Synthesis, characterization and evaluation of in vitro antitumor activities of novel chalcone-quinolinone hybrid compounds

Article abstract of DOI:10.21577/0103-5053.20180108

Chalcone-quinolinone hybrid compounds, as well as the synthesis of such compounds, have few reports in the literature. Such compounds may be quite useful in therapeutics, since various biological activities are reported for both chalcones and quinolinones. In the present work, several novel chalcone-quinolinone compounds have been synthesized. The reaction conditions developed allowed to obtain the compounds in a single step of synthesis from the chalcones. The products precipitated pure and were isolated by filtration. The yields of such reactions, from 45 to 94percent, were promising. The product structures were confirmed by nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS) techniques. Their antitumor activities were evaluated in HCT-116 (colon) cell lines by the 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) test. The half maximal inhibitory concentration (IC₅₀) values obtained for the most active chalcones were between 2.9 and 7.5 and for active quinolinone was 19.3 mg L^-1. The antitumor activities results suggest that the class of compounds studied has potential for use in cancer research.

Full text of DOI:10.21577/0103-5053.20180108

http://dx.doi.org/10.21577/0103-5053.20180108
J. Braz. Chem. Soc., Vol. 00, No. 00, 1-18, 2018
Article
Printed in Brazil - ©2018 Sociedade Brasileira de Química
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities of Novel
Chalcone-Quinolinone Hybrid Compounds
a
b
b
a
Giulio D. C. d’Oliveira, Andrea F. Moura, Manoel O. de Moraes, Caridad N. Perez
,
a
and Luciano M. Lião*
a
Instituto de Química, Universidade Feredal de Goiás, Campus Samambaia,
4690-900 Goiânia-GO, Brazil
7
b
Núcleo de Pesquisas e Desenvolvimento de Medicamentos, Universidade Federal do Ceará,
0430-275 Fortaleza-CE, Brazil
6
Chalcone-quinolinone hybrid compounds, as well as the synthesis of such compounds, have
few reports in the literature. Such compounds may be quite useful in therapeutics, since various
biological activities are reported for both chalcones and quinolinones. In the present work, several
novel chalcone-quinolinone compounds have been synthesized. The reaction conditions developed
allowed to obtain the compounds in a single step of synthesis from the chalcones. The products
precipitated pure and were isolated by filtration. The yields of such reactions, from 45 to 94%,
were promising. The product structures were confirmed by nuclear magnetic resonance (NMR)
and electrospray ionization mass spectrometry (ESI-MS) techniques. Their antitumor activities
were evaluated in HCT-116 (colon) cell lines by the 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl-
2
-H-tetrazolium bromide (MTT) test. The half maximal inhibitory concentration (IC ) values
50
obtained for the most active chalcones were between 2.9 and 7.5 and for active quinolinone was
-
1
1
9.3 mg L . The antitumor activities results suggest that the class of compounds studied has
potential for use in cancer research.
Keywords: chalcone-quinolinone hybrids, chacone sulfonamide, Claisen-Schmidt
condensation, antitumor activity
23
24
Introduction
trans-sialidase. Our search in the Scifinder®, for the
sub-structure shown in Figure 1, resulted in only 11
different structures.
Several chalcones and chalcone analogs have been
found in nature or have been synthesized, and sundry
biological activities have been reported for this class of
compound. Some reviews summarize the synthetic routes
and applications of chalcones. Anticancer activities of
synthetic and natural chalcones, and chalcone analogs, are
1
-4
5-18
reported in the literature, involving diverse mechanisms
related to various aspects of cancer progression.
A wide range of biological activities of quinolinones
has also been reported, such as the inhibitory activity of
1
9
20
21
GSK-3β and antimicrobial, anti-HIV, antimalarial and
Figure 1. Sub-structure of chalcone-quinolinone searched on Scifinder®
22
24
antitumor activity. However, the synthesis of chalcone-
quinolinone compounds, possessing the moiety shown
in the Figure 1, is rarely described in the literature, and
only one study reports the biological activity of such
compounds; in this case inhibition of Trypanosoma cruzi
database.
23
Kim et al. described the synthesis of two compounds
with this nucleus via acid catalysis in methanol. All
compounds synthesized had identical substituents in rings B
23
25
and C. Saito et al. reported the synthesis of a compound
*e-mail: lucianoliao@ufg.br
with these nuclei, exploiting the reactivity of an alkyne

2
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities
J. Braz. Chem. Soc.
group. Rings B and C also come from the same aldehyde
between the peaks assigned to the structure and the total
area of all peaks attributed to the material under analysis.
For compounds 16, 22, 31, 32, 33, 34 and 35, in which
considerable amounts of solvent were in evidence, the
degree of purity was calculated on the dry basis, i.e.,
disregarding the peaks of the solvents.
25
26
added to the reaction system. Black et al. started from
an acetophenone with N at the ortho position and reacted
with an aldehyde, by a Claisen-Schmidt condensation
reaction, using an amide and sodium hydride as a basic
catalyst to obtain the final compounds in two steps, with
27
different substituted aldehydes. Ma et al. also started from
an acetophenone with N at the ortho position and reacting
with aldehyde. The yield was 29%, and rings B and C had
Mass spectrometric (MS) analyses were performed
using a MicroTOF-Q® III spectrometer (Bruker Daltonics,
Bremen, Germany) equipped with a commercial ESI
(electrospray ionization) ion source.Analyses were by direct
28
identical substituents. Wang et al. synthesized a series
of similar compounds via acid catalysis starting from an
alkyne group, with nitrogen in the ortho position of the ring.
The substituents of rings B and C were identical.
-1
infusion (3 μLmin ) after extraction under acetonitrile and
1 mM formic acid.All analyses were carried out in positive
mode. The configuration of the ESI(+) was: nitrogen gas
nebulizer with a temperature of 200 °C, pressure of 0.4 bar
In recent years, our research group has been dedicated
to synthesis, characterization and antitumor evaluation
-1
and a drying gas flow of 4 L min ; voltage in the capillary
of –4 kV; temperature of 200 °C in the transfer capillary;
end plate offset of –500 V; 35 V skimmer and –1.5 V
collision voltage. Each spectrum was acquired using two
microscans and processed using Data Analysis Software
(Bruker Daltonics, Bremen, Germany).
2
9-34
of chalcone derivatives.
The bioactivity of these
compounds is associated with cellular thiols as glutathione
reduced (GSH). Therefore, our group reported the reaction
of Mannich bases and hydroxychalcone with GSH and the
stereochemistry of non-enzyme nucleophilic addition of
GSH to hydroxychalcone and Mannich base derivative at
The infrared spectroscopy analyses were performed
at the State University of Goiás, CCET campus, in
Anápolis, Goiás, on a PerkinElmer, Frontier Dual Range
FT-IR/MIR Spectrometer (Massachusetts, USA), read in
ATR (attenuated total reflectance) apparatus. The melting
points were determined with the solid supported on glass
coverslips and subjected to heating in a melting point
apparatus (Karl Kolb, Frankfurt a.M., Germany).
32,33
different pH. Among these derivatives, the sulfonamide
chalcones have been synthesized and evaluated against
29-31
several strains of human cancer with relevant results.
The synthesis of 3-(p-nitrobenzylidene) quinolinone, with
31
nitro group in rings B and C, reported by de Castro et al.,
motivated the subsequent study of chalcone-quinolinones.
Therefore, the aim of this work was the development of a
synthetic route for chalcone-quinolinone synthesis in such a
way as to incorporate different substituents in B and C rings
and evaluate the antitumor activity of these compounds
against HCT-116 (colon) human tumor cell lines.
Synthesis of compounds 1 to 9
Compounds 1 to 9 were synthesized using the
29
methodology reported by de Castro et al. with apropriate
Experimental
reagents.
General procedures
1-(2-(Phenylsulfonylamine)phenyl)ethanone (1)
1
White crystalline solid, yield 63.8%; H NMR
Nuclearmagneticresonance(NMR)spectrawereacquired
on a Bruker Avance III 500 spectrometer (Rheinstetten,
(500.13 MHz, CDCl ) d 2.56 (s, 3H), 7.08 (ddd, J 7.98, 7.33,
3
1.18 Hz, 1H), 7.42-7.46 (m, 2H), 7.46 (dddd, J 8.44, 7.34,
1.56, 0.41 Hz, 1H), 7.51-7.54 (m, 1H), 7.70 (ddd, J 8.40,
1.15, 0.45 Hz, 1H), 7.80 (ddd, J 8.01, 1.59, 0.46 Hz, 1H),
1
Germany) operating at 11.75T, observing H at 500.13 MHz
13
and C at 125.76 MHz. The spectrometer was equipped
1
2
13
13
with a 5 mm inverse-detection three-channel ( H, H, C
and XBB) and 5 mm broadband observe (BBO) probes. The
samples (ca. 10 mg) were dissolved in 600μL of deuterated
7.84-7.87 (m, 2H), 11.50 (s, 1H); C NMR (125.76 MHz,
CDCl ) d 28.2, 119.2, 122.4, 122.8, 127.2, 129.0, 131.9,
3
133.0, 135.0, 139.5, 139.9, 202.4; HRMS (high-resolution
mass spectrometry) calculated for C H NO S 276.0694,
chloroform (CDCl ), containing tetramethylsilane (TMS) as
3
14 14
3
the internal standard. Complete signal assignment was also
obtained by correlation spectroscopy (COSY), heteronuclear
multiple bond correlation (HMBC) and heteronuclear single
quantum correlation (HSQC) experiments.
found 276.0725.
(E)-3-(2-Methoxyphenyl)-1-(2-(phenylsulfonylamine)phenyl)
prop-2-en-1-one (2)
The degree of purity of the compounds was determined
by the H spectra, from the proportion of the areas
Yellow crystalline solid, yield 93.5%, purity of 99.1%,
1
1
mp 118-120 °C; H NMR (500.13 MHz, CDCl ) d 3.94 (s,
3

Vol. 00, No. 00, 2018
d’Oliveira et al.
3
1
3
3H), 6.96 (d, J 8.35 Hz, 1H), 7.00 (t, J 7.53 Hz, 1H), 7.13
8.48 Hz, 1H), 7.81-7.84 (m, 3H), 11.22 (s, 1H); C NMR
(
(
ddd, J 1.13, 7.35, 7.88 Hz, 1H), 7.36-7.44 (m, 4H), 7.46
d, J 15.65 Hz, 1H), 7.46-7.49 (m, 1H), 7.57 (dd, J 1.58,
(125.76 MHz, CDCl ) d 55.5, 114.6, 119.7, 120.9, 123.2,
3
125.2, 127.2, 127.3, 129.0, 130.4, 130.5, 132.8, 134.0,
-
1
7
2
1
1
1
1
.68 Hz, 1H), 7.75 (dd, J 0.85, 8.30 Hz, 1H), 7.82-7.84 (m,
H), 7.85 (dd, J 1.40, 8.10 Hz, 1H), 8.00 (d, J 15.65 Hz,
139.5, 139.7, 146.0, 162.1, 192.7; IR (ATR) ν / cm
1639 (m), 1494 (m), 1329 (m), 924 (m), 755 (m); HRMS
13
H), 11.30 (s, 1H); C NMR (125.76 MHz, CDCl ) d 55.6,
calculated for C H NO SNa 416.0932, found 416.0833.
3
22 19
4
11.4, 120.6, 120.8, 122.7, 123.1, 123.5, 125.0, 127.3,
29.0, 129.4, 130.7, 132.3, 132.8, 134.1, 139.5, 139.9,
(E)-3-(2-Chlorophenyl)-1-(2-(phenylsulfonylamine)phenyl)
prop-2-en-1-one (6)
-1
41.7, 159.0, 193.3; IR (ATR) ν / cm 1632 (m), 1489
m), 1328 (m), 934 (m), 749 (s); HRMS calculated for
C H NO S 394.1113, found 394.1002.
(
Yellow crystalline solid, yield 79.9%, purity of 98.1%,
1
mp 150-152 °C; H NMR (500.13 MHz, CDCl ) d 7.14
2
2
20
4
3
(ddd, J 1.04, 7.41, 7.94 Hz, 1H), 7.32 (d, J 15.60 Hz, 1H),
(
E)-3-(2-Bromophenyl)-1-(2-(phenylsulfonylamine)phenyl)
7.31-7.34 (m, 1H), 7.35-7.41 (m, 3H), 7.42-7.47 (m, 2H),
7.50 (ddd, J 1.56, 7.31, 8.36 Hz, 1H), 7.69 (dd, J 1.73,
7.63 Hz, 1H), 7.77 (dd, J 0.85, 8.30 Hz, 1H), 7.81-7.84
prop-2-en-1-one (3)
Yellow crystalline solid, yield 77.4%, purity of 96.7%,
1
13
mp 151-153 °C; H NMR (500.13 MHz, CDCl ) d 7.15
(m, 3H), 8.03 (d, J 15.55 Hz, 1H), 11.10 (s, 1H); C NMR
3
(ddd, J 1.19, 7.39, 7.99 Hz, 1H), 7.26 (d, J 15.55 Hz, 1H),
(125.76 MHz, CDCl ) d 120.9, 123.2, 124.7, 124.7, 127.2,
3
7
7
7
.26-7.30 (m, 1H), 7.35-7.37 (m, 1H), 7.38-7.46 (m, 3H),
.50 (ddd, J 1.53, 7.40, 8.35 Hz, 1H), 7.65-7.67 (m, 2H),
.77 (dd, J 1.05, 8.40 Hz, 1H), 7.82-7.85 (m, 3H), 7.99 (d,
127.3, 127.8, 129.0, 130.5, 130.8, 131.6, 132.8, 132.9,
134.5, 135.7, 139.4, 139.9, 141.7, 192.7; IR (ATR) ν / cm
1641 (m), 1494 (m), 1331 (m), 932 (m), 747 (s); HRMS
-1
13
J 15.55 Hz, 1H), 11.10 (s, 1H); C NMR (125.76 MHz,
calculated for C H ClNO SNa 420.0437, found 420.0327.
21
16
3
CDCl ) d 120.9, 123.2, 124.6, 124.9, 126.1, 127.3, 127.8,
3
1
1
27.9, 129.0, 130.8, 131.8, 132.9, 133.7, 134.5, 139.4,
39.9, 144.3, 192.7; IR (ATR) ν / cm 1641 (m), 1493
(E)-3-(4-Chlorophenyl)-1-(2-(phenylsulfonylamine)phenyl)
prop-2-en-1-one (7)
-1
(
m), 1330 (m), 932 (m), 751 (s); HRMS calculated for
Yellow crystalline solid, yield 70.9%, purity of 98.2%,
1
C H BrNO SNa 463.9932, found 463.9837.
mp 150-155 °C; H NMR (500.13 MHz, CDCl ) d 7.14
2
1
16
3
3
(ddd, J 1.16, 7.34, 7.94 Hz, 1H), 7.33 (d, J 15.55 Hz, 1H),
(
E)-3-(4-Ethoxyphenyl)-1-(2-(phenylsulfonylamine)phenyl)
7.37-7.42 (m, 4H), 7.43-7.46 (m, 1H), 7.50 (ddd, J 1.55,
7.40, 8.40 Hz, 1H), 7.52-7.55 (m, 2H), 7.63 (d, J 15.55 Hz,
prop-2-en-1-one (4)
Yellow crystalline solid, yield 76.1%, purity of 98.1%,
1H), 7.75 (dd, J 1.08, 8.33 Hz, 1H), 7.82-7.85 (m, 3H), 11.18
1
13
mp 137-140 °C; H NMR (500.13 MHz, CDCl ) d 1.45
(s, 1H); C NMR (125.76 MHz, CDCl ) d 120.7, 122.5,
3
3
(
(
t, J 7.00 Hz, 3H), 4.09 (q, J 7.00 Hz, 2H), 6.91-6.94
m, 2H), 7.13 (ddd, J 1.25, 7.38, 7.88 Hz, 1H), 7.20 (d,
123.2, 124.6, 127.3, 129.0, 129.4, 129.7, 130.6, 132.9, 132.9,
134.5, 137.0, 139.5, 140.0, 144.5, 192.5; IR (ATR) ν / cm
-1
J 15.50 Hz, 1H), 7.35-7.39 (m, 2H), 7.40-7.44 (m, 1H),
1641 (m), 1492 (m), 1329 (m), 928 (m), 756 (m); HRMS
7
7
7
.47 (ddd, J 1.45, 7.40, 8.38 Hz, 1H), 7.53-7.56 (m, 2H),
.65 (d, J 15.50 Hz, 1H), 7.75 (dd, J 1.03, 8.33 Hz, 1H),
.80-7.84 (m, 3H), 11.22 (s, 1H); C NMR (125.76 MHz,
calculated for C H ClNO S 398.0618, found 398.0462.
21
17
3
13
(E)-3-(3-Nitrophenyl)-1-(2-(phenylsulfonylamine)phenyl)
prop-2-en-1-one (8)
CDCl ) d 14.7, 63.8, 115.0, 119.5, 120.9, 123.2, 125.3,
3
1
1
1
27.0, 127.3, 129.0, 130.4, 130.5, 132.8, 134.0, 139.5,
39.7, 146.1, 161.6, 192.7; IR (ATR) ν / cm 1637 (m),
497 (m), 1329 (s), 927 (m), 761 (s); HRMS calculated for
Yellow crystalline solid, yield 39.7%, purity of 98.4%,
-1
1
mp 190-195 °C; H NMR (500.13 MHz, CDCl ) d 7.17
3
(t, J 7.70 Hz, 1H), 7.40-7.43 (m, 2H), 7.46-7.47 (m, 1H),
7.50 (d, J 15.55 Hz, 1H), 7.53 (t, J 8.03 Hz, 1H), 7.64 (t,
J 7.95 Hz, 1H), 7.72 (d, J 15.60 Hz, 1H), 7.76 (d, J 8.35 Hz,
1H), 7.85 (d, J 7.50 Hz, 2H), 7.89 (d, J 7.80 Hz, 2H), 8.28
(dd, J 1.18, 8.08 Hz, 1H), 8.47 (t, J 1.80 Hz, 1H), 11.18 (s,
C H NO SNa 430.1089, found 430.1103.
2
3
21
4
(E)-3-(4-Methoxyphenyl)-1-(2-(phenylsulfonylamine)phenyl)
prop-2-en-1-one (5)
13
Yellow crystalline solid, yield 87.7%, purity of 98.8%,
1H); C NMR (125.76 MHz, CDCl ) d 120.5, 122.3, 123.2,
3
1
mp 124-126 °C; H NMR (500.13 MHz, CDCl ) d 3.87 (s,
124.0, 124.7, 125.0, 127.3, 129.1, 130.2, 130.8, 133.0,
134.5, 135.0, 136.2, 139.5, 140.2, 142.7, 148.8, 192.0; IR
3
3
1
H), 6.93-6.96 (m, 2H), 7.13 (ddd, J 1.09, 7.26, 7.99 Hz,
H), 7.21 (d, J 15.50 Hz, 1H), 7.35-7.39 (m, 2H), 7.40-7.44
-1
(ATR) ν / cm 1646 (m), 1450 (m), 1333 (m), 930 (m),
(
(
m, 1H), 7.47 (ddd, J 1.53, 7.43, 8.25 Hz, 1H), 7.54-7.57
m, 2H), 7.65 (d, J 15.50 Hz, 1H), 7.75 (dd, J 0.98,
747 (m); HRMS calculated for C H N O S 409.0858,
found 409.0562.
2
1
17
2
5

4
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities
J. Braz. Chem. Soc.
(
E)-3-(4-Bromophenyl)-1-(2-(phenylsulfonylamine)phenyl)
(d, J 0.75 Hz, 1H), 6.78-6.81 (m, 2H), 7.10-7.12 (m, 2H),
7.22-7.26 (m, 2H), 7.28-7.34 (m, 5H), 7.53 (tt, J 1.23,
7.49 Hz, 1H), 7.57 (ddd, J 1.66, 7.36, 8.16 Hz, 1H), 7.59
(s, 1H), 7.71 (dd, J 0.98, 8.18 Hz, 1H), 7.90 (dd, J 1.63,
prop-2-en-1-one (9)
Yellow crystalline solid, yield 52.0%, purity of 97.1%,
1
mp 157-159 °C; H NMR (500.13 MHz, CDCl ) d 7.14
(
3
13
ddd, J 1.15, 7.35, 7.90 Hz, 1H), 7.34 (d, J 15.55 Hz, 1H),
7.83 Hz, 1H), 8.25-8.28 (m, 2H); C NMR (125.76 MHz,
7
7
1
1
1
1
.37-7.40 (m, 2H), 7.42-7.47 (m, 3H), 7.49 (ddd, J 1.54,
.34, 8.41 Hz, 1H), 7.55-7.58 (m, 2H), 7.61 (d, J 15.55 Hz,
H), 7.75 (dd, J 0.80, 8.35 Hz, 1H), 7.81-7.84 (m, 3H),
CDCl ) d 14.8, 59.5, 63.5, 114.9, 124.2, 127.2, 127.4,
3
128.1, 128.2, 128.5, 128.8, 129.0, 130.6, 133.4, 134.0,
135.0, 136.7, 137.5, 139.0, 139.9, 148.1, 159.2, 182.3; IR
1
3
-1
1.17 (s, 1H); C NMR (125.76 MHz, CDCl ) d 120.7,
(ATR) ν / cm 1677 (m), 1601 (m), 1472 (w), 1344 (s),
3
22.6, 123.2, 124.6, 125.4, 127.3, 129.0, 129.9, 130.6,
32.4, 132.9, 133.3, 134.5, 139.4, 140.0, 144.5, 192.5; IR
1306 (w), 1250 (s); HRMS calculated for C H N O S
3
0
25
2
6
541.1433, found 541.1332.
-1
(
ATR) ν / cm 1640 (m), 1489 (m), 1331 (m), 924 (m),
7
51 (s); HRMS calculated for C H BrNO S 442.0113,
(E)-3-(4-Bromobenzylidene)-2-(4-ethoxyphenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (12)
21
17
3
found 442.0004.
Pale yellow crystalline solid, yield 76.6%, purity of
1
Synthesis of compounds 10 to 41
98.4%, mp 196-198 °C; H NMR (500.13 MHz, CDCl )
3
d 1.36 (t, J 7.00 Hz, 3H), 3.95 (q, J 7.00 Hz, 2H), 6.55
(d, J 0.60 Hz, 1H), 6.76-6.79 (m, 2H), 7.03-7.06 (m, 2H),
7.10-7.13 (m, 2H), 7.19-7.23 (m, 2H), 7.27-7.31 (m, 3H),
7.49 (tt, J 1.20, 7.46 Hz, 1H), 7.50 (s, 1H), 7.54 (ddd, J 1.73,
7.30, 8.20 Hz, 1H), 7.53-7.56 (m, 2H), 7.70 (dd, J 0.90,
Chalcones 10 to 41 (1.0 mmol) and benzaldeyde
2.0 mmol) were dissolved in 15 mL of basic ethanol
56.1 mg of potassium hydroxide dissolved) and reacted
25 °C) for 48 h. The solution was filtered and the
precipitate was rinsed with 15 mL of ethanol. The
precipitate was dissolved in dichloromethane (10 mL) and
this solution was extracted with water. The organic phase
was allowed to evaporate slowly, yielding the product. The
compounds 14, 16, 17, 23, 27, 31, 32 and 33 were further
purified by recrystalization by dissolving in dicloromethane
and exposing to ethyl ether vapor.
(
(
(
13
8.15 Hz, 1H), 7.88 (dd, J 1.63, 7.83 Hz, 1H); C NMR
(125.76 MHz, CDCl ) d 14.8, 59.6, 63.4, 114.7, 124.9,
3
127.2, 127.9, 128.3, 128.5, 128.5, 128.8, 128.9, 131.4,
131.5, 132.4, 132.6, 133.2, 134.6, 137.5, 138.6, 139.0,
-1
159.0, 182.7; IR (ATR) ν / cm 1676 (m), 1608 (m), 1474
(w), 1355 (s), 1305 (w), 1245 (s); HRMS calculated for
C H BrNO S 574.0688, found 574.0327.
30
25
4
(
E)-3-(3-Nitrobenzylidene)-2-(4-ethoxyphenyl)-2,3-dihydro-
(E)-3-(4-Chlorobenzylidene)-2-(4-ethoxyphenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (13)
1
-(phenylsulfonyl)-quinolin-4(1H)-one (10)
Pale yellow crystalline solid, yield 78.1%, purity of
Pale yellow crystalline solid, yield 66.2%, purity of
1
1
9
8.6%, mp 187-189 °C; H NMR (500.13 MHz, CDCl )
98.0%, mp 190-192 °C; H NMR (500.13 MHz, CDCl )
3
3
d 1.37 (t, J 6.98 Hz, 3H), 3.96 (q, J 7.02 Hz, 2H), 6.48
d, J 0.75 Hz, 1H), 6.79-6.82 (m, 2H), 7.09-7.12 (m, 2H),
d 1.36 (t, J 7.00 Hz, 3H), 3.95 (q, J 7.00 Hz, 2H), 6.56
(d, J 0.60 Hz, 1H), 6.77-6.80 (m, 2H), 7.10-7.13 (m, 4H),
7.19-7.23 (m, 2H), 7.27-7.32 (m, 3H), 7.37-7.40 (m, 2H),
7.49 (tt, J 1.25, 7.45 Hz, 1H), 7.52 (s, 1H), 7.54 (ddd,
J 1.66, 7.36, 8.19 Hz, 1H), 7.71 (dd, J 1.05, 8.20 Hz, 1H),
(
7
7
.24-7.27 (m, 2H), 7.28-7.34 (m, 3H), 7.40-7.42 (m, 1H),
.54-7.59 (m, 4H), 7.70 (dd, J 0.98, 8.13 Hz, 1H), 7.92
(
(
dd, J 1.73, 7.83 Hz, 1H), 8.04 (t, J 1.95 Hz, 1H), 8.28
ddd, J 0.88, 2.25, 8.23 Hz, 1H); C NMR (125.76 MHz,
13
13
7.89 (dd, J 1.65, 7.80 Hz, 1H); C NMR (125.76 MHz,
CDCl ) d 14.8, 59.6, 63.4, 114.9, 124.4, 125.2, 127.2, 127.4,
CDCl ) d 14.8, 59.6, 63.4, 114.7, 127.2, 127.9, 128.3,
3
3
1
1
1
28.0, 128.1, 128.4, 128.5, 128.9, 129.0, 130.3, 133.5,
33.5, 134.5, 135.0, 135.3, 136.7, 137.6, 139.0, 148.5,
59.2, 182.4; IR (ATR) ν / cm 1675 (m), 1603 (m), 1475
128.5, 128.5, 128.8, 128.9, 129.4, 131.3, 131.3, 132.2,
133.2, 134.6, 136.4, 137.6, 138.6, 138.9, 159.0, 182.7; IR
(ATR) ν / cm 1677 (m), 1609 (m), 1474 (w), 1354 (s),
-1
-1
(
m), 1349 (s), 1306 (w), 1242 (s); HRMS calculated for
1306 (w), 1247 (s); HRMS calculated for C H ClNO S
30
25
4
C H N O S 541.1433, found 541.1026.
530.1193, found 530.1083.
3
0
25
2
6
(
E)-3-(4-Nitrobenzylidene)-2-(4-ethoxyphenyl)-2,3-dihydro-
(E)-3-(3-Nitrobenzylidene)-2-(4-methoxyphenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (14)
1
-phenylsulfonyl)-quinolin-4(1H)-one (11)
Pale yellow crystalline solid, yield 78.1%, purity of
Pale yellow to white amorphous solid, yield 93.6%,
1
1
9
9.1%, mp 208-209 °C; H NMR (500.13 MHz, CDCl )
purity of 96.3%; H NMR (500.13 MHz, CDCl ) d 3.75 (s,
3
3
d 1.37 (t, J 7.00 Hz, 3H), 3.96 (q, J 7.02 Hz, 2H), 6.53
3H), 6.50 (s, 1H), 6.81-6.84 (m, 2H), 7.11-7.13 (m, 2H),

Vol. 00, No. 00, 2018
d’Oliveira et al.
5
1
3
7
1
1
8
.24-7.29 (m, 2H), 7.30-7.34 (m, 3H), 7.42 (d, J 7.70 Hz,
H), 7.54-7.58 (m, 3H), 7.59 (s, 1H), 7.71 (d, J 8.10 Hz,
H), 7.93 (dd, J 1.50, 7.80 Hz, 1H), 8.04 (t, J 1.98 Hz, 1H),
1H), 7.89 (dd, J 1.58, 7.83 Hz, 1H); C NMR (125.76 MHz,
CDCl ) d 55.2, 59.6, 114.3, 127.2, 127.3, 127.9, 128.3,
128.4, 128.7, 128.8, 128.9, 129.4, 131.2, 131.3, 132.1,
133.2, 134.7, 136.4, 137.5, 138.6, 138.9, 159.6, 182.7; IR
3
13
.28 (dd, J 1.88, 8.23 Hz, 1H); C NMR (125.76 MHz,
-1
CDCl ) d 55.2, 59.5, 114.5, 124.4, 125.2, 127.2, 127.4,
(ATR) ν / cm 1671 (m), 1605 (m), 1475 (w), 1355 (s),
3
1
1
1
28.0, 128.1, 128.5, 128.6, 128.9, 129.0, 130.3, 133.5,
33.5, 134.5, 135.0, 135.3, 136.7, 137.5, 139.0, 148.5,
59.8, 182.4; IR (ATR) ν / cm 1673 (m), 1606 (m), 1477
1303 (m), 1253 (m); HRMS calculated for C H ClNO S
516.1036, found 516.0902.
29
23
4
-1
(
w), 1348 (s), 1305 (m), 1257 (m); HRMS calculated for
(E)-3-(3-Nitrobenzylidene)-2-(4-chlorophenyl)-2,3-dihydro-
1-(phenylsulfonyl)-quinolin-4(1H)-one (18)
C H N O S 527.1277, found 527.1193.
2
9
23
2
6
Pale yellow crystalline solid, yield 90.4%, purity of
1
(
E)-3-(4-Nitrobenzylidene)-2-(4-methoxyphenyl)-
98.3%, mp 212-215 °C; H NMR (500.13 MHz, CDCl )
3
2
,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (15)
d 6.49 (s, 1H), 7.09-7.11 (m, 2H), 7.24-7.30 (m, 4H),
7.32-7.37 (m, 3H), 7.36-7.39 (m, 1H), 7.55-7.61 (m, 3H),
7.62 (s, 1H), 7.70 (dd, J 0.83, 8.18 Hz, 1H), 7.91 (dd,
J 1.55, 7.80 Hz, 1H), 8.02 (t, J 1.93 Hz, 1H), 8.30 (dd,
Yellow crystalline solid (390 mg, 74.1%), purity of
1
97.8%, mp 211-213 °C; H NMR (500.13 MHz, CDCl )
3
d 3.77 (s, 3H), 6.54 (s, 1H), 6.80-6.83 (m, 2H), 7.10-7.13
m, 2H), 7.22-7.26 (m, 2H), 7.29-7.34 (m, 5H), 7.53 (tt,
J 1.17, 7.46 Hz, 1H), 7.57 (ddd, J 1.65, 7.43, 8.13 Hz, 1H),
1
3
(
J 2.18, 8.28 Hz, 1H); C NMR (125.76 MHz, CDCl3)
d 59.4, 124.6, 125.1, 127.2, 127.7, 127.9, 128.2, 128.4,
128.9, 129.1, 129.4, 130.4, 132.8, 133.7, 134.3, 134.9,
135.1, 135.2, 135.4, 137.4, 138.8, 148.5, 182.0; IR (ATR)
7.60 (s, 1H), 7.71 (dd, J 0.95, 8.25 Hz, 1H), 7.91 (dd, J 1.65,
13
7.85 Hz, 1H), 8.25-8.28 (m, 2H); C NMR (125.76 MHz,
-1
CDCl ) d 55.3, 59.5, 114.5, 124.2, 127.2, 127.4, 128.1,
ν / cm 1674 (m), 1613 (m), 1478 (w), 1353 (s), 1305 (m),
3
1
1
28.4, 128.5, 128.8, 129.0, 130.6, 133.4, 134.0, 135.1,
36.7, 137.5, 139.0, 139.9, 148.1, 159.8, 182.3; IR (ATR)
1237 (m); HRMS calculated for C H ClN O S 531.0781,
found 531.0540.
28
20
2
5
-1
ν / cm 1674 (m), 1600 (m), 1476 (w), 1353 (s), 1304 (m),
1
250 (s); HRMS calculated for C H N O S 527.1277,
(E)-3-(4-Nitrobenzylidene)-2-(4-chlorophenyl)-2,3-dihydro-
1-(phenylsulfonyl)-quinolin-4(1H)-one (19)
2
9
23
2
6
found 527.1229.
Yellow crystalline solid, yield 81.9%, purity of 98.5%,
1
(
E)-3-(4-Bromobenzylidene)-2-(4-methoxyphenyl)-
mp 224-226 °C; H NMR (500.13 MHz, CDCl ) d 6.55 (s,
3
2
,3-dihydro-1-(phenylsulfonyl)quinolin-4(1H)-one (16)
1H), 7.09-7.12 (m, 2H), 7.22-7.26 (m, 2H), 7.27-7.29 (m,
2H), 7.29-7.32 (m, 2H), 7.33-7.36 (m, 3H), 7.54 (tt, J 1.25,
7.50 Hz, 1H), 7.59 (ddd, J 1.68, 7.35, 8.18 Hz, 1H), 7.63
(s, 1H), 7.71 (dd, J 1.00, 8.20 Hz, 1H), 7.90 (dd, J 1.60,
Pale yellow crystalline solid, yield 44.6%, purity of
1
9
3
2
7
8.2%, mp 137-139 °C; H NMR (500.13 MHz, CDCl ) d
3
.74 (s, 3H), 6.56 (s, 1H), 6.78-6.81 (m, 2H), 7.03-7.06 (m,
H), 7.10-7.13 (m, 2H), 7.19-7.23 (m, 2H), 7.29 (dt, J 1.07,
.50 Hz, 1H), 7.30-7.33 (m, 2H), 7.48-7.51 (m, 1H), 7.51
13
7.75 Hz, 1H), 8.27-8.29 (m, 2H); C NMR (125.76 MHz,
CDCl ) d 59.4, 124.3, 127.2, 127.7, 127.9, 128.2, 128.4,
3
(
7
s, 1H), 7.53-7.57 (m, 3H), 7.71 (dd, J 0.85, 8.20 Hz, 1H),
.89 (dd, J 1.63, 7.78 Hz, 1H); C NMR (125.76 MHz,
128.9, 129.1, 129.4, 130.5, 133.3, 133.6, 134.9, 135.3,
137.3, 138.8, 139.6, 148.3, 181.9; IR (ATR) ν / cm 1673
13
-1
CDCl ) d 55.2, 59.6, 114.3, 124.9, 127.2, 127.3, 127.9,
(m), 1602 (m), 1480 (w), 1354 (s), 1298 (m), 1255 (w);
3
1
1
28.3, 128.5, 128.7, 128.8, 128.9, 131.3, 131.5, 132.4,
32.5, 133.3, 134.7, 137.5, 138.7, 138.9, 159.6, 182.7; IR
HRMS calculated for C H ClN O SNa 553.0601, found
553.0601.
28
29
2
5
-1
(ATR) ν / cm 1677 (m), 1607 (m), 1474 (w), 1354 (s),
1
306 (w), 1247 (s); HRMS calculated for C H BrNO S
(E)-3-(4-Bromobenzylidene)-2-(4-chlorophenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (20)
29
23
4
560.0531, found 560.0422.
Pale yellow crystalline solid, yield 76.1%, purity of
1
(
E)-3-(4-Chlorobenzylidene)-2-(4-methoxyphenyl)-
98.2%, mp 202-204 °C; H NMR (500.13 MHz, CDCl )
3
2
,3-dihydro-1-(phenylsulfonyl)quinolin-4(1H)-one (17)
d 6.57 (s, 1H), 7.00-7.03 (m, 2H), 7.10-7.12 (m, 2H),
7.19-7.23 (m, 2H), 7.24-7.27 (m, 2H), 7.31 (dt, J 1.13,
7.59 Hz, 1H), 7.34-7.37 (m, 2H), 7.50 (tt, J 1.21, 7.48 Hz,
1H), 7.53 (s, 1H), 7.54-7.58 (m, 3H), 7.71 (dd, J 0.80,
Pale yellow crystalline solid, yield 47.5%, purity of
1
98.4%, mp 166-167 °C; H NMR (500.13 MHz, CDCl )
3
d 3.74 (s, 3H), 6.57 (s, 1H), 6.78-6.81 (m, 2H), 7.10-7.13
13
(
(
(
m, 4H), 7.19-7.23 (m, 2H), 7.28-7.33 (m, 3H), 7.37-7.40
m, 2H), 7.49 (tt, J 1.23, 7.48 Hz, 1H), 7.53 (s, 1H), 7.55
ddd, J 1.65, 7.38, 8.18 Hz, 1H), 7.71 (dd, J 0.80, 8.15 Hz,
8.20 Hz, 1H), 7.88 (dd, J 1.58, 7.78 Hz, 1H); C NMR
(125.76 MHz, CDCl ) d 59.5, 125.2, 127.2, 127.5, 128.1,
3
128.1, 128.4, 129.0, 129.0, 129.3, 130.7, 131.4, 132.3,

6
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities
J. Braz. Chem. Soc.
-1
1
1
1
32.5, 133.4, 134.6, 134.9, 135.6, 137.3, 138.7, 139.3,
82.3; IR (ATR) ν / cm 1674 (m), 1608 (m), 1487 (m),
359 (m), 1304 (m), 1237 (m); HRMS calculated for
138.8, 139.6, 148.3, 181.9; IR (ATR) ν / cm 1677 (m),
1598 (m), 1485 (m), 1347 (s), 1301 (m), 1238 (m); HRMS
calculated for C H BrN O S 575.0276, found 575.0358.
-1
28
20
2
5
C H BrClNO SNa 585.9855, found 585.9952.
2
8
19
3
(
E)-3-(4-Bromobenzylidene)-2-(4-bromophenyl)-
(
E)-3-(4-Chlorobenzylidene)-2-(4-chlorophenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (24)
2
,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (21)
Pale yellow crystalline solid, yield 82.5%, purity of
1
Pale yellow crystalline solid, yield 75.9%, purity of
98.9%, mp 205-206 °C; H NMR (500.13 MHz, CDCl )
3
1
9
9.3%, mp 192-195 °C; H NMR (500.13 MHz, CDCl )
d 6.55 (s, 1H), 7.00-7.03 (m, 2H), 7.10-7.12 (m, 2H),
7.19-7.23 (m, 2H), 7.27-7.30 (m, 2H), 7.31 (ddd, J 1.09,
7.44, 7.74 Hz, 1H), 7.40-7.43 (m, 2H), 7.50 (tt, J 1.23,
7.48 Hz, 1H), 7.53 (s, 1H), 7.54-7.58 (m, 3H), 7.71 (dd,
J 0.95, 8.20 Hz, 1H), 7.88 (dd, J 1.55, 7.80 Hz, 1H);
3
d 6.58 (s, 1H), 7.07-7.10 (m, 2H), 7.10-7.12 (m, 2H), 7.19-
7
7
.23 (m, 2H), 7.24-7.27 (m, 2H), 7.31 (ddd, J 1.14, 7.36,
.79 Hz, 1H), 7.34-7.37 (m, 2H), 7.38-7.41 (m, 2H), 7.50
(
7
tt, J 1.60, 7.80 Hz, 1H), 7.56 (s, 1H), 7.56 (ddd, J 1.68,
.35, 8.18 Hz, 1H), 7.71 (dd, J 0.93, 8.18 Hz, 1H), 7.88
13
C NMR (125.76 MHz, CDCl ) d 59.5, 122.8, 125.2, 127.2,
3
13
(
dd, J 1.60, 7.80 Hz, 1H); C NMR (125.76 MHz, CDCl )
127.5, 128.1, 128.1, 128.4, 129.0, 129.3, 130.6, 131.4,
132.2, 132.3, 132.5, 133.4, 134.9, 136.1, 137.3, 138.7,
3
d 59.4, 127.2, 127.5, 128.0, 128.1, 128.3, 129.0, 129.0,
-1
1
1
1
29.3, 129.6, 130.6, 131.2, 131.9, 133.4, 134.6, 134.8,
139.3, 182.3; IR (ATR) ν / cm 1674 (m), 1608 (m), 1484
(m), 1359 (m), 1302 (m), 1236 (m); HRMS calculated for
C H Br NO S 607.9531, found 607.9590.
-
1
35.6, 136.7, 137.3, 138.7, 139.2, 182.3; IR (ATR) ν / cm
675 (m), 1609 (m), 1475 (w), 1358 (m), 1302 (m), 1237
28
20
2
3
(m); HRMS calculated for C H Cl NO S 520.0541, found
28 20 2 3
5
20.0569.
(E)-3-(4-Chlorobenzylidene)-2-(4-bromophenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (25)
(
E)-3-(3-Nitrobenzylidene)-2-(4-bromophenyl)-2,3-dihydro-
Pale yellow crystalline solid, yield 78.6%, purity of
1
1
-(phenylsulfonyl)-quinolin-4(1H)-one (22)
97.8%, mp 198-200 °C; H NMR (500.13 MHz, CDCl )
3
Pale yellow to white crystalline solid, yield 93.3%,
purity of 98.4%, mp 206-208 °C; H NMR (500.13 MHz,
d 6.56 (s, 1H), 7.07-7.10 (m, 2H), 7.10-7.12 (m, 2H),
7.19-7.23 (m, 2H), 7.28-7.31 (m, 2H), 7.31 (dt, J 1.10,
7.55 Hz, 1H), 7.38-7.43 (m, 4H), 7.50 (tt, J 1.25, 7.46 Hz,
1H), 7.56 (s, 1H), 7.54-7.58 (m, 1H), 7.71 (dd, J 0.78,
1
CDCl ) d 6.47 (s, 1H), 7.08-7.11 (m, 2H), 7.24-7.28 (m,
3
2
1
3
H), 7.28-7.30 (m, 2H), 7.34 (ddd, J 1.11, 7.41, 7.74 Hz,
H), 7.36-7.38 (m, 1H), 7.43-7.45 (m, 2H), 7.55-7.61 (m,
H), 7.62 (s, 1H), 7.70 (dd, J 1.03, 8.18 Hz, 1H), 7.91 (dd,
13
8.18 Hz, 1H), 7.88 (dd, J 1.60, 7.80 Hz, 1H); C NMR
(125.76 MHz, CDCl ) d 59.5, 122.8, 127.2, 127.5, 128.1,
3
J 1.62, 7.83 Hz, 1H), 8.03 (t, J 1.32 Hz, 1H), 8.30 (ddd,
128.1, 128.3, 129.0, 129.3, 129.6, 130.5, 131.2, 131.9,
132.2, 133.4, 134.9, 136.1, 136.7, 137.3, 138.7, 139.3,
13
J 0.84, 2.21, 8.24 Hz, 1H); C NMR (125.76 MHz, CDCl )
3
-1
d 59.4, 123.1, 124.6, 125.1, 127.2, 127.7, 127.9, 128.2,
182.3; IR (ATR) ν / cm 1675 (m), 1610 (m), 1485 (m),
1358 (m), 1303 (m), 1237 (m); HRMS calculated for
C H BrClNO S 564.0036, found 563.9741.
1
1
28.4, 129.1, 129.2, 130.4, 132.4, 132.8, 133.7, 134.2,
35.1, 135.2, 135.9, 137.3, 137.4, 138.8, 148.5, 182.0; IR
28
20
3
-1
(
ATR) ν / cm 1675 (m), 1599 (m), 1478 (w), 1353 (s),
1
5
305 (w), 1236 (m); HRMS calculated for C H BrN O S
75.0276, found 575.0129.
(E)-3-(3-Nitrobenzylidene)-2-(2-methoxyphenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (26)
28
20
2
5
Pale yellow amorphous solid, yield 92.9%, purity of
1
(E)-3-(4-Nitrobenzylidene)-2-(4-bromophenyl)-2,3-dihydro-
98.7%; H NMR (500.13 MHz, CDCl ) d 3.92 (s, 3H), 6.71
3
1
-(phenylsulfonyl)-quinolin-4(1H)-one (23)
(dt, J 1.08, 7.49 Hz, 1H), 6.81 (dd, J 1.60, 7.70 Hz, 1H),
6.89 (s, 1H), 6.99 (dd, J 0.85, 8.35 Hz, 1H), 7.13-7.16 (m,
2H), 7.24-7.30 (m, 3H), 7.36 (ddd, J 2.50, 5.95, 7.80 Hz,
1H), 7.47-7.50 (m, 1H), 7.50-7.54 (m, 3H), 7.54 (s, 1H),
7.58 (t, J 7.93 Hz, 1H), 7.93 (t, J 2.10 Hz, 1H), 7.96-7.98
Pale yellow crystalline solid, yield 93.5%, purity of
1
9
8.3%, mp 229-231 °C; H NMR (500.13 MHz, CDCl )
3
d 6.53 (s, 1H), 7.10-7.12 (m, 2H), 7.23-7.27 (m, 2H),
7
7
.28-7.32 (m, 4H), 7.33 (dd, J 1.08, 7.59 Hz, 1H), 7.43-
.46 (m, 2H), 7.54 (tt, J 1.16, 7.45 Hz, 1H), 7.59 (ddd,
13
(m, 1H), 8.25 (ddd, J 1.09, 2.21, 8.19 Hz, 1H); C NMR
J 1.66, 7.36, 8.14 Hz, 1H), 7.64 (s, 1H), 7.72 (dd, J 0.73,
.08 Hz, 1H), 7.90 (dd, J 1.55, 7.85 Hz, 1H), 8.27-8.30
(125.76 MHz, CDCl ) d 55.7, 56.1, 111.8, 120.4, 124.2,
3
8
124.4, 125.9, 127.5, 127.5, 127.7, 128.8, 129.0, 129.3,
129.4, 129.9, 130.5, 133.3, 134.6, 134.6, 135.5, 135.6,
1
3
(
m, 2H); C NMR (125.76 MHz, CDCl ) d 59.4, 123.1,
3
-1
1
1
24.3, 127.2, 127.7, 127.9, 128.2, 128.4, 129.1, 129.2,
30.5, 132.4, 133.2, 133.6, 135.3, 135.8, 137.3, 137.4,
135.8, 137.4, 139.5, 148.5, 157.4, 182.6; IR (ATR) ν / cm
1670 (m), 1601 (m), 1489 (m), 1351 (s), 1300 (m), 1251

Vol. 00, No. 00, 2018
d’Oliveira et al.
7
(
m); HRMS calculated for C H N O SNa 549.1096,
(vw), 1349 (s), 1299 (m), 1244 (m); HRMS calculated for
C H ClNO S 516.1036, found 516.0979.
2
9
22
2
6
found 549.0998.
29
23
4
(
E)-3-(4-Nitrobenzylidene)-2-(2-methoxyphenyl)-
(E)-3-(3-Nitrobenzylidene)-2-(3-nitrophenyl)-2,3-dihydro-
1-(phenylsulfonyl)-quinolin-4(1H)-one (30)
2
,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (27)
Pale yellow crystalline solid, yield 88.1%, purity of
Pale yellow amorphous solid, yield 83.8%, purity of
1
1
9
7.6%, mp 212-213 °C; H NMR (500.13 MHz, CDCl )
99.1%, mp 217-219 °C; H NMR (500.13 MHz, CDCl )
3
3
d 3.92 (s, 3H), 6.73 (dt, J 0.97, 7.51 Hz, 1H), 6.84 (dd,
J 1.60, 7.70 Hz, 1H), 6.87 (s, 1H), 6.96 (dd, J 0.80, 8.35 Hz,
d 6.63 (s, 1H), 7.13-7.16 (m, 2H), 7.27-7.30 (m, 2H), 7.35
(ddd, J 1.09, 7.41, 7.79 Hz, 1H), 7.40-7.43 (m, 1H), 7.55 (t,
J 7.95 Hz, 1H), 7.57-7.60 (m, 1H), 7.60 (ddd, J 1.65, 7.47,
8.18 Hz, 1H), 7.62 (t, J 7.98 Hz, 1H), 7.72 (s, 1H), 7.75
(dd, J 0.95, 8.20 Hz, 1H), 7.84 (tdd, J 0.94, 1.89, 7.79 Hz,
1H), 7.93 (dd, J 1.58, 7.83 Hz, 1H), 8.03 (t, J 1.98 Hz,
1H), 8.16 (dddd, J 0.70, 1.05, 2.23, 8.20 Hz, 1H), 8.21
1
2
3
H), 7.13-7.15 (m, 2H), 7.24-7.28 (m, 3H), 7.28-7.31 (m,
H), 7.36 (ddd, J 2.11, 6.29, 7.81 Hz, 1H), 7.51-7.56 (m,
H), 7.54 (s, 1H), 7.96 (dd, J 1.35, 7.90 Hz, 1H), 8.23-8.26
1
3
(m, 2H); C NMR (125.76 MHz, CDCl ) d 55.8, 56.3,
3
1
1
1
1
11.9, 120.6, 124.1, 126.0, 127.5, 127.5, 127.7, 128.8,
29.2, 129.4, 130.5, 130.7, 133.3, 134.7, 135.0, 135.6,
37.3, 139.4, 140.2, 147.9, 157.4, 182.6; IR (ATR) ν / cm
673 (m), 1599 (m), 1475 (w), 1349 (s), 1298 (m), 1239
(t, J 2.48 Hz, 1H), 8.31 (ddd, J 0.85, 2.20, 8.25 Hz, 1H);
-1
13
C NMR (125.76 MHz, CDCl ) d 59.3, 122.3, 124.0, 124.8,
3
124.9, 127.2, 127.9, 127.9, 128.3, 128.4, 129.2, 130.4,
130.5, 132.1, 133.5, 133.9, 134.2, 134.9, 135.4, 137.2,
(m); HRMS calculated for C H N O S 527.1277, found
29 23 2 6
-1
527.1089.
138.2, 138.6, 139.4, 148.6, 148.9, 181.4; IR (ATR) ν / cm
675 (m), 1604 (m), 1478 (w), 1359 (m), 1305 (m); HRMS
calculated for C H N O SNa 564.0841, found 564.0779.
1
(
E)-3-(4-Bromobenzylidene)-2-(2-methoxyphenyl)-
28
19
3
7
2
,3-dihydro-1-(phenylsulfonyl)quinolin-4(1H)-one (28)
Pale yellow crystalline solid, yield 76.9%, purity of
(E)-3-(4-Nitrobenzylidene)-2-(3-nitrophenyl)-2,3-dihydro-
1-(phenylsulfonyl)-quinolin-4(1H)-one (31)
1
9
8.3%, mp 234-237 °C; H NMR (500.13 MHz, CDCl )
3
d 3.93 (s, 3H), 6.69 (dt, J 0.93, 7.51 Hz, 1H), 6.82 (dd,
J 1.50, 7.60 Hz, 1H), 6.91 (s, 1H), 6.93 (dd, J 0.70, 8.20 Hz,
Pale yellow crystalline solid, yield 85.9%, purity of
1
98.9%, mp 235-237 °C; H NMR (500.13 MHz, CDCl )
3
1
H), 7.01-7.04 (m, 2H), 7.13-7.16 (m, 2H), 7.20-7.25
d 6.69 (s, 1H), 7.12-7.15 (m, 2H), 7.25-7.29 (m, 2H),
7.33-7.37 (m, 3H), 7.54-7.59 (m, 2H), 7.61 (ddd, J 1.69,
7.34, 8.16 Hz, 1H), 7.73 (s, 1H), 7.77 (dd, J 0.73, 8.18 Hz,
1H), 7.83 (tdd, J 0.96, 1.93, 7.80 Hz, 1H), 7.91 (dd, J 1.43,
7.73 Hz, 1H), 8.15-8.17 (m, 1H), 8.22 (t, J 2.55 Hz, 1H),
(
m, 3H), 7.32 (dt, J 1.20, 7.48 Hz, 1H), 7.46 (s, 1H),
13
7.46-7.55 (m, 5H), 7.93 (dd, J 1.58, 7.83 Hz, 1H); C NMR
(125.76 MHz, CDCl ) d 55.8, 56.4, 111.9, 120.5, 124.5,
3
1
1
1
1
26.4, 127.3, 127.5, 127.6, 128.7, 128.8, 129.4, 129.5,
30.2, 131.6, 132.2, 132.3, 132.9, 133.1, 134.3, 137.4,
13
8.29-8.32 (m, 2H); C NMR (125.76 MHz, CDCl ) d 59.2,
3
-1
37.6, 139.4, 157.6, 183.0; IR (ATR) ν / cm 1673 (m),
604 (m), 1477 (vw), 1349 (m), 1298 (m), 1244 (m); HRMS
122.2, 124.1, 124.5, 127.2, 127.8, 128.0, 128.3, 128.4,
129.2, 130.4, 130.4, 132.4, 133.4, 133.8, 135.5, 137.0,
138.2, 138.5, 139.1, 139.3, 148.4, 148.8, 181.4; IR (ATR)
calculated for C H BrNO S 560.0531, found 560.0431.
29
23
4
-1
ν / cm 1682 (m), 1599 (m), 1475 (w), 1345 (s), 1301 (m),
(
E)-3-(4-Chlorobenzylidene)-2-(2-methoxyphenyl)-
1240 (m); HRMS calculated for C H N O SNa 564.0841,
28
19
3
7
2
,3-dihydro-1-(phenylsulfonyl)quinolin-4(1H)-one (29)
found 564.0804.
Pale yellow crystalline solid, yield 78.7%, purity of
1
9
8.8%, mp 219-221 °C; H NMR (500.13 MHz, CDCl )
(E)-3-(4-Bromobenzylidene)-2-(3-nitrophenyl)-2,3-dihydro-
1-(phenylsulfonyl)-quinolin-4(1H)-one (32)
3
d 3.93 (s, 3H), 6.69 (dt, J 1.10, 7.54 Hz, 1H), 6.83 (dd,
J 1.55, 7.70 Hz, 1H), 6.92 (s, 1H), 6.93 (dd, J 0.95, 8.35 Hz,
H), 7.08-7.11 (m, 2H), 7.13-7.15 (m, 2H), 7.20-7.25 (m,
H), 7.32 (ddd, J 1.29, 7.26, 7.71 Hz, 1H), 7.35-7.37 (m,
H), 7.48 (s, 1H), 7.48 (tt, J 1.28, 7.43 Hz, 1H), 7.49 (ddd,
J 1.59, 7.21, 8.14 Hz, 1H), 7.54 (dd, J 1.13, 8.13 Hz, 1H),
.93 (dd, J 1.53, 7.78 Hz, 1H); C NMR (125.76 MHz,
CDCl ) d 55.8, 56.4, 111.9, 120.5, 126.4, 127.3, 127.5,
27.6, 128.7, 128.8, 129.2, 129.4, 129.5, 130.2, 131.4,
32.2, 132.5, 133.1, 134.3, 136.1, 137.5, 137.5, 139.4,
Pale yellow amorphous solid, yield 73.7%, purity of
1
1
3
2
98.9%; H NMR (500.13 MHz, CDCl ) d 6.71 (s, 1H),
3
7.02-7.06 (m, 2H), 7.12-7.15 (m, 2H), 7.22-7.26 (m, 2H),
7.33 (dt, J 1.08, 7.59 Hz, 1H), 7.50-7.55 (m, 2H), 7.58
(ddd, J 1.66, 7.39, 8.14 Hz, 1H), 7.57-7.60 (m, 2H), 7.63
(s, 1H), 7.76 (dd, J 0.75, 8.20 Hz, 1H), 7.81 (tdd, J 0.96,
1.91, 7.84 Hz, 1H), 7.89 (dd, J 1.50, 7.80 Hz, 1H), 8.12-8.15
13
7
3
13
1
1
1
(m, 1H), 8.24 (t, J 2.35 Hz, 1H); C NMR (125.76 MHz,
CDCl ) d 59.4, 122.4, 123.8, 125.5, 127.3, 127.8, 128.1,
3
-1
57.6, 183.0; IR (ATR) ν / cm 1674 (m), 1603 (m), 1476
128.3, 128.3, 129.1, 129.8, 130.2, 131.3, 132.1, 132.7,

8
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities
J. Braz. Chem. Soc.
1
3
1
1
1
33.5, 133.7, 135.1, 137.0, 138.4, 139.5, 140.2, 148.8,
81.7; IR (ATR) ν / cm 1677 (m), 1606 (m), 1478 (w),
349 (s), 1301 (m), 1240 (m); HRMS calculated for
1H), 8.28-8.31 (m, 2H); C NMR (125.76 MHz, CDCl )
3
-1
d 60.7, 124.4, 124.8, 127.4, 127.8, 128.1, 128.2, 128.6,
129.3, 130.0, 130.1, 130.5, 130.6, 133.6, 134.4, 134.9,
135.0, 136.2, 136.4, 137.1, 139.1, 139.8, 148.3, 182.2; IR
C H BrN O S 575.0276, found 575.0102.
2
8
20
2
5
-1
(
ATR) ν / cm 1677 (m), 1596 (m), 1471 (m), 1343 (s),
(E)-3-(4-Chlorobenzylidene)-2-(3-nitrophenyl)-2,3-dihydro-
1295 (m), 1239 (m); HRMS calculated for C H BrN O S
28
20
2
5
1
-(phenylsulfonyl)-quinolin-4(1H)-one (33)
575.0276, found 575.0035.
Pale yellow amorphous solid, yield 73.1%, purity of
1
9
9.1%, mp 207-210 °C; H NMR (500.13 MHz, CDCl )
(E)-3-(4-Bromobenzylidene)-2-(2-bromophenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (36)
3
d 6.72 (s, 1H), 7.10-7.13 (m, 2H), 7.13-7.16 (m, 2H),
.21-7.25 (m, 2H), 7.32 (dt, J 1.05, 7.59 Hz, 1H), 7.41-7.43
m, 2H), 7.49-7.54 (m, 2H), 7.57 (ddd, J 1.66, 7.41,
7
(
Pale yellow crystalline solid, yield 55.6%, purity of
1
98.6%, mp 219-221 °C; H NMR (500.13 MHz, CDCl )
3
8
7
7
.11 Hz, 1H), 7.65 (s, 1H), 7.76 (dd, J 0.63, 8.18 Hz, 1H),
.81 (tdd, J 0.95, 1.90, 7.85 Hz, 1H), 7.89 (dd, J 1.60,
.85 Hz, 1H), 8.11-8.14 (m, 1H), 8.24 (t, J 2.53 Hz, 1H);
d 6.74 (dd, J 1.48, 7.83 Hz, 1H), 6.91 (s, 1H), 6.98 (dt,
J 1.23, 7.61 Hz, 1H), 7.03-7.06 (m, 2H), 7.09-7.13 (m, 3H),
7.22-7.26 (m, 2H), 7.34 (ddd, J 3.55, 5.05, 7.75 Hz, 1H),
7.49-7.53 (m, 3H), 7.56 (s, 1H), 7.56-7.59 (m, 2H), 7.70
13
C NMR (125.76 MHz, CDCl ) d 59.3, 122.4, 123.8, 127.3,
3
13
1
1
1
1
27.8, 128.1, 128.2, 128.3, 129.1, 129.7, 129.7, 130.2,
31.2, 131.7, 133.5, 133.6, 135.1, 137.0, 137.1, 138.4,
(dd, J 1.23, 7.98 Hz, 1H), 7.86-7.89 (m, 1H); C NMR
(125.76 MHz, CDCl ) d 60.9, 124.8, 125.1, 127.2, 127.6,
3
-1
39.5, 140.1, 148.8, 181.7; IR (ATR) ν / cm 1674 (m),
605 (m), 1478 (w), 1348 (s), 1302 (m), 1238 (m); HRMS
128.0, 128.1, 128.5, 129.3, 130.2, 130.3, 130.3, 131.4,
131.5, 132.5, 132.6, 133.5, 134.7, 134.8, 136.4, 136.4,
-1
calculated for C H ClN O S 531.0781, found 531.0619.
139.0, 139.1, 182.6; IR (ATR) ν / cm 1675 (m), 1605 (m),
474 (w), 1351 (s), 1292 (m), 1239 (m); HRMS calculated
for C H Br NO S 607.9531, found 607.9454.
2
8
20
2
5
1
(E)-3-(3-Nitrobenzylidene)-2-(2-bromophenyl)-2,3-dihydro-
28
20
2
3
1
-(phenylsulfonyl)-quinolin-4(1H)-one (34)
Pale yellow to white amorphous solid, yield 79.4%,
(E)-3-(4-Chlorobenzylidene)-2-(2-bromophenyl)-
2,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (37)
1
purity of 98.5%; H NMR (500.13 MHz, CDCl ) d 6.74 (dd,
3
J 1.53, 7.83 Hz, 1H), 6.86 (s, 1H), 7.01 (dt, J 1.32, 7.63 Hz,
Pale yellow crystalline solid, yield 47.1%, purity of
1
1H), 7.11-7.14 (m, 2H), 7.14 (ddd, J 1.60, 7.43, 7.83 Hz,
1H), 7.27-7.31 (m, 2H), 7.38 (ddd, J 1.51, 7.06, 7.76 Hz,
1H), 7.44 (tdd, J 0.85, 1.70, 7.70 Hz, 1H), 7.51 (ddd, J 0.45,
1.50, 8.05 Hz, 1H), 7.53-7.58 (m, 2H), 7.63 (t, J 7.98 Hz,
2H), 7.66 (s, 1H), 7.74 (dd, J 1.28, 7.98 Hz, 1H), 7.91 (ddd,
98.8%, mp 204-205 °C; H NMR (500.13 MHz, CDCl )
3
d 6.75 (dd, J 1.75, 7.85 Hz, 1H), 6.91 (s, 1H), 6.98 (dt,
J 1.48, 7.60 Hz, 1H), 7.09-7.13 (m, 5H), 7.22-7.26 (m, 2H),
7.34 (ddd, J 3.35, 5.23, 7.75 Hz, 1H), 7.40-7.43 (m, 2H),
7.49-7.53 (m, 3H), 7.59 (s, 1H), 7.70 (dd, J 1.38, 7.98 Hz,
13
J 0.50, 1.58, 7.78 Hz, 1H), 7.99 (t, J 1.98 Hz, 1H), 8.29
1H), 7.86-7.89 (m, 1H); C NMR (125.76 MHz, CDCl )
3
13
(
ddd, J 0.90, 2.20, 8.23 Hz, 1H); C NMR (125.76 MHz,
d 60.9, 124.8, 127.2, 127.6, 128.0, 128.1, 128.5, 129.3,
129.6, 130.2, 130.3, 130.3, 131.3, 131.4, 132.0, 133.5,
134.7, 134.8, 136.4, 136.7, 139.0, 139.1, 182.6; IR (ATR)
CDCl ) d 60.8, 124.6, 124.7, 124.9, 127.3, 127.8, 128.1,
3
1
1
1
1
28.2, 128.7, 129.4, 130.1, 130.1, 130.4, 130.6, 133.7,
33.9, 134.8, 134.9, 135.0, 135.2, 136.2, 136.4, 137.1,
39.1, 148.7, 182.2; IR (ATR) ν / cm 1672 (m), 1599 (m),
-1
ν / cm 1676 (m), 1605 (m), 1474 (w), 1351 (s), 1293
-1
(m), 1239 (m); HRMS calculated for C H BrClNO SNa
28
19
3
471 (m), 1351 (s), 1294 (m), 1242 (m); HRMS calculated
585.9855, found 585.9566.
for C H BrN O S 575.0276, found 575.0015.
2
8
20
2
5
(E)-3-(3-Nitrobenzylidene)-2-(2-chlorophenyl)-2,3-dihydro-
(E)-3-(4-Nitrobenzylidene)-2-(2-bromophenyl)-2,3-dihydro-
1-(phenylsulfonyl)-quinolin-4(1H)-one (38)
1
-(phenylsulfonyl)-quinolin-4(1H)-one (35)
Pale yellow to white amorphous solid, yield 81.7%,
purity of 98.9%, mp 224-226 °C; H NMR (500.13 MHz,
1
Pale yellow crystalline solid, yield 69.7%, purity of
1
9
9.7%, mp 207-209 °C; H NMR (500.13 MHz, CDCl )
CDCl ) d 6.76 (dd, J 1.68, 7.83 Hz, 1H), 6.91 (s, 1H),
3
3
d 6.74 (dd, J 1.58, 7.88 Hz, 1H), 6.90 (s, 1H), 7.01 (dt,
J 1.30, 7.60 Hz, 1H), 7.11-7.14 (m, 2H), 7.14 (dt, J 1.63,
6.98 (dt, J 1.40, 7.65 Hz, 1H), 7.12-7.14 (m, 2H), 7.24 (dt,
J 1.52, 7.75 Hz, 1H), 7.28-7.32 (m, 2H), 7.38 (ddd, J 1.76,
6.76, 7.76 Hz, 1H), 7.42 (tdd, J 0.85, 1.70, 7.70 Hz, 1H),
7.51-7.58 (m, 4H), 7.63 (t, J 8.08 Hz, 1H), 7.64 (s, 1H),
7.93 (dd, J 1.40, 7.70 Hz, 1H), 7.97 (t, J 2.00 Hz, 1H), 8.29
7
.73 Hz, 1H), 7.25-7.29 (m, 2H), 7.31-7.34 (m, 2H), 7.37
ddd, J 1.51, 7.06, 7.74 Hz, 1H), 7.51 (ddd, J 0.55, 1.53,
.08 Hz, 1H), 7.52-7.56 (m, 2H), 7.66 (s, 1H), 7.72 (dd,
J 1.33, 7.98 Hz, 1H), 7.90 (ddd, J 0.51, 1.59, 7.76 Hz,
(
8
13
(ddd, J 0.94, 2.19, 8.14 Hz, 1H); C NMR (125.76 MHz,

Vol. 00, No. 00, 2018
d’Oliveira et al.
9
-1
CDCl ) d 58.6, 124.6, 124.6, 126.8, 127.8, 127.9, 128.1,
136.7, 139.0, 139.0, 182.6; IR (ATR) ν / cm 1674 (m),
1604 (m), 1474 (w), 1359 (m), 1294 (m), 1239 (m); HRMS
calculated for C H Cl NO S 520.0541, found 520.0458.
3
1
1
1
1
28.7, 129.3, 129.8, 129.8, 130.3, 130.4, 131.4, 133.7,
33.7, 134.8, 135.0, 135.2, 136.6, 137.1, 139.1, 148.6,
82.2; IR (ATR) ν / cm 1670 (m), 1609 (m), 1474 (w),
28
20
2
3
-1
352 (s), 1295 (m), 1245 (m); HRMS calculated for
General procedure for antitumor tests
C H ClN O S 531.0781, found 531.0478.
2
8
20
2
5
The cytotoxicity of the chalcones and chalcone-
quinolinone compounds were evaluated against tumor
cell line by the 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl-
2-H-tetrazolium bromide (MTT) method. Human tumor
cell line HCT-116 (colon) was used. The cells were given
by the National Cancer Institute (USA) and cultured in
Roswell Park Memorial Institute (RPMI) 1640 medium,
supplemented with 10% fetal bovine serum and 1%
(
E)-3-(4-Nitrobenzylidene)-2-(2-chlorophenyl)-2,3-dihydro-
1
-(phenylsulfonyl)-quinolin-4(1H)-one (39)
Pale yellow amorphous solid, yield 79.5%, purity of
1
9
7.1%, mp 216-219 °C; H NMR (500.13 MHz, CDCl )
3
d 6.76 (dd, J 1.55, 7.85 Hz, 1H), 6.94 (s, 1H), 6.98 (td,
J 1.28, 7.64 Hz, 1H), 7.12-7.14 (m, 2H), 7.23 (ddd, J 1.59,
7
6
.49, 7.96 Hz, 1H), 7.26-7.32 (m, 4H), 7.37 (ddd, J 1.91,
.66, 7.74 Hz, 1H), 7.51-7.57 (m, 4H), 7.65 (s, 1H), 7.92
antibiotic, kept in an oven at 37 °C and 5% CO atmosphere.
2
(
ddd, J 0.55, 1.50, 7.78 Hz, 1H), 8.27-8.30 (m, 2H);
The samples were diluted in pure sterile dimethyl sulfoxide
(DMSO) and were tested in a single concentration of
25 μg mL . Tumor cells were plated at 0.7 × 10 cells mL
1
3
C NMR (125.76 MHz, CDCl ) d 58.5, 124.3, 126.8, 127.8,
3
-1
5
-1
1
1
1
1
27.9, 128.1, 128.7, 129.2, 129.7, 129.8, 130.4, 131.3,
33.6, 134.2, 134.8, 134.9, 135.1, 136.6, 137.1, 139.1,
for HCT-116 lineage. After 24 h of incubation to adhere to
the plate, the cells were treated with the test compounds at
-1
39.8, 148.3, 182.2; IR (ATR) ν / cm 1679 (m), 1597 (m),
-1
474 (w), 1340 (s), 1295 (m), 1244 (m); HRMS calculated
the single concentration of 25 μg mL and incubated for
for C H ClN O SNa 553.0601, found 553.0431.
72 h in a 5% CO oven at 37 °C. After this time, they were
2
8
19
2
5
2
centrifuged, and the supernatant removed. Then 150 μL
of 1% MTT solution (tetrazolium salt) was added, and the
plates were incubated for 3 h. The absorbance was read after
dissolution of the precipitate with 150 μL of pure DMSO in
a plate spectrophotometer at 595 nm. The statistical analysis
of the experiments was performed according to the mean
and standard error of the mean (SEM) of the percentage of
(
E)-3-(4-Bromobenzylidene)-2-(2-chlorophenyl)-
2
,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (40)
Pale yellow crystalline solid, yield 64.8%, purity of
1
9
8.3%, mp 229-231 °C; H NMR (500.13 MHz, CDCl )
3
d 6.76 (dd, J 1.58, 7.83 Hz, 1H), 6.94 (dt, J 1.32, 7.61 Hz,
1
7
H), 6.95 (s, 1H), 7.01-7.04 (m, 2H), 7.10-7.13 (m, 2H),
.20 (dt, J 1.55, 7.73 Hz, 1H), 7.23-7.26 (m, 2H), 7.35
35
cell growth inhibition, using the program GraphPad Prism.
(
(
(
1
1
1
1
ddd, J 2.60, 5.98, 7.75 Hz, 1H), 7.48-7.54 (m, 4H), 7.55
s, 1H), 7.56-7.58 (m, 2H), 7.88-7.91 (m, 1H); C NMR
Compounds which showed a percentage of inhibition of
tumor cell growth greater than 75% in the tumor line tested
were tested again by serial dilution (dilution factor = 2),
1
3
125.76 MHz, CDCl ) d 58.7, 125.1, 126.7, 127.7, 127.9,
3
-
1
28.6, 129.2, 129.9, 130.0, 130.2, 131.2, 131.4, 132.5,
32.5, 133.4, 134.7, 134.9, 135.0, 136.6, 139.0, 139.1,
starting from the highest 25 μg mL concentration for
determination of concentration capable of inhibiting 50%
of cell proliferation (IC ). The experiments were analyzed
-1
82.6; IR (ATR) ν / cm 1674 (m), 1603 (m), 1474 (w),
50
358 (m), 1294 (m), 1238 (m); HRMS calculated for
by a non-linear regression curve for the calculation of IC
50
3
5
C H BrClNO S 564.0036, found 563.9567.
using the GraphPad Prism program. Doxorubicin was
2
8
20
3
36
used as a positive control.
(
E)-3-(4-Chlorobenzylidene)-2-(2-chlorophenyl)-
2
,3-dihydro-1-(phenylsulfonyl)-quinolin-4(1H)-one (41)
Results and Discussion
Pale yellow crystalline solid, yield 57.6%, purity of
1
9
9.2%, mp 226-228 °C; H NMR (500.13 MHz, CDCl )
Synthesis of chalcones 2 to 9
3
d 6.76 (dd, J 1.35, 7.75 Hz, 1H), 6.95 (dt, J 1.30, 7.58 Hz,
1
7
7
2
H), 6.96 (s, 1H), 7.08-7.11 (m, 2H), 7.11-7.13 (m, 2H),
.20 (ddd, J 1.51, 7.44, 7.96 Hz, 1H), 7.23-7.26 (m, 2H),
.35 (ddd, J 2.46, 6.09, 7.76 Hz, 1H), 7.40-7.43 (m,
H), 7.49-7.54 (m, 4H), 7.57 (s, 1H), 7.89-7.91 (m, 1H);
2’N-Phenylsulfonyl-acetophenone (1) was synthesized
by reaction between benzenesulfonyl chloride and
2
9
2-aminoacetophenone in dichloromethane. After, eight
2’N-sulfonamide chalcones were synthesized (2 to 9) by
Claisen-Schmidt condensation between the intermediate 1
and benzaldehyde derivative via basic catalysis in ethanolic
1
3
C NMR (125.76 MHz, CDCl ) d 58.7, 126.7, 127.7,
3
1
1
28.0, 128.6, 129.2, 129.6, 129.9, 130.0, 130.2, 131.2,
31.2, 131.3, 132.1, 133.4, 134.7, 134.9, 135.0, 136.6,
29
medium, as shown in Scheme 1.

1
0
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities
J. Braz. Chem. Soc.
be synthesize a quinolinone compound, as those at upper
right of Scheme 3, and react it by Claisen-Schimdt
condensation with a second specie of aldehyde. The
synthesis of such compound were made as described by
37
Zheng et al. However, the synthesis of the final product
starting from these quinolinones, previously synthesized
and purified, was not convenient, since in the homogenous
basic ethanolic medium the quinolinone readily converted
to the respective precursor chalcone after dissolution,
with the reaction soon reaching a balance more favorable
to chalcone. The synthesis of chalcone-quinolinones was
then performed by reacting chalcone sufonamide (2 to 9)
in a basic reaction medium with an aromatic aldehyde,
with a configuration of ligands different from the aldehyde
that led to the configuration of the ring B as shown on
Scheme 2. The substitution on ring C would correspond to
the substitution pattern of the second aldehyde. Scheme 2
shows the general conditions used to obtain the compounds
from 10 to 41.
Scheme 1. Claisen-Schmidt condensation for the synthesis of the
chalcones 2 to 9. (a) Ethanol, cat. KOH, room temperature.
The yields of the reactions were from 45 to 94%.
Scheme 3 shows the proposed reaction mechanism that
justifies obtaining the products. The sulfonamide nitrogen is
added to the β-carbon of the α-β unsaturated ketone of the
chalcone (conjugated addition). Two mechanism hypotheses
can justify this step: the first supposes that the hydrogen
of the sulfonamide is abstracted, and the nitrogen, with
partial negative charge, is added to the β carbon; the second
presumes that the nitrogen attacks the β-carbon directly,
resulting in a nitrogen with four ligands, and therefore
with partial positive charge, which then has the proton
abstracted by the available hydroxide. Scheme 3 illustrates
the first hypothesis. Subsequently, the enolate ion attacks the
aldehyde and form a β-hydroxyketone. Finally, dehydration
is favored by the conjugate system that can be formed.
1
The H NMR spectra of compounds 2 to 9 show the
presence of two doublets in the region between d 7.18
and 8.06, with coupling constant of 15.5 Hz, which
demonstrates the presence of a trans α-β carbonyl group.
The singlet signals observed near d 11.3, a chemical shift
typical for sulfonamide hydrogens, corroborate the amino
sulfonyl linkage. Intramolecular hydrogen bonding between
carbonyl and NH groups, forming a six-member ring,
justify this high chemical shift. Figure 2 highlights these
assignments for compound 4.
Synthesis of chalcone-quinolinone
One option for obtaining the target compounds might
1
Figure 2. H NMR spectrum for compound 4 (500 MHz, CDCl ), highlighting the sulfonamide hydrogen (d 11.2 ppm) and the doublets associated to
3
trans α-β carbonyl group.

Vol. 00, No. 00, 2018
d’Oliveira et al.
11
Scheme 2. Established conditions for the synthesis of chalcone-quinolinone compounds starting from chalcone sulfonamide. (a) Ethanol, cat. KOH, room
temperature.
Scheme 3. Proposed mechanism that explains the achievement of products under the conditions employed.
Scheme 2 shows the numbering system of the atoms
of the common nucleus of the chalcone-quinolinone
compounds for purposes of the following discussion. The
B and C rings were numbered so that the substituents were
at the lowest-numbered carbon possible. One piece of
spectroscopic evidence of the formation of compounds 10
to 41 is the existence of two singlets corresponding to
the two non-aromatic β carbonyl hydrogens observed

1
2
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities
J. Braz. Chem. Soc.
at d 7.46 to 7.85 (H9) and at d 6.47 to 6.96 (H10). The
nonobservance of the signal from sulfonamide hydrogens
in the d 11.3 region, observed for chalcones 2 to 9 and
in Tables S1 to S9 (Supplementary Information (SI)
section), were supported by COSY, HSQC and HMBC
experiments (e.g. Figures 4 to 6, for compound 22). The
most deshielded carbon signal, near to d 181, assigned to
carbonyl carbon (C7), was a good starting point to complete
assignment of NMR signals. The hydrogens H6, H9 and
2’N-phenylsulfonyl-acetophenone 1, reinforce the proposed
compound structure. Figure 3 highlights these signals and
absence of sulfonamide hydrogen for compound 22.
Complete assignment of the multiplets for each
H10 were assigned based on cross-peak with C7 in the
1
13
3
hydrogen on the H and C NMR spectra, presented
HMBC experiment ( J ). Moreover, the correlations of
CH
1
Figure 3. H NMR spectrum for compound 22 (500 MHz, CDCl ), highlighting the signals for H9 and H10, and absence of sulfonamide hydrogen in
3
region near to d 11.2 ppm.
Figure 4. COSY correlation map of compound 22 (500 and 125 MHz, CDCl3).

Vol. 00, No. 00, 2018
d’Oliveira et al.
13
Figure 5. HMBC correlation map of compound 22 (500 and 125 MHz, CDCl3).
Figure 6. HSQC correlation map of compound 22 (500 and 125 MHz, CDCl3).

1
4
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities
J. Braz. Chem. Soc.
these hydrogens with their respective carbons, by HSQC
to 41, whose configuration we intend to determine); on
the right it is illustrated what might be the Z configuration
of the same compound, obtained by rotating the dihedral
angle C10–C8–C9–H9 by 180°. This figure highlights how
the relative distance of H10 to H9 and the distance of H10
to any hydrogen at the position 12 or 16 (H12 or H16) is
expected to be different in each case (E or Z isomer). In
the case of the E isomer, H10 is at 1.99 Å from H12/H16
(ortho to the C ring), and at 3.55Å from H9. In the Z isomer,
H10 is 2.40 Å from H9 and at least 4.49 Å from H12/H16.
This last minimum value was obtained by pure geometric
rotation of the C ring over the C9–C11 bond of the Z isomer.
The differential NOE spectra were obtained by
irradiating H10. Table 1 shows the proportion of areas
between the peaks related to H9, H10, the sum of H12 and
H16, and the sum of H24 and H28 in the differential NOE
experiments (Figure 8, for compound 22). The sums of the
signal areas of H12/H16 and H24/H28 were used because
the rotational freedom presented by the aromatic ring in
solution allows for an interaction between H10/H18 or
H10/H22, for example. The results confirm that all
compounds (10 to 41) were E isomers, since the proportion
of the peak area related to H12 and/or H16 was much larger
than that related to H9.
1
experiment ( J ), enabled the assignment of the carbons C9
CH
and C10. The H9, H18 and H22 hydrogens were assigned
based on cross peak with C10 in HMBC. In the same way,
3
H12 and H16 were attributed based on J with C9 in
CH
HMBC.
The H26 hydrogen was a good starting point for the
assignments of aromatic H/C on the D ring. Its signal
was a triple-triplet with signal area corresponding to one
hydrogen and cross-peak with H25 and H27 in COSY. On
the other hand, these last hydrogens present cross-peaks
with H24 and H28. HSQC and HMBC experiments were
used to corroborate these assignments. The same strategy
was used for assignment of other aromatic hydrogens on
rings A, B and C.
1
The complete hydrogen assignments of the H NMR
spectra for compounds 10 to 41 can be observed in
Tables S1 to S8, in SI section. Table S9, also in SI section,
shows the chemical shifts of C7, C9, C10, C12 and C16
carbons, important for the assignment of some hydrogens
by means of the 2D experiments previously discussed. The
HMBC, HSQC and COSY contour maps are also presented
in the SI section.
The determination of the E configuration of the
compounds, since these do not possess a pair of vinyl
hydrogens, demanded a study of NOE (nuclear Overhauser
effect) differential. In this experiment, the intense
spatial interaction between H9 and H10 represents a
Z configuration. On the other hand, an intense interaction
between H10 and ortho hydrogens of the C ring (H12 or
H16) represents E. Figure 7 shows the two isomers: on
the left is the adaptation of the crystallography structure
Antitumor tests
Cytotoxicity analysis by the MTT method is one of
the methods used in the screening program of the National
Cancer Institute of the United States (NCI), which tests more
38
than 10,000 samples each year. It is a quick, sensitive and
39
inexpensive method. It was first described by Mosmann,
23
deposited by Kim et al., which has the E configuration (it
possesses the same common nucleus as the compounds 10
and has the ability to analyze the viability and the metabolic
state of the cell. It is a colorimetric analysis based on the
2
3
Figure 7. (Left) Adaptation of crystallographic structure deposited by Kim et al., (E) configuration; (right) (Z) configuration, obtained by rotating the
dihedral angle C10–C8–C9–H9 by 180°.

Vol. 00, No. 00, 2018
d’Oliveira et al.
15
Table 1. Signal area proportion for hydrogens 9, 12, 16, 18, 22, 24 and 28 in the NOE differential experiments of chalcone-quinolinones 10 to 41
entry
H9
H12-16
0.60
H18-22
0.25
0.25
0.22
0.22
0.24
0.28
0.22
0.21
0.24
0.21
0.20
0.21
0.23
H24-28
0.12
entry
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
H9
H12-16
0.76
0.71
0.76
0.75
0.61
0.61
0.65
H18-22
0.07
0.11
0.07
0.07
0.24
0.23
0.21
0.21
0.08
0.10
0.03
0.04
0.10
0.07
0.23
0.25
H24-28
0.14
0.14
0.15
0.14
0.12
0.13
0.12
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
5
0.03
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.03
0.02
0.03
0.02
0.03
0.03
0.03
0.02
0.03
0.04
0.03
0.03
0.02
0.03
0.02
0.02
0.06
0.04
0.04
0.03
0.03
0.04
0.04
0.02
0.60
0.13
0.63
0.13
a
a
0.76
–
0.60
0.57
0.64
0.13
0.13
0.13
a
a
a
a
0.77
–
0.77
–
0.60
0.64
0.64
0.64
0.61
0.13
0.13
0.12
0.13
0.13
0.13
0.12
0.66
0.73
0.79
0.21
0.13
0.14
a
a
0.93
–
0.74
0.74
0.63
0.13
0.14
0.10
b
b
0.84
–
0.64
0.21
0.21
a
a
a
a
2
0.77
–
0.73
–
a
b
The chemical shifts related to H12/H16 and H24/H28 were overlapped; the chemical shifts related to H12/H16 and H18/H22 were overlapped.
Figure 8. NOE differential spectrum for compound 22 (500 MHz, CDCl ), irradiating H10.
3
conversion of the 3-(4,5-dimethyl-2-thiazole)-2,5-diphenyl-
-H-tetrazolium bromide (MTT) salt into formazan, by
mitochondrial enzymes present only in metabolically active
easy definition of cytotoxicity, but not the mechanism of
40
2
action. Table 2 shows the results of cytotoxicity evaluation
using chalcones, quinolinones and chalcone-quinolinones
against HCT-116 (colon) human tumor cell lines.
36
cells. The cytotoxic study by the MTT method enables an

1
6
Synthesis, Characterization and Evaluation of in vitro Antitumor Activities
J. Braz. Chem. Soc.
-1
Table 2. Percentage inhibition of tumor cell growth in vitro at a single concentration of 25 μg mL against HCT-116 (colon) tumor cell line after 72 h of
treatment determined by the MTT method
entry
HCT-116 / %
76.2 ± 21.8
83.6 ± 16.9
66.9 ± 3.9
56.3 ± 16.7
100.0 ± 0.0
78.8 ± 21.7
66.8 ± 0.9
100.0 ± 0.0
23.8 ± 0.2
28.9 ± 3.3
entry
12
13
14
15
16
17
18
19
20
21
HCT-116 / %
20.4 ± 14.0
35.4 ± 2.6
3.2 ± 5.2
entry
22
23
24
25
26
27
28
29
30
31
HCT-116 / %
48.1 ± 3.3
72.2 ± 0.5
71.1 ± 1.0
60.9 ± 2.9
70.4 ± 0.4
58.8 ± 1.7
56.6 ± 3.8
63.7 ± 3.0
55.1 ± 6.0
63.6 ± 3.1
entry
32
33
34
35
36
37
38
39
40
41
HCT-116 / %
72.9 ± 1.9
68.5 ± 3.4
65.3 ± 1.0
42.5 ± 0.2
33.8 ± 2.8
46.6 ± 1.3
72.8 ± 0.5
73.4 ± 2.4
55.5 ± 5.0
66.6 ± 2.9
2
3
4
5
6
7
8
9
31.5 ± 1.2
49.8 ± 0.7
44.7 ± 3.0
53.0 ± 2.0
56.9 ± 1.0
69.0 ± 0.3
68.2 ± 1.3
1
1
0
1
Among the tested compounds, only 2, 3, 6, 7, 9 and
9 (Table 2, in bold) were cytotoxic to the tumor cell line
used for testing, with a percentage of inhibition of tumor
cell growth greater than 75 ± 2%, and the values of IC50
were determined. Table 3 presents the results of the IC50
tests of these compounds.
The type of chalcone moiety in chalcone-quinolinones
(compounds 10 to 41), i.e., the substitution in C ring of
m-nitro, p-nitro, p-chlorine or p-bromine, did not have a
demonstrable influence on the biological effect of these
compounds. The average growth inhibition percentage
for all the p-nitro, m-nitro, p-chlorine and p-bromine
compounds were 49.1, 50.8, 51.1 and 56.2%, respectively.
The decrease in the tumor inhibition of chalcone-
quinolinones relative to the precursor chalcones could be
explained by the steric impediment or by the absence of the
H at C8 of the α-β-unsaturated double bond, making the C9
more acid. α-β-Unsaturated compounds, such as chalcones,
can be converted in conjugates with glutathione reduced
3
Table 3. Determination of IC50 of synthetic chalcones, and the chalcone-
quinolinone compound 39, in tumor cell line after 72 h of treatment, as
determined by the MTT method
-
1
entry
HCT-116 / (μg mL )
6.9 (6.2-7.7)
2
3
6
7
9
7.5 (6.8-8.3)
(GSH) by nucleophilic attack of the sulfhydryl group by
5.1 (4.8-5.4)
Michael reaction. This reaction leads to the reduction of
GSH levels, which are related to cytotoxic effects, such as
the activation of apotoses or to make the cells susceptible
2.4 (2.1-2.6)
5.9 (5.2-6.9)
3
9
19.3 (13.7-27.2)
0.12 (0.09-0.17)
32,33,39-41
to oxidative damage.
Doxorubicin
Conclusions
Although none of the samples tested had values close
to those of the positive control, such values encourage the
study of these compounds as possible candidates for anti-
cancer drugs. Further studies must be done to test whether
these compounds are mutagenic, and what happens in the
cell cycle with the use of these compounds, among other
considerations. It was not possible to identify a single
trend relating the ring substitution of the chalcones 2 to 9
to the antitumor activity. In this sense, ortho-substituted
chlorine and bromine chalcones (compounds 6 and 3),
showed, respectively, higher and lower inhibition results
than the para-substituted chlorine and bromine chalcones
The results of the anti-tumor tests suggest that the
classes of compounds studied have potentials for use in
cancer research. The antitumor activities of the chalcone-
quinolinone compounds were lower than those of the
chalcone precursors. The type and orientation of the
substituents in the chalcone moiety of the compounds
influenced the activity of the precursor chalcones, but
did not influence the activity of the chalcone-quinolinone
compounds. The reaction conditions used for the synthesis of
the chalcone-quinolinone compounds, focused on obtaining
diferents patterns of substitution on rings B and C, allowed
the formation of desired compounds in good yield, besides
allowing the products of the reactions to be recovered by
filtration. The synthetic procedure represents a case of
(
compounds 7 and 9) (Table 3). In contrast, the inhibition
results for ortho-substituted methoxy chalcone 2 was higher
than the results of the para-substituted 5 (Table 2).

Vol. 00, No. 00, 2018
d’Oliveira et al.
17
intramolecular 1-4 addition, thermodynamically induced
by the subsequent formation of a conjugated system, a
concept that can be adapted to circumstances in which the
intermediate is not stable enough to be isolated. The second
Claisen-Schmidt condensation can lead to the formation of
a conjugated system, inducing the previously unfavorable
cyclization. The results obtained by NMR analysis confirmed
that all chalcone-quinolinone compounds were E isomers.
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3. Pingaew, R.; Saekee, A.; Mandi, P.; Nantasenamat, C.;
Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V.; Eur.
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Supplementary information ( H and C NMR spectra
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1
H NMR spectra for compounds 10 to 41 in Tables S1 to
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NOE experiment of compouns 10 to 41) is available free
of charge at http://jbcs.sbq.org.br as PDF file.
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Jiang, X.; Li, H.; Yang, J.; Wu, C.; Eur. J. Med. Chem. 2015,
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The authors thank the Coordenadoria de
Aperfeiçoamento de Pessoal de Ensino Superior (CAPES,
grant numbers 88881.134665/2016-01), MCT/FINEP/CT-
INFRA, Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq, grant number 478337/2013-2) for
scholarship and financial support, and Dr Pál Perjési for
the technical support.
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Submitted: April 12, 2018
Published online: June 4, 2018
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