Design, synthesis and anti-HIV integrase evaluation of N-(5-chloro-8- hydroxy-2-styrylquinolin-7-yl)benzenesulfonamide derivatives

Article abstract of DOI:10.3390/molecules15031903

Styrylquinoline derivatives are demonstrated to be HIV-1 integrase inhibitors. On the basis of our previous CoMFA analysis of a series of styrylquinoline derivatives, N-[(2-substituted-styryl)-5-chloro-8- hydroxyquinolin-7-yl]-benzenesulfonamide derivatives were designed and synthesized,and their possible HIV IN inhibitory activity was evaluated.

Full text of DOI:10.3390/molecules15031903

Molecules 2010, 15, 1903-1917; doi:10.3390/molecules15031903
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Design, Synthesis and Anti-HIV Integrase Evaluation of N-(5-
Chloro-8-Hydroxy-2-Styrylquinolin-7-yl)Benzenesulfonamide
Derivatives
Zi-Guo Jiao, Hong-Qiu He, Cheng-Chu Zeng *, Jian-Jun Tan, Li-Ming Hu and Cun-Xin Wang *
College of Life Science & Bioengineering, Beijing University of Technology, Beijing, China;
E-Mail: jiaoziguo@emails.bjut.edu.cn (Z.-G.J.)
* Authors to whom correspondence should be addressed; E-Mails: zengcc@bjut.edu.cn (C-C.Z.);
cxwang@bjut.edu.cn (C-X.W.); Tel.: +86-10-67396211; Fax: +86-10-67392001.
Received: 21 October 2009; in revised form: 8 December 2009 / Accepted: 14 December 2009 /
Published: 16 March 2010
Abstract: Styrylquinoline derivatives are demonstrated to be HIV-1 integrase inhibitors.
On the basis of our previous CoMFA analysis of a series of styrylquinoline derivatives, N-
[(2-substituted-styryl)-5-chloro-8-hydroxyquinolin-7-yl]-benzenesulfonamide derivatives
were designed and synthesized,and their possible HIV IN inhibitory activity was evaluated.
Keywords: styrylquinoline derivatives; HIV-1 IN inhibitors; N-(styryl-8-hydroxyquinolin-
7-yl)-benzenesulfonamide derivatives
Introduction
There has been an increasing attention in the development of HIV integrase (IN) as a promising
anti-HIV target, due to the fact that HIV IN is essential in the replication of HIV-1 and there are no
similar enzymes involved in human cellular functions [1,2]. Therefore, extensive efforts have been
made, resulting in a large number of HIV IN inhibitors [3,4], among which polyhydroxylated
styrylquinolines have displayed an antiviral activity in a de novo infection assay of CEM4 cells,
thereby opening an exciting structural platform for the design of new anti-HIV drugs [5–8]. The
structure-activity-relationship of these compounds reveals that for in vitro activity a carboxyl group at
C-7, a hydroxyl group at C-8 (salicylic acid structure) in the quinoline subunit and an ancillary phenyl

Molecules 2010, 15
1904
ring are required. For example, FZ-41 in Figure 1 is one of the typical styrylquinoline-type HIV IN
inhibitors [5–8].
Figure 1. The design of N-(2-styrylquinolin-7-yl)benzenesulfonamides as potential HIV IN inhibitors.
Cl
R2
H O
R1
R3
N S
O
N
II
OH
R
(E)-N-phenyl-2-styrylquinoline-7-sulfonamides
HO
OH
OH
C
O
N
OH
FZ-41
Isoster of COOH
OCH3
Cl
Styrylquinoline HIV IN inhibitor
O
R2
S N
N
Bulky
hydrophobic group
H
O
OH
R1
III
(E)-N-(2-styrylquinolin-7-yl)benzenesulfonamides
To better understand the pharmacophore properties of styrylquinoline derivatives and to further
design potential HIV-IN inhibitors, we recently investigated 38 styrylquinoline derivatives employing
a comparative molecular field analysis (CoMFA) method [9]. The results indicated that inhibitory
activity should be increased if a bulky group was near the carboxyl group at C-7 in the quinoline ring.
Simultaneously, the presence of H-bonding donor is favorable near the C-7 atom, which might form a
stable H-bond with some protein residues.
On the basis of the above information, we decided to modify the basic scaffold of styrylquinoline-
type HIV IN inhibitors by replacing the carboxylic functionality at the C-7 position with an aromatic
sulfonamide as its bioisosteric functionality, bearing a bulky aromatic group and, meanwhile,
maintaining the feature of the H-bonding donor. In addition, to increase the acidic properties of the
C-8 phenolic OH, a chloride atom was introduced at the C-5 of the quinoline ring. Such a design
resulted in the target N-phenyl-2-styrylquinoline-7-sulfonamides II and N-(styrylquinolin-7-yl)-
benzenesulfonamides III (Figure 1). Very recently, we have reported the synthesis and HIV IN
screening of type II compounds [10]. In this work, we further describe the synthesis of type III
compounds and their inhibitory activity against HIV IN. It should be pointed out that most of the work
on the modification of styrylquinoline-type HIV IN concentrated on the modification of ancillary
phenyl ring and linker unit. To the best of our knowledge, this is the first report concerning the
replacement of salicyclic acid moiety of styrylquinoline HIV-IN inhibitors modified by sulfonamide.

Molecules 2010, 15
1905
Results and Discussion
Synthesis of N-(2-styrylquinolin-7-yl)benzenesulfonamide derivatives
The synthesis of styrylquinoline-type HIV IN is well-documented in the literature [5–8,11]. The
typical procedures are involved in the Perkin condensation of 2-methylquinoline and aromatic
aldehyde [5–8], or the Wittig reaction between triphenylphosphonium salts and various benzaldehydes
under basic conditions [11]. Obviously, the Perkin reaction process is more convenient than the Wittig
reaction. Consequently, the synthesis of designed N-(5-chloro-8-hydroxy-2-styrylquinolin-7-
yl)benzenesulfonamide derivatives was carried out as shown in Scheme 1. The starting 5-chloro-
quinolin-8-ol (2) was easily prepared from 2-amino-4-chlorophenol (1) according to the known
procedure [16]. The Perkin condensation between 2 and various aromatic aldehydes generated 5-
chloro-2-styrylquinolin-8-yl acetates 3 with pure E geometry, which were hydrolyzed in
pyridine/water to give 5-chloro-2-styrylquinolin-8-ols 4. After nitration and reduction, compounds 4
was converted to 2-styryl-7-amino-5-chloroquinolin-8-ols 6. The title styrylquinolin-7-yl-
benzenesulfonamide derivatives III were finally produced in 16-56% yield after reaction with
benzenesulfonyl chloride derivatives (Scheme 1 and Table 1).
Scheme 1. Synthesis of styrylquinolin-7-yl-benzenesulfonamide derivatives III.
Cl
Cl
Cl
R1
CHO
Ac2O, reflux
Paraldehyde/HCl
NH2
N
CH3
N
OH
OH
OAc
3a-3d
R1
2
3a: R1 = H; 3b: R1 = Br;
3c: R1 = OCH3; 3d: R1 = benzyloxy
1
Cl
Cl
HNO3
Pyridine, H2O
N
O2N
N
OH
5a-5e
R1
OH
R1
4a-4d
4a: R1 = H; 4b: R1 = Br;
4c: R1 = OCH3; 4d: R1 = benzyloxy
5a: R1 = H; 5b: R1 = Br;5c: R1 = OCH3;
5d: R1 = benzyloxy; 5e: R1 = OH
Cl
Cl
R2
SO2Cl
Na2S2O4
CH3OH, H2O
O
R2
S N
N
Pyridine, DMAP
R1
H2N
N
H
O
OH
OH
R1
6a-6d
IIIa-q
5a: R1 = H; 5b: R1 = Br;
5c: R1 = OCH3; 5d: R1 = OH
During the synthetic processes, the construction of the styryl scaffold by Perkin condensation
reaction between 2-methylquinoline derivatives and various aldehydes was one of the key steps.
According to a modified procedure [5,6], the 5-chloro-2-styrylquinolin-8-ols 4a-4d were isolated in
32–57% yield by column chromatography. It is noteworthy that the smooth Perkin condensation is

Molecules 2010, 15
1906
likely dependent on the nature of the 2-methylquinoline component. In an initial attemption to
construct the styryl scaffold, we tried to carry out Perkin conditions with 5-chloro-2-methyl-7-nitro-
quinolin-8-ol, but after refluxing in acetic anhydride for 7 days, no condensation product was detected
and only 5-chloro-2-methyl-7-nitroquinolin-8-yl acetate was isolated (Scheme 2).
Scheme 2. Reaction between 5-chloro-2-methyl-7-nitroquinolin-8-ol and aldehydes.
Cl
Cl
Cl
R1
CHO
HNO3
O2N
N
N
CH3
O2N
N
CH3
Ac2O, reflux
5a-5e
OH
R1
OH
OH
2
R1
Ac2O, reflux
CHO
Ac2O, reflux
Cl
O2N
N
CH3
OAc
Selective sulfonylation reaction was also observed to be essential for the synthesis of title products
III. In the presence of either pyridine or triethylamine, reaction of 2-styryl-7-amino-5-chloroquinolin-
8-ols 6 and sulfonyl chloride always generated a mixture of N- and O-sulfonylation products, that
proved to be hard to separate by conventional techniques. These results are quite different from the
case of o-aminophenol, which was reported to give selective N-tosylation or O-tosylation by using 1
equiv. of pyridine or triethylamine, respectively [12]. Finally, we found that utilizing DMAP as a
catalyst and pyridine as the solvent, the desired sulfonamide analogues could be synthesized
smoothly [13].
Table 1. The yields of styrylquinolin-7-yl-benzenesulfonamide derivatives III.
Cl
O
R2
S N
N
H
O
OH
R1
IIIa-q
No.
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
R1
OCH3
OCH3
OCH3
OCH3
H
R2
OCH3
CH3
Cl
H
Cl
CH3
OCH3
H
Yield
45%
42%
49%
53%
52%
51%
54%
46%
56%
No.
IIIj
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
IIIq
R1
Br
Br
Br
Br
OH
OH
OH
OH
R2
OCH3
CH3
H
Yield
25%
51%
38%
35%
33%
31%
25%
16%
Cl
OCH3
CH3
H
H
H
H
H
Cl
NO2

Molecules 2010, 15
1907
The structures of styrylquinolin-7-yl-benzenesulfonamide derivatives III were confirmed by
1H-NMR, 13C-NMR, IR, and ESI-MS. Taking compound IIIa as an example, in its 1H-NMR spectrum,
there are two AA’BB’ systems coupling in the range of 7.02 and 8.23 ppm, attributed to the proton
signals of two benzene rings. The ethenyl linker shows two signals at 7.29 and 8.23 ppm (AB system)
with a coupling constant of 16.0 Hz. This observation indicates that the styrylquinoline scaffold is in a
trans configuration. In addition, the signals of three protons in quinoline ring (C-3, C-4 and C-6)
exhibited a couple of doublets and a singlet at slightly low field at 7.75 (doublet), 8.34 (doublet) and
7.56 (singlet) ppm, respectively. The structure of IIIa (as well as for all compounds) was also
characterized by ESI-MS. Strong peaks at 496.8 and 518.8 were recorded, which correspond to
[M+H]+ and [M+Na]+.
HIV IN inhibitory activity
All title compounds IIIa-q were preliminarily tested against purified HIV IN to determine any
inhibitory activity possessed on the strand transfer reaction of IN. Using the high-throughput format
assay approach developed by us [14], the inhibition percentages of styrylquinolin-7-yl-
benzenesulfonamide derivatives IIIa-q were calculated based on the positive (baicalein) and negative
(10% DMSO) controls and are listed in Table 2. For comparison, the IC50 data of baicalein and FZ-41
were also included.
As shown in Table 2, compounds IIIn-IIIq, in which a free para-hydroxy group is present,
showed higher inhibitory activity than that of the positive control, whereas, when the hydroxyl group
was replaced by an electron-donating group (such as methoxy, compounds IIIa-IIId), hydrogen (IIIe-
IIIi), or an electron-withdrawing group (such as bromide, compounds IIIj-IIIm), only a moderate
inhibitory rate was observed. This observation means that the free hydroxyl moiety of styrylquinolin-
7-yl-benzenesulfonamide derivatives is required for the inhibitory activity against HIV-IN. In addition,
it was observed that the electron-withdrawing group at the para-position of benzenesulfonamide, such
as nitro, may favor the inhibitory activity. For example, compound IIIi exhibits 96.7% inhibitory rate
which decreases to 82.0% and 72.9% when the nitro was replaced by methyl (IIIf) and methoxy
groups (IIIg), respectively. This results is not surprising because the electron-withdrawing group at the
para-position of benzenesulfonamide moiety will increase the acidity of the benzenesulfonamide and
lead to easier chelating with co-enzyme (mostly metallic ions), which is essential for the HIV IN
inhibitory activity [15].
Table 2. Inhibitory rate of synthesized styrylquinolin-7-yl-benzenesulfonamide derivatives III.
Inhibitory rate %
(0.05 mmol/L)
100
Inhibitory rate %
(0.05 mmol/L)
0
Compound
Compound
Baicalein (positive
Negative control (10%
control)
FZ41
IIIa
IIIb
IIIc
(IC50 = 1.06 μM)a
(IC50 = 0.7 μM)b
11.8
DMSO)
IIIi
IIIj
IIIk
IIIl
96.7
53.6
59.5
74.7
67.8
54.6
58.2
60.3
IIId
IIIm

Molecules 2010, 15
1908
Table 2. Cont.
IIIe
IIIf
IIIg
IIIh
82.7
82.0
72.9
95.9
IIIn
IIIo
IIIp
IIIq
101.0
100.6
101.4
101.4
a Value of IC50 cited from reference [14]; b Value of IC50 cited from reference [6].
Experimental
General
All solvents were of commercial quality and were dried and purified by conventional methods.
Melting points (mp) were determined on an XT4A Electrothermal apparatus equipped with a
microscope and are uncorrected. Infrared spectra (IR) were recorded as thin films on KBr plates with a
1
Bruker IR spectrophotometer and are expressed in v (cm-1). The H- and 13C-NMR spectra were
obtained using an AV 400M Bruker spectrometer in CDCl3 or DMSO-d6 with TMS as internal
reference. The MS spectra (ESI) were recorded on a Bruker Esquire 6000 mass spectrometer.
General procedure for the Synthesis of (E)-5-Chloro-2-styryl-substituted Quinolin-8-ol Derivatives 4
A mixture of 5-chloro-2-methylquinolin-8-ol (2, 20 mmol) [16] and the appropriate benzaldehydes
(60 mmol) in acetic anhydride (50 mL) was heated under reflux for 48 hrs and concentrated in vacuo.
The black residue that formed was dissolved in a mixed solution of pyridine (40 mL) and water
(10 mL), and the resulting solution was subjected to reflux for 3 hrs. After removal of pyridine, the
formed solid was dissolved in CH2Cl2, washed three times by water, and dried over MgSO4. The
solvent was removed under rotary evaporation. The desired compounds 4 were finally isolated by
column chromatograph eluted using a mixture of petroleum ether and ethyl acetate.
1
(E)-5-Chloro-2-styrylquinolin-8-ol (4a): Yield: 50%; mp: 146–147 oC; H-NMR (400 MHz, CDCl3) δ
7.08 (d, 1H, J = 8.0 Hz, Ar-H), 7.33 (d, 1H, J = 16 Hz, -CH=CH-), 7.36 (t, 1H, J = 8.0 Hz, Ar-H),
7.43 (t, 2H, J = 8.0 Hz, Ar-H), 7.44 (d, 1H, J = 8.0 Hz, Ar-H), 7.64 (d, 2H, J = 7.2 Hz, Ar-H), 7.72 (d,
1H, J = 8.8 Hz, pyridine-H), 7.74 (d, 1H, J = 16.4 Hz, -CH=CH-), 8.44 (d, 1H, J = 8.8 Hz, pyridine-
H); 13C-NMR (100 MHz, CDCl3) δ 110.3, 120.4, 121.0, 125.2, 126.9, 127.3, 127.4, 128.9, 129.1,
133.8, 135.4, 136.1, 151.1, 154.1; IR (KBr): ν 3,382, 3,022, 1,628, 1,500, 1,451, 1,251, 1,198 cm-1;
ESI-MS: m/z 281.8 (M+H)+, 303.8 (M+Na)+.
1
(E)-2-(4-Bromostyryl)-5-chloroquinolin-8-ol (4b): Yield: 57%; mp: 195–196 oC; H-NMR (400 MHz,
CDCl3) δ 7.08 (d, 1H, J = 8.0 Hz, Ar-H), 7.30 (d, 1H, J = 16 Hz, -CH=CH-), 7.44 (d, 1H, J = 8.4 Hz,
Ar-H), 7.48 (d, 2H, J = 8.4 Hz, Ar-H), 7.54 (d, 2H, J = 8.8 Hz, Ar-H), 7.65 (d, 1H,
J = 16.4 Hz, -CH=CH-), 7.68 (d, 1H, J = 8.8 Hz, pyridine-H), 8.23 (s br, 1H, OH), 8.44 (d, 1H,
J = 8.8 Hz, pyridine-H); IR (KBr): ν 3,434, 1,638, 1,586, 1,557, 1,497, 1,458, 1,392, 1,312, 1,172 cm-
1; ESI-MS: m/z 359.6 (M+H)+, 357.6 (M--H).

Molecules 2010, 15
1909
(E)-2-(4-Methoxystyryl)-5-chloroquinolin-8-ol (4c): Yield: 57%; mp: 195–196 oC; 1H-NMR
(400 MHz, CDCl3) δ 3.86 (s, 3H, OCH3), 6.94 (dt, 2H, J = 8.8 Hz, J = 2.0 Hz, Ar-H), 7.06 (d, 1H,
J = 8.0 Hz, Ar-H), 7.20 (d, 1H, J = 16 Hz, -CH=CH-), 7.41 (d, 1H, J = 8.4 Hz, Ar-H), 7.57 (dt, 2H, J
= 8.4 Hz, J = 2.0 Hz, Ar-H), 7.68 (d, 1H, J = 8.8 Hz, pyridine-H), 7.68 (d, 1H, J = 17.6 Hz, -CH=CH-
), 8.41 (d, 1H, J = 8.8 Hz, pyridine-H); 13C-NMR (100 MHz, CDCl3) δ 55.4, 110.4, 114.4, 120.4,
121.0, 125.0, 125.3, 126.6, 128.8, 128.9, 133.5, 135.0, 138.4, 151.1, 154.6, 160.5; IR (KBr): ν 3,411,
3,031, 2,934, 2,841, 1,603, 1,513, 1,460, 1,152 cm-1; ESI-MS: m/z 312.0 (M+H)+ , 309.7 (M--H).
(E)-2-(4-Benzyloxystyryl-5-chloroquinolin-8-ol (4d): Yield: 32%;mp: 168–170 oC; 1H-NMR
(400 MHz, CDCl3) δ 5.12 (s, 2H, -CH2), 7.02 (d, 2H, J = 8.4 Hz, Ar-H), 7.07 (d, 1H, J = 8.4 Hz, Ar-
H), 7.21 (d, 1H, J = 16.4 Hz, -CH=CH-), 7.36 (tt, 1H, J = 7.2 Hz, J = 2.4 Hz, Ar-H), 7.39-7.47 (m,
5H, Ar-H), 7.58 (d, 2H, J = 8.8 Hz, Ar-H), 7.69 (d, 1H, J = 8.8 Hz, pyridine-H), 7.70 (d, 1H, J = 15.6
Hz, -CH=CH-), 8.45 (d, 1H, J = 8.8 Hz, pyridine-H); IR (KBr): ν 3,370, 1,622, 1,601,1,508, 1,456,
1,307, 1,237, 1,169 cm-1; ESI-MS: m/z 387.9 (M+H)+ 385.7 (M--H).
General Procedure for the Synthesis of (E)-5-Chloro-7-nitro-2-styryl-substituted Quinolin-8-ol
Derivatives 5a-d
To a three-necked flask (250 mL) charged with a mixed solution of nitric acid (50 mL, 65–68%)
and water (50 mL) and cooled by ice-water bath was added the appropriate 2-styryl substituted
quinolin-8-ol 4a-d (10 mmol). The reaction solution was stirred for 12 hrs under ice-water cooling and
then 24 hrs at room temperature. After addition of water (100 mL), precipitate formed which was
filtered, washed by water for three times and dried to generate the desired 7-nitro-2-styrylquinolin-8-
ols 5a-d.
o
1
(E)-5-Chloro-7-nitro-2-styrylquinolin-8-ol (5a): Yield: 90%; mp: 170–172 C; H-NMR (400 MHz,
DMSO-d6) δ 7.40 (t, 1H, J = 7.2 Hz, Ar-H), 7.48 (t, 2H, J = 7.2 Hz, Ar-H), 7.55 (d, 1H, J = 16 Hz,
-CH=CH-), 7.73 (d, 2H, J = 7.6 Hz, Ar-H), 8.09 (d, 1H, J = 8.8 Hz, pyridine-H), 8.13 (s, 1H, Ar-H),
13
8.35 (d, 1H, J = 16 Hz, -CH=CH-), 8.53 (d, 1H, J = 8.8 Hz, pyridine-H), 11.66 (s, br, 1H, OH); C-
NMR (100 MHz, DMSO-d6) δ 119.2, 121.2, 125.5, 126.7, 127.6, 128.0, 129.4, 129.7, 132.7, 134.1,
136.5, 137.7, 140.1, 150.0, 156.3; IR (KBr): ν 3,435, 1,568, 1,511, 1,328, 1,301, 1,252 cm-1; ESI-MS:
m/z 324.5 (M--H).
o
(E)-2-(4-Bromostyryl)-5-chloro-7-nitroquinolin-8-ol (5b): Yield: 89%; mp: 215–217 C；1H-NMR
(400 MHz, DMSO-d6) δ 7.58 (d, 1H, J = 16.4 Hz, -CH=CH-), 7.67 (s, 4H, Ar-H), 8.07 (d, 1H, J = 8.4
Hz, pyridine-H), 8.13 (s, 1H, Ar-H), 8.32 (d, 1H, J = 16.4 Hz, -CH=CH-), 8.54 (d, 1H, J = 8.4 Hz,
pyridine-H), 11.66 (s, br, 1H, OH); 13C-NMR (100 MHz, DMSO-d6) δ 119.3, 121.3, 122.8, 125.6,
127.5, 127.6, 129.8, 132.4, 132.7, 134.2, 135.8, 136.3, 140.2, 150.0, 156.0; IR (KBr): ν 3,436, 1,631,
1,566, 1,518, 1,394, 1,344 cm-1; ESI-MS: m/z 404.5 (M--H).
o
(E)-2-(4-Methoxystyryl)-5-chloro-7-nitroquinolin-8-ol (5c): Yield: 85%; mp: 154–156 C；1H-NMR
(400 MHz, DMSO-d6) δ 3.83 (s, 3H, OCH3), 7.04 (d, 2H, J = 8.4 Hz, Ar-H), 7.40 (d, 1H, J = 16 Hz,

Molecules 2010, 15
1910
-CH=CH-), 7.68 (d, 2H, J = 8.0 Hz, Ar-H), 8.05 (d, 1H, J = 8.4 Hz, pyridine-H), 8.11 (s, 1H, Ar-H),
8.29 (d, 1H, J = 16 Hz, -CH=CH-), 8.50 (d, 1H, J = 8.4 Hz, pyridine-H), 11.48 (s, br, 1H, OH); IR
(KBr): ν 3,436, 2,968, 1,595, 1,567, 1,514, 1,380, 1,256 cm-1; ESI-MS: m/z 354.7 (M--H).
o
1
(E)-2-(4-Benzyloxystyryl)-5-chloro-7-nitroquinolin-8-ol (5d): Yield: 94%; mp: 207–208 C; H-NMR
(400 MHz, DMSO-d6) δ 5.18 (s, 2H, -CH2-), 7.13 (d, 2H, J = 8.8 Hz, Ar-H), 7.36 (t, 1H, J = 8.8 Hz,
Ar-H), 7.42 (t, 2H, J = 7.2 Hz, Ar-H), 7.42 (d, 1H, J = 15.2 Hz, -CH=CH-), 7.48 (d, 2H, J = 6.8 Hz,
Ar-H), 7.69 (d, 2H, J = 8.4 Hz, Ar-H), 8.05 (d, 1H, J = 8.8 Hz, pyridine-H), 8.11 (s, 1H, Ar-H), 8.30
(d, 1H, J = 16 Hz, -CH=CH-), 8.51 (d, 1H, J = 8.8 Hz, pyridine-H), 11.66 (s, br, 1H, OH); IR (KBr): ν
3,433, 1,566, 1,513, 1,385, 1,330, 1,237, 1,176 cm-1; ESI-MS: m/z 430.8 (M--H).
(E)-2-(4-Hydroxystyryl)-5-chloro-7-nitroquinolin-8-ol (5e): To a 1:1 mixture of HCl and acetic acid
(30 mL) in a round-bottle flask (100 mL) was added 5d (5 mmol). The mixture was heated under
reflux for 3 hrs till the completion of the reaction. After removal of solvent under reduced pressure, the
1
yellow powder was washed with water to give compound 5e. H-NMR (400 MHz, DMSO-d6) δ 6.85
(d, 2H, J = 8.8 Hz, Ar-H), 7.22 (d, 1H, J = 16 Hz, -CH=CH-), 7.53 (d, 2H, J = 8.4 Hz, Ar-H), 7.70 (d,
1H, J = 16.4 Hz, -CH=CH-), 7.82 (d, 1H, J = 8.4 Hz, pyridine-H), 7.96 (s, 1H, Ar-H), 8.13 (d, 1H,
J = 8.4 Hz, pyridine-H), 9.81 (s, br, 1H, OH); 13C-NMR (100 MHz, DMSO-d6) δ 109.0, 116.3, 122.8,
123.7, 125.3, 127.8, 128.6, 129.1, 131.1, 132.8, 134.2, 148.4, 153.8, 158.8, 164.2; IR (KBr): ν 3,436,
2,979, 2,681, 1,635, 1,604, 1,555, 1,515, 1,466, 1,278, 1,247, 1,170 cm-1; ESI-MS: m/z 340.7 (M--H).
General Procedure for the Synthesis of (E)-7-Amino-5-chloro-2-styryl-substituted Quinolin-8-ol
Derivatives 6a-d
To a suspension of (E)-5-chloro-7-nitro-2-styryl substituted quinolin-8-ol 5a-d (5 mmol) in
methanol (50 mL) and water (50 mL) was added 40 equivalents of sodium dithionite. The reaction
mixture was stirred for 24 hrs at room temperature and then quenched by adding water (100 mL). The
formed precipitate was filtered, washed and dried to get desired (E)-7-amino-5-chloro-2-styryl
substituted quinolin-8-ol derivatives 6a-d.
o
(E)-7-Amino-5-chloro-2-styrylquinolin-8-ol (6a): Yield: 86%; mp: 193–195 C；1H-NMR (400 MHz,
DMSO-d6) δ 5.38 (s, br, 2H, NH2), 7.23 (s, 1H, Ar-H), 7.36 (t, 1H, J = 7.2 Hz, Ar-H), 7.44 (d, 1H,
J = 16 Hz, -CH=CH-), 7.46 (t, 2H, J = 7.2 Hz, Ar-H), 7.54 (d, 1H, J = 8.8 Hz, pPyridine-H), 7.72 (d,
2H, J = 7.2 Hz, Ar-H), 8.15 (d, 1H, J = 16.4 Hz, -CH=CH-), 8.22 (d, 1H, J = 8.8 Hz, pyridine-H),
9.03 (s, br, 1H, OH); IR (KBr): ν 3,436, 1,634, 1,508, 1,465, 1,290, 1,193 cm-1; ESI-MS: m/z 286.9
(M+H)+, 294.5 (M--H) -.
o
1
(E)-2-(4-Bromostyryl)-7-amino-5-chloroquinolin-8-ol (6b): Yield: 94%;mp: 201–202 C; H-NMR
(400 MHz, DMSO-d6) δ 7.59 (d, 1H, J = 16 Hz, -CH=CH-), 7.66 (s, 1H, OH), 7.68 (s, 4H, Ar-H), 8.08
(d, 1H, J = 8.8 Hz, pyridine-H), 8.15 (s, 1H, Ar-H), 8.34 (d, 1H, J = 16.4 Hz, -CH=CH-), 8.56 (d, 1H,
J = 8.8 Hz, pyridine-H); IR (KBr): ν 3,432, 3,080, 1,628, 1,566, 1,516, 1,342, 1,180 cm-1; ESI-MS:
m/z 376.8 (M+H)+.

Molecules 2010, 15
1911
(E)-2-(4-Methoxystyryl)-7-amino-5-chloroquinolin-8-ol (6c): Yield: 60%; mp: 154–156 oC；1H-NMR
(400 MHz, DMSO-d6) δ 3.81 (s, 3H, OCH3), 5.42 (s br, 2H, NH2), 7.02 (d, 2H, J = 8.4 Hz, Ar-H),
7.21 (s, 1H, Ar-H), 7.29 (d, 1H, J = 16.4 Hz, -CH=CH-), 7.49 (d, 1H, J = 8.4 Hz, pyridine-H), 7.66 (d,
2H, J = 8.4 Hz, Ar-H), 8.08 (d, 1H, J = 16 Hz, -CH=CH-), 8.19 (d, 1H, J = 8.8 Hz, pyridine-H), 8.99
(s, br, 1H, OH); IR (KBr): ν 3,450, 3,376, 3,338, 1,606, 1,513, 1,305, 1,176 cm-1; ESI-MS: m/z 326.9
(M+H)+ 324.8 (M--H).
o
1
(E)-2-(4-Hydroxystyryl)-7-amino-5-chloroquinolin-8-ol (6d): Yield: 30%；mp:＞300 C; H-NMR
(400 MHz, DMSO-d6) δ 5.75 (s, br, 2H, NH2), 6.85 (d, 2H, J = 8.4 Hz, Ar-H), 7.22 (s, 1H, Ar-H), 7.30
(d, 1H, J = 16 Hz, -CH=CH-), 7.54 (d, 1H, J = 8.4 Hz, pyridine-H), 7.55 (d, 2H, J = 8.4 Hz, Ar-H),
8.03 (d, 1H, J = 16 Hz, -CH=CH-), 8.23 (d, 1H, J = 8.4 Hz, pyridine-H), 9.11 (s, br, 1H, OH), 9.88 (s,
1H, OH); IR (KBr): ν 3,413, 3,369, 1,621, 1,514, 1,279, 1,171 cm-1; ESI-MS: m/z 312.9 (M+H)+,
310.7 (M--H)-.
General Procedure for the Synthesis of (E)-N-(2-substituted-styryl)-5-chloro-8-hydroxyquinolin-7-yl)-
benzenesulfonamides III
To a flask (50 mL) charged with the appropriate compound 6 (0.5 mmol) and DMAP (0.05 mmol)
dissolved in pyridine (10 mL) was added dropwise benzenesulfonic chloride (0.55 mmol) in pyridine
(5 mL). After addition, the reaction mixture was stirred for 2 hrs at room temperature and then the
solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and
washed with water, dried by MgSO4. The desired product III was obtained after column
chromatograph and then recrystallization using petroleum ether and ethyl acetate.
(E)-N-(2-(4-Methoxystyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-methoxybenzenesulfonamide (IIIa):
o
1
Yield: 44%; mp: 192–193 C; H-NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 7.02 (d, 2H, J = 8.8 Hz, Ar-H), 7.02 (d, 2H, J = 8.8 Hz, Ar-H), 7.29 (d, 1H, J = 16 Hz, -
CH=CH-), 7.56 (s, 1H, Ar-H), 7.64 (d, 2H, J = 8.8 Hz, Ar-H), 7.72 (d, 2H, J = 8.8 Hz, Ar-H), 7.75 (d,
1H, J = 8.8 Hz, pyridine-H), 8.23 (d, 1H, J = 16 Hz, -CH=CH-), 8.34 (d, 1H, J = 8.8 Hz, pyridine-H),
13
9.91 (s, br, 2H, OH, NH); C-NMR (100 MHz, DMSO-d6) δ 55.7, 56.0, 114.7, 114.9, 118.6, 121.2,
122.8, 124.3, 124.9, 129.3, 129.3, 129.3, 129.4, 132.6, 133.4, 136.3, 138.9, 145.4, 155.4, 160.5, 162.8;
IR (KBr): ν 3,420, 3,293, 2,930, 1,620, 1,593, 1,512, 1,258, 1,158 cm-1; ESI-MS: m/z 494.7 (M--1),
496.8 (M++1), 518.8 (M++Na).
(E)-N-(2-(4-Methoxystyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-methylbenzenesulfonamide
(IIIb):
o
1
Yield: 42%; mp: 202–204 C; H-NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H, CH3), 3.81 (s, 3H,
OCH3), 7.02 (d, 2H, J = 8.8 Hz, Ar-H), 7.29 (d, 1H, J = 16 Hz, -CH=CH-), 7.31 (d, 2H, J = 8.0 Hz,
Ar-H), 7.57 (s, 1H, Ar-H), 7.64 (d, 2H, J = 8.4 Hz, Ar-H), 7.69 (d, 2H, J = 8.0 Hz, Ar-H), 7.75 (d, 1H,
J = 8.8 Hz, pyridine-H), 8.24 (d, 1H, J = 16 Hz, -CH=CH-), 8.34 (d, 1H, J = 8.4 Hz, pyridine-H), 9.90
13
(s, br, 1H, OH), 10.01 (s, br, 1H, NH); C-NMR (100 MHz, DMSO-d6) δ 21.4, 55.7, 114.9, 118.6,
121.1, 122.4, 122.8, 124.3, 124.9, 127.1, 129.3, 129.4, 130.0, 133.3, 136.3, 138.2, 138.9, 143.5, 145.4,

Molecules 2010, 15
1912
155.4, 160.5; IR (KBr): ν 3,448, 3,290, 1,634, 1,589, 1,513, 1,461, 1,249, 1,158 cm-1; ESI-MS: m/z
478.8 (M--1), 480.8 (M++1), 502.8 (M++Na).
(E)-N-(2-(4-Methoxystyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-chlorobenzenesulfonamide
(IIIc):
o
1
Yield: 49%; mp: 219–221 C; H-NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H, OCH3), 7.02 (d, 2H,
J = 8.8 Hz, Ar-H), 7.30 (d, 1H, J = 16.4 Hz, -CH=CH-), 7.54 (s, 1H, Ar-H), 7.60 (d, 2H, J = 8.8Hz,
Ar-H), 7.64 (d, 2H, J = 8.8 Hz, Ar-H), 7.78 (d, 2H, J = 8.8 Hz, Ar-H), 7.78 (d, 1H, J = 8.8 Hz,
pyridine-H), 8.23 (d, 1H, J = 16 Hz, -CH=CH-), 8.36 (d, 1H, J = 8.8 Hz, pyridine-H), 9.90 (s br, 1H,
OH), 10.23 (s br, 1H, NH); 13C-NMR (100 MHz, DMSO-d6) δ 55.7, 114.9, 118.7, 120.4, 122.5, 123.2,
124.9, 125.2, 129.0, 129.3, 129.4, 129.7, 133.4, 136.4, 138.1, 139.0, 140.0, 146.2, 155.5, 160.5; IR
(KBr): ν 3,291, 1,632, 1,589, 1,512, 1,464, 1,327, 1,259, 1,161 cm-1; ESI-MS: m/z 499.7 (M--1),
500.8 (M++1).
(E)-N-(2-(4-Methoxystyryl)-5-chloro-8-hydroxyquinolin-7-yl)benzenesulfonamide (IIId): Yield: 53%;
mp: 237–238 oC；1H-NMR (400 MHz, DMSO-d6) δ 3.80 (s, 3H, OCH3), 7.00 (d, 2H, J = 8.8 Hz, Ar-
H), 7.27 (d, 1H, J = 16 Hz, -CH=CH-), 7.51 (t, 2H, J = 7.2 Hz, Ar-H), 7.55 (s, 1H, Ar-H), 7.57 (t, 1H,
J = 7.2 Hz, Ar-H), 7.62 (d, 2H, J = 8.8 Hz, Ar-H), 7.73 (d, 1H, J = 8.8 Hz, pyridine-H), 7.81 (d, 2H,
J = 8.8 Hz, Ar-H), 8.22 (d, 1H, J = 16 Hz, -CH=CH-), 8.31 (d, 1H, J = 8.8 Hz, pyridine-H), 10.10 (s,
13
br, 2H, OH, NH); C-NMR (100 MHz, DMSO-d6) δ 55.7, 114.8, 118.7, 120.9, 122.3, 122.9, 124.5,
124.9, 127.0, 129.3, 129.4, 129.5, 133.2, 133.3, 136.3, 138.9, 141.0, 145.7, 155.5, 160.5; IR (KBr): ν
3,371, 3,241, 1,627, 1,513, 1,455, 1,329, 1,249, 1,172 cm-1; ESI-MS: m/z 464.8 (M—1), 466.8 (M++1),
488.8 (M++Na); Anal. Calcd for C24H19ClN2O4S: C 61.73, H 4.10, N 6.00; found C 61.48, H 3.98, N
6.00 .
(E)-N-(5-Chloro-8-hydroxy-2-styrylquinolin-7-yl)-4-chlorobenzenesulfonamide (IIIe): Yield: 52%;
mp: 159–160 oC; 1H-NMR (400 MHz, DMSO-d6) δ 7.36 (t, 1H, J = 7.2 Hz, Ar-H), 7.45 (t, 2H, J = 7.2
Hz, Ar-H), 7.45 (t, 1H, J = 16 Hz, -CH=CH-), 7.56 (s, 1H, Ar-H), 7.59 (d, 2H, J = 7.2Hz, Ar-H), 7.69
(d, 2H, J = 7.6 Hz, Ar-H), 7.78 (d, 2H, J = 7.2Hz, Ar-H), 7.82 (d, 1H, J = 8.8 Hz, pyridine-H), 8.28
(d, 1H, J = 16.4 Hz, -CH=CH-), 8.38 (d, 1H, J = 8.8 Hz, pyridine-H), 10.00 (s, br, 1H, OH), 10.26 (s,
br, 1H, NH); 13C-NMR (100 MHz, DMSO-d6) δ 118.7, 120.5, 122.7, 123.4, 125.5, 127.3, 127.8, 129.0,
129.4, 129.7, 133.5, 136.6, 136.7, 138.1, 139.0, 140.0, 146.3, 155.1; IR (KBr): ν 3,430, 3,299, 1,633,
1,587, 1,465, 1,328, 1,094 cm-1; ESI-MS: m/z 468.8 (M--1), 470.8 (M++1).
(E)-N-(5-Chloro-8-hydroxy-2-styrylquinolin-7-yl)-4-methylbenzenesulfonamide (IIIf): Yield: 51%;
mp: 186–188 oC; 1H-NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H, CH3), 7.31 (d, 2H, J = 8.0 Hz, Ar-H),
7.37 (t, 1H, J = 7.2 Hz, Ar-H), 7.45 (t, 2H, J = 7.2 Hz, Ar-H), 7.45 (d, 1H, J = 15.6 Hz, -CH=CH-),
7.59 (s, 1H, Ar-H), 7.68 (d, 2H, J = 8.2 Hz, Ar-H), 7.69 (d, 2H, J = 7.2 Hz, Ar-H), 7.79 (d, 1H,
J = 8.8 Hz, pyridine-H), 8.30 (d, 1H, J = 16 Hz, -CH=CH-), 8.38 (d, 1H, J = 8.4 Hz, pyridine-H),
10.03 (s, br, 2H, OH, NH); 13C-NMR (100 MHz, DMSO-d6) δ 21.4, 118.6, 121.1, 122.6, 123.0, 124.6,
127.1, 127.3, 127.8, 129.4, 130.0, 133.5, 136.5, 136.7, 138.2, 138.9, 143.5, 145.6, 155.0; IR (KBr): ν
3,437, 3,295, 1,633, 1,592, 1,462, 1,322, 1,158, 1089 cm-1; ESI-MS: m/z 448.7 (M--1), 450.9 (M++1).

Molecules 2010, 15
1913
(E)-N-(5-Chloro-8-hydroxy-2-styrylquinolin-7-yl)-4-methoxybenzenesulfonamide (IIIg): Yield: 54%;
1
mp: 193–195 oC; H-NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H, OCH3), 7.03 (d, 2H, J = 8.8 Hz, Ar-
H), 7.37 (t, 1H, J = 7.2 Hz, Ar-H), 7.45 (t, 2H, J = 8.0 Hz, Ar-H), 7.45 (d, 1H, J = 16 Hz, -CH=CH-),
7.58 (s, 1H, Ar-H), 7.69 (d, 2H, J = 7.6 Hz, Ar-H), 7.72 (d, 2H, J = 8.8 Hz, Ar-H), 7.80 (d, 1H,
J = 8.8 Hz, pyridine-H), 8.29 (d, 1H, J = 16 Hz, -CH=CH-), 8.38 (d, 1H, J = 8.4Hz, pyridine-H), 9.92
(s, br, 2H, OH, NH); 13C-NMR (100 MHz, DMSO-d6) δ 56.0, 114.7, 118.6, 121.3, 122.5, 123.0, 124.6,
127.3, 127.8, 129.3, 129.38, 132.6, 133.5, 136.5, 136.8, 138.9, 145.5, 155.0, 162.8; IR (KBr): ν 3,376,
3,236, 1,627, 1,595, 1,499, 1,459, 1,262, 1,155, 1,092 cm-1; ESI-MS: m/z 464.7 (M--1), 466.9 (M++1),
488.9 (M++Na); Anal. Calcd for C24H19ClN2O4S: C 61.73, H 4.10, N 6.00; found C 61.67, H 4.14,
N 6.02 .
(E)-N-(5-Chloro-8-hydroxy-2-styrylquinolin-7-yl)benzenesulfonamide (IIIh): Yield: 46%; mp:
200–201 oC; 1H-NMR (400 MHz, DMSO-d6) δ 7.37 (t, 1H, J = 7.2 Hz, Ar-H), 7.45 (d, 1H, J = 16 Hz
-CH=CH-), 7.45 (t, 2H, J = 7.6 Hz, Ar-H), 7.52 (t, 2H, J = 7.2 Hz, Ar-H), 7.57 (s, 1H, Ar-H), 7.60 (t,
1H, J = 7.2 Hz, Ar-H), 7.70 (d, 2H, J = 7.2 Hz, Ar-H), 7.81 (d, 2H, J = 7.2 Hz, Ar-H), 7.81 (d, 1H,
J = 8.8 Hz, pyridine-H), 8.29 (d, 1H, J = 16 Hz, -CH=CH-), 8.38 (d, 1H, J = 8.8 Hz, pyridine-H), 9.98
(s, br, 1H, OH), 10.08 (s, br, 1H, NH); 13C-NMR (100 MHz, DMSO-d6) δ 118.7, 121.0, 122.5, 123.1,
124.8, 127.0, 127.3, 127.8, 129.4, 129.6, 133.3, 133.5, 136.5, 136.7, 138.9, 141.0, 145.8, 155.1; IR
(KBr): ν 3,304, 1,633, 1,589, 1,506, 1,314, 1,160, 1,090 cm-1; ESI-MS: m/z 434.7 (M--1), 436.9
(M++1).
(E)-N-(5-Chloro-8-hydroxy-2-styrylquinolin-7-yl)-4-nitrobenzenesulfonamide (IIIi): Yield: 56%; mp:
247–249 oC; 1H-NMR (400 MHz, DMSO-d6) δ 7.36 (t, 1H, J = 7.2 Hz, Ar-H), 7.45 (t, 2H, J = 8.0 Hz,
Ar-H), 7.45 (d, 1H, J = 16 Hz, -CH=CH-), 7.58 (s, 1H, Ar-H), 7.68 (d, 2H, J = 7.2 Hz, Ar-H), 7.85 (d,
1H, J = 8.8 Hz, pyridine-H), 8.03 (dt, 2H, J = 8.8 Hz, J = 2.4 Hz, Ar-H), 8.25 (d, 1H, J = 16 Hz, -
CH=CH-), 8.35 (dt, 2H, J = 8.8 Hz, J = 2.4 Hz, Ar-H), 8.41 (d, 1H, J = 8.8 Hz, pyridine-H), 9.98 (s,
13
br, 1H, OH), 10.53 (s, br, 1H, NH); C-NMR (100 MHz, DMSO-d6) δ 118.8, 120.0, 122.8, 123.6,
124.9, 125.9, 127.3, 127.8, 128.7, 129.4, 133.5, 136.6, 136.7, 139.0, 146.7, 146.8, 150.2, 155.2; IR
(KBr): ν 3,388, 3,255, 1,519, 1,347, 1,313, 1,172 cm-1; ESI-MS: m/z 479.6 (M--1), 503.9 (M++Na);
Anal. Calcd for C23H16ClN3O5S: C 57.32, H 3.35, N 8.72; found C 57.56, H 3.46, N 8.66 .
(E)-N-(2-(4-Bromostyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-methoxybenzenesulfonamide
(IIIj):
Yield; 25%; mp: 206–208 C；1H-NMR (400 MHz, DMSO-d6) δ 3.76 (s, 3H, OCH3), 7.02 (dt, 2H,
J = 8.8 Hz, J = 2.4 Hz, Ar-H), 7.47 (d, 1H, J = 16 Hz, -CH=CH-), 7.60 (s, 1H, Ar-H), 7.62 (s, 4H, Ar-
H), 7.72 (dt, 2H, J = 8.8 Hz, J = 2.4 Hz, Ar-H), 7.76 (d, 1H, J = 8.8 Hz, pyridine-H), 8.26 (d, 1H,
J = 16 Hz, -CH=CH-), 8.36 (d, 1H, J = 8.8 Hz, pyridine-H), 9.94 (s, br, 2H, OH, NH); 13C-NMR (100
MHz, DMSO-d6) δ 56.0, 114.7, 118.7, 121.3, 122.4, 122.6, 123.0, 124.7, 128.1, 129.3, 129.7, 132.3,
132.6, 122.6, 135.1, 136.0, 138.9, 145.5, 154.7, 162.8; IR (KBr): ν 3,291, 1,594, 1,463, 1,261, 1,157,
1,090 cm-1; ESI-MS: m/z 544.7 (M--1); Anal. Calcd for C24H18BrClN2O4S: C 52.81, H 3.32, N 5.13;
found C 52.73, H 3.45, N 5.11.
o

Molecules 2010, 15
1914
(E)-N-(2-(4-Bromostyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-methylbenzenesulfonamide
(IIIk):
o
1
Yield: 51%; mp: 234–236 C; H-NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H, CH3), 7.31 (d, 2H,
J = 8.0 Hz, Ar-H), 7.48 (d, 1H, J = 16 Hz, -CH=CH-), 7.59 (s, 1H, Ar-H), 7.63-7.64 (m, 4H, Ar-H),
7.68 (d, 2H, J = 8.0 Hz, Ar-H), 7.78 (d, 1H, J = 8.8 Hz, pyridine-H), 8.29 (d, 1H, J = 16 Hz, -
CH=CH-), 8.38 (d, 1H, J = 8.4 Hz, pyridine-H), 9.98 (s, br, 1H, OH), 10.04 (s, br, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6) δ 21.4, 118.6, 121.2, 122.4, 122.7, 123.1, 124.8, 127.1, 128.1, 129.7, 130.0,
132.4, 133.6, 135.1, 136.1, 138.2, 138.9, 143.5, 145.5, 154.7; IR (KBr): ν 3,291, 1,634, 1,585, 1,460,
1,310, 1,158 cm-1; ESI-MS: m/z 528.6 (M--1).
(E)-N-(2-(4-Bromostyryl)-5-chloro-8-hydroxyquinolin-7-yl)benzenesulfonamide (IIIl): Yield: 38%;
o
1
mp: 238–239 C; H-NMR (400 MHz, DMSO-d6) δ 7.48 (d, 1H, J = 16 Hz, -CH=CH-), 7.52 (t, 2H,
J = 7.2 Hz, Ar-H), 7.58 (s, 1H, Ar-H), 7.60 (t, 1H, J = 8.4 Hz, Ar-H), 7.64 (s, 4H,, Ar-H), 7.65 (d, 2H,
J = 9.6Hz, Ar-H), 7.78 (d, 1H, J = 8.8 Hz, pyridine-H), 7.80 (d, 2H, J = 7.2 Hz, Ar-H), 8.28 (d, 1H,
J = 16 Hz, -CH=CH-), 8.39 (d, 1H, J = 8.8 Hz, pyridine-H), 9.98 (s, br, 1H, OH), 10.14 (s, br, 1H,
NH); 13C-NMR (100 MHz, DMSO-d6) δ 118.6, 121.0, 122.4, 122.7, 123.2, 124.9, 127.0, 128.1, 129.5,
129.7, 132.4, 133.3, 133.6, 135.2, 136.0, 138.9, 141.0, 145.8, 154.7; IR (KBr): ν 2,924, 2,853, 1,459,
1,310, 1,159 cm-1; ESI-MS: m/z 514.5 (M--1), 538.9(M++Na).
(E)-N-(2-(4-Bromostyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-chlorobenzenesulfonamide
(IIIm):
o
1
Yield: 35%; mp: 238–240 C; H-NMR (400 MHz, DMSO-d6) δ 7.44 (d, 1H, J = 16 Hz, -CH=CH-),
7.57 (s, 1H, Ar-H), 7.60 (d, 2H, J = 7.2 Hz, Ar-H), 7.61 (s, 4H, Ar-H), 7.76 (d, 1H, J = 8.8 Hz,
pyridine-H), 7.79 (d, 2H, J = 7.2 Hz, Ar-H), 8.24 (d, 1H, J = 16 Hz, -CH=CH-), 8.35 (d, 1H, J = 8.8
13
Hz, pyridine-H), 10.15 (s, br, 2H, OH, NH); C-NMR (100 MHz, DMSO-d6) δ 118.7, 120.5, 122.4,
122.7, 123.4, 125.6, 128.1, 129.0, 129.7, 132.3, 133.6, 135.2, 136.0, 138.1, 138.9, 139.9, 146.3, 154.8;
IR (KBr): ν 3,435, 3,292, 1,633, 1,461, 1,326, 1,161 cm-1; ESI-MS: m/z 548.5 (M--1), 572.9(M++Na).
(E)-N-(2-(4-Hydroxystyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-methoxybenzenesulfonamide (IIIn):
o
1
Yield: 33%; mp: 212–213 C; H-NMR (400 MHz, DMSO-d6) δ 3.76 (s, 3H, OCH3), 6.84 (d, 2H,
J = 8.8 Hz, Ar-H), 7.01 (dt, 2H, J =7.2 Hz, J = 2.4 Hz, Ar-H), 7.21 (d, 1H, J = 16 Hz, -CH=CH-),
7.53 (d, 2H, J = 8.4 Hz, Ar-H), 7.55 (s, 1H, Ar-H), 7.72 (dt, 2H, J = 7.2Hz, J = 2.4 Hz, Ar-H), 7.73 (d,
1H, J = 8.8 Hz, pyridine-H), 8.17 (d, 1H, J = 16.4 Hz, -CH=CH-), 8.31 (d, 1H, J = 8.8 Hz, pyridine-
H), 9.80-9.95 (m, br, 3H, OH, NH); 13C-NMR (100 MHz, DMSO-d6) δ 56.0, 114.7, 116.3, 118.6,
121.2, 122.2, 122.7, 124.0, 124.2, 127.8, 129.3, 129.5, 132.6, 133.2, 136.7, 138.9, 145.3, 155.6, 159.0,
162.8; IR (KBr): ν 3,430, 3,251, 1,630, 1,590, 1,498, 1,438, 1,319, 1,264, 1,147 cm-1; ESI-MS: m/z
480.7 (M--1), 483.0 (M++1), 505.0 (M++Na); Anal. Calcd for C24H19ClN2O5S: C 59.69, H 3.97, N
5.80; found C 59.41 , H 4.05, N 5.64.
(E)-N-(2-(4-Hydroxystyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-methylbenzenesulfonamide
(IIIo):
o
1
Yield: 31%; mp: 214–215 C; H-NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H, CH3), 6.84 (d, 2H,
J = 8.4 Hz, Ar-H), 7.21 (d, 1H, J = 16 Hz, -CH=CH-), 7.31 (d, 2H, J = 8.0 Hz, Ar-H), 7.53 (d, 2H,
J = 8.8 Hz, Ar-H), 7.55 (s, 1H, Ar-H), 7.68 (d, 2H, J = 8.0 Hz, Ar-H), 7.73 (d, 1H, J = 8.8 Hz,
pyridine-H), 8.19 (d, 1H, J = 16 Hz, -CH=CH-), 8.32 (d, 1H, J = 8.4 Hz, pyridine-H), 9.83 (s, 1H,

Molecules 2010, 15
1915
OH), 9.89 (s, 1H, OH), 10.02 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6) δ 21.4, 116.3, 118.6,
121.0, 122.3, 122.7, 123.9, 124.2, 127.1, 127.8, 129.5, 130.0, 133.3, 136.8, 138.2, 138.9, 143.5, 145.4,
155.6, 159.0; IR (KBr): ν 3,434, 3,258, 1,589, 1,515, 1,458, 1,279, 1,185, 1,150 cm-1; ESI-MS: m/z
464.8 (M--1), 466.9 (M++1), 488.9 (M++Na); Anal. Calcd for C24H19ClN2O4S: C 61.73, H 4.10,
N 6.00.
(E)-N-[2-(4-Hydroxystyryl)-5-chloro-8-hydroxyquinolin-7-yl]benzenesulfonamide (IIIp): Yield: 25%;
o
1
mp: 191–193 C; H-NMR (400 MHz, DMSO-d6) δ 6.84 (d, 2H, J = 8.8 Hz, Ar-H), 7.22 (d, 1H,
J = 16 Hz, -CH=CH-), 7.50-7.54 (m, 5H, Ar-H), 7.60 (tt, 1H, J = 6.8 Hz, J = 2.0 Hz, Ar-H), 7.74 (d,
1H, J = 8.8 Hz, pyridine-H), 7.79 (dt, 2H, J = 7.2 Hz, J = 2.0 Hz, Ar-H), 8.19 (d, 1H, J = 16 Hz, -
CH=CH-), 8.33 (d, 1H, J = 8.8 Hz, pyridine-H), 9.86 (s, 1H, OH), 9.91 (s, 1H, OH), 10.15 (s, 1H,
NH); 13C- NMR (100 MHz, DMSO-d6) δ 116.3, 118.6, 120.8, 122.3, 122.8, 1238, 124.4, 127.0, 127.8,
129.5, 129.6, 133.3, 136.8, 138.8, 140.9, 145.6, 155.6, 159.0; IR (KBr): ν 3,392, 1,625,1,585, 1,513,
1,455, 1,337, 1,154, 1,091 cm-1; ESI-MS: m/z 450.7 (M--1), 475.0 (M++Na).
(E)-N-(2-(4-Hydroxystyryl)-5-chloro-8-hydroxyquinolin-7-yl)-4-chlorobenzenesulfonamide
(IIIq):
Yield: 16%; mp: 189–191 oC; 1H-NMR (400 MHz, acetone-d6) δ 6.91 (d, 2H, J = 8.4 Hz, Ar-H), 7.24
(d, 1H, J = 16 Hz, -CH=CH-), 7.53 (d, 2H, J = 8.4 Hz, Ar-H), 7.57 (d, 2H, J = 8.8 Hz, Ar-H), 7.77 (s,
1H, Ar-H), 7.79 (d, 1H, J = 8.8 Hz, pyridine-H), 7.86 (d, 2H, J = 8.4 Hz, Ar-H), 8.05 (d, 1H, J = 16
13
Hz, -CH=CH-), 8.40 (d, 1H, J = 8.8 Hz, pyridine-H), 8.82 (s, br, 3H, OH, OH, NH); C-NMR (100
MHz, acetone-d6) δ 115.8, 119.6, 120.2, 121.6, 122.8, 123.4, 123.8, 128.1, 128.9, 129.1, 129.2, 133.1,
136.73, 136.2, 138.4, 138.5, 144.0, 155.8, 158.6; IR (KBr): ν 3,252, 1,630, 1,514, 1,274, 1,168, 1,091
cm-1; ESI-MS: m/z 484.8 (M--1), 486.9 (M++1), 508.9 (M++Na).
HIV-IN inhibitory activity evaluation
Compounds III (5 × 10-5 mmol) diluted in DMSO (1 mL) were pre-incubated with 800 ng IN at
37 °C in the reaction buffer in the absence of Mn2+ for 10 min. Subsequently, 1.5 pmol donor DNA
and 9 pmol target DNA were added and the reaction was initiated by the addition of Mn2+ (10 mmol/L)
into the final reaction volume. The reactions were carried out at 37 oC for 1 h and subsequent detection
procedure was applied to detect the assay signals. In these experiments, baicalein, a known IN
inhibitor with both viral replication inhibitory effect in vivo and IN reaction activities inhibitory effect
in vitro, was used as the control compound (positive control), whereas 10% DMSO solution without
sample was set as the drug-free control (negative control).
Conclusions
In summary, on the basis of our previous CoMFA analysis of styrylquinoline derivatives, we have
designed and synthesized for the first time a series of N-[(2-substituted-styryl)-5-chloro-8-
hydroxyquinolin-7-yl]-benzenesulfonamide derivatives. The structures of these compounds were
characterized and their HIV IN inhibitory activities were evaluated. Results indicate that most of the
title compounds exhibit moderate inhibitory activity. Improved inhibitory activity can be achieved
when free hydroxyl at the styryl moiety and nitro group at the benzenesulfonamide moiety are present.

Molecules 2010, 15
1916
Acknowledgements
This work was supported by Grants from the National Natural Science Foundation of China (No.
20402001, 20772010), the National Basic Research Program of China (No. 2009CB930200) and
Beijing Novel Project (No. 2005B10).
References and Notes
1. Debyser, Z.; Cherepanov, P.; Maele, B.V.; De Clercq, E. Witvrouw, M. In search of authentic
inhibitors of HIV-1 integration. Antivir. Chem. Chemother. 2002, 13, 1–15.
2. De Clercq, E. Strategies in the design of antiviral drugs. Nat. Rev. Drug Disc. 2002, 1, 13–25.
3. Reader, J.C. Automation in medicinal chemistry. Curr. Top. Med. Chem. 2004, 4, 671–686
4. Neamati, N. Patented small molecule inhibitors of HIV-1 integrase: A 10-year saga. Exp. Opin.
Ther. Pat. 2002, 12, 709–724.
5. Mekouar, K.; Mouscadet, J.F.; Desmaele, D.; Subra, F.; Leh, H.; Savoure, D.; Auclair, C.;
d’Angelo, J. Styrylquinoline derivatives: A new class of potent HIV-1 integrase inhibitors that
block HIV-1 replication in CEM cells. J. Med. Chem. 1998, 41, 2846–2857.
6. Zouhiri, F.; Mouscadet, J.F.; Mekouar, K.; Desmaele, D.; Savoure, D.; Leh, H.; Subra, F.; Bret,
M.L.; Auclair, C.; d’Angelo, J. Structure-activity relationships and binding mode of
styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture. J.
Med. Chem. 2000, 43, 1533–1540.
7. Polanski, J.; Zouhiri, F.; Jeanson, L.; Desmaele, D.; d’Angelo, J.; Mouscadet, J.-F.; Gieleciak, R.;
Gasteiger, J.; Bret, L.M. Use of the Kohonen neural network for rapid screening of ex vivo anti-
HIV activity of styrylquinolines. J. Med. Chem. 2002, 45, 4647–4654.
8. Normand-Baylea, M.; Bénarda, C.; Zouhiria, F.; Mouscadetc, J.F.; Lehb, H.; Thomasb, C.M.;
Mbembac, G.; Desmaëlea, D.; d’Angeloa, J. New HIV-1 replication inhibitors of the
styrylquinoline class bearing aroyl/acyl groups at the C-7 position: Synthesis and biological
activity. Bioorg. Med. Chem. Lett. 2005, 15, 4019–4022.
9. Ma, X.H.; Zhang, X.Y.; Tan, J.J. Chen, W.Z.; Wang, C.X. Exploring binding mode for
styrylquinoline HIV-1 integrase inhibitors using comparative molecular field analysis and
docking studies. Acta Pharmacol. Sin. 2004, 25, 950–958.
10. Zeng, C.C.; Niu, L.T.; Ping, D.W.; Zhong, R.G. Design and synthesis of 2-styrylquinoline-7-
sulfonamide derivatives as potential HIV integrase inhibitors (in Chinese). Chin. J. Org. Chem.
2009, 29, 1105–1114.
11. Yoo, H.; Lee, J.Y.; Park, J.H.; Chung, B.Y.; Lee, Y.S. Synthesis of styrylbenzofuran derivatives
as styrylquinoline analogues for HIV-1 integrase inhibitors. Farmaco 2003, 58, 1243–1250.
12. Kurita, K. Selectivity in tosylation of o-aminophenol by choice of tertiary amine Chem. Ind. 1974,
345–346.
13. Sellarajah, S.; Lekishvili, T.; Bowring, C.; Thompsett, A.R.; Rudyk, H.; Birkett, C.R.; Brown,
D.R.; Gilbert, I.H. Synthesis of analogues of congo red and evaluation of their anti-prion activity.
J. Med. Chem. 2004, 47, 5515–5534.

Molecules 2010, 15
1917
14. He, H.Q.; Ma, X.H.; Liu, B.; Zhang, X.Y.; Chen, W.Z.; Wang, C.X.; Cheng, S.H. A novel high-
throughput format assay for HIV-1 integrase strand transfer reaction using magnetic beads. Acta
Pharmacol. Sin. 2008, 29, 397–404.
15. Zouhiri, F.; Danet, M.; Bénard, C.; Normand-Bayle, M.; Mouscadet, J.F.; Leh, H.; Thomas, C.M.;
Mbemba, G.; d’Angelo, J.; Desmaële, D. Tetrahedron Lett. 2005, 46, 2201–2205.
16. Weizmann, M.; Bograchov, E. Derivatives of 5-chloro-8-hydroxyquinoline. J. Am. Chem. Soc.
1947, 69, 1222–1223.
Sample Availability: Samples of the compounds IIIa-m are available from the authors.
© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).