Synthesis and antimicrobial activities of some new thiazole and pyrazole derivatives based on 4,5,6,7-tetrahydrobenzothiophene moiety

Article abstract of DOI:10.1016/j.ejmech.2009.12.020

2-(5-oxothiazolidinone)-cyanoacetamido derivative 3 was prepared in two steps by reaction of 2-(2-cyano-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (1) with phenyl isothiocyanate and chloroacetyl chloride, which diazocoupled with p-tolyldiazonium chloride in pyridine to afford the corresponding hydrazono derivative 4. Also, condensation of 3 with p-anisaldehyde gave the corresponding arylidine derivative 5. Treatment of 2 with dimethyl sulfate afforded the ketene N,S-acetal 9 which give 5-amino pyrazole derivative 10 upon treatment with hydrazine hydrate. Compound 10 was used as key intermediate for synthesis of pyrazolo[5,1-c][1,2,4]triazine 13a, b, pyrazolo[5,1-a]pyrimidine 14-17 and pyrolo pyrazole 18 derivatives. Finally, condensation of 1 with DMF-DMA afforded the corresponding acryloamide derivative 19, which afforded the corresponding pyrazole derivative 20 upon heating with hydrazine hydrate. All new synthesized compounds were evaluated as antimicrobial agents; some of them exhibited promising activities.

Full text of DOI:10.1016/j.ejmech.2009.12.020

European Journal of Medicinal Chemistry 45 (2010) 1338–1345
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimicrobial activities of some new thiazole and pyrazole
derivatives based on 4,5,6,7-tetrahydrobenzothiophene moiety
*
M.A. Gouda , M.A. Berghot, Ghada E. Abd El-Ghani, A.M. Khalil
Chemistry Department, Faculty of Science, Mansoura University, El-Gomhoria Street, Mansoura 35516, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(5-oxothiazolidinone)-cyanoacetamido derivative 3 was prepared in two steps by reaction of 2-
(2-cyano-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (1) with phenyl iso-
thiocyanate and chloroacetyl chloride, which diazocoupled with p-tolyldiazonium chloride in pyridine to
afford the corresponding hydrazono derivative 4. Also, condensation of 3 with p-anisaldehyde gave the
corresponding arylidine derivative 5. Treatment of 2 with dimethyl sulfate afforded the ketene N,S-acetal
9 which give 5-amino pyrazole derivative 10 upon treatment with hydrazine hydrate. Compound 10 was
used as key intermediate for synthesis of pyrazolo[5,1-c][1,2,4]triazine 13a, b, pyrazolo[5,1-a]pyrimidine
14–17 and pyrolo pyrazole 18 derivatives. Finally, condensation of 1 with DMF-DMA afforded the cor-
responding acryloamide derivative 19, which afforded the corresponding pyrazole derivative 20 upon
heating with hydrazine hydrate. All new synthesized compounds were evaluated as antimicrobial
agents; some of them exhibited promising activities.
Received 3 August 2009
Received in revised form
21 November 2009
Accepted 10 December 2009
Available online 21 December 2009
Keywords:
Thiophene
Thiazole
Triazine
Pyrazolopyrimidine
Antimicrobial evaluation
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
a part of our program directed towards developing new approaches
to variety of heterocycles incorporating thiophene moiety [24,28–
Thiazoles and their derivatives have attracted continuing
interest over the years because of their varied biological activities
[1,2], recently found application in drug development for the
treatment of allergies [3], hypertension [4], inflammation [5],
schizophrenia [6], bacterial [7], HIV infections [8], hypnotics [9] and
more recently for the treatment of pain [10], as fibrinogen receptor
antagonists with antithrombotic activity [11] and as new inhibitors
of bacterial DNA gyrase B [12].
30] of expected potential activity we reported herein of the utility
of the highly versatile multifunctional intermediate (1) as building
block for the synthesis of the title compounds.
2. Results and discussion
2.1. Chemistry
On the other hand, the class of pyrazoles and isoxazoles possess
a broad spectrum of biological effectiveness such as antiviral [13],
antidepressant [14] and antibacterial activity [15]. Recently,
substituted pyrazole derivatives were used as analytical reagents in
the complexation of transition metal ions [16–20]. Besides, great
interest in the pyrazole molecule has been stimulated by some
promising pharmacological, agrochemical and analytical applica-
tions of its derivatives [21,22]. Furthermore, tetrahydrbenzothio-
phene derivatives were found to possess analgesic and
antiinflammatory activities [23].
The synthetic procedures adopted to obtain the target
compounds are depicted in Schemes 1–3. The starting compound
2-(2-cyano-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-
3-carboxamide (1) was prepared according to the previous
reported method [24]. Compound 1 reacted with phenyl iso-
thiocyanate in dry DMF in the presence of potassium hydroxide
followed by addition of chloroacetyl chloride to afford 2-(5-
oxothiazolidinone)-cyanoacetamido derivative 3, via the inter-
mediate 2. The structure of 3 was characterized by the presence
In view of the above biological importance and in continuation
our studies on the chemistry of 2-(2-cyano-acetylamino)-4,5,6,7-
tetrahydro-benzo[b]thiophene-3-carboxamide (1) [24–27] and as
of a singlet signal equivalent to two protons at
d 4.10 ppm in the
1H NMR spectrum, which represent the C5 protons of the thia-
zolidinone ring. Also, the 13C NMR spectrum of compound 3
reveals a signal at
ring. Diazocoupling of compound
d
77.28 ppm corresponding to C-4 of thiazoline
with p-tolyldiazonium
3
chloride in pyridine afforded the corresponding 2-[4-(tolyl-
hydrazono)-5-oxothiazolidinone]-cyanoacetamido derivative 4.
* Corresponding author. Tel.: þ20 50 6432235; fax: þ20 50 2246781.
E-mail address: dr_mostafa_chem@yahoo.com (M.A. Gouda).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.12.020

M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1338–1345
1339
O
O
NH2
NH
NH2
NH
O
O
PhNCS
CN
CN
KOH / DMF
S
S
S K
PhHN
1
2
CHO
O
O
NH2
Cl
O
Cl
CN
NH
Ph
OCH3
DMF / TEA
S
N
S
O
NH2
O
N
O
H3CO
CN
NH
Ph
5
S
N2+Cl-
S
O
NH2
3
O
O
CN
NH
Ph
S
CH3
N
S
pyridine
N
O
H3C
N
H
4
Scheme 1.
Its 1H NMR spectrum exhibited three singlet signals at
d
2.32,
heterocyclic amine is an excellent building block for the synthesis
11.37, 12.31 ppm due to CH3, NH]N, NHCO protons, respectively.
Condensation of compound 3 with p-anisaldehyde in DMF
and in the presence of a catalytic amount of piperidine gave 2-[4-
(4-methoxy-benzylidene)-5-oxo-3-phenyl-thiazolidin-2-ylidene]-
acetylamino derivative 5. The structure of 5 was compatible with
of the target compound. Thus, coupling of compounds 1 or 6 [24],
with
4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl-diazonium
chloride [31], in pyridine at 0–5 ꢀC afforded the corresponding
hydrazono compound 7, also compound 7 was obtained by
coupling of 3 (which obtained by acidification with dilute HCl [24]),
with the previous diazonium chloride, the formation of 7 may be
its 1H NMR spectrum which displayed singlet signal at
corresponding to three protons of methoxy group.
d 3.93 ppm
interpreted through a-phenyl thiocarbamoyl cleavage [32], when
In continuation of our interest in the synthesis of bridged head
nitrogen heterocyclic systems [30], we have found that diazotized
compound 7 is refluxed in acetic acid, it can be cyclized to pyr-
azolo[5,1-c][1,2,4]triazine-derivative 8 (Scheme 2). Its 1H NMR
CH3
N2+Cl-
O
NH2
N
O
N
H
H3C
N
dil. HCl
CN
SH
2
NH
PhHN
S
Pyridine
6 or 1
6
O
S
O
S
NH2
NH
NH2
O
O
NH2
N
CN
N
AcOH
NH
N
N
N
N
CH3
HN
CH3
H3C
8
N
N
H
H3C
N
7
Scheme 2.

1340
M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1338–1345
O
O
NH2
NH
NH2
NH
O
O
NH2
NH
NH2NH2
EtOH
(Me)2SO4
CN
2
S
S
N
HN
PhHN
SMe
9
10
Ph
NaNO2 / HCl
NH2
O
X
NH2
NH
O
Y
O
HN N
O
N2+Cl-
Y
X
S
NH
pyridine
NH
S
N
HN
Ph
12a, X=CN,Y=CN
NH
N
HN
Ph
11
12b, X=COCH3,Y=COCH3
AcOH
O
NH2
O
N
N
Y
NH
S
N
X
N
HN
Ph
13a, X=NH2 ,Y=CN
13b, X=CH3 ,Y=COCH3
Scheme 3.
spectrum revealed two singlet signals at
two methyl groups of pyridine.
d
2.82 and 2.97 ppm due to
displayed the molecular ion peak at m/z 504 (Mþ ꢁ 3H), which
matching with its molecular formula C24H25N7O4S. Also, compound
13a, displayed the molecular ion peak at m/z 391 (Mþ ꢁ (N2C–CN))
and the base peak at m/z 51 (acrylonitrile moiety), finally,
compound 13b displayed the molecular ion peak at 470 (Mþ ꢁ H2O)
and the base peak at 77 (phenyl).
Moreover, treatment of 2 with dimethyl sulfate afforded the
ketene N,S-acetal 9. The 1H NMR spectrum displayed singlet signal
at d
2.19 equvalent to three protons of SCH3 group, also, its 13C NMR
revealed a signal at 17.1 due to SCH3 group.
5-Amino pyrazole derivative 10 was achieved by the refluxing of
Pyrazolo[3,4-a]pyrimidine are of considerable chemical and
pharmacological importance as purine analogues [33,34]. Various
related compounds of these also have antitumor, anti-leukemic
activities. Several biological activities have been established for some
pyrazolo derivatives [35,36]. Also, the insecticidal activities have been
investigated for some pyrazolo derivatives [37,38]. Thus, compound
10 interacted with acetylacetone, 5-chloro-3-methyl-phenyl-
pyrazolo-4-carboxaldehyde[39],1-chloro-3,4-dihydro-naphthalene-
2-carboxaldehyde [40] and 1-phenyl-3-(pipridin-1-yl)propan-1-one
hydrochloride [41] in the appropriate solvent to afford the corre-
sponding pyrazolo[1,5-a]pyrimidine derivatives 14–17, respectively.
The structures 14–17 were confirmed on the basis of the
analytical and spectral data. The protons of two methyl groups in
9 with hydrazine hydrate in ethanol. Its 1H NMR spectrum dis-
played two broad signals at
groups, three singlet signals at
d
6.00 and 6.82 corresponding to 2NH2
8.30, 11.33 and 11.89 due to
d
(NH–Ph), (NH-pyrazole) and (NH–CO) protons, respectively. We
found also, diazotized 5-amino-3-phenylamino-1H-pyrazole-4-
carboxylic acid (3-carbamoyl-4,5,6,7-tetrahydro-benzo[b]thio-
phen-2-yl)-amide 10 is an excellent building block for the synthesis
of bridge head nitrogen heterocyclic system. Thus, diazotization of
compound 10 with sodium nitrite and conc. HCl gave the corre-
sponding diazonium chloride 11, which was coupled with different
active methylene, namely; malononitrile and acetylacetone in
pyridine to afford the corresponding hydrazono derivatives 12a,
b respectively. When compounds 12a, b were refluxed in glacial
acetic acid, the target pyrazolo[5,1-c][1,2,4]triazine derivatives 13a,
b were obtained. The formation of 13a, b may be interpreted
through the nucleophilic attack of ring nitrogen on cyano or acetyl
group. The structures 12a, b and 13a, b were elucidated on the basis
of analytical and spectral data. The IR spectra of 12a, b revealed the
azo peaks at 1522 and 1560 cmꢁ1, respectively. Furthermore, the 1H
compound 14 resonated as two singlet at
NMR spectrum. Also, 15 reveals a singlet signal at
methyl protons and 16 displayed multiplite signals at
d
2.68, 2.69 in the 1H
2.51 due to
2.94 and
d
d
3.03 ppm due to C7-2H, C6-2H protons of quinazoline moiety. The
mass spectrum of 14 showed the molecular ion peak at m/z 460
(Mþ) and the base peak at m/z 265 (5,7-dimethyl-2-(phenyl-
amino)pyrazolo[5,1-a]pyrimidine-3-carbonyl
moiety).
Also,
NMR spectrum of compound 12b displayed a broad signal at
d
2.56,
compound 16 exhibited the molecular ion peak at m/z 530 (Mþ ꢁ 2)
which in agreement with molecular formula C30H26N6O2S and the
fragment ion peak at m/z 338 due to 2-anilino-6,7-dihydro-
benzo[h]pyrazolo[5,1-a]quinozoline-3-carbonyl moiety. Finally,
compound 17 showed the molecular ion peak at m/z 508 (Mþ)
which corresponding to six protons of two methyl groups. The 1H
NMR spectrum of compound 13a displayed multipliet signals at
d
7.10–7.62 due to two NH2 group, aromatic protons and a broad
signal at 8.30 for NH–Ph proton. The Mass spectrum of 12b
d

M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1338–1345
1341
which in agreement with molecular formula C28H24N6O2S and the
fragment ion peak at m/z 313 due to 7-phenyl-2-(phenylamino)
pyrazolo[5,1-a]pyrimidine-3-carbonyl moiety. Moreover, cyclo-
condensation reaction of 10 with 2,5-hexadione in boiling acetic
acid furnished the corresponding pyrrole derivative 18. Its 1H NMR
spectrum revealed appearance of a characteristic broad signal at
measured as an indicator for the activity of the compounds;
Ampicillin is used as reference drug.
The results for antibacterial activities depicted in Table 1
revealed that compounds 3, 4, 5, 10, 18 and 20 exhibited good
activities against the reference chemotherapeutics, while
compounds 8, 14, 15, 16 and 17 showed moderate antibacterial
activity. Also, compound 13b exhibited moderate activities against
Klebsiella pneumoniae and negative against Bacillus theringiensis, on
the other hand, most of the prepared compounds exhibited
moderate antifungal activities against the reference drugs,
whereas, 4, 14, 18 and 20 exhibited good antifungal activities
against Fusarium. oxysporum. Also, compounds 13a, 13b exhibited
good antifungal activities against F. oxysporum and negative against
B. fabe. It is worth mentioning that the incorporation of benzo-
thiophene nucleus to thiazole or pyrazole moieties caused signifi-
cant activity against B. theringiensis, K. pneumoniae, B. fabe and
F. oxysporum.
d
2.00 due to two methyl protons (Scheme 4).
On the other hand, the reaction of 1 with DMF-DMA in dry
dioxane afforded 2-[2-cyano-3-(dimethylamino)acryloamido]thio-
phene derivative 19, which afforded the corresponding pyrazole
derivative 20 upon heating with hydrazine hydrate. The structures
19 and 20 were established on the basis of analytical and spectral
data. The IR spectrum of compound 20 was characterized by the
disappearance of CN group. The 1H NMR spectrum of compound 19
displayed two singlet signals at
groups of dimethylamine group. Also, the 1H NMR spectrum of 20
displayed two broad signals at 6.05 and 7.60 due to protons of
2NH2 groups and another three singlet signals at 8.21, 11.00 and
d 3.25 and 3.31 due to two methyl
d
d
In conclusion, we reported herein a simple and convenient route
for the synthesis of some new heterocyclic based on benzothio-
phene for antimicrobial evaluation.
12.23 assignable to ]CH, NH and NH2CO protons, respectively. The
mass spectrum of compound 19 showed a molecular ion peak at
m/z 300 (Mþ ꢁ H2O) and the base peak at m/z 51 (acrylonitrile
moiety). In addition, to the mass spectrum of compound 20 dis-
played the molecular ion peak at m/z 305 (Mþ) which is in agree-
ment with the molecular formula C13H15N5O2S and the fragment
ion peak at 110 due to 1H-pyrazole-4-carbonyl moiety Scheme 5.
4. Experimental
4.1. General
All melting points are recorded on Gallenkamp electric melting
point apparatus. The IR spectra
y
cmꢁ1 (KBr) were recorded on
3. Antimicrobial activity
Perkin Elmer Infrared Spectrophotometer Model 157, Grating. The
1H NMR spectra were obtained on a Varian Spectrophotometer at
200 MHz using TMS as an internal reference and DMSO-d6 as
solvent. The 13C NMR spectra were recorded on JEOL-ECA500
(National Research Center, Egypt). The mass spectra (EI) were
recorded on 70 eV with Kratos MS equipment and/or a Varian MAT
311 A Spectrometer. Elemental analyses (C, H, and N) were carried
out at the Micro Analytical Center of Cairo Univ., Giza, Egypt. The
results were found to be in good agreement (ꢂ0.3%) with the
calculated values. Microbiology screening was carried out in Botany
Department, Faculty of Science Mansoura University, under
supervision Prof. Dr. Yhia A. O. Ellazeik.
Compounds 2-(2-cyano-acetylamino)-4,5,6,7-tetrahydro-benzo[b]
thiophene-3-carboxamide (1) [24–27] and 2-(2-cyano-3-mercapto-3-
phenylamino-acryloylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-
3-carboxamide (6) [24] were prepared according to the previously
reported method.
Some of the new synthesized compounds were screened in vitro
for their antimicrobial activity. The diameter of inhibition zone was
O
CH3
NH2
O
O
O
N
NH
N
S
AcOH
CH3
N
N
N
PhHN
14
O
NH2
O
CHO
Cl
H3C
N
CH3
N
N
NH
N
N
S
Ph
N
PhHN
DMF
Ph
15
O
NH2
O
4.1.1. Synthesis of 2-[2-cyano-2-(5-oxo-3-phenyl-thiazolidin-2-
ylidene)-acetylamino]-4,5,6,7-tetrahydro-benzo[b]thiophene-3-
carboxamide (3)
Cl
N
CHO
NH
N
S
To a cold suspension of finally divided KOH (0.22 g, 4 mmol) in
dry DMF (25 ml) were added compound 1 (1.05 g, 4 mmol) followed
by phenyl isothiocyanate (0.54 g, 4 mmol). The mixture was stirred
at room temperature for 12 h, then cooled again to 0 ꢀC, treated
with chloroacetyl chloride (0.45 g, 4 mmol) and left to stand at
room temperature for 24 h. The mixture was poured into ice cold-
water. The resulting precipitate was filtered off, dried and recrys-
tallized from mixture of EtOH:DMF to give compound 3.
10
PhHN
DMF
16
O
O
NH2
O
N
N
Ph
HCl
NH
N
AcOH
S
Ph
N
N
PhHN
17
Yellow crystals; Yield 75%; 1.32 g; mp 291 ꢀC; IR (KBr):
n
/cmꢁ1
¼
3420, 3329, 3265 (NH), 2200 (CN), 1726, 1644 (br) (3C]O); 1H NMR
(DMSO): dppm ¼ 1.78 (m, 4H, C5-2H, C6-2H), 2.69 (m, 2H, C4-2H),
2.75 (m, 2H, C7-2H), 4.10 (s, 2H, C5-2H-thiazolidinone), 7.19–7.61
O
H3C
O
NH2
O
N
O
AcOH
CH3
NH
(m, 7H, Ar-H, NH2), 12.57 (s, 1H, NH–CO); 13C NMR (DMSO): dppm
¼
NH
S
173.2 (C2-thiophene), 171.0, 167.3, 160.9 (3CO), 142.6, 130.5, 129.3,
129.2, 128.8, 126.3 (sp2, C), 115.4 (CN), 112.4 (C2, acetylamino), 77.2
(C4-thiazoline), 29.1, 28.9, 22.2 (2C), (cyclohexene ring); EIMS (m/z)
(%) ¼ 439 (Mþ þ 1, 4.3), 438 (Mþ, 11.3), 421 (1.9), 243 (19.6), 215
PhHN
18
Scheme 4.

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M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1338–1345
O
O
NH2
NH
NH2
O
O
NH2
NH
NH2NH2.H2O
DMF-DMA
Dioxane
CN
1
NH
S
S
N
NMe2
20
19
Scheme 5.
(48.6), 179 (16.1), 151 (10.4), 132 (32.1), 116 (10.1), 77 (100), 51
(44.4). Anal. for C21H18N4O3S2 (438.52): calcd.: C, 57.52; H, 4.14; N,
12.78%; found: C, 57.61; H, 4.18; N, 12.86%.
C4-2H), 2.79 (m, 2H, C7-2H), 3.93 (s, 2H, OCH3), 7.29–8.01 (m, 12H,
Ar-H,]CH, NH2), 12.78 (s,1H, NH). Anal. for C29H24N4O4S2 (556.66):
calcd.: C, 62.57; H, 4.35; N, 10.06%; found: C, 62.51; H, 4.29; N,
10.01%.
4.1.2. Synthesis of 2-{2-cyano-2-[5-oxo-3-phenyl-4-(p-tolyl-
hydrazono)-thiazolidin-2-ylidene]-acetylamino}-4,5,6,7-
tetrahydro-benzo[b]thiophene-3-carboxamide (4)
4.1.4. Synthesis of 2-{2-cyano-2-[(4,6-dimethyl-1H-pyrazolo[3,4-
b]pyridin-3-yl)-hydrazono]-acetylamino}-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxamide (7)
To a well-stirred cooled solution of p-toluidine (0.43 g, 4 mmol)
in (1.5 ml) conc. HCl and (2 ml), a solution of NaNO2 (0.28 g, 4.1
mmol in 5 ml H2O) was added drop wise. The above cooled dia-
zonium solution was added slowly to a well-stirred solution of 3
(1.75 g, 4 mmol) in pyridine (10 ml). The reaction mixture was
stirred for 2 h. The crude product was filtered off, dried well and
recrystallized from the EtOH:benzene to give 4.
Preparation of the diazonium salt: A solution of sodium nitrite
(0.28 g, 4.1 mmol, in 2 ml water) was gradually added to a well
cooled solution of 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl-
amine (0.65 g, 4 mmol) in conc. hydrochloric acid [(1.5 ml) in water
(2 ml)]. The diazonium salt solution was added drop wise with
continuous stirring to cold solution of 1 (1.05 g, 4 mmol) or 6 (1.59
g, 4 mmol) in pyridine (10 ml) the reaction mixture was stirred at
0–5 ꢀC for 2 h and left to stand at room temperature. The solid
products that obtained were filtered off, dried and recrystallized
from mixture of EtOH:DMF.
Orange crystals; Yield 75%; 1.67 g; mp 307 ꢀC; IR (KBr):
n
/cmꢁ1
¼
3408, 3252, 3222, 3170 (NH), 2202 (CN), 1725, 1683 (br, 3C]O),
1551 (N]N); 1H NMR (DMSO): dppm ¼ 1.80 (m, 4H, C5-2H, C6-2H),
2.32 (s, 3H, CH3), 2.70 (m, 2H, C4-2H), 2.73 (m, 2H, C7-2H), 7.23–7.33
(m, 11H, Ar-H, NH2), 11.37 (s, 1H, NH]N), 12.31 (br, 1H, NHCO);
EIMS (m/z) (%) ¼ 557 (Mþ þ 1, 0.8), 556 (Mþ, 1.0), 539 (1.1), 306
(11.2), 222 (19.0), 179 (23.0), 77 (100). Anal. for C28H24N6O3S2
(556.66): calcd.: C, 60.41; H, 4.35; N, 15.10%; found: C, 60.48; H,
4.42; N, 15.16%.
Black crystals; Yield 80%; 1.397 g, when using compound 1;
Yield 60%; 1.05 g, while using compound 6, mp > 320 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3370, 3335, 3263, 3203 (br, NH), 2216 (CN), 1637 (br,
2C]O), 1521 (N]N); EIMS (m/z) (%) ¼ 436 (Mþ, 1.21), 324 (1.2), 293
(100), 262 (13), 26 (14), 212 (25), 183 (68), 149 (20), 138 (15), 96
(16), 77 (2.18). Anal. for C20H20N8O2S (436.49): calcd.: C, 55.03; H,
4.62; N, 25.67%; found: C, 55.12; H, 4.70; N, 25.73%.
4.1.3. Synthesis of 2-{2-cyano-2-[4-(4-methoxy-benzylidene)-5-
oxo-3-phenyl-thiazolidin-2-ylidene]-acetylamino}-4,5,6,7-
tetrahydro-benzo[b] thiophene-3-carboxamide (5)
4.1.5. Synthesis of 8-amino-2,4-dimethyl-1,5,6,8a,9-pentaaza-
fluorene-7-carboxylic acid (3-carbamoyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-2-yl)-amide (8)
To a well-stirred solution of compound 3 (1.75 g, 4 mmol) in
DMF (20 ml), TEA (0.2 ml) and p-anisaldehyde (0.54 g, 4 mmol)
were added. The reaction mixture was stirred at 80 ꢀC for 3 h. The
separated crystals was filtered, dried and recrystallized from
mixture of EtOH:benzene to give compounds 5.
A solution of compound 7 (1.75 g, 4 mmol) in glacial acetic acid
(20 ml) was refluxed for 4 h. The reaction mixture was left to stand
at room temperature overnight, and the separated solid product
was filtered and crystallized from a mixture of EtOH:benzene to
give 8.
Brown crystals; Yield 60%; 1.34 g; mp > 320 ꢀC; IR (KBr): /cmꢁ1
n
¼ 3403, 3255, 3025 (NH), 2200 (CN), 1707, 1640 (br, 3C]O); 1H
NMR (DMSO): dppm ¼ 1.79 (m, 4H, C5-2H, C6-2H), 2.73 (m, 2H,
Black powders; Yield 80%; 1.397 g; mp > 320 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3377–3215 (NH), 1656, 1630 (br, 2C]O); 1H NMR
Table 1
(DMSO): dppm ¼ 1.82 (m, 4H, C5-2H, C6-2H), 2.68 (m, 2H, C4-2H),
2.74 (m, 2H, C7-2H), 2.82 (s, 3H, C10-CH3), 2.97 (s, 3H, C8-CH3), 7.18
(br., 2H, CONH2), 7.40 (s, 1H, pyridine), 9.45 (br., 2H, NH2), 13.45 (s,
1H, NH). Anal. for C20H20N8O2S (436.49): calcd.: C, 55.03; H, 4.62; N,
25.67%; found: C, 55.10; H, 4.69; N, 25.73%.
Inhibition zone (mean diameter of inhibition in mm) as a criterion of antibacterial
and antifungal activities of the newly synthesized compounds.
Compound
no.
Inhibition zone in mm
Bacteria
Fungi
Gram positive
bacteria
Bacillus theringiensis
Gram negative
bacteria
K. pneumoniae
B. fabe
F. oxysporum
4.1.6. Synthesis of 2-(2-cyano-3-methylsulfanyl-3-phenylamino-
acryloylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-
3
4
5
8
10
13a
13b
14
15
16
17
18
21
22
20
16
24
16
–
15
16
15
15
18
17
17
19
19
23
18
22
18
12
17
18
17
19
22
20
20
16
16
15
13
14
–
12
18
13
13
–
16
18
15
16
–
carboxamide (9)
To a stirred solution of potassium hydroxide (0.22 g, 4 mmol) in
DMF (20 ml) was added compound 1 (1.05 g, 4 mmol). After the
mixture was stirred for 30 min, phenyl isothiocyanate (0.54 g, 4
mmol) was added to the resulting mixture. Stirring was continued
for 6 h, and then dimethyl sulfate (0.50 g, 4 mmol) was added and
stirring was continued for additional 6 h. The reaction mixture was
poured on to ice water. The solid product that formed was filtered
off, dried and recrystallized from mixture of EtOH:DMF to afford 9.
–
13
14
17
19
14
12
17
15
18
16
15
Yellow crystals; Yield 86%; 1.42 g; mp 238 ꢀC; IR (KBr):
n
/cmꢁ1
¼
3294, 3237, 3157 (2NH), 2195 (C^N), 1624 (br, 2C]O); 1H NMR
(DMSO): dppm ¼ 1.72 (m, 4H, C5-2H, C6-2H), 2.19 (s, 3H, CH3), 2.59
20
Ampicillin

M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1338–1345
1343
(m, 2H, C4-2H), 2.70 (m, 2H, C7-2H), 7.28–7.42 (m, 7H, Ar-H, NH2),
11.74 (br., 1H, NH–Ph), 12.53 (br, 1H, NH); 13C NMR (DMSO): dppm
4.1.9. Synthesis of pyrazolo[5,1-c][1,2,4]triazine compounds 13a, b
¼
General procedure: A solution of compound 12a (1.89 g, 4 mmol)
or 12b (2.03 g, 4 mmol) in glacial acetic acid (30 ml) was refluxed
for 3 h, and then allowed to cool. The precipitate that formed was
filtered off, washed with ethanol, dried and recrystallized from
mixture of EtOH:DMF to give compounds 13a and 13b.
168.7 (C2-thiophene), 168.1, 162.0 (2CO), 143.3, 138.6, 129.8, 127.1,
126.8, 124.9 (sp2, C), 118.1 (CN), 112.4 (C2, acryloyl), 25.7, 24.3, 22.8
(2C), (cyclohexene ring), 17.1 (SCH3); EIMS (m/z) (%) ¼ 379 (Mþ
ꢁ
[H2O, CH3], 10.6), 328 (12.8), 256 (27.7), 93 (57.4), 55 (100). Anal. for
C20H20N4O2S2 (412.53): calcd.: C, 58.23; H, 4.89; N, 13.58%; found:
C, 58.34; H, 4.98; N, 13.69%.
4.1.9.1. Synthesis of 4-amino-3-cyano-7-phenylamino-pyrazolo[5,1-
c][1,2,4]triazine-8-carboxylic acid (3-carbamoyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-2-yl)-amide (13a). Black crystals; Yield 55%; 1.04
4.1.7. Synthesis of 5-amino-3-phenylamino-1H-pyrazole-4-
carboxylic acid (3-carbamoyl-4,5,6,7-tetrahydro-benzo[b]thiophen-
2-yl)-amide (10)
g; mp 308 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3385 (br, NH), 2223 (C^N), 1628
(2C]O); 1H NMR (DMSO): dppm ¼ 1.79 (m, 4H, C5-2H, C6-2H), 2.51
(m, 2H, C4-2H), 2.68 (m, 2H, C7-2H), 6.84–8.10 (m, 7H, Ar-H, NH2),
8.3 (br, 1H, NH–Ph), 11.89 (br, 1H, NH–CO); EIMS (m/z) (%) ¼ 391
(Mþ ꢁ N2–C–CN, 27.3), 135 (18.2), 134 (22.7), 127 (22.7), 114 (27.3),
79 (22.7), 65 (31.8), 51 (100). Anal. for C22H19N9O2S (473.51): calcd.:
C, 55.80; H, 4.04; N, 26.62%; found: C, 55.87; H, 4.13; N, 26.71%.
A mixture of compound 9 (1.65 g, 4 mmol) and hydrazine
hydrate 98% (0.2 g, 4 mmol) was heated on water bath for 3 h, then
left to cool. The reaction mixture was triturated with ethanol and
the resulting solid was filtered off and recrystallized from mixture
of EtOH:DMF to give compound 10.
Pale yellow crystals; Yield 80%; 1.27 g; mp 268 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3433, 3381, 3296, 3210 (NH), 1634 (2C]O); 1H NMR
4.1.9.2. Synthesis of 3-acetyl-4-methyl-7-phenylamino-pyrazolo[5,1-
c][1,2,4]triazine-8-carboxylic acid (3-carbamoyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-2-yl)-amide (13b). Pale yellow crystals; Yield
(DMSO): dppm ¼ 1.73 (m, 4H, C5-2H, C6-2H), 2.62 (m, 2H, C4-2H),
2.70 (m, 2H, C7-2H), 6.00 (br, 2H, NH2), 6.82 (br, 2H, NH2), 7.18–7.31
(m, 5H, Ar-H), 8.30 (s, 1H, NH–Ph), 11.33 (s, 1H, NH-pyrazole), 11.89
(s, 1H, NHCO); 13C NMR (DMSO): dppm ¼ 170.0 (C2-thiophene),
167.9, 161.2 (2CO), 143.75, 143.68, 129.08, 125.68, 119.5, 116.8,
115.34, (sp2, C), 88.2 (C4, pyrazole), 25.8, 24.3, 23.1 (2C), (cyclo-
hexene ring); EIMS (m/z) (%) ¼ 397 (Mþ þ 1, 14.5), 396 (Mþ, 4.8),
379 (14.5), 201 (77.2), 174 (33.1), 77 (100), 51 (86.9). Anal. for
C19H20N6O2S (396.47): calcd.: C, 57.56; H, 5.08; N, 21.20%; found:
C, 57.51; H, 5.02; N, 21.12%.
55%; 1.08 g; mp > 320 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3335 (br, NH), 1628
(2C]O); 1H NMR (DMSO): dppm ¼ 1.77 (m, 4H, C5-2H, C6-2H), 2.08
(s, 3H, CH3), 2.51 (s, 3H, COCH3), 2.68 (m, 4H, C4-2H, C7-2H), 7.27–
7.48 (m, 5H, Ar-H), 8.3 (br, 1H, NH–Ph), 11.89 (br, 1H, NH–CO); EIMS
(m/z) (%) ¼ 470 (Mþ ꢁ H2O, 5.9), 234 (3.7), 172 (10.4), 152 (25.3),120
(70.9), 91 (85.8), 77 (100). Anal. for C24H23N7O3S (489.55): calcd.: C,
58.88; H, 4.74; N, 20.03%; found: C, 58.93; H, 4.83; N, 20.16%.
4.1.10. Synthesis of 5,7-dimethyl-2-phenylamino-pyrazolo[1,5-
a]pyrimidine-3-carboxylic acid (3-carbamoyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-2-yl)-amide (14)
4.1.8. Coupling of 5-amino pyrazole derivative 10 with
malononitrile and acetylacetone
General procedure: Preparation of the diazonium salt: A solution
of sodium nitrite (0.32 g, 4 mmol; in 2 ml water) was gradually
added to a well cooled solution of 10 (1.59 g, 4 mmol) in a mixture
of acetic acid and conc. HCl [(8:2) 10 ml (1/4) Vol.]. The diazonium
salt solution was added drop wise with continuous stirring to cold
solution of malononitrile (0.26 g, 4 mmol) and acetylacetone (0.4 g,
4 mmol) in pyridine (10 ml) the reaction mixture was stirred at 0–5
ꢀC for 2 h and left to stand at room temperature. The separated solid
products that obtained were filtered off, dried and recrystallized
from mixture of EtOH:benzene to give 12a, b.
A mixture of compound 10 (1.59 g, 4 mmol) and acetylacetone
(0.40 g, 4 mmol) in glacial acetic acid (20 ml) was refluxed for 3 h,
then the reaction mixture was poured into crushed-ice, and the
separated solid was filtered off, dried well and recrystallized from
mixture of EtOH:benzene to give 14.
Yellow crystals; Yield 86%; 1.58 g; mp 328 ꢀC; IR (KBr):
n
/cmꢁ1
¼
3484, 3316, 3270, 3167 (NH), 1642 (2C]O); 1H NMR (DMSO): dppm
¼ 1.77 (m, 4H, C5-2H, C6-2H), 2.68 (s, 3H, C7-CH3), 2.69 (s, 3H, C5-
CH3), 2.73 (m, 4H, C4-2H, C7-2H), 7.02–7.79 (m, 8H, Ar-H, NH2), 9.29
(br., 1H, NH–Ph) and 12.44 (br, 1H, NH); EIMS (m/z) (%) ¼ 462 (Mþ þ
2,1.3), 461 (Mþ þ 1, 3.4), 460 (Mþ, 8.8), 265 (100), 65 (21.4). Anal. for
C24H24N6O2S (460.55): calcd.: C, 62.59; H, 5.25; N, 18.25%; found: C,
62.64; H, 5.31; N, 18.32%.
4.1.8.1. Synthesis of 5-(N0-dicyanomethylene-hydrazino)-3-phenyl-
amino-1H-pyrazole-4-carboxylic acid (3-carbamoyl-4,5,6,7-tetrahy-
dro-benzo[b]thiophen-2-yl)-amide (12a). Black crystals; Yield 55%;
1.04 g; mp 328 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3338 (br, NH), 2142 (2C^N),
1632 (br,2C]O),1522 (N]N); 1H NMR (DMSO): dppm ¼ 1.75 (m, 4H,
C5-2H, C6-2H), 2.68 (m, 2H, C4-2H), 2.76 (m, 2H, C7-2H), 5.32 (s, 1H,
NH–N]C), 6.80 (br, 2H, NH2), 7.25–7.62 (m, 5H, Ar-H), 8.30 (br, 1H,
NH–Ph), 9.8 (br, 1H, NH-pyrazole), 11.80 (br, 1H, NH-C]O). Anal. for
C22H19N9O2S (473.51): calcd.: C, 55.80; H, 4.04; N, 26.62%; found: C,
55.87; H, 4.11; N, 26.71%.
4.1.11. Reaction of 10 with 5-chloro-3-methyl-phenylpyrazolo-4-
carboxaldehyde and 1-chloro-3,4-dihydronaphthalene-
carboxaldehyde
To a solution of compound 10 (1.59 g, 4 mmol) in DMF (30 ml),
5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (0.88 g,
4
mmol) or 1-chloro-3,4-dihydro-naphthalene-2-carbaldehyde
(0.76 g, 4 mmol) was added. The reaction mixture was heated under
reflux for 12 h, and then was poured into crushed-ice and the
separated solid was filtered and recrystallized from EtOH:benzene
to give compounds 15 and 16.
4.1.8.2. Synthesis of 5-[N0-(1-acetyl-2-oxo-propylidene)-hydrazino]-
3-phenylamino-1H-pyrazole-4-carboxylic acid (3-carbamoyl-4,5,6,7-
tetrahydro-benzo[b]thiophen-2-yl)-amide (12b). Pale yellow crys-
tals; Yield 50%; 1.02 g; mp > 320 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3298 (br,
NH),1721, 1632 (2C]O), 1560 (N]N); 1H NMR (DMSO): dppm ¼ 1.81
(m, 4H, C5-2H, C6-2H), 2.56 (br, 6H, 2CH3), 2.73 (m, 2H, C4-2H), 2.74
(m, 2H, C7-2H), 7.02 (br, 2H, NH2), 7.52–8.07 (m, 5H, Ar-H), 9.08
(s, 1H, NH–Ph), 12.5 (br, 1H, NH-pyrazole), 13.8 (s, 1H, NH–C¼O);
EIMS (m/z) (%) ¼ 504 (Mþ ꢁ 3, 16.2), 265 (21.6), 157 (27.0), 91 (67.6)
58 (100). Anal. for C24H25N7O4S (507.56): calcd.: C, 56.79; H, 4.96; N,
19.32%; found: C, 56.81; H, 5.01; N, 19.41%.
4.1.11.1. Synthesis
of
3-methyl-1-phenyl-7-phenylamino-1H-
1,2,5,8,8a-pentaaza-as-indacene-6-carboxylic acid (3-carbamoyl-
4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-amide (15). Black crystals;
Yield 66%; 1.49 g; mp > 320 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3450, 3432 (NH),
1636 (br, 2C]O); 1H NMR (DMSO): dppm ¼ 1.81 (m, 4H, C5-2H, C6-
2H), 2.51 (s, 3H, CH3), 2.89 (m, 2H, C7-2H), 5.69 (s, 1H, C4-H-pyrim-
idine), 6.83 (br, 2H, NH2), 8.5 (br, 1H, NH–Ph), 13.39 (br, 1H, NH–CO),

1344
M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1338–1345
13.39 (s, 1H, NH). Anal. for C30H26N8O2S (562.64): calcd.: C, 64.04; H,
4.66; N, 19.92%; found: C, 64.12; H, 4.72; N, 19.98%.
4.1.15. Synthesis of 5-amino-1H-pyrazole-4-carboxylic acid (3-
carbamoyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-amide (20)
A solution of compound 19 (1.27 g, 4 mmol) in DMF (30 ml) and
hydrazine hydrate 98% (0.2 g, 4 mmol) was refluxed for 4 h and
then separated solid was filtered and recrystallized from a mixture
of EtOH:benzene to give 20.
4.1.11.2. Synthesis of 2-phenylamino-6,7-dihydro-1,4,11c-triaza-
cyclopenta[c]phenanthrene-3-carboxylic acid (3-carbamoyl-4,5,6,7-
tetrahydro-benzo[b]thiophen-2-yl)-amide (16). Brown crystals;
Yield 85%; 1.82 g; mp 251 ꢀC; IR (KBr):
n
/cmꢁ1 ¼ 3415, 3300 (br,
Gray crystals; Yield 65%; 0.79 g; mp > 320 ꢀC; IR (KBr):
n
/cmꢁ1
¼
NH), 1639 (2C]O); 1H NMR (DMSO): dppm ¼ 1.85 (m, 4H, C5-2H,
C6-2H), 2.73 (m, 2H, C4-2H), 2.79 (m, 2H, C7-2H-quinazoline), 2.94
(m, 2H, C7-2H-quinazoline), 3.03 (m, 2H, C6-H2-quinazoline), 6.88–
8.01 (m,12H, Ar-H, CH-pyrimidine, NH2), 9.41 (br.,1H, NH–Ph),11.11
(br, 1H, NH–CO); EIMS (m/z) (%) ¼ 530 (Mþ ꢁ 2, 22.7), 338 (27.3),
205 (59.1), 170 (31.8), 119 (45.5), 77 (100). Anal. for C30H26N6O2S
(534.63): calcd.: C, 67.40; H, 4.90; N, 15.72%; found: C, 67.37; H,
4.86; N, 15.69%.
3200 (br., NH), 1644 (br, 2C]O); 1H NMR (DMSO): dppm ¼ 1.75 (m,
4H, C5-2H, C6-2H), 2.71 (m, 2H, C4-2H), 2.85 (m, 2H, C7-2H), 6.05
(br., 2H, NH2-pyrazole), 7.60 (br., 2H, NH2), 8.21 (s, 1H, C3-H, pyr-
azole), 11.00 (s, 1H, NH-pyrazole), 12.24 (s, 1H, NHCO); EIMS (m/z)
(%) ¼ 306 (Mþ þ 1, 25.0), 305 (Mþ, 62.5), 163 (75.0), 110 (75.0), 71
(100). Anal. for C13H15N5O2S (305.36): calcd.: C, 51.13; H, 4.95; N,
22.94%; found: C, 51.22; H, 5.02; N, 23.06%.
4.2. In vitro antimicrobial activity
4.1.12. Synthesis of 7-phenyl-2-phenylamino-pyrazolo[1,5-
a]pyrimidine-3-carboxylic acid (3-carbamoyl-4,5,6,7-tetrahydro-
benzo[b]thiophen-2-yl)-amide (17)
The tested compounds were evaluated by the agar diffusion
technique [42] using a 2 mg mlꢁ1 solution in DMSO. The test
organisms were two bacterial strains: B. theringiensis, K. pneumo-
niae, and two fungi: B. fabe and F. oxysporum. A control using DMSO
without the test compound was included for each organism.
Ampicillin was purchased form The Egyptian market and used in
a concentration 2 mg/ml as reference drugs. The bacteria and fungi
were tested on nutrient agar and potato dextrose agar media,
respectively. Three plates were used for each compound as repli-
cates. The plates were incubated for 24 h, and seven days for
bacteria and fungi, respectively. After the incubation period, the
diameter of inhibition zone was measured as an indicator for the
activity of the compounds.
A solution of compound 10 (1.59 g, 4 mmol) in glacial acetic acid
(20 ml) which was treated with 1-phenyl-3-piperidin-1-yl-propan-
1-one hydrochloride (1.02 g, 4 mmol) was heated under reflux for 5
h. The reaction mixture was poured into crushed-ice and the
separated solid was the separated solid was filtered off, dried well
and recrystallized from mixture of benzene:ethanol to give 17.
Yellow crystals; Yield 75%; 1.53 g; mp 240 ꢀC; IR (KBr):
n
/cmꢁ1
¼
3392, 3311, 3202 (NH), 1635 (br, 2C]O); 1H NMR (DMSO): dppm
¼
1.82 (m, 4H, C5-2H, C6-2H), 2.70 (m, 2H, C4-2H),2.77 (m,2H, C7-2H),
6.95 (br, 2H, CONH2), 7.31–7.76 (m, 10H, Ar-H), 8.75 (br, 1H, NH–Ph),
12.81 (br, 1H, CONH); EIMS (m/z) (%) ¼ 508 (Mþ, 12.2), 421 (52.4),
379 (14.6), 313 (81.7), 243 (11.0), 116 (45.1), 77 (100). Anal. for
C28H24N6O2S (508.59): calcd.: C, 66.12; H, 4.76; N, 16.52%; found: C,
66.18; H, 4.82; N, 16.59%.
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n
/cmꢁ1
¼
3379, 3337 (NH), 1633 (br, 2C]O); 1H NMR (DMSO): dppm ¼ 1.71
(m, 4H, C5-2H, C6-2H), 2.00 (br, 6H, CH3), 2.62 (m, 2H, C4-2H), 2.68
(m, 2H, C7-2H), 5.83 (m, 2H, C3-H,C4-H pyrole), 6.91, (br, 2H, NH2),
7.28–7.53 (m, 5H, Ar-H), 8.69 (br, 1H, NH–Ph), 11.06 (br, 1H, NH
pyrole), 13.27 (br, 1H, NH). Anal. for C25H26N6O2S (474.58): calcd.: C,
63.27; H, 5.52; N, 17.71%; found: C, 63.35; H, 5.61; N, 17.78%.
¨
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4.1.14. Synthesis of 2-(2-cyano-3-dimethylamino-acryloylamino)-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid amide (19)
To a solution of compound 1 (1.05 g, 4 mmol) in dioxane (20 ml)
the DMF–DMA (0.48 g, 4 mmol) was added. The reaction mixture
was heated under reflux for 4 h, then filtered and recrystallized
from benzene: ethanol to give 19.
Yellow crystals; Yield 60%; 0.76 g; mp 235 ꢀC; IR (KBr):
n
/cmꢁ1
¼
3474, 3430, 3331, 3246 (NH) 2190 (CN), 1636 (br, 2C]O); 1H NMR
(DMSO): dppm ¼ 1.78 (m, 4H, C5-2H, C6-2H), 2.65 (m, 2H, C4-2H),
2.74(m, 2H, C7-2H), 3.25 (s, 3H, CH3), 3.31 (s, 3H, CH3), 6.95 (br., 2H,
NH2), 8.24 (s, 1H, CH¼), 12.30 (s, 1H, NHCO); EIMS (m/z) (%) ¼ 300
(Mþ ꢁ 18, 34.0), 222 (40.4), 178 (48.9), 123 (95.7), 91 (85.1), 51
(100). Anal. for C15H18N4O2S (318.39): calcd.: C, 56.58; H, 5.70; N,
17.60%; found: C, 56.63; H, 5.76; N, 17.71%.

M.A. Gouda et al. / European Journal of Medicinal Chemistry 45 (2010) 1338–1345
1345
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