In vivo antihyperlipidemic activity of a new series of N-(Benzoylphenyl) and N-(Acetylphenyl)-1-benzofuran-2-carboxamides in rats

Article abstract of DOI:10.1002/ardp.201100225

A new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2- carboxamides (3a-3d and 4a'-4c') were synthesized. Compounds (3a, 3b, and 4a'-4c') were tested in vivo using Triton-WR-1339-induced hyperlipidemic rats as an experimental model for their hypolipidemic activity. The tested animals were divided into eight groups: control, hyperlipidemic, 3a, 3b, 4a', 4b', 4c', and bezafibrate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were significantly reduced in compounds 3b (p <0.0001) and 4c' (p <0.05) after 12 and 24 h compared to the normal control group. Furthermore, high-density lipoprotein-cholesterol levels were remarkably increased in compounds 3b (p <0.001) and 4c' (p <0.05). Meanwhile, compound 4b' slightly reduced the TG levels after 12 and 24 h. The present study demonstrated new properties of the novel series of benzofuran-2-carboxamides 3b and 4c' as potent lipid-lowering agents. It is, therefore, reasonable to assume that compounds 3b and 4c' may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases. A new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides (3a-3d and 4a'-4c') were synthesized and most of them were tested in vivo for their hypolipidemic activity. Compounds 3b and 4c' turned out to be potent lipid-lowering agents and thus may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases. Copyright

Full text of DOI:10.1002/ardp.201100225

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
1
Full Paper
In Vivo Antihyperlipidemic Activity of a New Series of
N-(Benzoylphenyl) and N-(Acetylphenyl)-1-benzofuran-2-
carboxamides in Rats
Tariq Al-Qirim1, Ghassan Shattat1, Kamal Sweidan2, Waseem El-Huneidi1, Ghassan Abu Sheikha1,
Reema Abu Khalaf1, and Suhair Hikmat1
1 Faculty of Pharmacy, Al-Zaytoonah University, Amman, Jordan
2 Faculty of Science, Department of Chemistry, University of Jordan, Amman, Jordan
A new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides (3a–3d and
4a0–4c0) were synthesized. Compounds (3a, 3b, and 4a0–4c0) were tested in vivo using Triton-WR-
1339-induced hyperlipidemic rats as an experimental model for their hypolipidemic activity. The
tested animals were divided into eight groups: control, hyperlipidemic, 3a, 3b, 4a0, 4b0, 4c0, and
bezafibrate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were significantly
reduced in compounds 3b (p <0.0001) and 4c0 (p <0.05) after 12 and 24 h compared to the normal
control group. Furthermore, high-density lipoprotein-cholesterol levels were remarkably increased in
compounds 3b (p <0.001) and 4c0 (p <0.05). Meanwhile, compound 4b0 slightly reduced the TG levels
after 12 and 24 h. The present study demonstrated new properties of the novel series of benzofuran-2-
carboxamides 3b and 4c0 as potent lipid-lowering agents. It is, therefore, reasonable to assume that
compounds 3b and 4c0 may have a promising potential in the treatment of hyperlipidemia and
coronary heart diseases.
Keywords: High-density lipoprotein-cholesterol / Hypolipidemic activity / N-(Benzoylphenyl) and N-(acetylphenyl)-1-
benzofuran-2-carboxamides / Triglycerides / Triton-induced hyperlipidemia
Received: June 28, 2011; Revised: November 14, 2011; Accepted: November 25, 2011
DOI 10.1002/ardp.201100225
Introduction
Triglycerides (TG) are energy-rich compounds, primarily
stored in liver and adipose tissue, and are mobilized in
response to various metabolic signals. In plasma, TG, which
are water insoluble, circulate as the neutral lipid core of
lipoproteins, mainly chylomicrons, which carry dietary fat
and are secreted by the small intestine, and very low-density
lipoprotein-cholesterol (VLDL-C), which carries TG from the
liver [8].
Atherosclerosis, the underlying cause of heart attack, stroke,
and peripheral vascular disease, is a main cause of morbidity
and mortality worldwide [1–3]. One of the initial events in the
development of atherosclerosis is the accumulation of cells
containing excess lipids within the arterial wall [4, 5].
Hyperlipidemia is defined as an elevation of lipids in
plasma. Several studies have showed that an intimate corre-
lation exists between coronary heart diseases and hyperlipi-
demia; consequently a rational approach to the treatment
and prevention of coronary heart diseases could be by
decreasing any elevated levels of lipids in plasma [6, 7].
Fibrates and their derivatives are a group of drugs which
have been widely used for a long time to treat hyperlipopro-
teinemia, among which is the well-known commercially
available drug bezafibrate [9–11]. The major pharmacological
mechanism of fibrates, including bezafibrate, is supposed
to be an increased hydrolysis of TG by the induction of
lipoprotein lipase and reduction of apolipoprotein C-III
synthesis [12, 13].
Correspondence: Dr. Tariq Al-Qirim, Faculty of Pharmacy, Department of
Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan.
E-mail: grah7781@yahoo.com
Triton WR-1339 (a nonionic detergent resulting in milky
serum that lasts up to 48 h) has been widely used to produce
acute hyperlipidemia in animal models in order to screen
Fax: 00962 6 4291432
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T. Al-Qirim et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
natural and chemical drugs [14]. The accumulation of plasma
lipid by Triton WR-1339 appears to be due to the inhibition of
lipoprotein lipase activity [15].
administration in comparison with the normal control
group (NC). In fact, the increases of plasma TC concentration
in the HG were 16 and 11.6% after 12 and 24 h as compared to
the NC. TG and LDL-C levels in the HG were also elevated
by 767 and 108% and 671 and 100% after 12 and 24 h,
respectively.
During the last decade, a lot of attention has been given to
studies focused on the synthesis of benzofuran-containing
agents and their pharmacological activities [16, 17]. From
these studies, which include our previous published data, it
was found that compounds containing the benzofuran ring
have a promising potential effect as lipid-lowering agents
[18–20].
Meanwhile a significant decrease (p <0.001) in the HDL-C
level occurred at 12 and 24 h after Triton injection compared
to the NC.
For this purpose, this study has been conducted to evaluate
the potential hypolipidemic effects of a new series of N-(ben-
zoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carbox-
amides (3a, 3b, and 4a0–4c0).
Effect of 3a, 3b, 4a0, 4b0, 4c0, and bezafibrate on rat
plasma lipid profile
The plasma TC, TG, HDL-C, and LDL-C levels of BF-, 3a-, 3b-, 4a0-,
4b0-, and 4c0-treated rats after 12 and 24 h are shown in
Table 1. Importantly, the elevated plasma TG levels produced
by Triton WR-1339 administration after 12 h were signifi-
cantly suppressed by 73% (p <0.0001) in BF, and by 61%
(p <0.0001), and 27% (p <0.05) in 3b- and 4c0-treated rats,
respectively, with respect to the hyperlipidemic control HG.
TG levels were also significantly decreased by 68%, 65%
(p <0.0001), and 16% (p <0.05) in BF-, 3b- and 4c0-treated rats
after 24 h, respectively.
Meanwhile, compound 4b0 showed a slight decrease in TG
levels by 12 and 8% after 12 and 24 h, respectively.
The HDL-C levels were significantly increased after 12 h of
Triton administration, þ31%, þ28% (p <0.001), and þ21%
(p <0.05) in BF-, 3b-, and 4c0-treated rats, respectively, com-
pared to HG-treated rats and were maintained until 24 h
after Triton injection.
Results
Induction of hyperlipidemia by Triton WR-1339
The plasma total cholesterol (TC), TG, high-density lipopro-
tein-cholesterol (HDL-C), and low-density lipoprotein-choles-
terol (LDL-C) levels of all groups treated for 12 and 24 h are
shown in Fig. 1. Triton WR-1339 caused a significant increase
in plasma TC, TG, and LDL-C (p <0.0001) levels in the hyper-
lipidemic control group (HG) at 12 and 24 h after Triton
600
A)
**
500
400
300
NC
HG
With the exception of compound 3b none of the treated
groups showed a significant reduction in plasma TC levels
after 12 and 24 h of Triton administration. In fact, it was
found that TC levels in compound 3b were reduced by 19,
25% (p <0.001) after 12 and 24 h, respectively, of Triton
administration with respect to the hyperlipidemic control
HG (Table 1).
200
**
100
*
**
0
TC
LDL-C
HDL-C
TG
B)500
After 12 and 24 h of treatment, LDL-C levels in 3b were
lowered by 34 and 35% (p <0.001), respectively. Meanwhile,
there were no significant changes in LDL-C levels in 4b0 and
4c0 after 12 and 24 h.
**
450
400
350
300
250
200
150
100
50
NC
HG
After 12 and 24 h of treatment, no significant differences
in plasma TC, TG, HDL-C, and LDL-C levels in 3a and 4a0 were
observed compared to HG-treated rats (Table 1).
However, compounds 3c and 3d were not biologically
tested because they are derivatives of compound 3a which
was revealed inactive.
**
**
*
0
TC
LDL-C
HDL-C
TG
Figure 1. Effect of Triton WR-1339 on lipid profile after (A) 12 h
and (B) 24 h. Values are means W SD from eight animals in each
group. NC, control group; HG, hyperlipidemic control group; TC,
total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein
cholesterol; LDL-C, low density lipoprotein cholesterol. HG is
compared to NC. ꢀp <0.001 and ꢀꢀp <0.0001.
Discussion
The results of the current study showed the potential hypo-
lipidemic effects of compounds 3b and 4c0 (Table 1) in Triton
WR-1339-induced hyperlipidemic rats. Compounds 3b and
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
Antihyperlipidemic Activity of Benzofuran-2-carboxamides
3
Table 1. Effects of the novel 3a, 3b, 4a0, 4b0, 4c0, and BF on plasma lipid levels in Triton WR-1339-induced hyperlipidemic rats after 12 and
24 h.
Lipid profile
TC (mg/dL)
TG [mg/dL]
HDL-C [mg/dL]
LDL-C [mg/dL]
12 h
HG
3a
95.6 ꢁ 3.6
103.2 ꢁ 5.2
77.2 ꢁ 2.7a
100.1 ꢁ 6.2
94.3 ꢁ 2.2
83.5 ꢁ 2.6
92.0 ꢁ 3.1
487.5 ꢁ 7.7
468.0 ꢁ 4.9
188.3 ꢁ 5.3b
491.0 ꢁ 8.8
425.8 ꢁ 7.9
355.0 ꢁ 6.8c
129.7 ꢁ 4.0b
39.0 ꢁ 2.6
40.2 ꢁ 3.1
50.1 ꢁ 3.1a
38.6 ꢁ 2.3
42.5 ꢁ 1.6
46.1 ꢁ 1.3c
51.2 ꢁ 2.4a
35.2 ꢁ 1.9
37.5 ꢁ 3.2
19.3 ꢁ 2.2a
35.5 ꢁ 2.0
34.4 ꢁ 3.3
33.9 ꢁ 2.2
31.1 ꢁ 3.8
3b
4a0
4b0
4c0
BF
24 h
HG
3a
91.6 ꢁ 3.2
93.2 ꢁ 4.0
69.1 ꢁ 1.6a
96.3 ꢁ 5.1
93.3 ꢁ 1.7
84.5 ꢁ 2.2
94.4 ꢁ 3.1
433.5 ꢁ 8.3
430.1 ꢁ 3.2
153.3 ꢁ 3.0b
436.6 ꢁ 8.2
396.0 ꢁ 6.6
366.0 ꢁ 7.1c
140.7 ꢁ 3.0b
41.3 ꢁ 1.9
41.9 ꢁ 1.9
53.1 ꢁ 2.1a
40.6 ꢁ 1.5
44.1 ꢁ 0.9
48.1 ꢁ 1.3c
49.2 ꢁ 3.1a
33.8 ꢁ 1.1
34.5 ꢁ 2.1
22.1 ꢁ 1.9a
33.4 ꢁ 0.9
33.4 ꢁ 1.6
29.9 ꢁ 2.6
31.3 ꢁ 3.8
3b
4a0
4b0
4c0
BF
Values are expressed as means ꢁ SD from eight animals in each group. NC, normal control group; HG, hyperlipidemic þ 4% DMSO
control group; 3a, 3a þ 4% DMSO; 3b, 3b þ 4% DMSO; 4a0, 4a0 þ 4% DMSO; 4b0, 4b0 þ 4% DMSO; 4c0, 4c0 þ 4% DMSO; BF,
bezafibrate þ 4% DMSO; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low density
lipoprotein cholesterol.
3a, 3b, 4a0, 4b0, 4c0, and BF are compared with HG.
a
p <0.001.
p <0.0001.
p <0.05.
b
c
4c0 significantly reduced serum TG and increased serum HDL.
Meanwhile, compound 3b0 slightly reduced TG and increased
HDL.
pared to bezafibrate at a dose of 100 mg/kg body weight,
which in this study has been used as standard reference
hypolipidemic drug.
In the literature, it has been reported that parenteral
administration of Triton WR-1339 to adult rats could induce
hyperlipidemia. In such models, the maximum plasma TC
and TG levels were reached at 20 h followed by a decline to
standard values [21, 22]. In the course of this study, the same
model gave a similar pattern of lipid profile changes 12 and
24 h after Triton WR-1339 administration.
In addition, it seems that the presence of a large lipophilic
moiety is also important for the biological activity. So when
benzophenone (3b) was replaced by a small lipophilic ring, in
this case the actophenone (3b0 and 3c0), the activity was
remarkably reduced.
In parallel, the current study shows that the compounds
with a substitution in positions 3 and 4 were more active in
comparison with position 2. This observation could be
explained by the possible effect of the extended moiety of
diphenylketone when substituted at positions 3 and 4 which
encompass the best fit with the proposed three essential
components of the proposed target which determine the
activity that was proposed by our group previously [25]. On
the contrary, the substitution at position 2 does not resemble
the same fit with the proposed active component.
Overall, these preliminary observations lead us to conclude
that the presence of a large lipopholic moiety, a carboxamide
linker along with a heterocylic ring (able to form hydrogen
bonds) are three important requirements to obtain hypo-
lipidemic activity.
Plasma TG levels are controlled by a good balance between
hepatic TG synthesis and secretion on one hand and plasma
TG clearance on the other. Thus the observed reduction in
plasma TG levels by compounds 3b, 4b0, and 4c0 could be
consummate by reduced synthesis, reduced hepatic output,
improved clearance, or a combination of these factors [23].
In addition, compounds 3b, 4b0, and 4c0 increased the HDL
level, which is known for its preventive role against athero-
genesis. HDL also promotes substantial cholesterol egress
from the liver by facilitating the mobilization of TG and
cholesterol from plasma to liver where it undergoes catabo-
lism and then is eliminated in the form of bile acids [24, 25].
Promisingly, compound 3b at a dose of 15 mg/kg body
weight 12 and 24 h after Triton injection was more potent
in reducing TG levels and in increasing HDL-C levels com-
In summary, compounds 3b and 4c0 were shown to
improve lipid abnormalities such as hypertriglyceridemia
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T. Al-Qirim et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
O
O
Et3N
and hypercholesterolemia, and then elevated HDL levels in
Triton induced rats, suggesting them as possible useful can-
didates in the treatment of patients with lipid abnormalities.
Cl
O
Cl
O
Et
N
Et
Et
2
5
Scheme 2. Synthesis of the reactive species 5 in situ.
Experimental
Chemistry
Benzofuran-2-acyl chloride (2) was prepared in good yield by the
reaction of benzofuran-2-carboxylic acid (1) with an excess
amount of thionyl chloride under reflux (Scheme 1).
In spite of the weakness of 3-amino- and 4-aminobenzo-
phenone derivatives as nucleophiles, their reaction with benzo-
furan-2-carboxylic acid (2) produced the target products by
employment of an excess amount of triethylamine which con-
verted compound (2) into more reactive species (5) (Scheme 2); in
addition to its basic role as a soluble organic base.
H
H
N
O
Figure 2. Intra hydrogen bonding in 2-aminobenzophenone.
On the other hand, 2-aminobenzophenone derivatives failed
to produce the corresponding compounds according to the for-
mer procedure, this may be attributed due to the intra hydrogen
bonding in 2-aminobenzophenone derivatives. Instead a stron-
ger base, sodium ethoxide, was used (Fig. 2).
the residue was stirred for 10 min in CHCl3 followed by purifi-
cation using silica gel column chromatography (eluents: CHCl3/
MeOH) in a ratio of 993:7.
All starting materials were purchased from Sigma–Aldrich
(St. Louis, MO, USA) and used without further purification.
Experiments were performed in purified solvents. Benzofuran-
2-acyl chloride (2) was prepared according to the published
procedure [19]. Melting points were determined using a Stuart
Scientific electrothermal melting point apparatus and were
uncorrected. Nuclear magnetic resonance (NMR), 1H NMR, and
13C spectra were acquired by a Bruker DRX 400 MHz instrument
operating at 400.13 (1H) and 100.61 MHz (13C) relative to TMS as
reference standard.
Infrared (IR) spectra were recorded on an Avatar Thermo
Nicolet Impact 400 FT-IR spectrophotometer using the Smart
Omni-Transmission software; all samples were prepared as
potassium bromide (Acros, Belgium) discs. The EI-mass spectra
were acquired on a Finnigan TQS 70, by 70 eV at 2008C.
Elemental analyzer model is EA3000 A, Italy.
General procedure for the synthesis0of benzofuran
carboxamide derivatives (3b and 4b,c0)
A solution of 4.4 mmol of benzofuran-2-acyl chloride (2) was
added to a solution containing 4.4 mmol of 3-aminobenzo-
phenone (or 3 (4)-aminoacetophenone) and 1.3 mL (8.8 mmol)
of triethylamine (Et3N) in dry N,N-DMF. The reaction mixture was
refluxed for 24 h, and then cooled to room temperature. DMF
and the excess Et3N were evaporated under reduced pressure.
The residue was extracted with dichloromethane and water; the
organic layer was separated, then dried over anhydrous sodium
sulfate, filtered, and evaporated to dryness. The residue was
recrystallized from dichloromethane/diethylether.
N-(2-Benzoylphenyl)-1-benzofuran-2-carboxamide (3a)
Yield, 39%; mp 168–1708C; 1H-NMR (CDCl3, 400.16 MHz) d (ppm):
7.33–7.49 (m, 10H), 7.65 (d, 1H, J ¼ 8.5 Hz), 7.70 (s, 1H), 7.73
(d, 1H, J ¼ 8.1 Hz), 8.10 (d, 1H, J ¼ 8 Hz), 8.91 (major), and
10.62 (s, 1H, NH, rotamors); 13C-NMR (CDCl3, 100.61 MHz)
d (ppm): 112.4, 114.9, 117.1, 124.9, 125.2, 126.7, 127.3, 128.2,
129.4, 130.3, 131.8, 132.5, 133.2, 134.7, 138.2, 139.1, 150.3, 159.2,
160.1, 199.2; IR (KBr) cmꢂ1: 1669, 1709 (CO), 3381 (NH); MS
(EI/70 eV): m/z (%) ¼ 118 (44) [M–CONHPhCOPh]þ, 146 (100)
[M–NHPhCOPh]þ, 341 (25) [M]þ. Anal. Calcd. for C22H15NO3:
C, 77.41; H, 4.43; N, 4.10. Found: C, 77.01; H, 4.78; N, 3.84.
General procedure for the synthesis of benzofuran
carboxamide derivatives (3a,c,d and 4a0)
A solution of 4.4 mmol of benzofuran-2-acyl chloride (2) was
added to a solution containing 4.4 mmol of a specified 2-amino-
benzophenone (or 2-aminoacetophenone) and 0.6 g (8.8 mmol)
of sodium ethoxide in dry N,N-dimethylformamide (DMF). The
reaction mixture was refluxed for 36 h, and then cooled to room
temperature. DMF was evaporated under reduced pressure and
O
O
O
(ii)
O H
CH3
SOCl2
reflux
Cl
OH
N
O
O
O
1
2
4
(ii)
a': 2-aminoacetophenone
b': 3-aminoacetophenone
c': 4-aminoacetophenone
(i)
a: 2-aminobenzophenone
(i)
b: 3-aminobenzophenone
c: 2-amino-4'-methylbenzophenone
d: 2-amino-5-chlorobenzophenone
Scheme 1. Reagents and conditions: (a)
SOCl2, THF, and reflux; (b) different amino-
benzophenones, base, and DMF; (c) different
aminoacetophenones, base, and DMF.
O
O H
N
O
_
3a d
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
Antihyperlipidemic Activity of Benzofuran-2-carboxamides
5
MS (EI/70 eV): m/z (%) ¼ 118 (47) [M–CONHPhCOCH3]þ, 146 (100)
[M–NHPhCOCH3]þ, 279 (21) [M]þ. Anal. Calcd. for C17H13NO3: C,
73.11; H, 4.69; N, 5.02. Found: C, 72.72; H, 4.91; N, 4.80.
N-(3-Benzoylphenyl)-1-benzofuran-2-carboxamide (3b)
Yield, 81%; mp 119–1218C; 1H-NMR (CDCl3, 400.16 MHz) d (ppm):
7.36–7.42 (m, 6H), 7.59 (d, 1H, J ¼ 8.1 Hz), 7.63–7.69 (m, 2H),
7.71 (d, 1H, J ¼ 8.4), 7.79 (s, 1H), 7.92 (d, 1H, J ¼ 8.0 Hz), 8.02
(dd, 1H, J ¼ 2.4, 8.1 Hz), 8.78 (s, 1H, NH); 13C-NMR (CDCl3,
100.61 MHz) d (ppm): 113.1, 114.8, 121.1, 121.7, 124.5, 125.1,
126.0, 126.8, 128.9, 130.5, 131.7, 132.4, 134.7, 136.0, 137.9,
143.3, 150.2, 158.3, 159.0, 197.1; IR (KBr) cmꢂ1: 1672, 1711
(CO), 3378 (NH); MS (EI/70 eV): m/z (%) ¼ 118 (43) [M–
CONHPhCOPh]þ, 146 (100) [M–NHPhCOPh]þ, 341 (19) [M]þ.
Anal. Calcd. for C22H15NO3: C, 77.41; H, 4.43; N, 4.10. Found:
C, 77.10; H, 4.82; N, 3.72.
N-(4-Acetylphenyl)-1-benzofuran-2-carboxamide (4c0)
Yield, 80%; mp 199–2018C; 1H-NMR (CDCl3, 400.16 MHz) d (ppm):
2.61 (s, 3H, COCH3), 7.21–7.28 (m, 2H), 7.31–7.45 (m, 3H), 7.70
(d, 1H, J ¼ 8.5 Hz), 7.76 (s, 1H), 7.85–7.96 (m, 2H), 8.64 (s, 1H, NH);
13C-NMR (CDCl3, 100.61 MHz) d (ppm): 26.1, 113.1, 114.6, 118.2,
123.2, 123.9, 127.4, 129.1, 130.1, 134.8, 143.9, 148.1, 158.2,
166.1, 196.1; IR (KBr) cmꢂ1: 1679, 1715 (CO), 3372 (NH); MS
(EI/70 eV): m/z (%) ¼ 118 (46) [M–CONHPhCOCH3]þ, 146 (100)
[M–NHPhCOCH3]þ, 279 (24) [M]þ. Anal. Calcd. for C17H13NO3:
C, 73.11; H, 4.69; N, 5.02. Found: C, 72.83; H, 4.851; N, 4.91.
N-[2-(40-Methylbenzoyl)phenyl]-1-benzofuran-2-
carboxamide (3c)
Yield, 45%; mp 163–1658C; 1H-NMR (CDCl3, 400.16 MHz) d (ppm):
7.23–7.51 (m, 9H), 7.64 (d, 1H, J ¼ 8.5 Hz), 7.73 (s, 1H), 7.83 (d, 1H,
J ¼ 8.1 Hz), 8.15 (d, 1H, J ¼ 8.0 Hz), 9.02 (major), and 10.53 (s, 1H,
NH, rotamors); 13C-NMR (CDCl3, 100.61 MHz) d (ppm): 23.1, 112.7,
114.5, 117.3, 124.7, 125.3, 126.1, 127.9, 128.1, 129.1, 129.7, 130.1,
133.0, 138.0, 138.3, 141.2, 150.6, 159.2, 160.2, 199.7; IR (KBr)
cmꢂ1: 1673, 1713 (CO), 3383 (NH); MS (EI/70 eV): m/z (%) ¼ 118
(39) [M–CONHPhCOPhCH3]þ, 146 (100) [M–NHPhCOPhCH3]þ, 355
(29) [M]þ. Anal. Calcd. for C23H17NO3: C, 77.73; H, 4.82; N, 3.94.
Found: C, 77.41; H, 5.08; N, 3.63.
Pharmacological assay
Triton WR-1339 was obtained from Sigma–Aldrich. The rest of
the chemicals (fine super grade) were purchased from Acros
Organics (Amman, Jordan).
Animals and treatments
Sixty-four adult male Wistar rats of 2 months age, weighing
around 180 g, bred in the animal care centre of the Faculty
of Pharmacy, Al-Zaytoonah University, Amman, Jordan, were
provided ad libitum access only to tap water throughout
the experimental duration. Rats were maintained in a 12 h
light–dark cycle under constant humidity and (22 ꢁ 28C).
All experiments were performed in accordance with the
Guidelines for Animal Welfare Committee of Al-Zaytoonah
University.
N-[2-(5-Chlorobenzoyl)phenyl]-1-benzofuran-2-
carboxamide (3d)
Yield, 37%; mp 194–1968C; 1H-NMR (CDCl3, 400.16 MHz) d (ppm):
7.31–7.52 (m, 8H), 7.71–7.79 (m, 2H), 7.91 (s, 1H), 8.11 (d, 1H,
J ¼ 4.0 Hz), 8.92 (d, 1H, J ¼ 8.1 Hz), 9.09 (major), and 10.58 (s, 1H,
NH, rotamors); 13C-NMR (CDCl3, 100.61 MHz) d (ppm): 112.1,
115.0, 119.1, 124.0, 124.9, 126.3, 128.1 130.2, 132.1, 132.7,
134.6, 135.2, 136.7, 139.0, 150.1, 159.0, 160.7, 203.2; IR (KBr)
cmꢂ1: 1679, 1715 (CO), 3388 (NH); MS (EI/70 eV): m/z (%) ¼ 118
(40) [M–CONHPhCOPhCl]þ, 146 (100) [M–NHPhCOPhCl]þ, 375,
377 (37, 11) [M]þ. Anal. Calcd. for C22H14ClNO3: C, 70.31;
H, 3.75; N, 3.73. Found: C, 70.11; H, 4.14; N, 3.46.
Triton model of hyperlipidemia
Triton WR-1339 was dissolved in (DMSO) and administered intra-
peritoneally to the rats (250 mg/kg body weight) in order to
induce hyperlipidemia.
Pharmacological experimental design
Overnight fasted rats were randomly divided into eight groups of
eight animals each. The first group, serving as NC, received an
intraperitoneal administration of normal saline; the second
hyperlipidemic group (HG) received an intraperitoneal injection
of Triton dissolved in 4% DMSO (in distilled water). In the third,
fourth, fifth, sixth, and seventh groups, rats were intraperito-
neally injected with Triton, followed by an intragastric admin-
istration (15 mg/kg body weight) of compounds 3a, 3b, 4a0, 4b0,
and 4c0, respectively, dissolved in 4% DMSO. The last group (BF)
was also intraperitoneally injected with Triton and intragastri-
cally treated with bezafibrate (100 mg/kg body weight) dissolved
in 4% DMSO.
After 12 and 24 h of treatment, animals were anaesthetized
with diethyl ether and blood was collected. The blood samples
were immediately centrifuged (3000 rpm for 10 min) and
the plasma was used for lipid analysis by an enzymatic method
with an automated analyzer (Model Erba XL-300, Germany,
Mannheim, Germany).
N-(2-Acetylphenyl)-1-benzofuran-2-carboxamide (4a0)
Yield, 44%; mp 204–2068C; 1H-NMR (CDCl3, 400.16 MHz) d (ppm):
2. 51 (s, 3H, COCH3), 7.31–7.40 (m, 5H), 7.68 (d, 1H, J ¼ 8.4 Hz),
7.78 (d, 1H, J ¼ 8.1 Hz), 7.85 (s, 1H), 8.10 (d, 1H, J ¼ 8.0 Hz), 9.12
(major), and 10.54 (s, 1H, NH, rotamors); 13C-NMR (CDCl3,
100.61 MHz) d (ppm): 27.1, 112.0, 113.8, 116.9, 124.5, 125.2,
127.1, 128.2, 129.9, 130.1, 136.1, 138.0, 140.1, 150.5, 159.0,
162.1, 204.2; IR (KBr) cmꢂ1: 1661, 1715 (CO), 3370 (NH);
MS (EI/70 eV): m/z (%) ¼ 118 (48) [M–CONHPhCOCH3]þ, 146
(100) [M–NHPhCOCH3]þ, 279 (29) [M]þ. Anal. Calcd. for
C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 72.67; H, 4.98;
N, 4.71.
N-(3-Acetylphenyl)-1-benzofuran-2-carboxamide (4b0)
Yield, 79%; mp 125–1278C; 1H-NMR (CDCl3, 400.16 MHz) d (ppm):
2.61 (s, 3H, COCH3), 7.30–7.39 (m, 3H), 7.60 (d, 1H, J ¼ 8.1 Hz),
7.69 (d, 1H, J ¼ 8.5 Hz), 7.75 (s, 1H), 7.90 (d, 1H, J ¼ 8.1 Hz), 8.05
(dd, 1H, J ¼ 2.4, 8.1 Hz), 8.31 (s, 1H), 8.45 (s, 1H, NH); 13C-NMR
(CDCl3, 100.61 MHz) d (ppm): 26.2, 113.9, 114.9, 119.8, 120.3,
122.9, 123.5, 124.1, 129.9, 130.4, 138.2, 141.1, 142.1, 150.1,
158.0, 164.1, 202.1; IR (KBr) cmꢂ1: 1678, 1719 (CO), 3381 (NH);
Statistical analysis
Results were expressed as mean ꢁ SD. Data obtained were ana-
lyzed using Student’s t-test, and the differences with p <0.05
were considered statistically significant.
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

6
T. Al-Qirim et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–6
The authors wish to express their sincere appreciation to Al-Zaytoonah
University of Jordan for financial support and to Sameer Al-kouz for
technical support.
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The authors have declared no conflict of interest.
[14] H. Hayashi, S. Niinobe, Y. Matsumoto, T. Suga, J. Biochem.
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