Design, Synthesis and Preliminary Evaluation of Novel Imperatorin Derivatives as Vasorelaxant Agents

Article abstract of DOI:10.2174/157340611794072715

A series of novel imperatorin derivatives were synthesized from commercially available xanthotoxin. The in vitro pharmacological evaluation indicated that all of the compounds possessed potent vasodilatory activity. Among them, compounds (5b), (5d) and (5e) exhibited higher vasdilatory activity (with EC₅₀ values of 0.68 μM, 0.59 μM and 0.49 μM, respectively) than imperatorin (EC₅₀ = 1.12 μM). The program Volsurf was used to predict the derivatives' ADMErelevant descriptors. The results suggested that these novel compounds had a potential interest for the development of novel and potent vasorelaxant agents.

Full text of DOI:10.2174/157340611794072715

18
Medicinal Chemistry, 2011, 7, 18-23
Design, Synthesis and Preliminary Evaluation of Novel Imperatorin De-
rivatives as Vasorelaxant Agents
Na Li, Jianyu He, Yingzhuan Zhan, Nan Zhou and Jie Zhang*
College of Medicine, Xi’an Jiaotong University, No. 76, Yanta Weststreet, Xi’an, Shaanxi Province, 710061, P.R. China
Abstract: A series of novel imperatorin derivatives were synthesized from commercially available xanthotoxin. The in vi-
tro pharmacological evaluation indicated that all of the compounds possessed potent vasodilatory activity. Among them,
compounds (5b), (5d) and (5e) exhibited higher vasdilatory activity (with EC50 values of 0.68 µM, 0.59 µM and 0.49 µM,
respectively) than imperatorin (EC50 = 1.12 µM). The program Volsurf was used to predict the derivatives’ ADME-
relevant descriptors. The results suggested that these novel compounds had a potential interest for the development of
novel and potent vasorelaxant agents.
Keywords: Imperatorin derivatives, vasodilatory activity, hypertension, vasorelaxant agents.
1. INTRODUCTION
which was also very important for the treatment of cardio-
vascular diseases. Therefore, development of potent impera-
torin derivatives would be very interesting, and may result in
new leads. This would be a good strategy for vasorelaxant
agents design.
Hypertension is the most common reversible risk factor
for cardiovascular disease and is a major risk for accelerated
atherogenesis and cardiovascular morbidity [1]. Conven-
tional therapy to treat hypertension often involves arterial
vasodilation. Recently, most interest has been focused on the
development of novel vasorelaxant agents to control blood
pressure [2].
However, some studies have demonstrated that the use of
imperatorin is limited by its poor solubility. Poor solubility is
a major problem in the biological testing of compounds,
which has made formulating the compounds a challenge for
in vivo studies of efficacy and pharmacokinetics [8]. This
notwithstanding, imperatorin remains a good lead compound
for the design of derivatives with increased activity and solu-
bility. Incorporation of a nitrogen atom in a molecule is
usually associated with the improvement of solubility. We
designed and synthesized a series of novel nitrogen-
containing imperatorin derivatives (Fig. 1) to improve the
solubility and drug-like properties. In this paper, we also
reported the evaluation of their vasorelaxant activity in iso-
lated rat mesenteric artery rings. Herein we used imperatorin
as lead compound and modified its structure to develop
novel vasorelaxant agents.
Imperatorin (IMP; 9-(3-methylbut-2-enyloxy)-7H-furo[3,
2-g]chromen-7-one) is a bioactive furanocoumarin isolated
from roots of Angelica dahurica and fruits of Angelica ar-
changelica (Umbelliferae) [3]. Furanocoumarin has been
reported to possess a wide range of biological activities. Im-
peratorin exhibits many pharmacological activities such as
anti-inflammatory and anticancer effects [4]. Moreover im-
peratorin has been reported to show antivirus, anti-HIV, anti-
fungal, antibacterial, antioxidant, β-secretase inhibitory and
hepatoprotective activities [5].
In our previous studies, we used vascular smooth mus-
cle/cell membrane chromatography (VSM/CMC) combined
with gas chromatography/mass spectrometry (GC/MS)
method for recognition, separation and identification of ac-
tive components from traditional Chinese medicines. Im-
peratorin was identified as the retention component from the
extracts in the VSM/CMC model [6]. Imperatorin was ini-
tially tested by us in vitro as a vasorelaxant agent. We found
that imperatorin could induce vasodilatation. The possible
mechanisms of the vasodilatation are mainly involved with
inhibiting voltage dependent calcium channel and receptor-
mediated Ca2+ influx and release, and might be partly due to
opening calcium-activated potassium channel and competi-
tive antagonism of 5-HT receptors [7]. Superior to traditional
vasodilators such as dihydropyridine and phenylalkylamine,
imperatorin possessed additional antiaggregatory activity,
O
O
O
O
O
O
O
O
R1
N
R2
2
1
Fig. (1). Structures of imperatorin (1) and derivatives (2).
2. CHEMISTRY
In this study, nine imperatorin derivatives have been de-
signed, synthesized and tested as vasorelaxant agents in or-
der to obtain potential antihypertensive lead compounds. All
the title compounds were synthesized from commercially
available xanthotoxin (Scheme 1 and Scheme 2). Synthesis
of xanthotoxol (4) was achieved by the demethylation of
xanthotoxin (3). Treatment with an excess of boron tribro-
mide afforded the desired phenol in good yields [9]. The
*Address correspondence to this author at the 54#, College of Medicine,
Xi’an Jiaotong University, No. 76, Yanta Weststreet, Xi’an, Shaanxi Prov-
ince, 710061, P.R. China; Tel: +86-29-82657740; Fax:+86-29-82655451;
E-mail: zhj8623@mail.xjtu.edu.cn
1573-4064/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Design, Synthesis and Preliminary Evaluation
Medicinal Chemistry, 2011, Vol. 7, No. 1 19
a
b or c
O
O
O
O
O
O
O
O
O
OMe
OH
3
4
OR
5a-5j
N
5a: R =
5b: R =
5c: R =
O
N
N
N
5e: R =
5f: R =
5d: R =
N
N
5h: R =
5g: R =
Scheme 1. Preparation of target compounds (5a-5h).
Reagents and Conditions: (a) BBr3, CH2Cl2, 0°C; (b) K2CO3, acetone, reflux; (c) K2CO3, DMF, 90°C.
HO
Cl
d
N
N
6
7
Cl
O
e
O
O
N
+
O
O
O
O
N
7
OH
4
5i
Scheme 2. Preparation of target compounds (5i).
Reagents and Conditions: (d) SOCl2, toluene, reflux; (e) K2CO3, DMF, 80°C.
synthesis of nitrogen-containing imperatorin derivatives (5c-
5h) were performed by alkylation of the xanthotoxol (4) with
chloro or bromo-substituted compounds under basic condi-
tions, affording the desired compound in good yields [10].
Another two compounds (5a, 5b) were synthesized in the
same way to research the individual contribution of the
methyl and carbon-carbon double bond of imperatorin to its
biological activity.
tively) than that of imperatorin (EC50 = 1.12 µM). In general,
all compounds showed excellent maximal relaxation compa-
rable to that of imperatorin. Compound (5e), which has the
better solubility than imperatorin, was identified as the most
potent vasodilator activity (EC50 = 0.49 µM). Comparing
(5a) (EC50 = 1.02 µM) and (5b) (EC50 = 0.68 µM) with im-
peratorin, we found that the dimethyl group and olefinc bond
in side chain was not essential for activity. Incorporation of
morpholine ring reduced the vasodilator activity. For exam-
ple, compound (5f) (EC50 = 7.59 µM) exhibited much lower
activity than other derivatives. The lesser vasorelaxant activ-
ity of (5g) (EC50 = 1.48 µM) and (5h) (EC50 = 2.95 µM) in
comparison to (5c) (EC50 = 1.15 µM) suggested that extend-
ing the length of the side chain was not favorable to activity.
Incorporation of hydrophobic benzene ring to the nitrogen
(5i) (EC50 = 1.66 µM) displayed slightly weaker vasorelaxant
activity than corresponding compound (5c) (EC50 = 1.15
µM), which indicated that hydrophobic groups was not desir-
able for activity. Data are expressed as mean values ± S.E.M.
On the basis of the structure of calcium channel blocker
nicardipine, we synthesized the other novel imperatorin de-
rivative (5i). We examined whether the incorporation of
pharmacophore of calcium channel blocker could improve
the vasorelaxation activity of target compound. Xanthotoxol
(4) also provided a good intermediate for the synthesis of
(5i) (Scheme 2). Structures of all synthesized compounds
were identified by 1H-NMR and EI-MS.
3. RESULTS AND DISCUSSION
3.1 Vasorelaxation Activity
Vasodilatory activity of imperatorin derivatives was also
evaluated. Vasodilatory activity was evaluated in mesenteric
artery rings with endothelium pre-contracted with 3 µM
phenylephrine (PE) [11]. Imperatorin was used as the posi-
tive control. All the tested compounds promoted relaxation
in a dose-dependent manner and their maximal effects was
observed at 100 µM. The vasodilatory activity of imperatorin
derivatives was shown in Table 1 and Fig. (2).
3.2. Prediction of ADME Properties by Volsurf
It is well known that a potential activity does not neces-
sarily imply an acceptable bioavailability. Therefore, the
molecular properties for adsorption, distribution, metabo-
lism, and excretion (ADME) are crucial for drug design. The
optimization of pharmacokinetic properties is still largely
based on trial and error and constitutes a major bottleneck in
lead compound optimization. The program VolSurf was used
to correlate 3D molecular structures with physicochemical
and pharmacokinetic properties. All compounds were fil-
tered by Lipinski’s rule of 5 [12], and then submitted to Vol-
Accroding to Table 1 and Fig. (2), we found that com-
pounds (5a), (5b), (5d) and (5e) exhibited stronger vasore-
laxant activity (EC50 = 1.02, 0.68, 0.59, 0.49 µM, respec-

20 Medicinal Chemistry, 2011, Vol. 7, No. 1
Li et al.
Table 1. Structures and Vasodilatory Activity of Imperatorin Derivatives
O
O
O
OR
Compound
R
n
EC50(µM)
pEC50
Emax%
Imperatorin
7
1.12
5.95 ± 0.21
99.5 ± 0.9
5a
5b
5c
7
7
7
1.02
0.68
1.15
5.99 ± 0.17
6.17± 0.28
5.94 ± 0.15
100.6 ± 0.7
100.8 ± 1.1
100.9 ± 1.2
N
5d
5e
5f
7
7
7
0.59
0.49
7.59
6.23 ± 0.17
6.31 ± 0.12
5.12 ± 0.24
102.3 ± 1.1
101.4 ± 1.1
102.6 ± 3.2
N
N
O
N
5g
5h
7
7
1.48
2.95
5.83 ± 0.18
5.53 ± 0.13
100.0 ± 1.3
100.3 ± 1.0
N
N
5i
7
7
1.66
5.78 ± 0.11
/
98.9 ± 1.5
15.9 ± 5.7
N
Control
Fig. (2). Effects of imperatorin derivatives (5a, A), (5b, B), (5d, C) (5e, D) on relaxation in mesenteric artery rings compared with IMP (n=7).

Design, Synthesis and Preliminary Evaluation
Medicinal Chemistry, 2011, Vol. 7, No. 1 21
surf in order to calculate predicted ADME properties such as
Caco-2 permeability and blood-brain barrier (BBB) distribu-
tion [13]. The ADME properties of compounds were sum-
marized in Table 2 including MW, LogP, number of H-bond
acceptors and rotatable bonds, Caco-2 and BBB calculated
values.
5. EXPERIMENTAL
5.1. Chemistry: General Procedures
All reactions except those in aqueous media were carried
out by standard techniques for the exclusion of moisture.
Solvents were purified before use according to standard pro-
cedures. All reactions were monitored by thin layer chroma-
tography on 0.25-mm silica gel plates (60GF-254) and visu-
alized with UV light. All melting points were determined on
a Beijing micro-melting point apparatus and were uncorrected.
1H-NMR spectra were recorded on a Bruker AVANCF 400
MHZ instrument in CDCl3 solution with TMS as internal
standard. Mass spectra were performed on a Shimadzu GC-
MS-QP2010 instrument.
In Caco-2 permeation experiment, Volsurf was used to
predict the behaviour of novel imperatorin derivatives. Most
of them (5b-5i) exhibited low Caco-2 cell permeability. The
polar surface areas of all the compounds were under 140 Å2,
which suggested that all of them were orally available. The
logBBB values of the most compounds were greater than 0.0
which indicated that the concentration of compounds in the
brain was greater than concentration in blood. The method
appears as a valuable new property filter in virtual screening
and as a novel tool in optimizing the pharmacokinetic profile
of pharmaceutically relevant imperatorin derivatives.
5.1.1. Preparation of Xanthoxol (4)
Xanthotoxia (3) (4.32 g, 20.00 mmol) was dissolved in
anhydrous CH2Cl2 (75 mL) and stirred under nitrogen at-
mosphere. Boron tribromide (6.88 mL in 73 mL CH2Cl2)
was added dropwise to the solution at 0℃ for 30 min. The
mixture was then allowed to stir at room temperature for
another 4 h. The reaction mixture was poured slowly into a
stirred solution of saturated aqueous sodium bicarbonate
(160 mL) and stirred for 1 h. The resulting colorless precipi-
tate was recovered by filtration. The filtrate was neutralized
with 2 M HCl to PH 7, to yield further product, which was
also recovered by filtration. Both solids were combined and
stirred in water (100 mL) for 1 h. Recovery by filtration and
drying under vacuum yield xanthoxol (4) as a white solid
(3.64 g, 90%). mp 249-251 ℃. 1H NMR (400MHz, CDCl3) δ
ppm 8.07 (d, J = 9.6 Hz, 1H), 8.04(d, J = 2.4 Hz, 1H), 7.42
(s, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.35 (d, J = 9.6 Hz, 1H));
EI-MS m/z 201.9 [M]+.
4. CONCLUSION
In summary, we have described the synthesis and evalua-
tion of a novel series of imperatorin derivatives as vasore-
laxant agents. In general, all the imperatorin derivatives
showed perfect maximal relaxation comparable to that of
imperatorin. Among the nine compounds, four of them, (5a),
(5b), (5d) and (5e) have been characterized as agents with
higher vasorelaxant effects on isolated rat mesenteric artery,
although further studies are needed to determine the mecha-
nisms underlying such activity. The most potent compound
(5e) would be a promising structural template for the devel-
opment of novel and more efficient vasorelaxant agents. The
pharmacokinetic profile of all the imperatorin derivatives
was predicted by means of Volsurf/SYBYL-X. Caco-2 cell
permeability and blood-brain barrier permeation of the com-
pounds were also predicted. Further studies on the mode of
action and pharmacology of these compounds and structure-
activity relationship around the core template will be re-
ported in due course.
5.1.2. N-benzyl-2-chloro-N-methylethanamine hydrochlo-
ride (7) [14]
2-(benzyl(methyl)amino)ethanol (6) (4.88 mL, 30 mmol)
was dissolved in anhydrous toluene (20 mL) and while stir-
Table 2. Volsurf Descriptors of Imperatorin Derivatives
Lipinski’s rule of 5
Compound
ADME predicted (Volsurf)
MW
logP(n-Oct)a
NHAb
NRBc
Caco-2d
PSAe
logBBBf
Imperatorin
270.28
272.30
242.23
273.28
313.35
327.37
315.32
287.31
301.34
349.38
3.900
3.863
2.697
2.023
3.049
3.472
1.627
2.514
2.854
3.424
4
4
4
5
5
5
6
5
5
5
3
4
3
4
4
4
4
5
5
6
1.28929
1.31802
1.16839
0.86373
0.97694
0.95962
0.93423
0.77206
0.87994
1.07284
50.87
50.87
50.87
62.28
62.28
62.28
66.64
62.28
62.28
54.11
0.429665
0.452264
0.315973
0.200474
0.332159
0.37025
5a
5b
5c
5d
5e
5f
-0.04459
0.276449
0.263576
0.199223
5g
5h
5i
f
a logP(n-Oct) = logP octanol/water; b NHA = number of H-bond Acceptors; c NRB= number of rotatable bonds; d Caco-2 = Caco-2 permeability; e PSA = polar surface areas (Å2);
logBB = log blood-brain barrier distribution.

22 Medicinal Chemistry, 2011, Vol. 7, No. 1
Li et al.
ring, so mixed with a solution of 2.84 mL (40 mmol) of
thionyl chloride in 10 mL anhydrous toluene such that the
temperature of the mixture remained between 25 and 30 ℃.
After boiling for a further 30 min, the hydrochloride was
filtered and washed with ether to give 2.64 g (12 mmol,
40%) of N-benzyl-2- chloro-N-methylethanamine hydrochlo-
ride (7) as a white solid and used in subsequent steps without
further purification.
Compounds (5d-5h) were prepared by using the general
procedure described above.
9-(2-(piperidin-1-yl)ethoxy)-7H-furo[3,2-g]chromen-7-one
(5d)
Yield: 67.0%, m.p.198-199℃; 1H-NMR(400MHz, CDCl3)
δ ppm 7.80 (d, J = 9.2Hz,1H), 7.71 (s, 1H), 7.45 (s, 1H),
6.85 (s, 1H), 6.39 (d, J = 9.4Hz, 1H), 5.01 (t, J = 9.4Hz, 2H),
3.82 (d, J = 11.6Hz, 2H), 3.06-3.14 (m,2H), 2.26-2.36
(m,2H),1.92-1.99 (m,3H), 1.52-1.71 (m,3H); EI-MS m/z
313.2 [M]+.
Compounds (5a-5i) were obtained by etherification of
compound (4) with halide in K2CO3/acetone or K2CO3/DMF
according to the approach in Reference 16.
9-(2-(azepan-1-yl)ethoxy)-7H-furo[3,2-g]chromen-7-one (5e)
5.1.3. 9-(isopentyloxy)-7H-furo[3,2-g]chromen-7-one (5a)
[15]
Yield: 66.0%, m.p.116-118℃; 1H-NMR (400MHz, CDCl3)
δ ppm 7.77 (d, J = 9.6Hz, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.36
(s, 1H), 6.82 (d, J = 2.4Hz, 1H), 6.37 (d, J = 9.6Hz, 1H),
4.59 (t, J = 5.8Hz, 2H), 3.05 (t, J = 6.2Hz, 2H), 2.76-2.78
(m, 4H),1.55-1.72 (m, 8H); EI-MS m/z 327.1 [M]+.
Anhydrous potassium carbonate (0.83 g, 6.0 mmol) was
added to a solution of xanthoxol (4) (0.40 g, 2.0 mmol) in 20
mL acetone under an atmosphere of nitrogen. After stirring
the suspension at room temperature for 30 min, (1-bromo-3-
methylbutane (0.37 mL, 3.0 mmol) was added. The reaction
mixture was stirred under reflux overnight (20 h) under ni-
trogen atmosphere. The mixture was filtered, and the filtrates
were collected and concentrated in vacuo. The oil residue
was purified by column chromatography (eluent petroleum
ether/ethyl acetate=5:1) to give the product as a white solid
(0.39 g, 72.2%). m.p.73-75℃. 1H-NMR (400MHz, CDCl3) δ
ppm 7.76 (d, J = 9.0Hz,1H), 7.69 (s,1H), 7.35 (s,1H), 6.82
(s,1H), 6.37 (d, J = 9.0Hz, 1H), 4.52 (t, J=7.5Hz, 2H), 1.91-
2.04 (m,1H), 1.80-1.74 (m, 2H), 1.0 (d, J=6.0Hz, 6H); EI-
MS m/z 272.1 [M]+.
9-(2-morpholinoethoxy)-7H-furo[3,2-g]chromen-7-one (5f)
Yield: 68.7%, m.p. 87-89℃; 1H-NMR (400MHz, CDCl3)
δ ppm 7.77 (d, J = 9.6Hz, 1H), 7.69 (d, J = 1.7Hz, 1H), 7.38
(s, 1H), 6.83 (d, J = 1.8Hz, 1H), 6.37 (d, J = 9.6Hz, 1H) ,
4.65 (s, 2H), 4.13 (t, J = 7.1Hz, 4H), 3.75 (s, 2H), 1.25 (t, J =
7.1Hz, 4H); EI-MS m/z 315.1 [M]+.
9-(3-(dimethylamino)propoxy)-7H-furo[3,2-g]chromen-7-one
(5g)
Yield: 43.9%, m.p. 188-191℃; 1H-NMR (400MHz,
CDCl3) δ ppm 7.81 (d, J = 9.6Hz, 1H), 7.72 (s, 1H), 7.45 (s,
1H), 6.85 (s, 1H), 6.39 (d, J = 9.6Hz, 1H), 4.55 (s, 2H), 3.58
(s, 2H), 2.93 (s, 6H), 2.45 (s, 2H); EI-MS m/z 287.0 [M]+.
9-(allyloxy)-7H-furo[3,2-g]chromen-7-one (5b)
This compound was prepared as described above for
(5a), starting from xanthoxol (4) (0.40 g, 2.0 mmol), anhy-
drous potassium carbonate (0.83 g, 6.0 mmol), and allyl
bromide (0.25 mL, 3.0 mmol). The crude product was puri-
fied by column chromatography (eluent petroleum
ether/ethyl acetate=3:1) to give a white solid. Yield: 93.0%,
m.p. 80-81℃. 1H-NMR (400MHz, CDCl3) δ ppm 7.77(d, J =
9.6Hz, 1H), 7.69 (d, J=1.8Hz, 1H), 7.37 (s, 1H), 6.82(d,
J=1.6Hz, 1H), 6.38(d, J=9.6Hz, 1H), 6.15-6.17 (m,1H),
5.43(d, J=17.2Hz, 1H), 5.25 (d, J = 10.4Hz, 1H), 5.03 (d,
J=5.2Hz, 2H); EI-MS m/z 242.2 [M]+.
9-(3-(dimethylamino)-2-methylpropoxy)-7H-furo[3,2-g]chro-
men-7-one (5h)
Yield: 74.2%, m.p.83-84℃; 1H-NMR (400MHz, CDCl3) δ
ppm 7.77 (d, J = 10.0Hz, 1H), 7.68 (s, 1H), 7.35 (s, 1H), 6.81
(s, 1H), 6.37 (d, J = 9.6Hz, 1H), 4.55 (m, 2H), 2.52 (m, 1H),
1.74 (m, 8H), 1.18 (d, J = 6.0Hz, 3H); EI-MS m/z 301.0 [M]+.
5.1.5. 9-(2-(benzyl(methyl)amino)ethoxy)-7H-furo[3,2-g]chro-
men-7-one (5i) [17]
Xanthoxol (4) (0.40 g, 2.0 mmol) was dissolved in anhy-
drous DMF (10 mL), and anhydrous potassium carbonate
(1.10 g, 8.0 mmol) was added. Then 0.66 g (3.0 mmol) of N-
benzyl-2-chloro-N-methylethanamine hydrochloride was
added to the mixture. The reaction mixture was stirred at
80℃for 20 h. The reaction was quenched by addition of ice
water (50 mL) and extracted with trichloromethane (6×15
mL). The dried (Na2SO4) organic layer was evaporated in
vacuo and the residue was purified by column chromatogra-
phy (eluent petroleum ether/ethyl acetate=10:1) to give a
white solid (0.50 g, 1.42 mmol). Yield: 72.1%, m.p. 119-
5.1.4. 9-(2-(dimethylamino)ethoxy)-7H-furo[3,2-g]chromen-
7-one (5c) [16]
Xanthoxol (4) (0.81 g, 4.0 mmol) was dissolved in anhy-
drous DMF (10 mL), and anhydrous potassium carbonate
(2.21 g, 16.0 mmol) was added. Then 0.86 g (6.0 mmol) of
2-chloro-N,N-dimethylethanamine hydrochloride was added
to the mixture. The reaction mixture was stirred at 90℃ for
25 h. The reaction was quenched by addition of ice water (50
mL) and extracted with trichloromethane (6×15 mL). The
dried (Na2SO4) organic layer was evaporated in vacuo and
the residue was purified by column chromatography (eluent
chloroform/methanol=10:1) to give a white solid (0.61 g,
2.20 mmol). Yield: 56.0%, m.p.77-78℃. 1H-NMR
(400MHz, CDCl3) δ ppm 7.77 (d, J = 9.6Hz, 1H), 7.69 (s,
1H), 7.37 (s, 1H), 6.82 (s, 1H), 6.37 (d, J = 10.0Hz, 1H),
4.57 (t, J = 5.4Hz, 2H), 2.84 (t, J = 5.6Hz, 2H), 2.40 (s, 6H);
EI-MS m/z 273.0 [M]+.
1
121℃; H-NMR (400MHz, CDCl3) δ ppm 7.75 (d, J = 9.5
Hz,1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.30-7.36 (m, 5H), 6.81
(s, 1H), 6.37 (d, J = 9.4 Hz, 1H), 5.55 (s, 2H), 4.11-4.13 (m,
2H), 2.05-2.06 (m, 2H), 1.61 (s, 3H); EI-MS m/z 349.5 [M]+.
5.2. Pharmacological Evaluation
Vascular rings were prepared from the mesenteric artery
of male Sprague-Dawley rats, and contraction studies were

Design, Synthesis and Preliminary Evaluation
Medicinal Chemistry, 2011, Vol. 7, No. 1 23
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performed following the general procedure detailed in the
literature [18]. After an equilibration period of 2 h, isometric
contractions induced by PE (3 µM) were obtained. When
contraction of the tissue in response to this vasoconstrictor
agent had stabilized, cumulatively increasing concentrations
of the tested compounds were added to the bath at 15-20 min
intervals. Control tissues were simultaneously subjected to
the same procedures, but omitting the compounds and add-
ing the vehicle. The imperatorins-induced maximal relaxa-
tion (Emax) in mesenteric artery rings was calculated as a
percentage of the contraction in response to PE (3 µM) [19].
All data were expressed as mean ± S.E.M. The half maxi-
mum effective concentration (EC50) was defined as the con-
centration of the imperatorins that induced 50% of maximum
relaxation from the contraction elicited by PE and was calcu-
lated from the concentration response curve by nonlinear
regression (curve fit) using GraphPad Prism.
[7]
[8]
[9]
[10]
[11]
[12]
ACKNOWLEDGEMENTS
[13]
[14]
This work was supported by the National Natural Science
Foundation (NNSF) of China (Grant Number 30730110 and
30901839). We are grateful to Prof. Zongru Guo for practi-
cal guidance during the course of the project.
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Received: September 03, 2010
Revised: November 04, 2010
Accepted: November 10, 2010