Synthesis and in vitro evaluation of leishmanicidal and trypanocidal activities of N-quinolin-8-yl-arylsulfonamides

Article abstract of DOI:10.1016/j.bmc.2007.09.007

In the present paper 12 N-quinolin-8-yl-arylsulfonamides synthesized by coupling 8-aminoquinolines with various arylsulfonylchlorides were assayed in vitro against Leishmania amazonensis, Leishmania chagasi and Trypanosoma cruzi strains. This series of ne

Full text of DOI:10.1016/j.bmc.2007.09.007

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 15 (2007) 7553–7560
Synthesis and in vitro evaluation of leishmanicidal and
trypanocidal activities of N-quinolin-8-yl-arylsulfonamides
b
c
Luiz Everson da Silva,a, Antoˆnio Carlos Joussef, Letıcia Kramer Pacheco,
*
´
c
c
d
´
Daniela Gaspar da Silva, Mario Steindel and Ricardo Andrade Rebelo
a
ˆ
Departamento de Quı´mica, Instituto de Ciencias Exatas e da Terra, Universidade Federal de Mato Grosso,
Cuiaba´, 78060-900 Mato Grosso, Brazil
b
ˆ
´
´
Departamento de Quı´mica, Centro de Ciencias Fısicas e Matematicas, Universidade Federal de Santa Catarina,
Campus Trindade, Floriano´polis, 88040-900 Santa Catarina, Brazil
c
ˆ
´
Departamento de Microbiologia e Parasitologia, Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina,
Campus Trindade, Floriano´polis, 88040-900 Santa Catarina, Brazil
d
ˆ
Departamento de Quı´mica, Centro de Ciencias Exatas e Naturais, Universidade Regional de Blumenau,
Blumenau, 89010-971 Santa Catarina, Brazil
Received 3 August 2007; revised 2 September 2007; accepted 7 September 2007
Available online 12 September 2007
Abstract—In the present paper 12 N-quinolin-8-yl-arylsulfonamides synthesized by coupling 8-aminoquinolines with various aryl-
sulfonylchlorides were assayed in vitro against Leishmania amazonensis, L. chagasi and Trypanosoma cruzi strains. This series of new
compounds were found to be selective for Leishmania spp. promastigote and amastigote forms. The most active compound was the
N-(8-quinolyl)-3,5-difluoro-benzenesulfonamide 10 with an IC50 against L. amazonensis and L. chagasi of 2.12 and 0.45 lM, respec-
tively. The less cytotoxic biphenyl derivative 7 was very effective against intracellular L. amazonensis with a reduction of macrophage
cell infection of 82.1% at 25 lM. In addition, a copper complex 17 of an inactive ligand was readily synthesized and showed high
leishmanicidal and trypanocidal activity against both extra and intracellular forms.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
somiases chemotherapy. For the last decade, new poten-
tial therapies have been introduced for leishmaniasis.
These include Amphotericin B, Miltefosine, Aminosi-
dine and Sitamaquine (Fig. 1). The latter has completed
phase II trials in India, Kenya and Brazil.2 In addition, a
great number of both natural and synthetic compounds
have been tested in recent years in antileishmanicidal
and antitrypanosomal assays.3
Diseases caused by protozoan parasites are severe global
public health problem, especially in the tropical and sub-
tropical regions of the world. Despite the socioeconom-
ical importance of these tropical infectious diseases,
efforts directed towards the discovery of new drugs
and/or vaccines are insufficient. In addition, most drugs
currently in use were developed several decades ago
showing variable efficacy. They promote serious side ef-
fects, are expensive, require long-term treatment, show
low activity in immunosuppressed patients and parasites
may be resistant to the drugs.1 Thus, the need for devel-
oping new, effective, cheap and safe drugs continues to
be a major goal in the field of leishmaniasis and trypano-
In this context, the use of quinoline derivatives as anti-
protozoal agents is well established.4 Although there is
a large amount of experimental work on this heterocy-
clic system, it still remains an area of active research.5
On the other hand, sulfonamides have long been the
subject of pharmaceutical interest as a result of their
potent biological activities.6 Indeed, the sulfonamide
derivatives have been reported to possess antitrypanos-
omal and antileishmanial activities.7 As part of our
efforts to develop new compounds aimed at the
therapy of parasitic infection,8 we have synthesized
and assayed against leishmania and trypanosome some
Keywords: Quinolinylarylsulfonamides; Quinolinylarylsulfonamide-
copper and zinc complexes; Leishmanicidal activity; Trypanocidal
activity; Vero cells; Macrophages.
*
Corresponding author. Tel.: +55 65 3615 8797; fax: +55 65 3615
8798; e-mail: luiz_everson@yahoo.de
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.09.007

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L. E. da Silva et al. / Bioorg. Med. Chem. 15 (2007) 7553–7560
OH
OH
OH
OH
H3C
HO
O
O
HO
HO
O
O
OH OH
OH OH
CH3
H
H2N
NH2
H3C
O
CH3
OH
O
O
O
NH2
HO
H2N
OH
OH
O
O
HO
HO
Amphotericin B
NH2 O
OH
H2N
Aminosidine
N
HN
O
P
N
H3C
N+(CH3)3
H3CO
(CH2)14
O
O
O-
CH3
Miltefosine
Sitamaquine
Figure 1. Drugs currently used in the treatment of leishmaniasis.
quinolinylarylsulfonamides and two of their copper
and zinc complexes.
nish the N-quinolin-8-yl-arylsulfonamide 16 in 70%
yield (Scheme 3).
Recent studies have suggested that the leishmanicidal
activity of copper complex could be associated with their
interaction with the parasite DNA.12 Furthermore
important biological activities have been associated to
chelated copper and zinc cations.13 These prompted us
to synthesize the copper and zinc complexes 17 and
1814 (Fig. 2). The copper and zinc cations were chelated
by two bidendate quinolinylsulfonamides in methanol at
room temperature. Their unambiguous structures were
established by X-ray analysis.15
2. Results and discussion
2.1. Chemistry
A series of quinolinylarylsulfonamides were obtained by
direct reaction of the corresponding commercial avail-
able 8-aminoquinoline
1 and arylsulfonylchlorides
in pyridine9 at 0 ꢁC (Scheme 1). The titled 3–12 were ob-
tained in good yields (65–97%) and their corresponding
octanol-water partition coefficients (ClogP) were calcu-
lated using free software available on the web ( Table 1).
2.2. Antiprotozoal activity
8-Aminoquinoline (1) was allowed to react with bromine
in acetic acid to afford the expected 5,7-dibromo-8-ami-
noquinoline 13.10 Reaction of the 5,7-dibromoderivative
13 with 4-n-propylbenzenesulfonylchloride in pyridine
at the 0 ꢁC gave the corresponding compound 14
(Scheme 2).
Due to the facility of cultivation, both promastigotes
and epimastigotes forms are largely used for in vitro
compounds screening. Therefore, the efficacy of the syn-
thesized quinolinylarylsulfonamides on promastigotes of
L. amazonensis, L. chagasi and epimastigotes of T. cruzi
was assessed by a previously described method.8 Results
are summarized in Table 2 and show a high selectivity
towards Leishmania spp. The only exception was
observed for compound 6, which presented a moderate
activity against T. cruzi (31.75 lM). However, its index
of selectivity (IS) defined as the ratio of the CC50 value
on Vero cells to the IC50 value on the epimastigotes
T. cruzi strains, was only 2.1.
The quinoline 15 containing a quite similar substitution
pattern of sitamaquine was prepared as described by
Kimber et al.11 and placed to react with 4-n-propyl-
benzenesulfonylchloride in pyridine at the 0 ꢁC to fur-
py
OoC
(65-97%)
+
The quinolinylarylsulfonamides 6, 10, 11 and 12 were
found to be the most active compounds against promas-
tigote forms of L. amazonensis and L. chagasi with IC50
ranging from 2.12 to 2.85 lM and 0.45 to 2.99 lM,
respectively. These are outstanding results since the
IC50 for compounds 6, 10 and 12 are just two times
greater than the IC50 of the control Amphotericin B in
the L. chagasi bioassay. The IS for these three com-
pounds was remarkable, where values ranging from 24
RSO2Cl
N
N
NH2
NH
SO2
R
1
3-12
Scheme 1. General structure of synthesized N-quinolin-8-yl-arylsulf-
onamides derivatives 3-12.

L. E. da Silva et al. / Bioorg. Med. Chem. 15 (2007) 7553–7560
7555
Table 1. N-Quinolin-8-yl-arylsulfonamides and the corresponding
partition coefficients (ClogP)
L. chagasi. The IS for the most active compound 7
within this set was 39 and 112 for L. amazonensis and
L. chagasi, respectively. The IS for compounds 8 and
9 dropped considerably, ranging from 4.4 to 11 for
L. amazonensis and 4.6 to 23 for L. chagasi.
Compound
ClogP
R
3
3.19
The presence of either a nitro group or fluorine atom at
4-position of the phenyl moiety as in compounds 3 and
5, respectively, induced total loss of activity
(IC50 > 100 lM). It is important to notice that bromine
at 4-position of the phenyl moiety promoted different
effect as described previously for 11. Similar result to
compounds 3 and 5 was observed for compound 4 con-
taining bulky groups on the aryl moiety.
NO2
4
5
6.23
2.68
Another interesting finding of the present study is the
sensitivity of this series towards the introduction of sub-
stituents on the quinoline ring. The presence of dibro-
mine as in compound 14 and methoxy and methyl
groups as in 16 led to the loss of activity.
F
6
2.92
A preliminary study related to metal complex of quinoli-
nylarylsulfonamides was undertaken. The readily made
and purified copper 17 and zinc 18 complexes were
assayed against L. amazonensis and L. chagasi promas-
tigote and T. cruzi epimastigote forms. The results are
summarized in Table 2. A drastically change in the anti-
protozoal activity was observed since the corresponding
sulfonamide ligands 5 and 3 were inactive. The copper
complex showed significant activity against Leishmania
amazonensis (IC50 = 2.28 lM), L. chagasi (IC50 = 1.10
lM) and T. cruzi (IC50 = 4.10 lM) whereas the zinc
complex was slightly less active against Leishmania
spp. strains (6.46 lM for L. amazonensis, and 3.00 lM
for L. chagasi). Moreover, compound 17 was found
more active than the reference compound benznidazole,
although its IS was only 3.3.
N
Br
Cl
7
8
4.20
3.87
NMe2
9
3.85
2.84
n
F
C3H7
10
It is well known that extracellular and intracellular
forms of these protozoans exhibit metabolic differences
and distinct levels of sensitivity to drugs. Amastigote is
the relevant clinical form for both diseases and its use
on the evaluation of antiparasitic activity of compounds
might be very useful.16
F
11
12
3.46
4.18
Br
S
Limited by the availability of some compounds repre-
sentatives of the quinolinylarylsulfonamide series were
selected and tested against intracellular amastigote
forms of L. amazonensis (infected macrophages) and
T. cruzi (infected Vero cells). Three different concentra-
tions of the selected compounds were considered and the
results are summarized in Table 3.
Br
Br
to 30 for L. amazonensis and 120 to 147 for L. chagasi
were observed. Structurally three different aryl moieties
are associated to these compounds: basic p-deficient in
6, homocyclic in 10 and p-excessive in 12, although they
have in common dihalide substituents.
Compounds 6 and 17 were active against both Leish-
mania and Trypanosoma as observed in the bioassay
against promastigote and epimastigote forms. These
compounds presented a significant activity against
L. amazonensis, promoting at the concentration 5 lM
a reduction of cell infection in 67.1% and 88.2%, respec-
tively. A remarkable result was obtained against T. cruzi
amastigote forms with a reduction of cell infection in
96.4% promoted by 6 at 25 lM concentration, and
98.0% reduction for the complex 17 at 5 lM concentra-
With respect to the sulfonamides 7, 8 and 9, which can
be regarded as the lipophilic members of this series
(ClogP from 3.85 to 4.20), their activity was inferior
to the previous set of compounds but still very signifi-
cant, with IC50 ranging from 6.27 to 14.47 lM against
L. amazonensis and from 2.18 to 13.96 lM against

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L. E. da Silva et al. / Bioorg. Med. Chem. 15 (2007) 7553–7560
Br
Br
AcOH
-15oC
4-n
-Pr-PhSO2Cl
+
Br2
0oC
py/
Br
N
N
Br
N
NH
NH2
NH2
SO2
13
1
14
Scheme 2. Synthesis of N-(5,7-dibromo-8-quinolyl)-4-n-propylbenzenesulfonamide 14.
H3CO
SO2Cl
H3CO
+
py
0oC
CH3
N
CH3
N
NH
SO2
NH2
15
16
Scheme 3. Synthesis of N-(6-methoxy-2-methyl-8-quinolyl)-4-n-propylbenzenesulfonamide 16.
necessary to investigate the activity of the former in the
cell infected bioassays. Furthermore, the lipophilicity
increment associated to the bromine atom could be
exploited in the preparation of derivatives of com-
pounds 6, 10 and 11.
F
F
O2N
NO2
SO2
N
SO2
SO2
N
SO2
N
N
Cu
In conclusion, several new quinolin-8-yl-arylsulfona-
mides were prepared from the reaction of 8-amino-
quinolines with various arylsulfonylchlorides in
pyridine. The in vitro bioassay showed the compounds
to possess significant antiprotozoal activity against
promastigote and amastigote forms of Leishmania
spp. The only representative of this series active
against T. cruzi was the sulfonamide containing a pyr-
idine moiety.
Zn
N
N
N
N
17
18
Figure 2. Chemical structures of copper and zinc complexes 17 and 18.
tion, which was also the most cytotoxic as previously
observed. These compounds were more active than the
control benznidazol that reduced in 92.0% the cell infec-
tion at 25 lM. With respect to the zinc complex 18, it
showed an activity against L. amazonensis inferior to
compounds 6 and 17. This result is compatible to the
bioassay with L. amazonensis culture.
The active general molecular structure may embody a
variety of features at the aryl moiety, but not at the
quinoline ring where the substituents investigated led
to the total loss of activity.
The lipophilic series 7–9 was also tested against in vitro L.
amazonensis. Compound 7, containing the biphenyl moi-
ety, was found to be the most active, promoting a reduc-
tion of cell infection in 82.1% at 25 lM concentration. In
fact its activity was similar to compound 6 confirming a
trend observed for other classes of antiparasitic com-
pounds where the increase of lipophilicity seems to favor
the compound distribution to the intracellular target.17
Copper and zinc complexes were prepared from the
corresponding sulfonamide and copper or zinc salt in
methanol. Their activity was investigated against
Leishmania and Trypanosoma strains. The complex in-
creased the sulfonamide activity although its cytotoxic-
ity as well.
No quantitative correlation was carried out and further
pharmacological study should be now investigated to
determine the target of action. These series has provided
leading compounds for further pharmacomodulations.
The ClogP observed for compound 12 (4.18) was simi-
lar to compound 7 (ClogP = 4.20) and indicates that is

L. E. da Silva et al. / Bioorg. Med. Chem. 15 (2007) 7553–7560
7557
Table 2. In vitro effect of N-quinolin-8-yl-arylsulfonamides and copper and zinc derivatives on the growth of Leishmania amazonensis and
Leishmania chagasi promastigotes, Trypanosoma cruzi epimastigotes and toxicity to Vero cells
Compound
L. amazonensis (575 strain)
IC50 (lM)
L. chagasi (PP75 strain)
IC50 (lM)
T. cruzi (Y strain)
IC50 (lM)
Vero cells
CC50 (lM)
3
>100
>100
>100
>100
>100
>100
>100
>100
ND
ND
4
5
>100
31.75 (26.63–37.85)
ND
6
2.25 (1.63–3.09)
6.27 (4.46–8.82)
7.18 (6.91–7.47)
14.47 (14.14–14.81)
2.12 (1.88–2.40)
4.94 (4.73–5.17)
2.85 (2.59–3.14)
>100
0.56 (0.51–0.63)
2.18 (1.65–2.88)
3.53 (2.28–5.46)
13.96 (12.09–16.13)
0.45 (0.14–1.45)
2.99 (2.73–3.26)
0.53 (0.51–0.55)
>100
67.38 (54.46–83.36)
244.93 (189.04–317.36)
84.22 (60.52–117.21)
64.36 (58.15–71.24)
66.33 (45.80–96.06)
88.70 (74.35–105.83)
68.73 (41.72–113.23)
ND
7
>100
>100
8
9
10
>100
>100
11
12
>100
>100
14
16
>100
>100
>100
>100
ND
17
18
2.28 (1.41–3.67)
6.46 (6.04–6.89)
0.31 (0.25–0.35)
—
1.10 (0.57–2.11)
3.00 (2.81–3.21)
0.25 (0.21–0.26)
—
4.10 (2.79–6.03)
>100
13.76 (9.59–19.75)
11.43 (11.33–11.53)
98.35 (78.85–115.06)
>1000
Amphotericin B
Benznidazole
—
14.58 (13.10–16.24)
IC50 with their respective 95% confidence limit; CC50 with their respective 95% confidence limit; ND, not determined.
Table 3. Activity of synthesized compounds against intracellular
amastigotes of L. amazonensis in mice peritoneal macrophages and
Trypanosoma cruzi in Vero cells after a 48 h treatment
tively, and 200 U/ml penicillin and 100 lg/ml of strepto-
mycin (Gibco, UK). Parasites were harvested from 4
days old culture and washed twice in phosphate-buffered
saline by centrifugation at 1000g for 10 min at 4 ꢁC. Par-
asite concentration was adjusted to 1 · 106 cells/ml in
Schneider’s or LIT medium supplemented with 5% or
10% of FBS. For leishmanicidal and trypanocidal activ-
ity assays, 150 ll of the parasite suspension was added
to 96-well microplates and incubated at 28 ꢁC for 72 h
in the presence or absence of the N-quinolin-8-yl-aryl-
sulfonamides (0.2–100 lM) and the standard drugs
Amphotericin B (0.1–10 lM) and benznidazole (10–
100 lM) were used as controls. For each compound
three experiments were carried out in triplicate and the
number of surviving parasites was determined in Neu-
bauer chambers.8
Compound
Concentration L. amazonensis T. cruzi
(lM)
(575 strain)
Reduction of
cell infection
(%)
(Y strain)
Reduction of
cell infection
(%)
6
25
5
84.8
67.1
96.4
85.2
78.6
NT
1
52.0
82.1
7
25
5
72.3
60.0
NT
NT
1
8
25
5
Citotoxic
48.2
25.7
NT
NT
1
NT
NT
9
25
5
63.7
52.2
3.1.2. Cell toxicity tests. Cytotoxic effects of N-quinolin-
8-yl-arylsulfonamides were evaluated in Vero cells using
the MTT (tetrazolium-dye) assay.18 Briefly, cells culti-
vated in the presence of different compounds for 72 h
at 37 ꢁC were incubated with MTT (2 mM/ml) for 4 h.
Thereafter supernatant was removed and 100 ll of
DMSO was added to solubilize the formazan crystals
from viable cells. The samples were read at a wavelength
of 540 nm using an ELISA plate reader.19 Benznidazole
and Amphotericin B were used as control drugs. Vari-
ance analysis followed by Dunnett’s multiple compari-
son tests were used for data analysis. The 50%
inhibitory concentration (IC50) for parasites and 50%
cell cytotoxicity (CC50) was determined by linear regres-
sion analysis using (GraphPad Software, San Diego,
California).
NT
NT
1
18.7
17
18
25
5
Citotoxic
88.2
76.0
Citotoxic
98.0
84.1
NT
1
25
5
Citotoxic
65.7
42.0
NT
NT
1
Amphotericin B 10
Benznidazol 25
97.0
NT
NT
92.0
The results represent the mean of two experiments. The infection rate
was determined evaluating 500 Giemsa stained cells chosen randomly
in each slide. NT, not tested.
3. Experimental
3.1. Biological assays
Macrophages were collected from the peritoneal cavity
of normal female albino Swiss mice and cultivated on
sterile 13 mm glass slides in DMEM supplemented with
20% of heat inactivated FBS at 37 ꢁC, 5% CO2 as de-
scribed previously.20 Vero cells (ATCC CCL81) were
cultivated on 13 mm glass slides in DMEM supple-
mented with 5% of FBS at 37 ꢁC, 5% CO2.20 Macrophages
3.1.1. In vitro L. amazonensis promastigotes and T. cruzi
epimastigotes culture and drug assays. L. amazonensis
(strain 575) promastigotes and T. cruzi (Y strain) epim-
astigotes were grown at 28 ꢁC in Schneider’s and LIT
media containing 5% and 10% of heat inactivated
(56 ꢁC for 30 min) fetal bovine serum (FBS), respec-

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L. E. da Silva et al. / Bioorg. Med. Chem. 15 (2007) 7553–7560
were infected with L. amazonensis promastigotes, using
a 1:10 cell:parasite ratio and after 4 h period of infection
cells were incubated at 37 ꢁC, 5% CO2 with different
concentrations of the compounds for 48 h. Slides were
washed with PBS, methanol fixed and stained with
Giemsa.21 Vero cells were incubated with cell culture de-
rived trypomastigotes at 1:10 cell:parasite ratio and after
6 h of infection cells were washed for removing the non-
adherent parasites and the cell monolayer incubated for
48 h with different concentrations of the compounds.20
Slides were methanol fixed and Giemsa stained and 500
random cells were microscopically examined (1000·).
The cell infection rate and the number of infected cells
as well as the number of parasite/cell were determined.
3.2.4. 4-Fluoro-N-(8-quinolyl)benzenesulfonamide (5).
Crystalline solid: 79%. Mp: 140 ꢁC.
1H NMR (CDCl3, 300 MHz) d 7.03 (t, J = 6 Hz, 2H-
H3-H6); 7.42–7.48 (m, 3H-H30-H40); 7.88 (dd, J = 2
and 7 Hz, 1H-H7); 7.90 (dd, J = 2 and 7 Hz, 2H-H3-
H6); 8.12 (dd, J = 1,6 and 8 Hz, 1H-H5); 8.76 (dd,
J = 2 and 6 Hz, 1H-H2); 9.24 (s, 1H-NH).
Mass spectrometry: m/z = 302 (M+; 35); 238 (90); 143
(100); 116 (60).
IR (KBr): 3260 (NH), 1307 (SO2N), 1160 (SO2N), 922,
666, 570, 545 cmꢀ1
.
3.2. Chemistry
3.2.5. N-(8-Quinolyl)-5-bromo-6-chloropyridine-3-sulfon-
amide (6). Yellow solid: 89%. Mp: 155–157 ꢁC.
1
The compounds were characterized by H NMR. The
purity of the compounds was determined by TLC using
several solvent systems of different polarity. Nuclear
magnetic resonance spectra were recorded with on a
Bruker AC-300 spectrometer using tetramethylsilane as
internal standard. Infrared spectra were determined with
a Perkin-Elmer 16PC spectrophotometer. Mass spectra
were obtained with on a Bruker-Franzen Esquire LC
instrument.
1H NMR (CDCl3, 300 MHz) d (m, 3H-Ar-H); 7.94 (dd,
J = 1.6 and 6 Hz, 1H-H5); 8.19 (dd, J = .6 and 6.7 Hz,
1H-H4); 8.41 (s,1H-H10); 8.79 (s, 1H-H20); 8.8 (dd,
J = 1.6 and 6 Hz, 1H, H2); 9.43 (s, 1H-NH).
Mass spectrometry: m/z = 399 (M+; 25); 334 (55); 143
(100); 116 (65).
IR (KBr): 3192 (NH), 1612,1584, 1368 (SO2N), 1173
3.2.1. General Procedure for the synthesis of the sulfon-
amides derivatives. To an ice-cooled solution of the ami-
noquinoline (1 equiv) in pyridine were added the
corresponding sulfonylchloride derivative (1.1 equiv).
The mixture was stirred at 0 ꢁC for 90 min and over-
night at room temperature. The reaction mixture was
quenched with ice water and the precipitated product fil-
tered off. The sulfonamide was recrystallized from
MeOH:CH2Cl2 solution.
(SO2N), 941, 776, 679, 587, 545 cmꢀ1
.
3.2.6. N-(8-Quinolyl)-n-biphenylsulfonamide (7). White
solid: 95%. Mp: 158–159 ꢁC.
1H RMN (CDCl3, 300 MHz) d 7.40–7.44 (m, 6H-Ar-
H); 7.57 (s, 2H-H200-H600); 7.89 (dd, J = 9 Hz, 1H-
H30-H50); 7.90 (s, 4H-H30-H50-H20-H60); 8.07 (d,
J = 9 Hz, 1H-H5); 8.71 (dd, J = 2 and 9 Hz, 1H-H2);
9.29 (s, 1H-NH).
3.2.2. 4-Nitro-N-(8-quinolyl)benzenesulfonamide (3).
Crystalline solid: 84%. Mp:170 ꢁC.
Mass spectrometry: m/z = 360 (M+); 296 (100); 143 (35);
116 (20).
1H NMR (CDCl3, 300 MHz) d 7.26–7.54 (m, Ar-H);
7.93 (dd, J = 1.6 and 8 Hz, 1H-H7); 8.08 (d, J = 8 Hz,
2H-H20-H60) 8.14 (d, J = 8 Hz, 2H-H30-H50); 8.78 (dd,
J = 1.6 and 6 Hz, 1H-H2); 11.45 (s, 1H-NH).
IR (KBr): 3250 (NH), 1317 (SO2N), 1123 (SO2N), 959,
664, 567, 552 cmꢀ1
.
3.2.7. N-(8-Quinolyl)-5-(dimethylamino)naphthalenesulf-
onamide (8). Green solid: 90%. Mp: 155–156 ꢁC.
Mass spectrometry: m/z = 329 (M+; 100); 202 (80).
IR (KBr): 3218 (NH), 1573, 1383, 1359 (SO2N), 1169
.
1H NMR (CDCl3, 300 MHz) d 2.79 (s, 6H-CH3); 7.10
(d, J = 7.5 Hz, 1H-H6); 7.32 (dd, J = 4,2 and 7 Hz,
2H-H60-H70); 7.44 (t, J = 7.5 Hz, 2H-H3-H6); 7.58 (t,
J = 7.8 Hz, 2H-H7-H30); 8.01 (d, J = 8.1 Hz, 1H-H5);
8.37 (d, J = 7.2 Hz, 1H-H40); 8.46 (d, J = 8.7, 1H-H80);
8.50 (d, J = 8.7,1H-H20); 8.69 (d, J = 4.2 Hz, 1H-H2);
9.45 (s, 1H-NH).
(SO2N), 926, 686, 585, 559 cmꢀ1
3.2.3. 2,4,6-Triisopropyl-N-(8-quinolyl)benzenesulfona-
mide (4). Crystalline solid: 65%. Mp:141 ꢁC.
1H NMR (CDCl3, 300 MHz) d 1.27 (s, 18H-CH3); 2.82
(m, 1H-CH); 4.37 (m, 2H-CH); 7.09 (s, 2H-CH-H30-
H50); 7.25–7.46 (m, 4H-Ar-H); 7.68 (dd, J = 2 and
6.7 Hz, 1H-H7); 8.09 (dd, J = 1.6 and 6 Hz, 1H-H5);
8.74 (dd, J = 1.6 and 6 Hz, 1H-H2); 9.31 (s, 1H-NH).
Mass spectrometry: m/z = 377 (M+; 75); 313 (100); 170
(40).
IR (KBr): 3248 (NH), 1314 (SO2N), 1139 (SO2N), 936,
678, 573, 551 cmꢀ1
.
Mass spectrometry: m/z = 433 (M+; 100).
IR (KBr): 3245 (NH), 1375 (SO2N), 1164 (SO2N), 918,
679, 558, 546 cmꢀ1
3.2.8. N-(8-Quinolyl)-4-n-propylbenzenesulfonamide (9).
White solid: 77%. Mp: 105 ꢁC.
.

L. E. da Silva et al. / Bioorg. Med. Chem. 15 (2007) 7553–7560
7559
1H NMR (CDCl3, 300 MHz) d 0.80 (t, J = 7.3 Hz, 3H-
CH3); 1.48 (q, J = 7.5 Hz, 2H-CH2); 2.10 (t, J = 7.2 Hz,
2H-CH2); 7.06 (d, J = 9 Hz, 2H-H30-H50); 7.36 (dd,
J = 2 and 7 Hz, 1H, H5); 7.38 (t, J = 6 Hz, 1H, H6); 7.40
(d, J = 7 Hz, 1H, H7); 7.69 (t, J = 6 Hz, 1H, H3); 7.75
(d, J = 9 Hz, 2H-H20-H60); 8.02 (dd, J = 2 and 6 Hz, 1H-
H2); 8.69 (dd, J = 2 and 6 Hz-H4); 9.17 (s, 1H-NH).
1H NMR (DMSO-d6, 300 MHz) d 1.12 (t, J = 7.3 Hz,
3H-CH3); 1.25 (q, J = 7.5 Hz, 2H-CH2); 2.95 (t,
J = 7.2 Hz, 2H-CH2); 6.31 (s, 1H-NH); 6.83 (d,
J = 9 Hz, 2H, H30–H50); 7.08 (t, J = 6 Hz, 1H, H3);
7.34 (s, 1H-H6); 7.56 (d, J = 7.5 Hz, 1H-H4); 7.90 (d,
J = 7.5 Hz, 2H-H20–H60); 8.25 (d, J = 6 Hz, 1H, H2).
Mass spectrometry: m/z = 484 (M+; 10); 420 (100); 391
(85); 301 (90); 220 (50); 141 (25).
Mass spectrometry: m/z = 326 (M+; 18); 262 (50); 233
(100); 143 (60); 116 (45).
IR (KBr): 3240 (NH), 1357 (SO2N), 1163 (SO2N), 929,
IR (KBr): 3218 (NH), 1359 (SO2N), 1169 (SO2N), 926,
.
667, 557, 545 cmꢀ1
.
686, 585, 559 cmꢀ1
3.2.14. N-(6-Methoxy-2-methyl-8-quinolyl)-4-n-propyl-
benzenesulfonamide (16). Crystalline solid: 70%. Mp:
111–113 ꢁC.
3.2.9. N-(8-Quinolyl)-3,5-difluoro-benzenesulfonamide (10).
White solid: 96%. Mp: 120–121 ꢁC.
1H NMR (CDCl3, 300 MHz) d 6.82 (t, J = 9 Hz, 1H-
H40); 7.21 (s, 2H-H20-H60); 7.36–7.50 (m, 3H-Ar-H);
7.79 (d, J = 6 Hz, 1H-H7); 8.06 (d, J = 6 Hz, 1H-H5);
8.70 (dd, J = 2 and 6 Hz, 1H-H2); 9.23 (s, 1H-NH).
1H NMR (CDCl3, 300 MHz) d 0.82 (t, J = 7.3 Hz, 3H-
CH3); 1.46 (q, J = 7.5 Hz, 2H-CH2); 2.45 (t, J= 7.2 Hz,
2H-CH2); 2.65 (s, 3H-CH3); 3.73 (s, 3H-OCH3); 6.48
(s, 1H-H7); 7.15 (d, J = 8.5 Hz, 2H, H30–H50); 7.18 (d,
J = 6 Hz, 1H, H3); 7.8 (d, J = 6 Hz, 1H, H4); 7.36 (s,
1H, H7); 7.76 (d, J = 8.5 Hz, 2H, H20–H60); 9.34 (s,
1H-NH).
Mass spectrometry: m/z = 320 (M+; 45); 256 (70); 143
(100); 116 (55).
IR (KBr): 3245 (NH), 1375 (SO2N), 1164 (SO2N), 952,
692, 596, 584 cmꢀ1
Mass spectrometry: m/z = 370 (M+; 90); 277 (30); 187
(75); 172 (100); 144 (30).
.
3.2.10. N-(8-Quinolyl)-4-bromobenzenesulfonamide (11).
White solid: 56%. Mp: 160–162 ꢁC.
IR (KBr): 3325 (NH), 1610,1600, 1317 (SO2N), 1166
(SO2N), 925, 686, 569, 554 cmꢀ1
.
1H NMR (CDCl3, 300 MHz) d 7.41–7.33 (m, 3H); 7.40
(d, J = 8 Hz, 2H-H30-H50) 7.68 (d, J = 8 Hz, 2H-H20-
H60); 7.75 (d, J = 7.2 Hz, 1H); 8.01 (d, J = 8 Hz, 1H);
8.66 (d, J = 7.2 Hz, 1H); 9.18 (s, 1H-NH).
3.2.15. Synthesis of the complexes. The copper complex
17 prepared according to a procedure given in the liter-
ature.22 Into 50 ml of a methanolic solution of copper
(II) acetate (0.1996 g, 1 mmol), 100 ml of a methanolic
solution containing 0.5965 g (2 mmol) of the ligand
was slowly added under stirring. The solution became
dark and after one day the crystals appeared.
IR (KBr): 3250 (NH), 1320 (SO2N), 1169 (SO2N), 961,
.
655, 570, 550 cmꢀ1
3.2.11. 4,5-Dibromo-N-(8-quinolyl)tiophene-2-sulfonamide
(12). White solid: 57%. Mp: 143 ꢁC.
3.2.16. Bis[4-Fluoro-N-(quinolin-8-yl)benzenesulfonami-
date-j2N,N0]copper(II) (17).15 Green dark solid: 80%.
Mp: 278 ꢁC.
1H NMR (CDCl3, 300 MHz) d 7.19 (s, 1H-H50); 7.44–
7.53 (m, 3H-Ar-H); 7.83 (dd, J = 2 and 6 Hz, 1H-H7);
8.10 (d, J = 9 Hz, 1H-H5); 8.73 (dd, J = 2 and 6 Hz,
1H-H2); 9.12 (s, 1H-NH).
IR (KBr): 1322, 1139, 580, 555, 948, 665 cmꢀ1
.
Mass spectrometry: m/z = 665 (M+ꢀ1; 48); 347 (25);
237(75); 143 (100).
Mass spectrometry: m/z = 448 (M+; 25); 384 (35); 303
(100); 223 (75); 143 (85); 116 (77).
The zinc complex 18 was prepared according to a proce-
dure found in the literature.23 About 1.5 mmol of the
sulfonamide was dissolved in 75 ml methanol and 2 ml
2 M NH4OH were added. While this solution was mag-
netically stirred, 0.75 mmol of ZnCl2 dissolved in 50 ml
methanol were added dropwise. When addition was
completed a green yellow precipitate was formed which
was separated by filtration.
IR (KBr): 3249 (NH), 1443, 1376 (SO2N), 1164 (SO2N),
.
920, 758, 685, 662, 585, 559 cmꢀ1
3.2.12. 5,7-Dibromoquinolin-8-amine (13). Brow solid.
mp: 119–122 ꢁC.
1H NMR (CDCl3, 300 MHz) d 5.36 (s, 2H-NH2); 7.40
(dd, J = 4.2 and 8.7 Hz, 1H-H3); 7.72 (s, 1H-H6); 8.32
(dd, J = 1.5 and 8.4 Hz, 1H-H4); 8.70 (dd, J = 1.8 and
4.2 Hz, 1H-H2).
3.2.17. Bis[4-Nitro-N-(quinolin-8-yl)benzenesulfonami-
date-j2N,N0]zinc(II) (18).15 Green/yellow crystalline
solid: 88%. Mp: >300 ꢁC.
3.2.13. N-(5,7-Dibromo-8-quinolyl)-4-n-propylbenzenesulf-
onamide (14). Crystalline solid: 50%. Mp: 150 ꢁC.
IR (KBr): 1324, 1284, 1142, 1120, 569, 554, 962,
656 cmꢀ1
.

7560
L. E. da Silva et al. / Bioorg. Med. Chem. 15 (2007) 7553–7560
Mass spectrometry: m/z = 720 (M+; 10); 329 (40); 265
(75); 143 (100).
Sevegny, G.; Yelle, J.; Perron, V.; Leberre, N.; Herbart,
D.; Wu, J. J. Bioorg. Med. Chem. Lett. 2006, 16, 3459.
´
7. Bhattacharya, G.; Herman, J.; Delfın, D.; Salem, M. M.;
Barszcz, T.; Mollet, M.; Riccio, G.; Brun, R.; Webovetz,
K. A. J. Med. Chem. 2004, 47, 1823.
8. Lunardi, F.; Guzela, M.; Rodrigues, A. T.; Correa, R.;
Acknowledgments
ˆ
Eger-Mangrich, I.; Steindel, M.; Grisard, E. C.; Assreuy,
J.; Calixto, J. B.; Santos, A. R. S. Antimicrob. Agents
Chemother. 2003, 47, 1449; da Silva, L. E.; Joussef, A. C.;
Pacheco, L. K.; Albino, D. B. L.; Duarte, A. M. C.;
Steindel, M.; Rebelo, R. A. Lett. Drug Des. Discov. 2007,
4, 154.
The authors are grateful to the Brazilian agencies CNPq
and CAPES for financial support.
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