Synthesis and anticancer activities of some novel 2-(benzo[d]thiazol-2-yl)- 8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones

Article abstract of DOI:10.1016/j.ejmech.2011.01.066

A series of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c] quinolin-3(5H)-ones (3a-g) have been synthesized and evaluated for their in vitro antiproliferative activities against four human cancer cell lines: MDA-MB-435 (breast), HL-60 (leukemia), HCT-8 (colon) and SF-295 (central nervous system). The results showed that the compounds 3b (2-(benzo[d]thiazol-2-yl)-8- methyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) and 3c (2-(benzo[d]thiazol-2-yl)-8- bromo-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) exhibited good cytotoxicity for three cell lines with IC₅₀ values lower than 5 μg/mL. Analysis of theoretical toxicity risks have shown medium tumorigenic and irritant risks related to 3b and 3c in contrast to doxorubicin, the positive control.

Full text of DOI:10.1016/j.ejmech.2011.01.066

European Journal of Medicinal Chemistry 46 (2011) 1448e1452
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Synthesis and anticancer activities of some novel 2-(benzo[d]thiazol-2-yl)-
8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones
Raísa da R. Reis a, Elisa C. Azevedo a, Maria Cecília B.V. de Souza a, Vitor Francisco Ferreira a,
Raquel C. Montenegro b, Ana Jérsia Araújo b, Cláudia Pessoa b, Letícia V. Costa-Lotufo b,
,
c
,
,d
Manoel O. de Moraes b, José D.B.M. Filho b, Alessandra M.T. de Souza a d, Natasha C. de Carvalho c
,
Helena C. Castro c, Carlos R. Rodrigues d, Thatyana R.A. Vasconcelos a
,
*
a Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Outeiro de São João Batista, s/no, Centro, Niterói 24020-141, RJ, Brazil
b Universidade Federal do Ceará, Departamento de Fisiologia e Farmacologia, Campus do Porangabussu, 60430-270 Fortaleza, CE, Brazil
c Universidade Federal Fluminense, Instituto de Biologia, Departamento de Biologia Celular e Molecular, LABioMol, Outeiro de São João Batista, s/no, Centro,
Niterói 24020-141, RJ, Brazil
d Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Laboratório de Modelagem Molecular e QSAR (ModMolQSAR), 21941-590, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones (3aeg) have
been synthesized and evaluated for their in vitro antiproliferative activities against four human cancer
cell lines: MDA-MB-435 (breast), HL-60 (leukemia), HCT-8 (colon) and SF-295 (central nervous system).
The results showed that the compounds 3b (2-(benzo[d]thiazol-2-yl)-8-methyl-2H-pyrazolo[4,3-c]-
quinolin-3(5H)-one) and 3c (2-(benzo[d]thiazol-2-yl)-8-bromo-2H-pyrazolo[4,3-c]quinolin-3(5H)-one)
Received 1 October 2010
Received in revised form
26 January 2011
Accepted 27 January 2011
Available online 3 February 2011
exhibited good cytotoxicity for three cell lines with IC50 values lower than 5 mg/mL. Analysis of theo-
retical toxicity risks have shown medium tumorigenic and irritant risks related to 3b and 3c in contrast
to doxorubicin, the positive control.
Keywords:
Benzothiazoles
Pyrazoles
Ó 2011 Elsevier Masson SAS. All rights reserved.
Quinolones
Anticancer
1. Introduction
is important pharmacophore with a wide range of therapeutical
activities such as antitumoral [13], antibacterial, anti-inflammatory
Cancer still remains a threat to men’s health, representing the
second leading cause of death worldwide [1]. It is estimated that 12
million people will die from cancer in 2030 [2]. In the last years,
many efforts have been made to develop new strategies for finding
safe and effective ways of treating this disease which include an
increased in the understanding of the biological process involved in
cancer cell survival and also the search for novel chemotherapeutic
agents [1]. In this context, the major challenge is the development
of more effective and safer drugs for the treatment of cancer.
In the search of new compounds, benzothiazole derivatives play
an important role on designing of new drugs, since they present an
interesting pharmacological profile [3], including antiallergic [4],
anti-inflammatory [5], antitumor [6], analgesic [7], antimicrobial
[8,9], anthelmintic [10], antileishmanial [11], anticonvulsant [12]
activity also with considerable efficacy as kinase, topoisomerase I/II
and trans-retinoic acid metabolism inhibitors [1]. Pyrazole nucleus
[14], hypotensive [14] and ligands for benzodiazepine receptors [15].
Finally, quinolone derivatives are reported in literature for varied
pharmacological activities like tuberculostatic [16], antiviral [17],
antiparasitic [18], antitumoral [19] and anti-ischemic [20].
In continuation of our work on synthesis of some pharmacolog-
ically important heterocycles [21e23], a novel series of 2-(benzo[d]
thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones
was designed (Fig.1), synthesized (Scheme 1) and evaluated against
different human cancer cell lines (Table 1).
2. Results and discussion
2.1. Chemistry
The target compounds 3aeg were synthesized according to
Scheme 1. On the basis of the previous studies carried out in our
laboratory, we designed and prepared 2-(benzo[d]thiazol-2-yl)-
8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones derivatives
(3aeg). The syntheses of 3aeg were started by the preparation of
* Corresponding author. Tel.: þ55 2126292230; fax: þ55 2126292144.
E-mail address: gqothatyana@vm.uff.br (T.R.A. Vasconcelos).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.01.066

R.R. Reis et al. / European Journal of Medicinal Chemistry 46 (2011) 1448e1452
1449
proton H7 appears together with the benzothiazole signal H70 as
a multiplet at 7.89e7.86 ppm. Proton H40 is shown as a dublet at
8.02 ppm (J ¼ 7.5 Hz) and protons H50 and H60 as double duplets at
7.48 ppm (J ¼ 8.1, 7.2 and 1.2 Hz) and 7.35 ppm (J ¼ 8.1, 8.1 and
1.2 Hz). The 13C NMR spectra exhibit the C3 signal at 161.8 ppm, C20
at 155.2 ppm and carbons C4 and C9 at 141.2 and 124.2 ppm,
respectively.
Cl
O
C
R
R
N
S
OEt
NH
NH2
N
H
2.2. Biological activity
Molecular
Hybridization
The in vitro anticancer activities of compounds 3aeg were
assessed against four human cancer cell lines in comparison to
doxorubicin, the positive control, by using MTT assay [24]. The
concentrations that induce 50% inhibition of cell growth (IC50) in
N
S
N
mg/mL are reported in Table 1.
Results showed that 3b and 3c exhibited a considerable effect
against three cancer cell lines. Based on data collected from three
independent experiments, compound 3b was considered active
N
R
O
against breast cancer (MDA-MB-435) with an IC50 value of 2.3
and with moderately profile against colon (HCT-8) and central
nervous system (SF-295) cell lines (IC50 values of 4.1 and 4.5 g/mL,
mg/mL
N
H
m
respectively). The compound 3c showed a good cytotoxicity aga-
inst MDA-MB-435 and HL-60 cell lines with IC50 values of 1.6 and
Fig. 1. A design for synthesis of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo
[4,3-c]quinolin-3(5H)-ones analogs.
3.0
activity against SF-295 with IC50 value of 4.1
lts are in accordance to National Cancer Institute (NCI) protocols,
mg/mL, respectively. Compound 3c also exhibited a moderate
m
g/mL. These resu-
quinolone derivatives 1aeg according to a procedure described in
the literature, which includes treatment of the appropriate aniline
with diethylethoxymethylenemalonate to obtain the enamine de-
rivatives followed by thermal cyclization in diphenyl ether.
Refluxing these quinolones in thionyl chloride afforded the corre-
sponding chloro-derivatives 2aeg [22], which were coupled with
2-hydrazinobenzothiazole to give the desired compounds 3aeg in
moderate to good yields, as described in the general procedure.
Spectral data of all compounds (1H NMR, 13C NMR, IR and ESI-MS)
are in full agreement with the proposed structures. 2D-NMR
techniques (COSY, HSQC and HMBC) helped us to assign the correct
signals of the compounds. As an example, the NMR 1H for
compound 3c exhibits two singlets at 13.26 and 8.86 ppm for NeH
and H4, respectively. Protons H6 and H9 are shown as dublets at
7.73 ppm (J ¼ 8.7 Hz) and 8.36 ppm (J ¼ 2.4 Hz), respectively, and
where compounds exhibiting IC50 values <4 mg/ml are considered
active [25].
The mechanical stability of red blood cells is a good parameter
for in vitro screening of unspecific cytotoxicity, since the membrane
of erythrocyte can suffer significant changes in its structural
properties [26]. The assay with the series showed the absence of
hemolytic activity (EC >250 mg/mL). Therefore we may suggest that
the mechanism involved in cytotoxicity against cancer cell may not
be related to nonspecific membrane damage (Table 1).
In this work we also performed a computational study for
predictionof physicalechemicalproperties ofall derivatives (Table 1).
In the effort to study the hydrophobic pattern, we analyzed the
theoretical parameters related to the oral bioavailability according to
Lipinski ‘rule of5’ [27]. Thisrule theoretically determines if a chemical
compound presents absorption and permeation across membranes
properties that would make it a likely orally active drug in humans.
Interestingly our results pointed that all compounds may have a good
oral biodisponibility (Table 1).
The analysis of theoretical toxicity risks (mutagenic, tumori-
genic, irritant and reproductive effects) for these series using Osiris
program showed compounds 3b and 3c with medium tumorigenic
and irritant risks in contrast to doxorubicin. Finally, we evaluated
these derivatives as potential drugs by calculating druglikeness and
drug-score [28] which showed positive values, despite better
values of doxorubicin (Fig. 2).
O
O
R
EtO2C
CO2Et
OEt
OEt
NH2
a
+
N
H
H
R
R
1a-g
5'
b
4'
6'
7'
3'
N
Cl
O
S
2
1
1'
2'
3
R
3. Conclusion
N
N
OEt
c
9
6
9a
5a
8
O
9b
N
N
A new series of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyr-
azolo[4,3-c]quinolin-3(5H)-ones was synthesized and their in vitro
antiproliferative activities were evaluated against four cancer cell
lines. Despite being less cytotoxic than doxorubicin, the results
herein reaffirm the cytotoxicity of 2-benzo[d]thiazole derivatives
against cancercell lines and pointed compound 3c as the most active
for breast cancer (MDA-MB-435) and as a promising lead molecule
for anticancer drug design. Regarding the hemolytic assay, none of
the compounds was capable to cause hemolysis in mouse erythro-
3a
4
7
2a-g
5
3a: R= F; 3b: R= CH3
H
3c: R= Br; 3d: R= OCH3
3e: R= Cl; 3f: H; 3g: R= NO2
a) 1- EtOH, reflux, 2-10h; 2- Diphenyl ether, reflux, 30min-6h
b) SOCl2, reflux, 17h
c) 1- 2-hydrazinobenzothiazole/toluene, reflux, 3h; 2- AcOH, reflux, 2h
cytes, even at the highest concentration (250
mg/mL). It suggests
that the mechanism of cytotoxicity of the substances is not related
Scheme 1. Synthetic route used for preparing the pyrazolo[4,3-c]quinolin-3-one
derivatives 3aeg.

1450
R.R. Reis et al. / European Journal of Medicinal Chemistry 46 (2011) 1448e1452
Table 1
Cytotoxic activity expressed by IC50 in
m
g/mL of compounds for cancer cell linesa. Lipophilicity, some physicalechemical properties and theoretical oral biodisponibility
(Lipinski ‘rule of 5’) predicted by using a molecular modeling approach.
Compound
MTT
Hemolysis
Lipinski RO5
b
IC50 mg/mL
MDA-MB-435
EC50
ELUMO EHOMO
(eV)
Dipole
(Debye)
MW
clogP HBA HBD
(
m
g/mL) (eV)
HL-60
HCT-8
SF-295
3a
3b
3c
3d
3e
3f
>5
>5
>5
>5
>5
>250
>250
>250
>250
>250
>250
>250
e
1.783
2.029
1.684
2.058
1.703
1.942
0.933
e
ꢀ7.692 8.156
ꢀ7.561 8.532
ꢀ7.729 7.965
ꢀ7.552 7.321
ꢀ7.723 8.017
ꢀ7.605 8.310
ꢀ7.891 8.565
336.35 3.43
332.38 3.69
397.25 4.07
348.38 3.27
352.80 3.98
318.36 3.37
363.35 3.24
5
5
5
6
5
5
8
e
0
0
0
0
0
0
0
e
2.3 (1.7e3.1)
1.6 (1.3e1.9)
>5
>5
>5
>5
4.1 (2.2e7.5)
4.5 (2.2e9.0)
4.1 (2.5e6.9)
>5
>5
>5
>5
3.0 (1.7e5.1)
>5
>5
>5
>5
>5
>5
>5
>5
>5
3g
Doxorubicin 0.69 (0.59e0.83) 0.03 (0.02e0.04)
0.06 (0.04e0.08) 0.41 (0.29e0.44)
e
e
e
e
a
Data are presented as IC50 values and 95% of confidence interval for breast (MDA-MB-435), leukemia (HL-60), colon (HCT-8) and central nervous system (SF-295) cancer
cells. Doxorubicin was used as positive control. Experiments were performed in triplicate.
b
EC50 ¼ effective concentration.
with membrane disruption and is probably related to more specific
pathways of the cells. Additional studies may be worth undertaking
to elucidate the molecular mechanism that underlies the cytotox-
icity of compounds 3b and 3c.
[4,3-c]quinolin-3(5H)-ones 3aeg as solids which were collected by
filtration under vacuum, washed with water and subsequent puri-
fied by washing with hot ethyl alcohol.
4.1.1.1. 2-(Benzo[d]thiazol-2-yl)-8-fluoro-2H-pyrazolo[4,3-c]quino-
lin-3(5H)-one (3a). Yield: 72%; m.p. 293e295 ꢁC. IR (KBr,
n )
cmꢀ1
4. Experimental protocols
3072 (NeH); 1687 (C]O); 1626 (C]N). 1H NMR (DMSO-d6,
300.00 MHz): 13.24 (s, 1H, NeH); 8.91 (s, 1H, H4); 8.36 (dd, 1H,
J ¼ 6.0 and 9.0 Hz, H7); 8.03 (d, 1H, J ¼ 7.2 Hz, H4 or H7 ); 7.90 (d, 1H,
d
4.1. Chemistry
0
0
0
0
0
0
J ¼ 8.1 Hz, H7 or H4 ); 7.56e7.46 (m, 3H, H5 or H6 , H6 and H9); 7.35
Melting points were determined on a FishereJohns apparatus
and are uncorrected. Infrared (IR) spectra were recorded on a Per-
kineElmer 1420 spectrometer as potassium bromide pellets and
frequencies are expressed in cmꢀ1. Mass spectra (ESI-MS) were
recorded on a ZQ single quadrupole massspectrometer. NMR spectra
were recorded on a Varian Unity Plus 300 spectrometer operating at
300.00 MHz (1H) and 75.0 MHz (13C), in deuterated dimethylsulf-
oxide. Chemical shifts are reported in ppm (d) relative to tetrame-
thylsilane. Reactions were routinely monitored by thin-layer
chromatography (TLC) on silica-gel precoated F254 Merck plates.
(ddd, 1H, J ¼ 8.1, 7.8 and 0.9 Hz, H6 or H5 ); ppm. 13C NMR (DMSO-
d6, 75.0 MHz): 161.9; 156.2; 155.0; 152.8; 149.4; 146.3; 141.5; 132.0;
126.3; 125.5; 123.9; 121.8; 121.3; 115.2; 106.0; 105.7; 104.0 ppm.
ESI-MS: m/z [M ꢀ H]ꢀ: 335.2.
0
0
4.1.1.2. 2-(Benzo[d]thiazol-2-yl)-8-methyl-2H-pyrazolo[4,3-c]quino-
lin-3(5H)-one (3b). Yield: 62%; m.p. 302e303 ꢁC. IR (KBr,
n )
cmꢀ1
3058 (NeH); 1695 (C]O); 1622 (C]N). 1H NMR (DMSO-d6,
300.00 MHz):
13.22 (s, 1H, NeH); 8.86 (d, 1H, J ¼ 2.7 Hz, H4); 8.11
(s, 1H, H9); 8.04 (d, 1H, J ¼ 8.1 Hz, H4 or H7 ); 7.88 (d, 1H, J ¼ 8.1 Hz,
d
0
0
0
0
H7 or H4 ); 7.69 (d, 1H, J ¼ 8.7 Hz, H6); 7.56 (dd, 1H, J ¼ 8.7 and
4.1.1. General procedure for the synthesis of 2-(benzo[d]thiazol-2-yl)-
8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones derivatives
(3aeg)
0
0
1.8 Hz, H7); 7.48 (dd, 1H, J ¼ 8.7 and 7.8 Hz, H5 or H6 ); 7.34 (dd, 1H,
J ¼ 8.1 and 8.1 Hz, H6 or H5 ); 2.50 (s, 3H, CH3) ppm. 13C NMR
(DMSO-d6, 75.0 MHz): 161.8; 155.3; 149.0; 146.2; 140.0; 137.0;
133.9; 132.3; 131.9; 126.2; 123.9; 122.2; 122.1; 121.8; 121.0; 120.0;
118.3; 103.1; 21.0 ppm. ESI-MS: m/z [M ꢀ H]ꢀ: 331.2.
0
0
The quinolone derivatives 1 were prepared by treating the
appropriate aniline (100 mmol) with diethyl ethoxymethylene-
malonate (100 mmol) under reflux in ethanol (5 mL) for 2e10 h to
obtain the enamine derivatives that were then cyclized in refluxing
diphenyl ether for 30 mine6 h [29]. These quinolones (13 mmol)
were refluxed in thionyl chloride (20 mL), for 17 h, affording the
corresponding chloro-derivatives 2aeg [22]. Reaction of 2aeg
(4 mmol) with 2-hydrazinobenzothiazole (8 mmol) in toluene
(30 mL), for 3 h, followed by a 2 h reflux in acetic acid gave the
corresponding 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo
4.1.1.3. 2-(Benzo[d]thiazol-2-yl)-8-bromo-2H-pyrazolo[4,3-c]quino-
lin-3(5H)-one (3c). Yield: 65%; m.p. 312e313 ꢁC. IR (KBr,
n )
cmꢀ1
3058 (NeH); 1709 (C]O); 1624 (C]N). 1H NMR (DMSO-d6,
300.00 MHz): 13.26 (s, 1H, NeH); 8.86 (s, 1H, H4); 8.36 (d, 1H,
J ¼ 2.4 Hz, H9); 8.02 (d, 1H, J ¼ 7.5 Hz, H4’ or H7’); 7.89e7.86 (m, 2H,
d
0
0
H4 or H7 and H7); 7.73 (d, 1H, J ¼ 8.7 Hz, H6); 7.48 (ddd, 1H, J ¼ 8.1,
0
0
0
7.2 and 1.2 Hz, H5 or H6 ); 7.35 (ddd, 1H, J ¼ 8.1, 8.1 and 1.2 Hz, H5 or
H ) ppm. 13C NMR (DMSO-d6, 75.0 MHz): 161.8; 155.2; 149.4; 145.2;
0
141.; 135.1; 134.1; 132.2; 126.5; 125.0; 124.2; 122.3; 122.0; 121.4;
120.2; 119.7; 104.1 ppm. ESI-MS: m/z [M ꢀ H]ꢀ: 395.8.
4.1.1.4. 2-(Benzo[d]thiazol-2-yl)-8-methoxy-2H-pyrazolo[4,3-c]qui-
nolin-3(5H)-one (3d). Yield: 65%; m.p. 323e324 ꢁC. IR (KBr, cmꢀ1
n )
3051 (NeH); 1707 (C]O); 1617 (C]N). 1H NMR (DMSO-d6,
300.00 MHz):
d 13.20 (s, 1H, NeH); 8.82 (s, 1H, H4); 8.04 (d, 1H,
0
0
0
0
J ¼ 7.5 Hz, H4 or H7 ); 7.90 (d, 1H, J ¼ 8.1 Hz, H7 or H4 ); 7.88 (d, 1H,
0
0
J ¼ 8.1 Hz, H7 or H4 ); 7.75 (d,1H, J ¼ 9.0 Hz, H6); 7.66 (d,1H, J ¼ 2.7 Hz,
0
0
0
H9); 7.49 (dd, 1H, J ¼ 8.1 and 6.9 Hz, H5 or H6 ); 7.38e7.33 (m, 2H, H6
or H5 andH7);3.97(s, 3H, OCH3)ppm.13C NMR(DMSO-d6, 75.0 MHz):
0
Fig. 2. (A) Druglikeness and drugscore values and (B) theoretical toxicity evaluation of
the active compounds (3b and 3c) compared to doxorubicin (doxo).
161.8; 157.9; 154.9; 148.9; 146.1; 139.2; 131.9; 130.1; 126.2; 123.8;

R.R. Reis et al. / European Journal of Medicinal Chemistry 46 (2011) 1448e1452
1451
121.8; 121.6; 121.0; 120.7; 119.6; 102.8; 102.3; 55.8 ppm. ESI-MS: m/z
[M ꢀ H]ꢀ: 347.2.
calculated effective dose that induced lysis on 50% that of the
Triton X-100.
4.1.1.5. 2-(Benzo[d]thiazol-2-yl)-8-chloro-2H-pyrazolo[4,3-c]quino-
4.4. Molecular modeling
lin-3(5H)-one (3e). Yield: 68%; m.p. 309e310 ꢁC. IR (KBr,
n )
cmꢀ1
3092 (NeH); 1693 (C]O); 1622 (C]N). 1H NMR (DMSO-d6,
300.00 MHz): 13.30 (s, 1H, NeH); 8.90 (s, 1H, H4); 8.25 (d, 1H,
J ¼ 2.7 Hz, H9); 8.04 (d,1H, J ¼ 7.8 Hz, H4’ or H7’); 7.89 (d,1H, J ¼ 8.1 Hz,
Molecular modeling was performed using Osiris programs.
Structures were minimized and the equilibrium geometry was
obtained in vacuum using a semi-empirical AM1 module. In
order to evaluate the electronic properties of the AM1 minimal
energy conformations, they were submitted to a single-point ab
initio calculation using Hartree-Fock method with a 6-31G**
basis set implemented in the programa. The electronic proper-
ties (HOMO and LUMO energy, dipole moment and lipophilicity-
cLogP) were calculated for all compounds. Hydrogen bond
acceptor and donor, molecular weight and the theoretical
toxicity properties were calculated in the Osiris Property
Explorer (http://www.organic-chemistry.org/) and in the in silico
screening program (http://www.molinspiration.com/cgi-bin/
properties).
d
0
0
H7 orH4 ’);7.79e7.78 (m, 2H, H6 and H7); 7.49(ddd,1H, J ¼ 7.2, 7.2 and
0
0
0
0
1.2 Hz, H5 orH6 ); 7.35 (ddd,1H, J ¼ 8.1, 8.1 and 1.2 Hz, H6 or H5 ) ppm.
13C NMR (DMSO-d6, 75.0 MHz): 162.0; 155.3; 149.6; 146.4; 141.2;
136.3; 132.3; 131.3; 127.3; 126.4; 124.0; 122.9; 122.0; 121.4; 120.3;
118.7; 103.6 ppm. ESI-MS: m/z [M ꢀ H]ꢀ: 351.2.
4.1.1.6. 2-(Benzo[d]thiazol-2-yl)-2H-pyrazolo[4,3-c]quinolin-3(5H)-
one (3f). Yield: 70%; m.p. 283e284 ꢁC. IR (KBr, cmꢀ1) 3053 (NeH);
n
1693 (C]O); 1623 (C]N). 1H NMR (DMSO-d6, 300.00 MHz):
d
13.26 (s,1H, NeH); 8.95 (s,1H, H4); 8.31 (d,1H, J ¼ 7.8 Hz, H6); 8.05
0
0
0
0
(d, 1H, J ¼ 7.8 Hz, H4 or H7 ); 7.91 (d, 1H, J ¼ 7.5 Hz, H7 or H4 );
7.77e7.74 (m, 2H, H8 and H9); 7.67e7.61 (m, 1H, H7); 7.49 (ddd, 1H,
0
0
J ¼ 8.4, 8.4 and 1.5 Hz, H5 or H6 ); 7.35 (ddd, 1H, J ¼ 8.4, 8.4 and
Acknowledgements
1.4 Hz, H6 or H5 ) ppm. 13C NMR (DMSO-d6, 75.0 MHz): 161.6;
154.8; 149.3; 145.3; 141.4; 135.0; 132.1; 131.3; 131.1; 126.3; 123.9;
122.4; 121.7; 121.2; 119.8; 103.27 ppm. ESI-MS: m/z [M ꢀ H]ꢀ: 317.2.
0
0
The authors thank FAPERJ, CAPES and UFF for financial
support. Fellowships granted to R.R.R by PIBIC-CNPq and to
M.C.B.V.S., V.F.F., C.P., L.V.C., M.O.M., H.C.C. and C.R.R. by CNPq
(Brazil).
4.1.1.7. 2-(Benzo[d]thiazol-2-yl)-8-nitro-2H-pyrazolo[4,3-c]quinolin-
3(5H)-one (3g). Yield: 67%; m.p. >360 ꢁC. IR (KBr,
n
cmꢀ1) 3094
(NeH); 1692 (C]O); 1624 (C]N).1H NMR (DMSO-d6, 300.00 MHz):
d
13.30 (s,1H, NeH); 9.04 (s,1H, H4); 8.97 (d,1H, J ¼ 2.4 Hz, H9); 8.51
References
0
(dd,1H, J ¼ 9.0 and 2.4 Hz, H7); 8.06 (d,1H, J ¼ 8.1 Hz, H4’ or H7 ); 7.93
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0
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