[2] J.A. Duncan, in: T.C. Cheng (Ed.), Molluscicides in Schistosomiasis Control,
Academic Press, New York, 1974, pp. 9–40.
[3] R. Gonnet, Bull. World Health Organ. 25 (1961) 483–501.
[4] L.S. Ritchie, I. Fox, Bull. World Health Organ. 39 (1968) 312–315.
[5] G.A. Nawwar, F.M. Abdelrazek, R.H. Swellam, Arch. Pharm. (Weinheim) 324
(1991) 875–877.
[6] G. Madulo-Leblond, P. Gayral, J.M. Clavel, R. Royer, Eur. J. Med. Chem. 16 (1981)
267–270.
[7] P. Gayral, J.P. Buisson, R. Royer, Eur. J. Med. Chem. 20 (1985) 187–189.
[8] F.M. Abdelrazek, P. Metz, E.K. Farrag, Arch. Pharm. Med. Chem. 337 (2004)
482–485.
[9] F.M. Abdelrazek, P. Metz, N.H. Metwally, S.F. Mahrouky, Arch. Pharm. Chem.
Life Sci. 339 (2006) 456–460.
Yellow crystal (Yield 74%), m.p. 226 ꢁC; IR (KBr):
n
/cmꢀ1 ¼3060
and 3065 for two (CH3), 1675 and 1660–1670 for three (C]O); 1H
NMR: (DMSO-d6),
d 1.97 (s, 3H, CH3), 2.3 (s, 3H, CH3), 7.1–7.8 (m,
14H, Ar); MS: m/z (%) 440 (Mþ, 26). Anal. Calcd for C26H20N2O3S
(440): C, 70.89; H, 4.58; N, 6.36; Found: C, 70.88; H, 4.50; N, 3.00.
5.1.10. (Z)-2-(3-(4-Methoxyphenyl)-1,3,4-thiadiazol-2-(3H)-
ylidene)-1-phenylbutane-1,3-dione (20c)
A mixture of 3 (2.97 g, 10 mmol) and 4-methoxyphenylazo-
phenacyl bromide (3.33 g, 10 mmol) in the presence of boiling
ethanol and TEA (4 drops) was heated for 2 h. The reaction mixture
[10] A.A. Fadda, M.M. Girges, M.A. Hanna, Chem. Pap. 47 (3) (1993) 186.

1256
A.A. Fadda et al. / European Journal of Medicinal Chemistry 44 (2009) 1250–1256
[11] G. Koyama, H.J. Umezawa, Antibiotiki 18A (1965) 175;
Chem. Abstr. 63 (1965) 15158d.
[12] P. Gayral, J.P. Busson, R. Royer, Eur. J. Med. Chem. 20 (1985) 187.
[13] S.W.R. Wang, S.X. Peng, Yao Hsueh Pao 27 (1992) 261. Chem. Abstr. 117 (1992)
131270.
[17] A.A. Fadda, F.A. Amer, Kh. Samir, Phosphorus, Sulfur Silicon Relat. Elem.182 (2007) 1845.
[18] H.A. Ead, S.O. Abdellah, N.A. Kassab, N.H. Metwalli, H. Saleh, Arch. Pharm.
(Weinheim) 320 (1997) 1227.
[19] S.K. Mallick, A.R. Martin, J. Med. Chem. 14 (1971) 528.
[20] S.R. Singh, J. Ind. Chem. Soc. 52 (1975) 734.
[14] A.A. Fadda, H.M. Refat, M.A. Zaki, Molecules 5 (2000) 701–709.
[15] A.A. Fadda, E. Abd EL-Latif, E. Rasha, EL-Mekawy, Phosphorus, Sulfur Silicon
Relat. Elem., 183 (8) (2008) 1940–1953.
[16] S.I. El-Desoky, H.A. Etman, S.B. Bondock, A.A. Fadda, M.A. Metwally, Sulfur Lett.
25 (2002) 199.
[21] A. Hantzsch, H. Weber, J. Ber. Dtsch. Chem. Ges. 20 (1887) 3118.
[22] R. Connert, Bull. World Health Organ. 25 (1961) 483–487.
[23] R. Connert, R. Strufe, Ciba Found. Symp. Billhaziasis (1962) 326–338;
Chem. Abstr. (1963) 5714.
[24] K. Memoranda, Bull. World Health Organ. 33 (1965) 567–581.