Design, synthesis and biological evaluation of new arylpiperazine derivatives bearing a flavone moiety as α1-adrenoceptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.12.080

Elaborate study on the three-dimensional model of α₁- adrenoceptor (α₁-AR) antagonists led to the development of a series of new arylpiperazine derivatives bearing a flavone nucleus as α₁-AR antagonists. The in vitro activities were evaluated and compounds 1, 4, 10, 13 and 15 showed activities close to the reference compound (Prazosin).

Full text of DOI:10.1016/j.bmcl.2010.12.080

Bioorganic & Medicinal Chemistry Letters 21 (2011) 909–911
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of new arylpiperazine
derivatives bearing a flavone moiety as a1-adrenoceptor antagonists
⇑
Jing Jin, Xiao-Bing Wang, Ling-Yi Kong
Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2010
Revised 7 December 2010
Accepted 16 December 2010
Available online 21 December 2010
Elaborate study on the three-dimensional model of
opment of a series of new arylpiperazine derivatives bearing a flavone nucleus as
in vitro activities were evaluated and compounds 1, 4, 10, 13 and 15 showed activities close to the
reference compound (Prazosin).
a
1-adrenoceptor (
a
1-AR) antagonists led to the devel-
1-AR antagonists. The
a
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
a1-Adrenoceptor antagonists
Flavone
Arylpiperazine derivatives
In recent years, the types of
a
1-adrenoceptor (
a
1-AR) antago-
terminal heterocyclic molecular portion, and the two portions are
linked at position 7 of 7-hydroxyflavone and position 1 of arylpip-
erazine moiety with polymethylene chain.
The corresponding pharmacophore of the designed compounds
could be identified as following: the N-1 atom at the arylpiperazine
corresponds to the PI, the phenyl of arylpiperazine and the flavone
moiety serve as the HY1 and HY2 portion, respectively, and the
oxygen atom from flavone as the HBA (Fig. 2).
nists are established not only by pharmacological studies but also
by binding studies. The 1-ARs belong to the super family of G pro-
tein coupled seven-transmembrane helix receptors (GPCR)1 and
are comprised of multiple subtypes including a1A a1B and a1D
which were defined in native tissues, and their corresponding
cloned counterparts a1a a1b and 1d. Great attentions had been
paid on the selective 1-adrenoceptor antagonists due to their
a
,
,
a
a
importance on the treatment of benign prostatic hyperplasia
(BPH) for more than two decades.2,3 In this study, the goal of our
research was to discover and develop new compounds with high
Furthermore, to investigate the influence of the length of poly-
methylene chain between flavone and arylpiperazine moieties on
the
characterizing by 2–4 methylene units. The pharmacophore model
suggests that the HY are necessary for
1-AR antagonist,4–6 so we
a1-AR antagonistic activities, the alkyl chain was designed
affinity for
According to the three-dimensional pharmacophore model of
1-AR antagonists,4–6 an ideal
1-AR antagonist pharmacophore
a1-AR antagonists.
a
a
a
conjectured that the intensification of the hydrophobicity in the
hydrophobic regions will increase the activities. To assess this
hypothesis, we have designed a series of compounds with an alkyl
at the HY1 portion and a halogen atom at the HY2 portion. Com-
pounds 10–18 with a chlorine atom at the 40-position of the
flavone moiety were synthesized. And also, compounds 4–9 and
13–18 which contain ortho- or para-substituted methyl group on
the phenyl ring attached to the piperazine nucleus were
consists of a positively ionizable group (PI), a polar group which
provides a hydrogen bond acceptor (HBA) feature, and hydropho-
bic regions (HY).
Many reports had shown that heterocyclic compounds contain-
ing an arylpiperazine moiety had high affinity for
a
1-ARs,7–10 and
those compounds match the pharmacophore model well. As one
of the most ubiquitous families of natural products, flavonoids pos-
sess a remarkable spectrum of biological activities.11–15 Based on
the above considerations, arylperazine derivatives bearing a fla-
vone moiety should have interesting
The flavone compounds have phenyl rings and hydroxyl groups
which can be acted as the HY and HBA of the 1-AR antagonists.
We therefore designed and synthesized a series of new arylpiper-
azine derivatives (1–18, Fig. 1) bearing a flavone moiety as the
a1-AR antagonistic activities.
R1
R2
N
a
N
O
O
n
O
⇑
Corresponding author. Tel.: +86 25 83271405; fax: +86 25 83271405.
E-mail address: cpu_lykong@126.com (L.-Y. Kong).
Figure 1. Structures of target compounds.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.080

910
J. Jin et al. / Bioorg. Med. Chem. Lett. 21 (2011) 909–911
Table 1
HBA
Chemical structures, physical data and
18
a
1-AR antagonists activities of compounds 1–
R1
R2
N
R1
R2 Mp (°C)
Yield pA2
(%)
a
Compound
n
N
O
n
O
O
1
2
3
4
5
6
7
8
9
2
3
4
2
3
4
2
3
4
2
3
4
2
3
4
2
3
4
H
H
H
p-CH3
p-CH3
p-CH3
o-CH3
o-CH3
o-CH3
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
137–140
156–158
106–109
139–142
169–172
105–107
127–131
135–138
167–171
171–175
176–179
161–163
190–194
188–191
145–149
152–154
152–158
125–128
240–242
275–278
21.2
23.1
22.7
18.4
23.7
25.5
24.1
24.6
23.6
19.7
23.4
20.9
19.4
23.5
20.6
20.1
22.7
24.7
74.9
72.8
8.526 0.126
HY1
8.177 0.210
8.333 0.137
8.647 0.098
7.684 0.073
6.709 0.128
7.383 0.105
6.930 0.210
7.710 0.079
8.579 0.081
8.072 0.112
7.914 0.087
8.930 0.108
8.088 0.145
8.498 0.064
8.207 0.156
7.772 0.143
7.471 0.189
6.609 0.201
6.845 0.177
6.897 0.117
6.925 0.136
6.409 0.095
6.168 0.169
6.538 0.155
6.368 0.114
9.112 0.082
PI
HY2
Figure 2. Target compounds superposed to the pharmacophore model for
a1-AR
10
11
12
13
14
15
16
17
18
24
25
29
30
31
32
33
34
Prazosin
antagonists.
H
H
p-CH3 Cl
p-CH3 Cl
p-CH3 Cl
o-CH3 Cl
o-CH3 Cl
o-CH3 Cl
synthesized to evaluate the influence of alkyl substituents on the
1-AR antagonistic activities.
a
The synthesis of the target compounds, as shown in Scheme 1,
is described as follows: to the solution of 19 and dry potassium
carbonate in acetone, benzoyl chloride was added slowly and re-
fluxed for 6 h. The crude product of immediate 20 was collected
by filtration and then stirred with 10% aqueous glacial acetic acid
and the intermediate 22 was obtained by filtration and rinsed with
water. The intermediate 22 was converted to 24 by treating it with
glacial acetic acid and anhydrous sodium acetate at reflux. Inter-
mediate 29 were obtained by alkylation of 24 with 1,2-dibromo-
ethane (26) in the presence of dry potassium carbonate. In turn,
the final compound 1 was prepared by reacting 29 and 35 in tolu-
ene refluxing for 48 h. The other compounds 2–18 were prepared
using the same procedure described above for compound 1.
H
Cl
H
Cl
H
Cl
H
2
2
3
3
4
4
Amorphous powder 75.5
Amorphous powder 76.3
Amorphous powder 71.6
Amorphous powder 75.2
Amorphous powder 73.3
Amorphous powder 76.9
Cl
a
Values are means standard derivation of three repeated experiments.
Compounds 1–18, were tested for their in vitro
a
1-AR antago-
eighteen compounds displayed lower potency (pA2) than that of
the control, Prazosin, and it can be noticed that the activities of
compounds 1, 4, 10, 13 and 15 are as potent as Prazosin. To illus-
trate the rationality and reliability of our molecular design, pA2
value of negative controls including flavones 24, 25 and intermedi-
ates 29–34 were also obtained (Table 1). The assay showed that
nistic properties in rat anococcygeal muscles and were assessed
by inhibition of phenylephrine-induced contraction. Antagonistic
potency of all the compounds is expressed as pA2. The pA2 value
was obtained from the linear regression of Schild plot and the val-
ues were taken from three repeated experiments (Table 1). All the
R2
R2
R2
O
O
HO
OH
O
a
R2
b
O
OH
O
O
O
O
O
O
20 R2=H
21 R2=Cl
22 R2=H
23 R2=Cl
19
R2
R2
HO
O
Br
O
O
O
c
d
n
O
24 R2=H
25 R2=Cl
29 n=2, R2=H; 30 n=2, R2=Cl
31 n=3, R2=H; 32 n=3, R2=Cl
2
2
33
34
n=4, R =H;
n=4, R =Cl
R1
R2
N
R1
e
O
O
N
O
n
N
NH
35 R1=H
36 R1=p-CH3
37 R1=o-CH3
1-18
Scheme 1. Reagents and conditions: (a) benzoyl chloride or 4-chlorobenzoyl chloride, dry K2CO3, acetone; (b) 10% glacial acetic acid solution; (c) glacial acetic acid,
anhydrous sodium acetate; (d) 26 1,2-dibromoethane, (27 1,3-dibromopropane, 28 1,4-dibromobutane), dry K2CO3, acetone; (e) 29 (30–34), toluene.

J. Jin et al. / Bioorg. Med. Chem. Lett. 21 (2011) 909–911
911
the in vitro a1-AR antagonistic activities of both the flavones 24, 25
References and notes
and the intermediates 29–34 were far lower than that of the target
compounds 1–18 and Prazosin.
In conclusion, a two carbon atoms which connects the flavone
moieties and arylpiperazine nucleus is the best polymethylene
chain for the activities for all the target compounds. With the
lengthening of the carbon chain, no remarkable variation exhibited
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1-AR antagonist than those of 1–9, so it suggested that a chlorine
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a1-AR antagonistic activity. Compounds 10–18, bearing a
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a
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onistic activity. Moreover, we found that whether the presence of
methyl group at the ortho- or para-position of the phenyl ring
attached to the piperazine or not leads to no increase on the activi-
ties, but the ortho-substituted derivatives are more potency than
that of the para-substituted derivatives. Furthermore, the target
compounds are more potency than that of negative controls includ-
ing flavones and synthetic intermediates, it demonstrates that the
arylpiperazine and polymethylene chain between flavone and aryl-
piperazine moieties are the necessary pharmacophore of the de-
signed compounds. These results were consistent with the
pharmacophore of the designed compounds and proved the reliabil-
ity of the molecular design. Further studies are under way to eluci-
date this result and to synthesize more potency a1-AR antagonists.