Synthesis of chlorovinyl sulfones as structural analogs of chalcones and their antiplasmodial activities

Article abstract of DOI:10.1016/j.ejmech.2008.09.044

The synthesis of novel chlorovinyl sulfone-like chalcone derivatives and their antimalarial activity against cultured Plasmodium falciparum parasites, hemozoin formation, hemoglobin hydrolysis and murine malaria model are described. Compounds were prepare

Full text of DOI:10.1016/j.ejmech.2008.09.044

European Journal of Medicinal Chemistry 44 (2009) 1457–1462
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of chlorovinyl sulfones as structural analogs of chalcones and their
antiplasmodial activities
,
b
c
c
Jose N. Dominguez a , Caritza Leon , Juan Rodrigues , Neira Gamboa de Dominguez ,
*
Jiri Gut d, Philip J. Rosenthal d
a
´
Laboratorio de S´ıntesis Organica, Facultad de Farmacia, Universidad Central de Venezuela, Caracas 1051, Venezuela
b Universidad Pedago´gica Experimental Libertador, Venezuela, Caracas
c Laboratorio de Bioqu´ımica, Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela
d Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, SFGH, 1001 Potrero Avenue, San Francisco, CA 94100, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2008
Received in revised form 23 September 2008
Accepted 26 September 2008
Available online 10 October 2008
The synthesis of novel chlorovinyl sulfone-like chalcone derivatives and their antimalarial activity
against cultured Plasmodium falciparum parasites, hemozoin formation, hemoglobin hydrolysis and
murine malaria model are described. Compounds were prepared via Claisen–Schmidt condensation from
available chloromethylphenyl sulfones with substituted aldehydes. Antiplasmodial IC50 activity of these
compounds ranged between 0.025 and 10 mM, those that blocked P. falciparum development at low micro
molar concentrations were tested in a murine Plasmodium berghei model, and these compounds delayed
the progression of malaria but did not eradicate infections. Much effort and attention are needed for
discovery and development of new and less toxic antimalarial drugs.
Keywords:
Antimalarial activity
Chlorovinyl sulfones
Chalcones
Ó 2008 Elsevier Masson SAS. All rights reserved.
Synthesis
1. Introduction
biological activity [14] has not obtained much attention. However,
some advances have been made as inhibitors of cysteine protease;
Malaria remains one of the principal diseases of the developing
world with an estimated 500 million cases each year and around
two million deaths [1]. In the absence of effective vaccines,
chemotherapy represents the mainstay of malarial control. Resis-
tance to currently used antimalarials, particularly chloroquine
(Fig. 1) and the antifolates, are seriously impeding efforts to control
the disease [2].
In continuation of previous studies [3–5] resulting from our
research program directed toward the preparation of new chalcone
derivatives and their antimalarial evaluation, we are diversifying
our work for pharmaceutically promising analogs of chalcones and
we have paid attention to synthesize a series of new vinyl sulfone
with a chlorine atom at position 2 (Fig. 1). The compounds could be
considered as derivatives of chalcones in which the carbonyl group
is replaced by, possessing similar electrophilic character, sulfone
group.
such compounds target multiple sites in the parasite as anti-
plasmodial agents [15–18]. There is a patent claiming anticancer
activity [19], their product is under development for treatment of
cellular proliferative disorders. The present study was undertaken
to evaluate in vitro activity in a series of 2-chlorovinyl sulfone
derivatives against Plasmodium falciparum. An attempt has been
made to correlate these in vitro data with in vivo activities of these
compounds against Plasmodium berghei infections in mice.
2. Chemistry
We prepare through a facile synthesis of 16 chlorovinyl sulfones
derivatives (Table 1), using the Claisen–Schmidt condensation
method [20]. One step synthesis protocols, as depicted in Scheme 1,
was used to prepare the compounds. Chloromethylphenyl sulfone 1
was condensed with a suitable aldehyde using solid sodium
hydroxide as catalyst in methanol at room temperature to yield
chlorovinyl sulfones derivatives 3–18. These conditions were found
to be satisfactory for the synthesis of chlorovinyl sulfone chalcones
in good yields. In most cases, products were formed immediately
after the addition of sodium hydroxide pellets to the stirred solu-
tion of substituted aldehydes and chloromethylphenyl sulfone. To
ensure the formation of solid a minimal amount of methanol was
Vinyl sulfones have been intensively studied due to their
synthetic utility [6,7] and can be obtained by condensation of
aromatic aldehydes with various phenyl sulfones [8–13] but their
* Corresponding author. Tel.: þ58 212 6052722; fax: þ58 212 6052707.
E-mail address: jdomingu@cantv.net (J.N. Dominguez).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.09.044

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J.N. Dominguez et al. / European Journal of Medicinal Chemistry 44 (2009) 1457–1462
Cl
N
Plates were incubated at 37 ꢀC for 48 h to allow completion of
the reaction and centrifuged (4000 rpm ꢁ 15 min, IEC-CENTRA,
O
1
MP4R). After discarding the supernatant, the pellet was washed
3
S
2
twice with DMSO (200 ml) and finally dissolved in NaOH (200 ml,
NH
R
O
N(C2H5)2
0.2 N). The solubilized aggregates were further diluted 1:2 with
NaOH (0.1 N) and absorbance recorded at 405 nm (Micro Plate
Reader, BIORAD-550). The results were expressed as a percentage
of inhibition of hemozoin formation.
Cl
Fig. 1. Structures of chloroquine and 2-chlorovinyl sulfones.
3.2. Inhibition of globin hydrolysis
used. The product, a,b-unsaturated vinyl sulfone, is almost always
obtained in the trans-alkene form (E-form), as judged by 1H NMR
spectroscopy, which have been fully characterized by analytical and
spectral data. The yields were not optimized and ranged between
36 and 88%.
Selected compounds that inhibited parasite development were
evaluated for the inhibition of globin hydrolysis (Fig. 2). The
proteolytic effect of parasite extracts on the native mouse hemo-
globin was assayed in 96-well plates (Greiner Bio-One). The assay
mixture contained mouse native hemoglobin (10 mL), parasite
extract (50 mL), GSH (10 mL, 10 mM), and acetate buffer (0.2 M, pH
5.4) to a final volume of 200 mL. Compounds, chloroquine, leu-
peptin and pepstatin (5 mM each) were incorporated in the incu-
bation mixture dissolved in DMSO. The incubations were carried
out at 37 ꢀC for 18 h and the reactions were stopped by addition of
reduced sample buffer. The degree of digestion was evaluated
electrophoretically by SDS-PAGE [22] and densitometric compar-
ison of the globin bands (14 kDa). A DMSO control was electro-
phoresed at the same time. The band density values were expressed
as intensity/mm2 ꢂ SD.
The homogeneity of the final compounds was ensured by
column chromatography (silica, mesh size 60–120) using chloro-
form as eluent. The Rf of all compounds was recorded in ethyl
acetate:hexane (1:1 v/v) as eluant. The antimalarial activities of the
compounds are presented in Table 1.
3. Pharmacology
3.1. Inhibition of hemozoin formation in vitro
The hemozoin formation assay was performed according to
Baelmans et al. [21]. Briefly, a solution of hemin chloride (50 ml,
4 mM), dissolved in DMSO (5.2 mg/mL), was distributed in 96-
well micro-plates. Different concentrations (1–100 mM) of the
compounds, dissolved in DMSO, were added in triplicate in test
3.3. Parasite inhibition flow cytometry
Effects of inhibitors on parasite development were determined
as follows. Sorbitol synchronized, 0.1% parasitemias, ring stage
P. falciparum strain W2 parasites were cultured under the atmo-
sphere of 3% O2, 6% CO2 and 91% N2 in RPMI-1640 medium
wells (50
ml) with a final concentration of 1.25–25 mM/well.
Controls contained either water or DMSO. Hemozoin formation
was initiated by the addition of acetate buffer (100
ml 0.2 M, pH 4.4).
Table 1
Antiplasmodial effect for compounds 3–18
O
1
3
S
2
O
R
Cl
Compound
R
Inhibition of hemozoin formationa (%)
Inhibition of hemoglobin hydrolysisb (%)
Peter’s testc,e (%P/SD)
FACSd (IC50
, mM)
Saline
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
LEU
PEP
CQ
26.2 ꢂ 3.03/10 ꢂ 1.09
2,4-diCl2
4-OMe
2,4,6-triOMe
3,4,5-triOMe
3,4-OCH2O-
4-Cl
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
<5
75.3 ꢂ 0.91
<5
<5
0.96
0.47
w10
w10
0.053
0.083
>10
0.059
0.058
>10
0.025
>10
0.073
0.075
>10
<5
37.34 ꢂ 1.08
74.92 ꢂ 1.25
52.72 ꢂ 1.13
95.04 ꢂ 0.78 ***y
84.59 ꢂ 1.36z
59.33 ꢂ 1.23
28.49 ꢂ 0.53
65.81 ꢂ 0.97
79.19 ꢂ 0.92
76.69 ꢂ 1.16
11.07 ꢂ 0.59
44.73 ꢂ 1.15
89.75 ꢂ 0.69
93.77 ꢂ 0.66
26.92 ꢂ 1.85
4-F
3,4-diCl2
2-(1-naphthyl)
H
2-Cl-3-quinolyl
2-Cl
(13.4 ꢂ 4.26 *)/(13 ꢂ 1.37)
(6.25 ꢂ 2.73 **)/(13.2 ꢂ 2.61)
4-NO2
1-naphthyl
2,4,5-triOMe
4-CN
<5
>10
f
f
84.16 ꢂ 1.37
3 ꢂ 0.6/30
a
% of inhibition of hemozoin formation.
Hemoglobin hydrolysis.
b
c
d
e
f
Peter’s test results of the most active drugs. CQ: chloroquine; LEU: leupeptin, PEP: pepstatin compared to LEU; P ¼ parasitemias, SD ¼ survival days.
IC50 for tested compounds as determined by flow cytometry.
The results are expressed by the mean ꢂ standard error of the mean ***p < 0.001 compared to LEP, yp > 0.05 compared to PEP; zp > 0.05 compared to LEP.
Unknown.

J.N. Dominguez et al. / European Journal of Medicinal Chemistry 44 (2009) 1457–1462
1459
O
S
4. Results and discussion
O
S
CHO
2´
Cl
2´´
Variation of substituent of aldehydes provided compounds with
antimalarial activity against P. falciparum. Nine of 16 compounds
among the mono- and disubstituted derivatives had IC50 of less
i
O
R
O
R
+
Cl
3-18
6´
6´´
4´
4´´
1
2a-p
than 10 mM against P. falciparum, but against P. berghei in vivo the
majority of these compounds were inactive.
Scheme 1. Reagents: (i) NaOH, MeOH R: (a) 20,40-diCl; (b) 40-OCH3; (c) 20,40,60-triOCH3;
(d) 30,40,50-triOCH3; (e) 30,40–OCH2O–; (f) 40-Cl; (g) 40-F; (h) 30,40-diCl; (i) 20-naphtyl; (j)
H; (k) 20-Cl-30-quinolinyl; (l) 20-Cl; (m) 40-NO2; (n) 10-naphthyl; (o) 20,40,50-triOCH3; (p)
40-CN.
On the other hand, activity against P. berghei was found in the
3,4-diCl2 and 2-(1-naphthyl) substitution (compounds 10 and 11).
Within these groups were also active against P. falciparum, but
placement of trimethoxy groups about the ring imparted inactivity
for both P. falciparum and P. berghei (compounds 5, 6, and 17).
The presence of chlorine (compounds 3, 8, 13), nitro (compound
15), or naphthyl (compound 16) maintained antimalarial activity,
none of these molecular modifications approached the level of
activity of compounds 10 and 11.
supplemented with 10% human serum in the presence of inhibi-
tors for 48 h without media change. Inhibitors were added from
1000 ꢁ DMSO stocks. After 48 h, the culture medium was removed
and replaced with 1% formaldehyde in PBS pH 7.4 for an additional
48 h at room temperature to fix cells. Fixed parasites were
transferred into 0.1% Triton-X-100 in PBS containing 1 nM YOYO
nuclear dye (Molecular Probes). Parasitemias were determined
from dot plots (forward scatter vs. fluorescence) acquired on an
FACS sort flow cytometer using Cell Quest software (Beckton
Dickinson) to count nucleated (parasitized) erythrocytes. IC50
values for growth inhibition were determined from plots of
percentage control parasitemias over inhibitor concentration
using the Prism 3.0 program (Graph Pad Software [23]), with data
from duplicate experiments fitted by nonlinear regression, as
previously described [24] (Table 1).
Based on our findings on the invitroantimalarial action of a series
of chlorovinyl sulfones against chloroquine-resistant P. falciparum,
these compounds warrant further definitive investigations.
These analyses of structure–activity relationships should serve
as a guide for synthesis and investigations of additional analogs.
Newer and more effective drugs are required because of the
relentless emergence of strains of human plasmodia (especially
P. falciparum) resistant to currently available antimalarial drugs.
A total of 16 compounds were identified showing properties for
their ability to inhibit parasite development by incubating parasites
in different concentrations for 48 h, beginning at the ring stage,
counting new ring forms by FACS (Fluorescence activated cell
sorting) analysis, and comparing parasitemias with those of
untreated controls, nine of those compounds show values ranging
3.4. Activity against murine malaria and data analysis
from 0.025 to 0.96 m
M, derivatives [2(30,40-methylendioxyphenyl)-
NIH mice (18–23 g) were infected intraperitoneally with 106
P. berghei-infected red blood cells. Treatment began 2 h after
infection. These compounds were dissolved in DMSO (0.1 M),
diluted with saline–Tween 20 solutions (2%). Each compound
(20 mg/kg) was administered once daily for 4 days. At day 4, the
parasitemias were counted by examination of Giemsa stained
smears. Chloroquine (25 mg/kg) was used as a positive control. The
survival time beyond the control group (without drug treatment)
was recorded. The results were expressed as percentage of para-
sitemias in relation to the control and percentage of mice survival
[25]. Data were statistically analyzed using one way ANOVA and
t-tests for specific group comparisons; assuming 95% of confidence
according to Graph Pad Prism 3.02 (Fig. 2).
1-chloro]ethenylphenyl sulfone 7 and [2(20-chloroquinolin-30-yl)-
1-chloro]ethenylphenyl sulfone 13 demonstrated the most potent
antimalarial effects against P. falciparum, with IC50 values of 0.053
and 0.025
suggest that the 30,40-methylendioxy substituted derivative located
in the aromatic ring of the -unsaturated chlorophenyl sulfone, as
mM, respectively, (Table 1). Considering this result, we
a,b
well as the 20-chloroquinolinyl group that form part of the aromatic
system (Scheme 1), play an important role in mediating activity
against P. falciparum. These results might be due to some chemical
interaction with the biological substrate or involvement of some
additional unknown mechanism of action.
The most active compounds for hemoglobin hydrolysis were 10
(95.04%) and 11 (84.59%) also tested for activity in mice infected
with P. berghei ANKA, a chloroquine susceptible strain of murine
malaria parasites. The mice were treated with compounds or
chloroquine (20 mg/kg, i.p once daily) for 4 consecutive days, and
their survival times and parasitemias on day 4 were compared with
those of control mice receiving only saline (Table 1).
The above compounds have significantly inhibited day 4 para-
sitemias (Fig. 2) and increased their survival times (Table 1). It is well
known that P. falciparum cysteine proteases hydrolyze hemoglobin
in an acidic food vacuole which provide amino acids for erythrocytic
malarial parasites and consequently, these results suggest that the
abovederivativesmight actas parasiteprotease inhibitors. However,
only for compounds 10 and 11 we observed a close relationship for
their antimalarial effects in vivo as in vitro. None of the resulting
compounds gave good inhibition against hemozoin formation. It
should also be noted that inhibitors identified in this study have IC50
values in the micro-molar range and thus may not be suitable for use
as drugs themselves. However, these compounds do provide much
needed drug like non-peptide leads against malaria.
30
20
10
0
Saline
10 11
TREATMENT
CQ
More work is needed to obtain second-generation version of
these interesting compounds to establish meaningful SAR.
Compounds 7 and 13 could be used as standard precursors for this
purpose.
Fig. 2. The % parasitemias at 4th day post-infection and survival days on mice treated
with 10, 11, *p < 0.05 and **p < 0.01 compared to saline-treated mice. yp > 0.05
compared to chloroquine-treated mice.

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J.N. Dominguez et al. / European Journal of Medicinal Chemistry 44 (2009) 1457–1462
5. Conclusions
J ¼ 8.67 Hz); 13C NMR 121.02 (C-Cl); 128.23 (C2 -6 ); 128.57 (C5 );
00 00
00
0
00 00
0
0
131.03 (C3 -5 ); 131.12 (C3 ); 133.16 (C5 ); 134.60 (C4 ); 135.18 (C-Ha);
In this study, derivatives [2(30,40-methylendioxyphenyl)-1-
chloro]ethenylphenyl sulfone 7 and [2(20-chloroquinolin-30-yl)-1-
chloro]ethenylphenyl sulfone 13 demonstrated the most potent
antimalarial effects against P. falciparum, with IC50 values of 0.053
137.78 (C4 ); 139.35 (C2 ); CIMS (m/z): 349 [M þ 1]; Anal. Calculated:
0
0
C, 48.37%, H, 2.61%. Found: C, 48.34%, H, 2.62%.
6.1.3. [2(40-Methoxyphenyl)-1-chloro] ethenyl phenyl sulfone (4)
Yield: 50%; m.p. 118–120 ꢀC. lmax (KBr): 1507, 1299, 1241, 1178,
and 0.025
suggest that the 30,40-methylendioxy substituted derivative located
in the aromatic ring of the -unsaturated chlorophenyl sulfone, as
mM, respectively (Table 1). Considering this result, we
1142 (cmꢃ1). 1H RMN dH: 3.71 (s, 3H, 40-OCH3), 6.83 (d, 2H, H3 ,5
,
,
0
0
00 00
0
0
a,
b
J ¼ 8.40 Hz), 7.04 (d, 2H, H3 -5 , J ¼ 8.64 Hz), 7.59 (d, 2H, H2 -6
well as the 20-chloroquinolinyl group that form part of the aromatic
system (Scheme 1), play an important role in mediating activity
against P. falciparum. These results might be due to some chemical
interaction with the biological substrate. Compounds 10 and 11
were also quite active in a P. berghei mouse model, with 50 and 72%,
respectively, drop in parasitemias compared to control 4 days after
infection and also an increase in survival.
J ¼ 7.91 Hz), 7.68 (s, 1H, Ha), 7.69 (d, 2H, H2 -6 , J ¼ 7.18 Hz); 13C NMR
00 00
55.63 (40-OMe), 114.24 (C3 -5 ), 120.68 (C-Cl), 128.49 (C2 -6 ), 129.71
0
0
00 00
00 00
0
0
0
0
(C3 -5 ), 132.75 (C2 -6 ),134.38 (C1 ),138.72 (C-Ha),159.86 (C4 ); CIMS
(m/z): 310 [M þ 1]; Anal. Calculated: C, 58.35%, H, 4.24%. Found: C,
58.37%, H, 4.26%.
6.1.4. [2(20,40,60-Trimethoxyphenyl)-1-chloro] ethenyl phenyl
sulfone (5)
Generally speaking, the inhibitory potency of all compounds in
the series against the cultured P. falciparum parasites did not
strongly correlate with inhibitory potency against hemozoin
formation for compounds tested, which was very weak, suggesting
other mechanisms of inhibition may also be involved. However,
good correlation for some compounds was observed for inhibitory
potency against hemoglobin hydrolysis that may involve some
interaction with some cysteine proteases present in murine model.
Compounds maintained an antimalarial efficacy in vitro and
moderate activity in vivo. It should also be noted that inhibitors
identified in this study have IC50 values in the micro-molar range
and thus may not be suitable for use as drugs themselves. However,
these compounds do provide much needed drug like non-peptide
leads against malaria.
Yield: 52%; m.p. 108–110 ꢀC. lmax (KBr): 1498, 1300, 1232, 1190,
1146 (cmꢃ1). 1H RMN dH: 3.43 (s, 6H, OMe), 3.75 (s, 3H, OMe), 6.12
0
0
00 00
00 00
,
(s, 2H, H3 -5 ), 7.61 (d, 2H, H3 -5 , J ¼ 8.15 Hz), 7.67 (d, 2H, H2 -6
J ¼ 8.15 Hz), 7.60 (s, 1H, Ha); 13C NMR 55.83 (OMe), 56.00 (OMe),
0
0
0
00 00
00 00
00
91.01 (C3 -5 ), 97.81 (C1 ), 128.45 (C2 -6 ), 129.26 (C3 -5 ), 133.92 (C4 ),
00
0
0
0
140.33 (C1 ), 159.74 (C2 ,6 ), 162.14 (C4 ); CIMS (m/z): 370 [M þ 1];
Anal. Calculated: C, 55.36%, H, 4.65%. Found: C, 55.39%, H, 4.66%.
6.1.5. [2(30,40,50-Trimethoxyphenyl)-1-chloro] ethenyl phenyl
sulfone (6)
Yield: 48%; m.p. 106–108 ꢀC. lmax (KBr): 1507, 1302, 1238, 1158,
1123 (cmꢃ1).1H RMN dH: 3.59 (s, 6H, OMe), 3.62 (s, 3H, OMe), 6.37 (s,
0
0
00 00
2H, H2 , H6 ), 7.57 (s, 1H, Ha), 7.62 (d, 2H, H3 -5 , J ¼ 7.16 Hz), 7.72 (d,
2H, H2 -6 , J ¼ 7.18 Hz); 13C NMR 56.29 (OMe), 60.65 (OMe), 108.95
00 00
0 0 00 00 00 00 00
(C2 -6 ), 124.50 (C-Cl), 128.73 (C2 -6 ), 129.68 (C3 -5 ), 134.38 (C4 ),
6. Experimental protocols
00
0
0
138.08 (C1 ), 138.51 (C-Ha), 152.94 (C3 -5 ); CIMS (m/z): 370 [M þ 1];
6.1. Chemistry
Anal. Calculated: C, 55.36%, H, 4.65%. Found: C, 55.38%, H, 4.66%.
Melting points were determined in a Thomas micro-hot stage
apparatus and are uncorrected. Infrared spectra were determined
as KBr pellets on a Shimadzu model 470 spectrophotometer and are
expressed in cmꢃ1. 1H NMR and 13C NMR spectra were recorded on
a JEOL GSX (270 MHz) spectrometer; chemical shifts are expressed
6.1.6. [2(30,40-Methylendioxyphenyl)-1-chloro] ethenyl phenyl
sulfone (7)
Yield: 62%; m.p. 104–106 ꢀC. lmax (KBr): 1501, 1300, 1254, 1158,
1123 (cmꢃ1). 1H RMN dH: 6.00 (s, 2H, 30,40–OCH2O–), 6.56 (dd, 1H,
0
0
0
0
0
0
H6 , JH6 -H2 ¼ 1.73 Hz, JH6 -H5 ¼ 7.91 Hz), 6.70 (d,1H, H2 , J ¼ 1.49 Hz),
0
00 00
in
d
(ppm) relative to tetra methyl silane are given. Mass spectral
6.81 (d, 1H, H5 , J ¼ 7.94 Hz), 7.61 (d, 2H, H3 -5 , J ¼ 7.18 Hz), 7.70 (s,
1H, Ha), 7.71 (d, 2H, H2 -6 , J ¼ 7.43 Hz); 13C NMR 101.69 (–OCH2O–),
00 00
data were obtained with a Varian CP3800 model coupled with
Saturn 2000/Gas Chromatograph ionization energy 70 eV, using
CIMS (Chemical Ionization Mass Spectrometry). Elemental analyses
were performed by Atlantic Microlab; Norcross, GA, USA, results
were within ꢂ0.4% of predicted values for all compounds. All
solvents were dried and distilled under nitrogen atmosphere.
Analytical TLCs were run on commercially pre-coated plates
(Merck, silica gel 60 F254) and visualized under UV lamps (254 nm).
The progress of the reactions was monitored by TLC with ethyl
acetate:hexane (1:1 v/v) as eluant.
0
0
0
00 00
108.61 (C5 ), 111.49 (C2 ), 122.43 (C-Cl), 125.36 (C1 ), 128.56 (C2 ,6 ),
00 00
00
00
0
0
129.70 (C3 -5 ), 134.39 (C4 ), 138.77 (C1 ), 147.51 (C3 ), 147.89 (C4 );
CIMS (m/z): 324 [M þ 1]; Anal. Calculated: C, 55.82%, H, 3.44%.
Found: C, 55.81%, H, 3.46%.
6.1.7. [2(40-Chlorophenyl)-1-chloro] ethenyl phenyl sulfone (8)
Yield: 59%; m.p. 114–116 ꢀC. lmax (KBr): 1520, 1315, 1277, 1174,
1130 (cmꢃ1). 1H RMN dH: 7.28 (d, 2H, H3 -5 , J ¼ 7.80 Hz); 7.57 (m, 2H,
0
0
00 00
0
0
00
H3 -5 ); 7.63 (d, 2H, H2 -6 , J ¼ 7.80 Hz); 7.67–7.71 (m, 1H, H4 ), 7.73
(s, 1H, Ha), 7.99–8.03 (m, 2H, H2 -6 ); 13C NMR 118.67 (C-Cl); 128.23
00 00
00 00 0 0 00 00 0 0 00
(C2 -6 ); 130.11 (C3 -5 ); 130.99 (C3 -5 ); 133.03 (C2 -6 ); 134.52 (C4 );
6.1.1. General procedure for the synthesis of chlorovinyl sulfones
0
00
00
3–18
135.46 (C1 ); 137.97 (C4 ); 139.10 (C1 ); 140.36 (C-Ha); CIMS (m/z):
314 [M þ 1]; Anal. Calculated: C, 53.69%, H, 3.22%. Found: C, 53.72%,
H, 3.24%.
A
mixture of commercially available chloromethylphenyl
sulfone (1 mmol), substituted aldehydes (1 mmol) and pulverized
sodium hydroxide (2.5 mmol) were suspended in dry methanol
(5 mL). The reaction mixture was stirred at room temperature for
10–24 h and the resulting precipitate was filtered off and crystal-
lized from methanol/water, yields 33–88%.
6.1.8. [2(40-Fluorophenyl)-1-chloro] ethenyl phenyl sulfone (9)
Yield: 36%; m.p. 117–118 ꢀC. lmax (KBr): 1507, 1293, 1235, 1152
(cmꢃ1). 1H RMN dH: 7.31 (d, 2H, H3 -5 , J ¼ 8.91 Hz), 7.35 (s, 1H, Ha),
00 00
00
0
0
7.60 (d, 1H, H4 , J ¼ 7.93 Hz), 7.70 (d, 2H, H2 -6 , J ¼ 7.42 Hz), 7.99 (d,
6.1.2. [2(20,40-Dichlorophenyl)-1-chloro] ethenyl phenyl sulfone (3)
Yield: 36%; m.p. >270 ꢀC (d), lmax (KBr): 1520, 1331, 1216, 1174
2H, H3 -5 , J ¼ 8.66 Hz), 8.01 (d, 2H, H2 -6 , J ¼ 8.64 Hz); 13C NMR
0
0
00 00
0
0
00 00
0
114.24 (C-Cl); 116.02 (C3 -5 ); 116.34 (C2 -6 ); 121.13 (C1 ); 127.91
(cmꢃ1). 1H RMN dH: 7.49 (d, 2H, H3 -5 , J ¼ 8.15 Hz), 7.67 (d, 1H, H5 ,
(C4 ); 128.57 (C1 ); 129.65 (C-Ha); 132.59 (C3 -5 ); 132.73 (C2 -6 );
00 00
0
00
00
00 00
0
0
0
00
0
J ¼ 8.64 Hz), 7.73 (d, 1H, H6 , J ¼ 6.70 Hz), 7.89 (t, 1H, H4
,
,
166.91 (C4 ); CIMS (m/z): 298 [M þ 1]; Anal. Calculated: C, 56.67%, H,
0
00 00
J ¼ 7.67 Hz), 7.94 (s, 1H, Ha), 7.99 (s, 1H, H3 ), 8.08 (d, 2H, H2 ,6
3.40%. Found: C, 56.65%, H, 3.41%.

J.N. Dominguez et al. / European Journal of Medicinal Chemistry 44 (2009) 1457–1462
1461
6.1.9. [2(30,40-Dichlorophenyl)-1-chloro] ethenyl phenyl
sulfone (10)
6.1.15. [2(10-Naphtyl)-1-chloro] ethenyl phenyl sulfone (16)
Yield: 67%; 1H RMN dH: 7.42–7.94 (m, 6H, H3 -5 , H4 , H6 , Ha,
00 00
00
0
Yield: 72%; m.p. 150–152 ꢀC. lmax (KBr): 1555, 1315, 1248, 1152,
H3 ); 8.02 (d, 1H, H2 , J ¼ 7.91 Hz); 8.09 (d, 2H, H2 -6 , J ¼ 7.67 Hz);
0
0
00 00
1114 (cmꢃ1). 1H RMN dH: 7.58 (d, 2H, H3 -5 , J ¼ 8.41 Hz), 7.61–7.65
8.19 (t, 1H, H7 , J ¼ 7.67 Hz); 8.29 (d, 1H, H5 , J ¼ 8.40 Hz); 8.86 (d, 1H,
00 00
0
0
(m, 1H, H4 ); 7.68–7.70 (m, 1H, H6 ); 7.72 (d, 1H, H5 , J ¼ 8.80 Hz);
H4 , J ¼ 8.40 Hz); 9.16 (d, 1H, H8 , J ¼ 8.42 Hz); 13C NMR 120.95 (C-
00
0
0
0
0
0
00 00
0 0 00 00 0
Cl); 124.99 (C8 ); 126.16 (C6 ); 128.03 (C2 -6 ); 128.85 (C3 ); 129.67
7.79 (s, 1H, Ha); 7.85 (d, 1H, H2 , J ¼ 1.24 Hz); 7.94 (d, 2H, H2 -6
,
J ¼ 8.66 Hz); 13C NMR 118.97 (C-Cl); 129.31 (C2 -6 ); 130.24 (C5 );
(C5 ); 130.24 (C3 -5 ); 132.78 (C4 ); 133.21 (C4 ); 134.93 (C2 ); 136.59
00 00
0
0
00 00
0
00
0
00 00
0
0
0
0
0
00
131.70 (C3 -5 ); 131.32 (C5 ); 131.77 (C6 ); 132.05 (C2 ); 133.25 (C1 );
(C4a); 139.56 (C1 ); 142.02 (C1 ); 142.14 (C-Ha); CIMS (m/z): 330
[M þ 1]; Anal. Calculated: C, 65.75%, H, 3.98%. Found: C, 65.76%, H,
3.98%.
0
00
0
00
133.58 (C3 ); 133.98 (C4 ); 135.11 (C4 ); 140.01 (C1 ); 141.76 (C-Ha);
CIMS (m/z): 349 [M þ 1]; Anal. Calculated: C, 48.37%, H, 2.61%.
Found: C, 48.36%, H, 2.60%.
6.1.16. [2(20,40,50-Trimethoxyphenyl)-1-chloro] ethenyl phenyl
sulfone (17)
6.1.10. [2(20-Naphthyl)-1-chloro] ethenyl phenyl sulfone (11)
Yield: 51%; m.p. 150–152 ꢀC. lmax (KBr): 1520, 1302, 1235, 1155,
Yield: 68%; m.p. 150–152 ꢀC. lmax (KBr): 1517, 1299, 1245, 1149,
1133 (cmꢃ1). 1H RMN dH: 7.59 (dd, 1H, H5 , JH5 -H6 ¼ 6.78 Hz, JH5 -
1114 (cmꢃ1). 1H RMN data: dH 3.43 (s, 3H, OMe); 3.56 (s, 3H, OMe);
0
0
0
0
0
0
0
0
0
0
0
00
H70
¼ 1.49 Hz); 7.63 (td, 1H, H7 , JH7 -H6 ¼ 8.10 Hz, JH7 -H5 ¼1.49 Hz);
3.75 (s, 3H, OMe); 6.53 (s, 1H, H3 ); 6.62 (s, 1H, H6 ); 7.58 (d, 2H, H3 -
0
0
0
0
0
00
500
7.67 (dd, 1H, H8 , JH8 -H7 ¼ 6.94 Hz, JH8 -H6 ¼ 1.49 Hz); 7.96 (d, 1H,
, J ¼ 6.91 Hz); 7.60 (s, 1H, Ha); 7.62 (d, 1H, H4 , J ¼ 6.43 Hz); 7.69 (d,
H1 , J ¼ 1.49 Hz); 7.99–8.03 (m, 6H, H2 -6 , H3 -5 , H4 , Ha); 8.12 (dd,
2H, H2 -6 , J ¼ 7.43 Hz); 13C NMR 55.43 (OMe); 55.70 (OMe); 56.17
0
00 00
00 00
00
00 00
1H, H3 , JH3 -H4 ¼ 9.15 Hz, JH3 -H1 ¼1.49 Hz); 8.61 (br, 1H, H4 ); 13C
(OMe); 97.99 (C3 ); 112.65 (C1 ); 118.02 (C-Cl); 121.12 (C6 ); 128.6
0
0
0
0
0
0
0
0
0
0
0
00 00
00 00
00 00
00
00
NMR 114.10 (C4 ); 118.36 (C-Cl); 127.02 (C6 ); 128.26 (C2 -6 ); 128.38
(C2 -6 ); 131.22 (C3 -5 ); 134.45 (C4 ); 140.11 (C1 ); 142.00 (C-Ha);
143.54 (OMe); 152.55 (OMe); 155.36 (OMe); CIMS (m/z): 370
[M þ 1]; Anal. Calculated: C, 55.36%, H, 4.65%. Found: C, 55.38%, H,
4.66%.
0
0
0
0
00 00
(C7 ); 129.00 (C5 ); 129.22 (C3 ); 129.53 (C1 ); 130.12 (C3 -5 ); 131.24
0
0
00
00
(C8 ); 132.99 (C1 ); 133.78 (C4 ); 138.35 (C8a); 139.33 (C1 ); 141.42
(C-Ha); CIMS (m/z): 330 [M þ 1]; Anal. Calculated: C, 65.75%, H,
3.98%. Found: C, 65.77%, H, 3.96%.
6.1.17. [2(40-Cyanophenyl)-1-chloro] ethenyl phenyl sulfone (18)
Yield: 60%; m.p. 134–136 ꢀC. lmax (KBr): 1504, 1321, 1286, 1155,
6.1.11. 2-Phenyl-1-chloroethenyl phenyl sulfone (12)
Yield: 33%; m.p. 132–134 ꢀC. lmax (KBr): 1510, 1312, 1254, 1171,
1129 (cmꢃ1). 1H RMN data: dH 7.50–7.74 (m, 6H, H3 -5 , H4 , Ha, H3 -
00 00
00
0
1110 (cmꢃ1). 1H RMN dH: 7.47–7.50 (m, 4H, H3 -5 , H3 -5 ); 7.53 (s, 1H,
5 ); 7.98 (d, 2H, H2 -6 , J ¼ 8.91 Hz); 8.08 (d, 2H, H2 -6 , J ¼ 8.64 Hz);
00 00
0
0
0
00 00
0
0
13
00
0
0
0
00 00
0 00 00
C NMR 116.48 (C4 ); 118.19 (C-Cl); 119.88 (CN); 128.19 (C2 -6 );
Ha); 7.58–7.71 (m, 4H, H4 , H4 , H2 -6 ); 7.94 (d, 2H, H2 -6
,
J ¼ 8.40 Hz); 13C NMR 118.77 (C-Cl); 128.63 (C2 -6 ); 129.10 (C3 -5 );
129.96 (C3 -5 ); 132.03 (C2 -6 ); 132.99 (C3 -5 ); 134.22 (C4 ); 140.44
00 00
0
0
00 00
0
0
0
0
00
00 00
0
0
0
00
00
0
130.03 (C3 -5 ); 131.22 (C2 -6 ); 132.78 (C4 ); 133.67 (C4 ); 136.67
(C1 ); 140.78 (C-Ha); 144.69 (C1 ); CIMS (m/z): 305 [M þ 1]; Anal.
Calculated: C, 59.31%, H, 3.32%, N, 4.61%. Found: C, 59.29%, H, 3.30%,
N, 4.63%.
0
00
(C1 ); 138.54 (C1 ); 140.89 (C-Ha); CIMS (m/z): 280 [M þ 1]; Anal.
Calculated: C, 60.32%, H, 3.98%. Found: C, 60.33%, H, 3.98%.
6.1.12. [2(20-Chloroquinolin-30-yl)-1-chloro] ethenyl phenyl
sulfone (13)
Acknowledgments
Yield: 56%; m.p. 250 ꢀC (d). lmax (KBr): 1549, 1302, 1254, 1142
This Work was supported by Consejo de Desarrollo Cientıfico y
Humanıstico (CDCH), Universidad Central de Venezuela (Grants PG
0630-5126, PG 0630-5125-2.003). Project CICNAT 04/070, UPEL-
IPC.
(cmꢃ1). 1H RMN dH: 7.25 (t, 2H, H3 -5 , J ¼ 7.67 Hz); 7.38 (t, 1H, H4
,
00 00
00
0
J ¼ 8.15 Hz); 7.44 (s, 1H, Ha); 7.52 (d, 1H, H8 , J ¼ 8.66 Hz); 7.66 (t,1H,
0
0
00 00
,
H7 , J ¼ 7.42 Hz); 7.78 (t, 1H, H6 , J ¼ 8.40 Hz); 7.92 (d, 2H, H2 -6
J ¼ 7.67 Hz); 8.05 (d, 1H, H5 , J ¼ 7.92 Hz); 8.51 (s, 1H, H4 ); 13C NMR
0
0
0
00 00
0
0
118.34 (C-Cl); 121.90 (C2 ); 128.26 (C2 -6 ); 128.50 (C6 ); 129.98 (C7 );
00 00
0
0
00
References
131.00 (C3 -5 ); 131.10 (C5 ); 133.98 (C8 ); 134.23 (C4 ); 135.02 (C-
0
00
0
Ha); 138.77 (C1 ); 141.11 (C1 ); 145.55 (C3 ); CIMS (m/z): 365 [M þ 1];
Anal. Calculated: C, 56.06%, H, 3.04%, N, 3.85%. Found: C, 56.07%, H,
3.01%, N, 3.88%.
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6.1.13. [2(20-Chlorophenyl)-1-chloro] ethenyl phenyl sulfone (14)
Yield: 88%; m.p. 118–122 ꢀC. lmax (KBr): 1540, 1312, 1264, 1152
(cmꢃ1). 1H RMN data: dH: 7.39–7.50 (m, 5H, H3 -5 , H4 , H4 , H5 );
00 00
00
0
0
0
00 00
7.54 (d, 1H, H3 , J ¼ 7.70 Hz); 7.78 (s, 1H, Ha); 8.08 (d, 2H, H2 -6
,
J ¼ 7.16 Hz); 13C NMR 119.70 (C-Cl); 128.17 (C2 -6 ); 129.32 (C5 );
00 00
0
00 00
0
0
0
0
130.35 (C3 -5 ); 130.41 (C3 ); 131.12 (C1 ); 132.00 (C6 ); 133.22 (C4 );
00
0
00
133.98 (C4 ); 134.60 (C-Ha); 138.54 (C2 ); 139.13 (C1 ); CIMS (m/z):
314 [M þ 1]; Anal. Calculated: C, 53.69%, H, 3.22%. Found: C, 53.70%,
H, 3.21%.
6.1.14. [2(40-Nitrophenyl)-1-chloro] ethenyl phenyl sulfone (15)
Yield: 65%; m.p. 152–156 ꢀC. lmax (KBr): 1520, 1344, 1286, 1171,
1123 (cmꢃ1). 1H RMN dH: 8.11 (d, 2H, H3 -5 , J ¼ 7.16 Hz); 8.17 (d, 2H,
00 00
0
0
00
H3 -5 , J ¼ 7.67 Hz); 8.22 (s, 1H, Ha); 8.26 (d, 1H, H4 , J ¼ 8.91 Hz);
8.33 (d, 2H, H2 -6 , J ¼ 7.61 Hz); 8.39 (d, 2H, H2 -6 , J ¼ 7.67 Hz); 13C
0
0
00 00
00 00
0
0
00 00
NMR 118.78 (C-Cl); 121.98 (C3 -5 ); 127.35 (C2 -6 ); 130.18 (C3 -5 );
0
0
00
00
133.56 (C2 -6 ); 134.02 (C4 ); 138.75 (C1 ); 140.89 (C-Ha); 141.88
0
0
(C1 ); 149.68 (C4 ); CIMS (m/z): 325 [M þ 1]; Anal. Calculated: C,
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51.94%, H, 3.11%, N, 4.33%. Found: C, 51.94%, H, 3.12%, N, 4.32%.

1462
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