Synthesis and antimicrobial evaluation of 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones and 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1H-pyrazoles

Article abstract of DOI:10.1016/j.ejmech.2008.09.029

2-Acetylbenzofuran 1 on treatment with substituted aldehydes affords the corresponding chalcones 2a-c. Treatment of the chalcones with nitromethane under Michael addition condition furnished the corresponding Michael adducts 3a-c. Cyclocondensation of the chalcones 2a and 2b with thiosemicarbazide under basic refluxing conditions gave 3-(benzofuran-2-yl)-5-(4-aryl)-4,5-dihydropyrazole-1-carbothioamides 4a,b. The pyrazolines 7a-d were synthesized by treating 4a,b with phenacyl bromides in refluxing ethanol. All the synthesized compounds were screened for their antibacterial and antifungal activities at 100 μg concentration. Some of our compounds showed excellent antimicrobial activities than control drugs.

Full text of DOI:10.1016/j.ejmech.2008.09.029

European Journal of Medicinal Chemistry 44 (2009) 2632–2635
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antimicrobial evaluation of 1-(benzofuran-2-yl)-4-nitro-3-
arylbutan-1-ones and 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,
3-thiazol-2-yl]-1H-pyrazoles
,
a
b
Bakr F. Abdel-Wahab a , Hatem A. Abdel-Aziz , Essam M. Ahmed
*
a Applied Organic Chemistry Department, National Research Center, Dokki, Giza, Egypt
b Natural and Microbial Products Chemistry Department, National Research Center, Dokki, Giza, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 February 2008
Received in revised form 7 September 2008
Accepted 18 September 2008
Available online 2 October 2008
2-Acetylbenzofuran 1 on treatment with substituted aldehydes affords the corresponding chalcones 2a–c.
Treatment of the chalcones with nitromethane under Michael addition condition furnished the corre-
sponding Michael adducts 3a–c. Cyclocondensation of the chalcones 2a and 2b with thiosemicarbazide
under basic refluxing conditions gave 3-(benzofuran-2-yl)-5-(4-aryl)-4,5-dihydropyrazole-1-carbothioa-
mides 4a,b. The pyrazolines 7a–d were synthesized by treating 4a,b with phenacyl bromides in refluxing
ethanol. All the synthesized compounds were screened for their antibacterial and antifungal activities at
Keywords:
Benzofuran
Nitromethane
100
m
g concentration. Some of our compounds showed excellent antimicrobial activities than control drugs.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Thiazolyl-pyrazoline
Antimicrobial activity
1. Introduction
microorganisms [27]. In the interest of the above suggestion, and in
continuation of our previous work in the synthesis of biologically
Widespread interest in the chemistry of benzofurans in a large
number of natural products has attracted due to their biological
activities and their potential applications as pharmacological agents.
Several benzofuran ring systems bearing various substituents at the
C-2 position are widely distributed in nature, e.g., ailanthoidol, is
a neolignan derivative, has been reported to have antiviral, antiox-
idant and antifungal activities [1]. Furthermore, most of compounds
prepared from 2-acetylbenzofurans have antimicrobial, antitumor,
antiflammatory, fungicidal weed-killing activity, and used for
treatment of cardiac arrhythmias [2–9]. On the other hand,
compounds including pyrazole nucleus are known to possess
analgesic, anti-inflammatory, antipyretic, antiarrhythmic, muscle
relaxant, psychoanaleptic, anticonvulsant, hypotensive, monoamine
oxidase inhibitor, antidiabetic and antibacterial activities [10–17].
Pyrazole derivative celebrex is a potential anti-inflammatory drug
[18]. In addition, 1,3-thiazole derivatives have been reported to
possess tuberculostatic, antibacterial and antifungal activities [19–
25]. It was also reported that fentiazac, 1,3-thiazole derivative, is
potent antinflammatory agent [26] (Fig. 1). Recently, we reported
that, some of 3-substituted-5-(benzofuran-2-yl)-pyrazole deriva-
tives showed significant antimicrobial activities towards various
active heterocycles [28–33], we planned to synthesize 1-(benzo-
furan-2-yl)-4-nitro-3-arylbutan-1-ones and thiazolyl-pyrazoline
derivatives for antimicrobial evaluation.
2. Chemistry
The synthetic route of compounds is outlined in Scheme 1 and
Scheme 2. In the present work, 1-(2-benzofuryl)-3-aryl-2-propen-
1-ones 2a–c were prepared by reaction of 2-acetylbenzofuran (1)
with aromatic aldehyde in accordance with the method described
in the literature [34].
The 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones 3a–c were
prepared by reacting equimolecular amounts of 2a–c with nitro-
methane in boiling ethanol and in the presence of piperidine as
a basic catalyst (Scheme 1).
On the other hand, the reaction of 1-(2-benzofuryl)-3-aryl-2-
propen-1-ones 2a or 2b with thiosemicarbazide in refluxing ethanol,
in the presence of excess sodium hydroxide, afforded 3-(2-benzo-
furyl)-5-aryl-1-thiocarbamoyl-2-pyrazolines 4a and 4b, respec-
tively. The condensation of pyrazolines 4a or 4b with the appropriate
1-aryl-2-bromethanone 5a or 5b resulted in the formation of 3-
(benzofuran-2-yl)-1-[4-(aryl)-1,3-thiazol-2-yl]-4,5-dihydro-5-aryl-
1H-pyrazoles 7a–d through the intermediate 6a–d (Scheme 2).
Analytical and spectral data (1H NMR, IR, and MS) confirmed the
structures of the new compounds.
* Corresponding author. Tel.: þ202 3371635; fax: þ202 7601877.
E-mail address: bakrfatehy@yahoo.com (B.F. Abdel-Wahab).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.09.029

B.F. Abdel-Wahab et al. / European Journal of Medicinal Chemistry 44 (2009) 2632–2635
2633
F3C
MeO
HO-CH2-HC=HC
C6H4-P-Cl
COOH
N
N
OH
C6H4-P-Me
N
O
Ph
C6H4-P-SO2NH2
S
Et
Ailanthoidol
Celebrex
Fentiazac
Fig. 1. Chemical structures of ailanthoidol, celebrex and fentiazac.
3. Biology
The synthesized compounds were tested, at 100
tion, for theirinvitro antimicrobial activityagainst theGram-positive
bacteria Staphylococcus aureus, Bacillus subtilis, the Gram-negative
bacteria Escherichia coli, and fungi Candida albicans and Aspergillus
niger. The primary screen was carried out by agar disc-diffusion
method [35] usingnutrient agar medium. Amoxicillin andFlucanazol
were used as control drugs. The observed data on the antimicrobial
activity of the compounds and control drugs are given in Table 1.
3.80–3.96 ppm (Hb). The CH (Hx) proton appeared as a doublet of
doublet at 5.57–5.74 ppm due to vicinal coupling with the two
magnetically non-equivalent protons of the methylene group at
position 4 of pyrazoline ring (Jab ¼ 17.0–17.5 Hz, Jax ¼ 6.9–7.4 Hz,
Jbx ¼ 11.94–12.1 Hz). The H5-proton of thiazole was observed as
a singlet in the region 6.79–6.85 ppm. The mass spectra of
compounds 7a–d revealed, in each case, a peak corresponding to
their molecular ion peaks.
The results of the compounds of preliminary antibacterial
testing are shown in Table 1. The results revealed that majority of
the synthesized compounds showed varying degrees of inhibition
against the tested microorganisms. In general, the inhibitory
activity against the Gram-negative bacteria was higher than that of
the Gram-positive bacteria. The 1-(thiazol-2-yl)pyrazoline 7a
showed excellent activity against Gram-negative bacteria (inhibi-
tory zone 25 mm), good activity against Gram-positive bacteria
(inhibitory zone 20 mm). On the other hand, compounds 3a–c and
7c showed weak activities against E. coli. The antifungal activities of
these compounds against C. albicans and A. niger are shown in Table
1. Compounds 3a, 3c, 7c and 7d showed inhibition zones and
therefore antifungal activities against C. albicans more than the
reference sample Flucanazol, while compound 3b, showed similar
antifungal activity against C. albicans. Most of the tested compounds
showed none or weak antifungal activity against A. niger.
mg concentra-
4. Results, discussion and conclusion
In this present work, a series of nine new benzofuran derivatives
were synthesized starting from 1-(2-benzofuryl)-3-aryl-2-propen-
1-ones 2a-c synthesized according to the literature method [34].
Thus, we have obtained 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-
1-ones 3a–c through the treatment of 2a–c with nitromethane
under Michael addition conditions. The IR spectra of the latter
compounds showed, in each case, stretching band of C]O group in
the region 1660–1665 cmꢀ1. Their 1H NMR spectra revealed, in each
case, the signals of two CH2 groups in the region 2.30–2.33 ppm
and 3.50–3.52 ppm in addition to the multiplet signal of CH–Ar in
the region 4.29–4.31 ppm.
According to structure–activity relationships (SAR), it can be
concluded that benzofuran, pyrazoline, and thiazole moieties are
essential for the antimicrobial activity.
Several authors have been reported the synthesis of 1-(thiazol-
2-yl)pyrazolines from the corresponding methyl ketones
[16,24,36]. In the same sense, the reaction of 2a,b with thio-
semicarbazide in refluxing ethanol, in the presence of sodium
hydroxide, afforded 3-(2-benzofuryl)-5-aryl-1-thiocarbamoyl-2-
pyrazolines 4a, 4b, respectively. The structures of compounds 4a
and 4b were confirmed under the bases of their spectral data. For
example, The IR spectrum of compound 4a showed the stretching
band of C]S at 1278 cmꢀ1 and the absorption bands of NH2 group
at 3475 and 3345 cmꢀ1, its 1H NMR spectrum showed the signals of
Ha, Hb, Hx of pyrazoline ring as doublet of doublet in the regions
3.09–3.30, 4.01–4.10 and 5.59–5.69 ppm, respectively, with
coupling constants Jab ¼ 17.07, Jax ¼ 6.30 and Jbx ¼ 11.05 Hz, in
5. Experimental
5.1. Chemistry
All melting points were taken on Electrothermal IA 9000 series
digital melting point apparatus. The IR spectra (KBr) were recorded
on a Shimadzu CVT-04 spectrophotometer. The 1H NMR spectra
were recorded at 270 MHz on a Varian EM-360 spectrometer using
TMS as an internal standard. Splitting patterns are designated as
follows: s, singlet; d, doublet; t, triplet; m, multiplet. Chemical shift
addition to the D2O exchangeable signal of amino group at
d 8.34.
The reaction of pyrazoline 4a or 4b with 1-aryl-2-bromoetha-
none 5a,b in refluxing ethanol gave thiazolyl-pyrazolines 7a–d via
the non-isolable intermediate 6a–d. In the 1H NMR spectra of the
latter compounds the CH2 protons of pyrazoline ring resonated as
two doublet of doublet signals at 3.23–3.58 ppm (Ha) and
(d) values are given in parts per million and coupling constants (J) in
Hertz. The mass spectra were performed using a Varian MAT CH-5
spectrometer (70 eV). All reactions were followed by TLC (silica gel,
aluminum sheets 60 F254, Merck). 2-Acetylbenzofuran (1) was
prepared according to reported method [37].
O
O
CH3NO2
ArCHO
O
O
CH3
Ar
1
2a-c
O
3
a
b
c
Ar
NO2
Ph
O
4-Cl-C6H4
Ar
3a-c
4-MeO-C6H4
Scheme 1. Route to 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones.

2634
B.F. Abdel-Wahab et al. / European Journal of Medicinal Chemistry 44 (2009) 2632–2635
S
H2N
Hb
O
NH2
Hx
N
Ha
H
Ar
O
N
NH2
O
N
Ar
2a-b
S
4a-b
4
a
b
Ar
O
Ph
Br
4-Cl-C6H4
Ar1
5a-b
Ar
Ar
S
N
NH
O
N
O
N
N
O
N
Ar1
S
Ar1
7a-d
6a-d
7
a
b
c
Ar
Ph
Ph
Ar1
Ph
4-Br-C6H4
Ph
4-Cl-C6H4
4-Cl-C6H4
d
4-Br-C6H4
Scheme 2. Synthetic route to 1,3-thiazolyl-pyrazoles.
5.1.1. General procedure for the synthesis of the compounds
5.1.1.1. 1-(2-Benzofuryl)-3-aryl-2-propen-1-ones (2a–c). A mixture
of 2-acetylbenzofuran (0.05 mol) (1), appropriate aromatic alde-
hyde (0.05 mol) and 10% aqueous sodium hydroxide (10 mL) in
ethanol (30 mL) was stirred at room temperature for about 3 h. The
resulting solid was filtered off, washed with water, dried and
crystallized from ethanol [35].
(m,1H, CH–C6H5); 6.78 (s,1H, furan-H); 7.21–7.89 (m, 9H, Ar-H). MS
(m/z): 309 [Mþ].
5.1.1.2.2. 1-(Benzofuran-2-yl)-3-(4-chlorophenyl)-4-nitrobutan-1-
one (3b). M.p.195–196 ꢁC; Yield, 81%. IR (cmꢀ1): 1662 (C]O, st.). 1H
NMR (DMSO-d6): 2.33 (d, 2H, CH2–C]O); 3.52 (d, 2H, CH2–NO2);
4.29 (m, 1H, CH–C6H4–4-Cl); 6.76 (s, 1H, furan-H); 7.22–7.90 (m, 8H,
Ar-H). MS (m/z): 344 [Mþ þ 1], 343 [Mþ].
5.1.1.2.3. 1-(Benzofuran-2-yl)-3-(4-methoxyphenyl)-4-nitrobutan-
1-one (3c). M.p. 170–172 ꢁC; Yield, 78%. IR (cmꢀ1): 1665 (C]O, st.).
1H NMR (DMSO-d6): 2.30 (d, 2H, CH2–C]O); 3.51 (d, 2H,
CH2–NO2); 3.68 (s, 3H, –OCH3); 4.30 (m, 1H, CH–C6H4–4-
OMe); 6.77 (s, 1H, furan-H); 7.21–7.88 (m, 8H, Ar-H). Ms (m/z): 339
[Mþ].
5.1.1.2. 1-(Benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones (3a–c). A
mixture of appropriate 1-(2-benzofuryl)-3-aryl-2-propen-1-ones
(2a-c) (10 mmol), nitromethane (0.93 g, 15 mmol) and piperidine
(0.5 mL) in absolute ethanol (30 mL) was heated at reflux temper-
ature for 3 h, left to cool, the formed solid was filtered off, dried and
crystallized from ethanol.
5.1.1.2.1. 1-(Benzofuran-2-yl)-4-nitro-3-phenylbutan-1-one (3a).
M.p. 200–202 ꢁC; Yield, 76%. IR (cmꢀ1): 1660 (C]O, st.). 1H NMR
(DMSO-d6): 2.32 (d, 2H, CH2–C]O); 3.50 (d, 2H, CH2–NO2); 4.31
5.1.1.3. 3-(Benzofuran-2-yl)-4,5-dihydro-5-arylpyrazole-1-carbothioa-
mide (4a,b). To a suspension of 1-(2-benzofuryl)-3-aryl-2-propen-
1-one derivatives 2a,b (0.01 mol) and sodium hydroxide (1.0 g,
0.025 mol) in ethanol (50 mL), thiosemicarbazide (1.1 g, 0.012 mol)
was added. The mixture was refluxed for 6 h, then left to cool; the
formed solid product was filtered off, washed with ethanol, dried,
and then crystallized from ethanol.
Table 1
The in vitro antimicrobial activity of compounds 3–7.
5.1.1.3.1. 3-(benzofuran-2-yl)-4,5-dihydro-5-phenylpyrazole-1-car-
bothioamide (4a). M.p. 230–231 ꢁC; Yield, 84%. IR (cmꢀ1): 1278
(C]S); 3475, 3345 (NH2). 1H NMR (DMSO-d6): 3.09–3.30 (dd, 1H,
Ha); 4.01–4.10 (dd,1H, Hb); 5.59–5.69 (dd,1H, Hx); 7.15 (s,1H, furan-
H); 7.21–7.72 (m, 9H, Ar-H); 8.34 (s, D2O exchangeable, 2H, NH2)
(Jab ¼ 17.07; Jax ¼ 6.30; Jbx ¼ 11.09 Hz). MS (m/z): 321 [Mþ].
5.1.1.3.2. 3-(Benzofuran-2-yl)-5-(4-chlorophenyl)-4,5-dihydropyr-
azole-1-carbothioamide (4b). M.p. 217–218 ꢁC; Yield, 86%. IR
(cmꢀ1): 1276 (C]S); 3472, 3344 (NH2). 1H NMR (DMSO-d6): 3.10–
3.30 (dd, 1H, Ha,); 4.00–4.10 (dd, 1H, Hb); 5.59–5.65 (dd, 1H, Hx);
7.10 (s, 1H, furan-H); 7.20–7.71(m, 8H, Ar-H); 8.36 (s, D2O
exchangeable, 2H, NH2) (Jab ¼ 17.02; Jax ¼ 6.22; Jbx ¼ 10.95 Hz). MS
(m/z): 321 [Mþ].
Compounds
Zone of inhibition (mm)
S. aureus
B. subtilis
E. coli
C. albicans
A. niger
3a
3b
3c
4a
4b
7a
7b
7c
0
0
0
0
12
12
12
0
15
25
0
12
0
20
–
30
20
25
5
0
0
0
15
0
0
15
0
0
15
0
–
20
0
0
0
0
0
17
0
12
0
0
0
0
0
25
25
–
7d
0
0
AmoxicillinÒ
FlucanazolÒ
20
–
20
–
20

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2635
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dihydro-1H-pyrazoles (7a–d). To a suspension of compounds 4a,b
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thiazol-2-yl)-1H-pyrazole (7a). M.p. 219–220 ꢁC; Yield, 90%. IR
(cmꢀ1): 1622 (C]N, st.). 1H NMR (DMSO-d6): 3.22–3.57 (dd, 1H,
Ha); 3.80–3.95 (dd, 1H, Hb); 5.57–5.74 (dd, 1H, Hx); 6.81 (s, 1H,
thiazole-H); 7.34–7.72 (m, 14H, Ar-H); 7.23(s, 1H, furan-H);
(Jab ¼ 17.2; Jax ¼ 7.0; Jbx ¼ 12.1 Hz). MS (m/z): 421 [Mþ].
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4,5-dihydro-5-phenyl-1H-pyrazole (7b). M.p. 212–213 ꢁC; Yield,
88%. IR (cmꢀ1): 1618 (C]N, st.). 1H NMR (DMSO-d6): 3.23–3.56 (dd,
1H, Ha); 3.80–3.96 (dd, 1H, Hb); 5.57–5.70 (dd, 1H, Hx); 6.79 (s, 1H,
thiazole-H); 7.32–7.71 (m, 13H, Ar-H); 7.73 (s, 1H, furan-H);
(Jab ¼ 17.1; Jax ¼ 6.94; Jbx ¼ 11.98 Hz). MS (m/z): 501 [Mþ þ 2]; 500
[Mþ þ 1]; 499 [Mþ].
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(4-phenylthiazol-2-yl)-1H-pyrazole (7c). M.p. 152–153 ꢁC; Yield,
90%. IR (cmꢀ1): 1624 (C]N, st.). 1H NMR (DMSO-d6): 3.25–3.58 (dd,
1H, Ha); 3.82–3.96 (dd, 1H, Hb); 5.58–5.73 (dd, 1H, Hx); 6.85 (s, 1H,
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5.1.1.4.4. 3-(Benzofuran-2-yl)-1-(4-(4-bromophenyl)thiazol-2-yl)-
5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole (7d). M.p. 170–171 ꢁC;
Yield, 82%. IR (cmꢀ1): 1620 (C]N, st.). 1H NMR (DMSO-d6): 3.24–
3.57 (dd, 1H, Ha); 3.80–3.92 (dd, 1H, Hb); 5.55–5.74 (dd, 1H, Hx);
6.80(s, 1H, thiazole-H); 7.19–7.71(m, 12H, Ar-H); 7.72(s, 1H, furan-
H); (Jab ¼ 17.2; Jax ¼ 7.01; Jbx ¼ 11.95 Hz). MS (m/z): 534 [Mþ þ 2];
533 [Mþ þ 1]; 532 [Mþ].
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