Convenient synthesis and antimicrobial activity of new 3-substituted 5-(benzofuran-2-yl)-pyrazole derivatives

Article abstract of DOI:10.1002/ardp.200800119

The reaction of ethyl 4-(benzofuran-2-yl)-2,4-dioxobutanoate 2 with two moles of hydrazine hydrate afforded 5-(benzofuran-2-yl)-1H-pyrazole-3- carbohydrazide 4a, while its reaction with equimolar amount of phenylhydrazine gave ester 3b which then converte

Full text of DOI:10.1002/ardp.200800119

734
Arch. Pharm. Chem. Life Sci. 2008, 341, 734–739
Full Paper
Convenient Synthesis and Antimicrobial Activity of New
3-Substituted 5-(Benzofuran-2-yl)-pyrazole Derivatives
Bakr F. Abdel-Wahab1, Hatem A. Abdel-Aziz1, and Essam M. Ahmed2
1 Applied Organic Chemistry Department, National Research Center, Dokki, Giza, Egypt
2 Natural and Microbial Products Chemistry Department, National Research Center, Dokki, Giza, Egypt
The reaction of ethyl 4-(benzofuran-2-yl)-2,4-dioxobutanoate 2 with two moles of hydrazine
hydrate afforded 5-(benzofuran-2-yl)-1H-pyrazole-3-carbohydrazide 4a, while its reaction with
equimolar amount of phenylhydrazine gave ester 3b which then converted to 5-(benzofuran-2-
yl)-1-phenyl-1H-pyrazole-3-carbohydrazide 4b. Various new compounds such as imides 5 and 6,
acyl hydrazones 7 and 8, bi-pyrazoles 9-12, and 1,3-thiazole derivatives 14 and 15 were prepared
from carbohydrazide derivatives 4a, b. The new compounds are tested for their antimicrobial
activity. Compounds 2, 5, 7, and 8 showed antifungal activities against C. albicans. Also, com-
pounds 2, 6, 8, and 15 showed antibacterial activities.
Keywords: 2-Acetylbenzofuran / Acid hydrazides / Antimicrobial activity / Bis-pyrazoles / Ethyl 4-(benzofuran-2-yl)-2,4-
dioxobutanoate / 4-Thiazolidinones /
Received: June 18, 2008; accepted: July 15, 2008
DOI 10.1002/ardp.200800119
arrhythmias, in particular in patients with heart insuffi-
Introduction
ciency, because it has no significant negative inotropic
effect [4]. Bufuralol is a non-selective b-adrenoceptor
antagonist developed by Hoffman La Roche [5]. On the
other hand, compounds including pyrazole nucleus are
known to possess analgesic, anti-inflammatory, antipy-
retic, antiarrhythmic, tranquillizing, muscle relaxant,
psychoanaleptic, anticonvulsant, hypotensive, mono-
amine oxidase inhibitor, antidiabetic, and antibacterial
activities [6–14]. In view of these reports and in continua-
tion of our previous work in the synthesis of biologically
active heterocycles [15–20] we have herein synthesized
some new benzofuran derivatives and tested them for
their antimicrobial activities.
Several benzofurans bearing various substituents at the
C-2 position are widely distributed in nature [1]. There
are other well known natural products having related
benzofuran ring structures, which can get isolated par-
ticularly from Machilus glaucescens, Ophryosporus charua,
Ophryosporus lorentzii, Krameria ramosissima, and Zanthox-
ylum ailanthoidol [2]. The most recognized benzofurans
are ailanthoidol, amiodarone, and bufuralol compounds
(Fig. 1). Ailanthoidol, a neolignan with a 2-arylbenzo-
furan skeleton, was isolated from the Chinese herbal
medicine Zanthoxylum ailanthoides. It has been reported
that neolignans and lignans possess a variety of biologi-
cal activities such as anticancer, antiviral, immunosup-
pressive, antioxidant, antifungal, and antifeedant activ-
ities [3]. Amiodarone is a highly effective anti-arrhythmic
agent with class-III activity according to the classification
of Vaughan–Williams. It is used in the treatment and
prophylaxis of both ventricular and supraventricular
Results and discussion
Chemistry
The reaction of 2-acetylbenzofuran 1 with diethyl oxalate
in sodium methoxide afforded ethyl 4-(benzofuran-2-yl)-
2,4-dioxobutanoate 2 [21] which is used as starting mate-
rial in this study. Reaction of 2 with two moles hydrazine
hydrate in refluxing ethanol gave directly 5-(benzofuran-
2-yl)-1H-pyrazole-3-carbohydrazide 4a via the non-isolable
Correspondence: Bakr F. Abdel-Wahab, Applied Organic Chemistry De-
partment, National Research Center, Dokki, Giza, Egypt.
E-mail: Bakrfatehy@yahoo.com
Fax: +20 2 760-1877
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2008, 341, 734–739
3-Substituted-5-(benzofuran-2-yl)-pyrazole Derivatives
735
Figure 1. Some benzofurans containing biologically active compounds.
Scheme 1. Schematic diagram showing the synthe-
sis of compounds 3 and 4.
intermediate 3a, while the reaction of 2 with phenylhy- bis(methylthio)acrylate in boiling ethanol afforded the
drazine in refluxing glacial acetic acid furnished the isol- bi-pyrazole derivatives 9–12 respectively (Scheme 2). The
able ester 3b which then reacted with hydrazine hydrate IR spectra of compounds 9 and 10 showed characteristic
in absolute ethanol to afford 5-(benzofuran-2-yl)-1-phe- absorption bands in the range 2219–2221 cm– 1 due to
nyl-1H-pyrazole-3-carbohydrazide 4b (Scheme 1). The the presence of the carbonitrile group. The IR spectra of
structure of compounds 3b, 4a, and 4b were established compounds 9–12 showed absorption bands in the range
under the basis of their elemental analysis and spectral 3288–3450 cm– 1 indicating the presence of amino
data. For example, the mass spectra of compounds 3b, 4a, groups.
and 4b showed the molecular ion peaks at m/z 332, 242,
and 318, respectively; these fit exactly with the calcu- isothiocyanates and a-haloketones to afford a variety of
lated masses. heterocyclic derivatives [22–27]. Thus, reaction of hydra-
Acid hydrazides have long been known to react with
Treatment of acid hydrazides 4a,b with phthalic anhy- zide 4b with phenyl isothiocyanate in absolute ethanol
dride in refluxing glacial acetic acid for 5 h afforded the afforded thiosemicarbazide 13, which was then treated
imides 5 and 6, respectively. The IR spectra of compounds with ethyl bromoacetate or phenacyl bromide in ethanol
5 and 6 showed three absorption bands in the region containing anhydrous sodium acetate to yield thiazoli-
1666–1747 cm– 1 characteristic for three carbonyl din-4-one 14 or 1,3-thiazole derivative 15, respectively
groups. In addition, the reaction of 4a with 2,4-dichloro- (Scheme 3).
benzaldehyde afforded hydrazone 7 while hydrazone 8
The mass spectrum of 13 showed a peak corresponding
was formed by the reaction of 4-nitrobenzaldehyde with to its molecular ion peak at m/z 453. The IR spectrum of
hydrazide 4b. The 1H-NMR of 7a showed a singlet proton 14 showed an absorption band at 1750 cm– 1 due to the
at 9.89 ppm attributed to -CH=N-. On the other hand, reac- carbonyl function of thiazolidinone moiety. The 1H-NMR
tion of hydrazides 4a,b with alkenes derivatives, namely, of compound 14 showed a singlet signal at 4.10 ppm cor-
2-(methoxymethylene)malononitrile or ethyl 2-cyano-3,3- responding to methylene protons of thiazolidene ring
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B. F. Abdel-Wahab et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 734–739
Scheme 2. Schematic diagram showing the syn-
thesis of compounds 5–12.
Scheme 3. Schematic diagram showing the syn-
thesis of compounds 13–15.
while 1H-NMR of compound 15 displayed one singlet at lus niger, Aspergillus fumigatus, Trycophyton mentgrophytes,
5.78 ppm corresponding to thiazole ring proton.
or Saccharomyas cerevisiae (Table 1).
From the results in Table 2 we can conclude that some
of our products have noticeable antibacterial activities.
Biology
Most of the new compounds were evaluated for their The inhibition zones of compounds 2, 4a, 6, 7, 8, 9, and
antimicrobial properties. Compounds 2, 5, 7, and 8 14 against Bacillus subitilis are larger than that of the con-
showed inhibition zones and, therefore, antifungal activ- trol Amoxicillin. While some of our compounds, such as
ities against C. albicans more than the reference com- 2, 6, 8, and 15 showed antibacterial activities more than
pound Flucanazol, while compounds 9, 10, and 14 the control against E. coli, some of the new compounds
showed similar antifungal activity against C. albicans, may be therefore considered as highly potential antibac-
when compared with Flucanazol. All the tested com- terial agents. On the other hand, all of the tested com-
pounds showed no antifungal activities against Aspergil- pounds showed no antibacterial activities against Pseudo-
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Arch. Pharm. Chem. Life Sci. 2008, 341, 734–739
Table 1. Antifungal activities.
3-Substituted-5-(benzofuran-2-yl)-pyrazole Derivatives
737
mental analytical data (in accord with the calculated values)
were obtained from the microanalytical unit, Cairo University,
Giza, Egypt. The IR spectra (KBr) were recorded on a Shimadzu
CVT-04 spectrophotometer (Shimadzu, Tokyo, Japan). The 1H-
NMR spectra were recorded at 270 MHz on a Varian EM-360 spec-
trometer (Varian Inc., Palo Alto, CA, USA) using TMS as an inter-
nal standard. Splitting patterns are designated as follows: s, sin-
glet; d, doublet; t, triplet; m, multiplet. Chemical shift (d) values
are given in parts per million. The mass spectra were performed
using a Varian MAT CH-5 spectrometer (Varian) (70 eV). 2-Acetyl-
benzofuran 1 [28] and ethyl 4-(benzofuran-2-yl)-2,4-dioxobuta-
noate 2 [21] were prepared according to the procedures reported
in literature.
Compounds
Inhibition zone [mm]
Aspergillus Aspergillus Trycophyton Candida Saccharomyas
niger
fumigatus mentgrophytes albicans cerevisiae
2
4a
5
6
7
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
30
–
30
–
30
30
20
20
–
–
–
20
–
20
–
–
–
–
–
–
–
–
–
–
–
–
–
8
9
10
11
12
13
14
15
Ethyl 5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-
carboxylate 3b
To a solution of ethyl 4-(benzofuran-2-yl)-2,4-dioxobutanoate 2
(2.6 g, 10 mmol) in glacial acetic acid (30 mL), phenylhydrazine
(1.1 g, 10 mmol) was added and the resulting mixture was boiled
under reflux for 30 min; it was then cooled and poured into
200 mL water. The precipitated was filtered off and recrystal-
lized from dilute ethanol, giving 82% of 3b with m.p.: 165–
1668C; IR (KBr) mmax/cm– 1: 1617 (C=N), 1754 (C=O);1H-NMR (DMSO-
d6) d: 1.51 (t, 3H,CH3), 4.22 (q, 2H, CH2), 6.63 (s, 1H, benzofuran-
H), 7.09 (s, 1H, pyrazole-H), 7.13–7.63 (m, 9H, Ar-H); Ms m/z (%):
332 [M+] (0.6), 318 (100). Anal. Calcd. for C20H16N2O3: C, 72.28; H,
4.85; N, 8.43. Found: C, 72.41; H, 4.98; N, 8.61.
Fluconazole 20
20
20
20
Table 2. Antibacterial activities.
Compounds
Inhibition zone [mm]
Escherichia Bacillus Pseudomonas Staphylo-
Strepto-
coli
subitilis aeroginosa
coccus aureus coccus sp.
2
4a
5
40
–
–
40
40
–
–
–
–
–
–
–
–
–
–
5-(Benzofuran-2-yl)-1H-pyrazole-3-carbohydrazide 4a
Hydrazine hydrate (1.0 g, 20 mmol) was given to ethyl 4-(benzo-
furan-2-yl)-2,4-dioxobutanoate 2 (2.6 g, 10 mmol) in absolute
ethanol (40 mL). The reaction mixture was boiled under reflux
for 4 h and was then cooled and poured into 200 mL ice-water.
The precipitate was filtered off and recrystallized from dilute
6
7
8
9
10
11
13
14
15
35
–
40
–
–
–
–
–
40
40
40
40
40
–
35
20
40
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
ethanol, giving 76% of 4a with m.p.: 291–2928C; IR(KBr) mmax
/
cm– 1: 1612 (C=N), 1666 (C=O); 1H-NMR (DMSO-d6) d: 4.47 (s, 2H,
NH2), 7.09 (s, 1H, pyrazole-H), 7.19 (s, 1H, benzofuran-H), 7.25–
7.69 (m, 4H, Ar-H), 9.90 (s, 1H, NH), 13.81 (s, 1H, NH); Ms m/z (%):
242 [M+] (100). Anal. Calcd. for C12H10N4O2: C, 59.50; H, 4.16; N,
13.21. Found: C, 59.71; H, 4.33; N, 13.41.
–
25
–
25
–
25
Amoxicilline 25
25
monas aeroginosa, Staphylococcus aurous and Streptococcus
sp.
5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-
carbohydrazide 4b
Structure-activity relationship of antimicrobial
activities (SAR)
To a solution of 3b (1.66 g, 5 mmol) in absolute ethanol (25 mL)
hydrazine hydrate (l1 mL, 15 mmol) was added and the mixture
was boiled for 4 h. The ethanol was distilled off and the residue
was poured into 200 mL ice-water, the precipitate was filtered
off and recrystallized from dilute ethanol, giving 83% of 4b with
(i) The benzofuran, pyrazole, thiazolidinone, and thia-
zole moieties are essential for antimicrobial activity. (ii)
Increasing the number of nitrogen atoms sharply
increases the antimicrobial activity. (iii) The phthalimide
moieties in compounds 5 and 6 are essential for the anti-
microbial activities of these compounds.
m.p.: 140–1428C; IR(KBr) mmax/cm– 1: 1614 (C=N), 1667 (C=O); H-
1
NMR (DMSO-d6) d: 4.21 (s, 2H, NH2), 6.74 (s, 1H, pyrazole-H), 6.83
(s, 1H, benzofuran-H), 7.15–7.60 (m, 9H, Ar-H), 9.21 (s, 1H, NH);
Ms m/z (%): 318 [M+] (100). Anal. Calcd. for C18H14N4O2: C, 67.91; H,
4.43; N, 17.60. Found: C, 68.08; H, 4.61; N, 17.79.
The authors have declared no conflict of interest.
Synthesis of imides 5 and 6
Experimental
A mixture of 4a,b (2 mmol) and phthalic anhydride (0.3 g,
2 mmol) in glacial acetic acid (25 mL) was refluxed for 5 h. The
reaction mixture was evaporated and the obtained residue was
solidified with ether, filtered off, and crystallized from AcOH-
H2O to give 5 and 6.
Chemistry
All melting points were taken on Electrothermal IA 9000 series
digital melting point apparatus (Electrothermal, Essex, U.K.). Ele-
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B. F. Abdel-Wahab et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 734–739
3.17; N, 26.40. Found: C, 60.53; H, 3.10; N, 26.51.
5-(Benzofuran-2-yl)-N-(1,3-dioxoisoindolin-2-yl)-1H-
pyrazole-3-carboxamide 5
Yield (82%); m.p.: 292–2948C; IR(KBr) mmax/cm– 1: 1612 (C=N),
1666, 1712, 1747 (3C=O); H-NMR (DMSO-d6) d: 6.52 (s, 1H, pyra-
zole-H), 6.77 (s, 1H, benzofuran-H), 7.28–7.99 (m, 8H, Ar-H), 9.09
(s, 1H, NH), 13.76 (s, 1H, NH); Ms m/z (%): 372 [M+] (43), 287 (100).
Anal. Calcd. for C20H12N4O4: C, 64.52; H, 3.25; N, 17.19. Found: C,
64.71; H, 3.07; N, 17.38.
5-Amino-1-(5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-
1
carbonyl)-1H-pyrazole-4-carbonitrile 10
Yield (81%); m.p.: 2108C; IR(KBr) mmax/cm– 1: 1629 (C=N), 1665
(C=O), 2221 (CN), 3288, 3224 (NH2); 1H-NMR (DMSO-d6) d: 6.18 (s,
1H, pyrazole-H), 7.10 (s, 1H, benzofuran-H), 7.28–7.70 (m, 9H, Ar-
H), 7.78 (s, 1H, CH), 9.96 (s, 2H, NH2); Ms m/z (%): 394 [M+] (26), 287
(100). Anal. Calcd. for C22H14N6O2: C, 67.00; H, 3.58; N, 21.31.
Found: C, 67.21; H, 3.62; N, 21.49.
5-(Benzofuran-2-yl)-N-(1,3-dioxoisoindolin-2-yl)-1-
phenyl-1H-pyrazole-3-carboxamide 6
Yield (86%); m.p.: A3008C; IR(KBr) mmax/cm– 1: 1610 (C=N), 1667,
1712, 1747 (3C=O); 1H-NMR (DMSO-d6) d: 6.55 (s, 1H, pyrazole-H),
6.76 (s, 1H, benzofuran-H), 7.28–7.99 (m, 13H, Ar-H), 9.09 (s, 1H,
NH); Ms m/z (%): 448 [M+] (48), 287 (100). Anal. Calcd. for
C26H16N4O4: C, 69.64; H, 3.60; N, 12.49. Found: C, 69.71; H, 3.69;
N, 12.53.
Ethyl 5-amino-1-(5-(benzofuran-2-yl)-1H-pyrazole-3-
carbonyl)-3-(methylthio)-1H-pyrazole-4-carboxylate 11
Yield (76%); m.p.: 258–2608C; IR(KBr) mmax/cm– 1: 1629 (C=N), 1659
1
(C=O), 1694 (C=O, ester), 3292, 3202 (NH2); H-NMR (DMSO-d6) d:
1.24 (t, 3H, CH3), 2.49 (s, 3H, SCH3), 4.39 (q, 2H, CH2), 7.19 (s, 1H,
pyrazole-H), 7.25 (s, 1H, benzofuran-H), 7.29–7.76 (m, 4H, Ar-H),
9.89 (s, 2H, NH2), 13.89 (s, 1H, NH); Ms m/z (%): 411 [M+] (43), 287
(100). Anal. Calcd. for C19H17N5O4S: C, 55.47; H, 4.16; N, 17.02.
Found: C, 55.31; H, 4.23; N, 17.22.
5-(Benzofuran-2-yl)-N'-arylidene-pyrazole-3-
carbohydrazides 7 and 8
A mixture of 4a,b (1 mmol) and appropriate aromatic aldehydes
(1 mmol) in 30 mL absolute ethanol in the presence of few drops
of glacial acetic acid was refluxed for 2 h. The formed solid was
filtered off, dried, and crystallized from EtOH / DMF (10 : 1 v/v) to
give 7 and 8.
Ethyl 5-amino-1-(5-(benzofuran-2-yl)-1-phenyl-1H-
pyrazole-3-carbonyl)-3-(methylthio)-1H-pyrazole-4-
carboxylate 12
Yield (78%); m.p.: 196–1988C; IR(KBr) mmax/cm– 1: 1623 (C=N), 1656
1
(C=O), 1697 (C=O, ester), 3292, 3228 (NH2); H-NMR (DMSO-d6) d:
1.32 (t, 3H, CH3), 2.51 (s, 3H, SCH3), 4.37 (q, 2H, CH2), 7.12 (s, 1H,
pyrazole-H), 7.22 (s, 1H, benzofuran-H), 7.30–7.78 (m, 9H, Ar-H),
9.98 (s, 2H, NH2); Ms m/z (%): 487 [M+] (36), 287 (100). Anal. Calcd.
for C25H21N5O4S: C, 61.59; H, 4.34; N, 14.36. Found: C, 61.37; H,
4.51; N, 14.48.
5-(Benzofuran-2-yl)-N9-(2,4-dichlorobenzylidene)-1H-
pyrazole-3-carbohydrazide 7
Yield (81%); m.p.: A3008C; IR(KBr) mmax/cm– 1: 1608 (C=N), 1671
1
(C=O); H-NMR (DMSO-d6) d: 6.89 (s, 1H, pyrazole-H), 7.21 (s, 1H,
benzofuran-H), 7.30–8.5 (m, 7H, Ar-H), 9.89 (s, 1H, CH), 12.3 (s,
1H, NH), 13.89 (s, 1H, NH); Ms m/z (%): 399 [M+] (100). Anal. Calcd.
for C19H12Cl2N4O2: C, 57.16; H, 3.03; N, 17.76. Found: C, 56.98; H,
3.12; N, 17.88.
2-(5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-
carbonyl)-N-phenylhydrazinecarbo-thioamide 13
A mixture of 4b (1.6 g, 5 mmol) and phenylisothiocyante (0.67 g,
5 mmol) in absolute ethanol (30 mL) was heated under reflux for
3 h. The formed solid was filtered off and recrystallized from
EtOH / DMF to give 13 in 83% yield; m.p.: 209–2108C; IR(KBr)
mmax/cm– 1: 1259 (C=S), 1614 (C=N), 1656 (C=O), 3315-3154 (NH);
1H-NMR (DMSO-d6) d: 6.61 (s, 1H, pyrazole-H), 7.15 (s, 1H, benzo-
furan-H), 7.25–7.64 (m, 14H, Ar-H), 9.47, 9.49, 10.48 (3s, 3H,
3NH); Ms m/z (%): 453 [M+] (2), 287 (100). Anal. Calcd. for
C25H19N5O2S: C, 66.21; H, 4.22; N, 15.44. Found: C, 66.42; H, 4.41;
N, 15.58.
5-(Benzofuran-2-yl)-N9-(4-nitrobenzylidene)-1-phenyl-1H-
pyrazole-3-carbohydrazide 8
Yield (84%); m.p.: 238–3408C; IR(KBr) mmax/cm– 1: 1611 (C=N), 1664
(C=O); 1H-NMR (DMSO-d6) d: 6.71 (s, 1H, pyrazole-H), 7.03 (s, 1H,
benzofuran-H), 7.19–8.12 (m, 12H, Ar-H), 9.88 (s, 1H, CH), 12.42
(s, 1H, NH); Ms m/z (%): 451 [M+] (100). Anal. Calcd. for C25H17N5O4:
C, 66.51; H, 3.80; N, 15.51. Found: C, 66.53; H, 3.69; N, 15.43.
Synthesis of bi-pyrazoles 9–12
To a solution of 4a,b (1 mmol) in anhydrous ethanol (20 mL), 2-
[bis(methylthio)methylene]malononitrile or ethyl 2-cyano-3,3-
bis(methylthio)acrylate (1 mmol) was added and the reaction
mixtures were refluxed for 2 h and 4 h, respectively. The prod-
ucts, which separated on cooling, were collected by filtration
and recrystallized from ethanol to give compounds 9–12.
5-(Benzofuran-2-yl)-N9-(4-oxo-3-phenylthiazolidin-2-
ylidene)-1-phenyl-1H-pyrazole-3-carbohydrazide 14
A mixture of 13 (0.45 g, 1 mmol) and ethyl bromoacetate (0.17 g,
1 mmol) in absolute ethanol (30 mL) containing anhydrous
sodium acetate (0.33 g, 4 mmol) was heated under reflux for 6 h.
The reaction mixture was cooled, diluted with water, and
allowed to stand overnight. The precipitate solid was filtered off
and recrystallized from ethanol to give 14 in 63% yield; m.p.:
159–1608C; IR(KBr) mmax/cm– 1: 1614 (C=N), 1643 (C=O), 1739
(C=O), 3423 (NH); 1H-NMR (DMSO-d6) d: 4.10 (s, 2H, CH2), 4.17 (s,
1H, NH), 6.66 (s, 1H, pyrazole-H), 7.07 (s, 1H, benzofuran-H), 7.22-
7.62 (m, 14H, Ar-H); Ms m/z (%): 493 [M+] (11), 77 (100). Anal. Calcd.
for C27H19N5O3S: C, 65.71; H, 3.88; N, 14.19. Found: C, 65.89; H,
3.96; N, 14.07.
5-Amino-1-(5-(benzofuran-2-yl)-1H-pyrazole-3-carbonyl)-
1H-pyrazole-4-carbonitrile 9
Yield (81%); m.p.: A3008C; IR(KBr) mmax/cm– 1: 1624 (C=N), 1655
(C=O), 2219 (CN), 3288, 3200 (NH2); 1H-NMR (DMSO-d6) d: 6.06 (s,
1H, pyrazole-H), 7.19 (s, 1H, benzofuran-H), 7.28–7.70 (m, 4H, Ar-
H), 7.72 (s, 1H, CH), 9.92 (s, 2H, NH2), 13.53 (s, 1H, NH); Ms m/z (%):
318 [M+] (32), 287 (100). Anal. Calcd. for C16H10N6O2: C, 60.38; H,
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Arch. Pharm. Chem. Life Sci. 2008, 341, 734–739
3-Substituted-5-(benzofuran-2-yl)-pyrazole Derivatives
739
[3] C. L. Kao, J. W. Chern, Tetrahedron Lett. 2001, 42, 1111–
5-(Benzofuran-2-yl)-N9-(3,4-diphenylthiazol-2-(3H)-
1113.
ylidene)-1-phenyl-1H-pyrazole-3-carbohydrazide 15
A mixture of 13 (0.45 g, 1 mmol) and phenacylbromide (0.2 g,
1 mmol) in absolute ethanol (30 mL) containing anhydrous
sodium acetate (0.33 g, 4 mmol) was heated under reflux for 6 h.
The reaction mixture was cooled; the formed solid was filtered
off, washed with water, and recrystallized from EtOH / DMF to
give 15 in 64% yield; m.p.: 279–808C; IR (KBr) mmax/cm– 1:1608
[4] M. Spaniol, R. Bracher, H. R. Ha, F. Follath, S. Kralhenbꢀhl,
J. Hepatol. 2001, 35, 628–636.
[5] S. Narimatsu, C. Takemi, S. Kuramoto, D. Tsuzuki, et al.,
Chirality 2003, 15, 333–339.
[6] L. G. Polevoi, Tr. Nauchn. Konf. Aspir. Ordin. 1-yi Mosk.
Med. Inst. Moscow 1966, 159–161 (CA: 65, 19147).
1
(C=N), 1641 (C=O), 3402 (NH); H-NMR (DMSO-d6) d: 5.78 (s, 1H,
[7] Y. M. Batulin, Farmacol Toksicol. 1969, 31, 533–536 (CA: 70,
thiazole-H), 6.63 (s, 1H, pyrazole-H), 7.03 (s, 1H, benzofuran-H),
7.22–7.62 (m, 19H, Ar-H), 10.32 (s, 1H, NH); Ms m/z (%): 553 [M+]
(19), 77 (100). Anal. Calcd. for C33H23N5O2S: C, 71.59; H, 4.19; N,
12.65. Found: C, 71.73; H, 4.24; N, 12.81.
2236a).
[8] S. S. Parmar, B. R. Pandey, C. Dwivedi, R. D. Harbison, J.
Pharm. Sci. 1974, 63, 1152–1155.
[9] N. Soni, K. Pande, R. Kalsi, T. K. Gupta, et al., Res. Commun.
Chem. Pathol. Pharmacol. 1987, 56, 129–132.
Biology
Antifungal activities
[10] E. Palaska, D. Erol, R. Demirdamar, Eur. J. Med. Chem. 1996,
31, 43–47.
Newly prepared compounds were screened for their antifungal
activity against Aspergillus flavus (NCIM no. 524), Aspergillus fumi-
gatus (NCIM no. 902), Candida albicans (NCIM no. 300), Penicillium
marneffei, and Trichophyton mentagrophytes (recultured) in DMSO
by serial plate dilution method [29, 30]. Sabourand's agar media
were prepared by dissolving peptone (1 g), D-glucose (4 g) and
agar (2 g) in distilled water (100 mL) and adjusting the pH to 5.7.
Normal saline was used to make a suspension of spores of the
fungal strain for lawning. A loopful of the articular fungal strain
was transferred to 3 mL saline to get a suspension of the corre-
sponding species. Agar media (20 mL) were poured into each
Petri dish. The excess suspension was decanted and the plates
were dried by placing them in an incubator at 378C for 1 h.
Using an agar punch, wells were made and each well were
labeled. A control was also prepared in triplicate and main-
tained at 378C for 3–4 days. The zone of inhibition was noted.
The activity of each compound was compared with Fluconazole
as the standard drug. The results of antifungal studies are given
in Table 1.
[11] O. Bruno, A. Ranise, F. Bondavalli, F. Schenone, et al., Farm-
aco 1993, 48, 949–966.
[12] F. Bondavalli, O. Bruno, A. Ranise, F. Schenone, et al., Farm-
aco 1988, 43, 725–743.
[13] O. Bruno, A. Ranise, F. Bondavalli, P. Schenone, Farmaco
1993, 48, 967–977.
[14] G. Mazzone, G. Puglisi, A. Corsaro, A. Panico, et al., Eur. J.
Med. Chem. 1986, 21, 277–284.
[15] B. F. Abdel-Wahab, H. A. Abdel-Aziz, E. M. Ahmed, Eur. J.
Med. Chem. (2008), submitted.
[16] F. A. Amer, M. Hammouda, A.-A. S. El-Ahl, B. F. Abdel-
Wahab, J. Chin. Chem. Soc. 2007, 54, 1543–1552.
[17] F. A. Amer, M. Hammouda, A.-A. S. El-Ahl, B. F. Abdel-
Wahab, Chem. Heterocycl. Comp. 2007, 43, 1559–1566.
[18] B. F. Abdel-Wahab, S. F. Mohamed, A. E. Amr, M. M.
Abdalla, Monatsh. Chem. 2008, 139, 1083–1091.
[19] A. E. Amr, N. M. Sabrry, M. M. Abdalla, B. F. Abdel-Wahab,
Antibacterial activities
Eur. J. Med. Chem. (2008) in press.
The new compounds were tested for their antibacterial activities
by the disc-diffusion method [31] using nutrient broth medium
(contained (g/L): beef extract 3 g; peptone 5 g; pH = 7.0). The
Gram-positive bacteria utilized in this study consisted of Bacillus
subitilis, Staphylococcus aureus, and Streptococcus sp. The Gram-
negative bacteria included Escherichia coli and Pseudomonas aeru-
ginos. In the disc-diffusion method, sterile paper discs (0.5 mm)
impregnated with compounds dissolved in dimethylsulfoxide
(DMSO) at a concentration of 200 lg/mL were used. Then, the
paper discs impregnated with the solution of the compound
tested were placed on the surface of the media inoculated with
microorganism. The plates were incubated at 358C for 24 h. The
growth inhibition zones measured after incubation, are docu-
mented in Table 2.
[20] B. F. Abdel-Wahab, A. E. Amr, M. M. Abdalla, Monatsh.
Chem. (2008) accepted.
[21] M. Payard, J. Paris, J. Couquelet, Trav. Soc. Pharm. Montp.
1976, 36, 115; Chem. Abstr., 85, 177–152.
[22] S. Schenone, O. Brunoa, A. Ranise, F. Bondavalli, et al.,
Farmaco 1998, 53, 586–589.
[23] E. Palaska, G. Sahin, P. Kelicen, N. T. Durlu, G. Altinok,
Farmaco 2002, 57, 101–107.
[24] M. M. Britto, T. M. G. Almeida, A. Leit¼o, C. L. Donnici, et
al., Synth. Commun. 2006, 36, 3359–3369.
[25] M. S. Karthikeyan, Eur. J. Med. Chem. (2008), accepted.
[26] X. Wang, Z. Zhang, Z. Quan, M. Wang, et al., Synth. Com-
mun. 2006, 36, 843–847.
Generally, the results were taken in duplicate. Results with
difference higher than 5% were neglected and repeated.
[27] X. Wang, Z. Li, Y. Da, Y. Ma, Synth. Commun. 2002, 32,
1121–1127.
[28] E. D. Elliott, J. Am. Chem. Soc. 1949, 73, 754–754.
References
[29] Z. K. Khan, Workshop UNIDO-CDRI, 1997, pp. 210–211.
[30] R. S. Varma (Ed.), National Academy of Chemistry & Biol-
[1] M. Koca, S. Servi, C. Kirilmis, M. Ahmedzade, et al., Eur. J.
Med. Chem. 2005, 40, 1351–1358.
ogy, India, Lucknow, 1998.
[2] Y. W. Kim, H. D. Choi, P. J. Seo, B. W. Son, J. Korea Chem.
Soc. 2001, 45, 391–394.
[31] D. T. Wilkins, V. L. Holdman, J. I. Abramson, E. W. Moore,
Antimicrob. Agents Chemother. 1972, 1, 451.
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