Synthesis and antimalarial activity of thioetherhydroxyethylsulfonamides, potential aspartyl protease inhibitors, Part 3

Article abstract of DOI:10.1016/j.ejmech.2011.09.025

A series of novel thioetherhydroxyethylsulfonamide derivatives has been synthesized from the coupling of intermediates 3-amino-4-phenyl-1- thioetherazine-butan-2-oles 6,7 with arenesulfonyl chlorides in good yields. Characterizations of products were achieved by NMR techniques and specifically for compound 8e by X-ray crystallography. Preliminary results of antimalarial activity in vitro against the Plasmodium falciparum W2 clone (chloroquine resistant and mefloquine sensitive) showed moderate activity for hydroxyethylsulfonamide 8f. In addition, none of the compounds tested showed cytotoxicity at high concentration tested against HepG2 and BGM cell lines.

Full text of DOI:10.1016/j.ejmech.2011.09.025

European Journal of Medicinal Chemistry 46 (2011) 5688e5693
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antimalarial activity of thioetherhydroxyethylsulfonamides,
potential aspartyl protease inhibitors, Part 3
,
,
Walcimar T. Vellasco Juniora b, Guilherme P. Guedesa e, Thatyana R.A. Vasconcelosa, Maria G.F. Vaza,
Marcus V.N. de Souzab, Antoniana U. Krettlic, Luisa G. Krettlic, Anna Caroline C. Aguiarc,
Claudia R.B. Gomesb, Wilson Cunicob
,d,
*
a Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, Outeiro de São João Batista, s/nꢀ, Centro, Niterói 24020-141, RJ, Brazil
b Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos e Farmanguinhos, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro 21041-250, RJ, Brazil
c Fundação Oswaldo Cruz, Centro de Pesquisa René Rachou, Laboratório de Malária, Belo Horizonte, 30190-002 MG, Brazil
d Universidade Federal de Pelotas, Centro de Ciências Químicas, Farmacêuticas e de Alimentos e CCQFA, Campus Universitário s/nꢀ, Pelotas 96010-900, RS, Brazil
e Universidade Federal Rural do Rio de Janeiro, Instituto de Ciências Exatas, Departamento de Química, BR 465, Km 47, Seropédica, Rio de Janeiro, 23070-200, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2011
Received in revised form
5 September 2011
Accepted 16 September 2011
Available online 22 September 2011
A series of novel thioetherhydroxyethylsulfonamide derivatives has been synthesized from the coupling
of intermediates 3-amino-4-phenyl-1-thioetherazine-butan-2-oles 6,7 with arenesulfonyl chlorides in
good yields. Characterizations of products were achieved by NMR techniques and specifically for
compound 8e by X-ray crystallography. Preliminary results of antimalarial activity in vitro against the
Plasmodium falciparum W2 clone (chloroquine resistant and mefloquine sensitive) showed moderate
activity for hydroxyethylsulfonamide 8f. In addition, none of the compounds tested showed cytotoxicity
at high concentration tested against HepG2 and BGM cell lines.
Keywords:
Ó 2011 Elsevier Masson SAS. All rights reserved.
Hydroxyethylsulfonamides
Thioetherhydroxyethylsulfonamides
Antimalarial
1. Introduction
initial steps of the degradation pathway and therefore make for an
attractive antimalarial drug target [3]. There are four aspartyl
Malaria is the most important tropical disease transmitted by
the bite of the female Anopheles mosquito. According to the World
Health Organization, this disease is endemic in 105 countries and
kills more than one million people every year, mostly children in
Africa [1]. Human malaria is caused by four different species of
Plasmodium, the most common worldwide is Plasmodium vivax and
the most deadly is Plasmodium falciparum. The Plasmodium resis-
tance to the current antimalarial drugs, such as chloroquine and
mefloquine, is one of the major obstacles in the fight against
malaria. Thus, there is a growing need to develop new effective
antimalarial drugs, especially compounds with new mechanism of
action. One of the critical stages of the cycle of the parasite during
human infection is the degradation of hemoglobin which provides
nutrients for its growth and maturation [2]. A family of aspartic
proteases, known as plasmepsins, appears to be involved in the
proteases present in the food vacuole of P. falciparum, plasmepsins
I, II, IV and Histo-Aspartic-Protease (HAP). The most attractive
target from this group of enzymes is the plasmepsin II [4] and the
literature has shown that HIV proteases inhibitors can inhibit this
enzyme in vitro [5] and in vivo [6] at pharmacologically relevant
concentrations.
Compounds that bear a hydroxyethylamine or
a hydrox-
yethylsulfonamide core are well recognized due to their capacity to
inhibit aspartyl protease enzymes considering the presence of
a secondary alcohol function that mimics the tetrahedral inter-
mediate during peptide bond cleavage (Fig. 1) and are widely used
as anti-HIV agents [7]. The HIV protease inhibitors were also
studied on treatment of leishmania/HIV-1 coinfections. [8]
Recently, the literature shows the application of hydroxyethyl-
amines as inhibitors of BACE-1 to combat Alzheimer’s disease [9].
In addition, sulfonamides derivatives have occupied a prom-
inent position in medicinal chemistry for exhibiting a wide range of
pharmacological activities like antimalarial [10], antimicrobial
[11,12], antitumoral [13,14], anti-inflammatory agents [15] and
carbonic anhydrase inhibitor [16,17].
* Corresponding author. Universidade Federal de Pelotas, Centro de Ciências
Químicas, Farmacêuticas e de Alimentos e CCQFA, Campus Universitário s/nꢀ,
Pelotas, 96010-900, RS, Brazil. Tel.: þ55 (53) 3275 7358; fax: þ55 (53) 3275 7354.
E-mail addresses: wjcunico@yahoo.com.br,wilson.cunico@ufpel.edu.br (W. Cunico).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.09.025

W.T. Vellasco Junior et al. / European Journal of Medicinal Chemistry 46 (2011) 5688e5693
5689
OH
OH
R
HO OH
N
H
N
H
N
H
N
S
N
S
S
H
R
O
O
R
O
O
R
O
thioether
hydroxyethysulfonamides
amino
hydroxyethysulfonamides
tetrahedral transition-state
intermediate of amide hydrolysis
Fig. 1. Transition-state mimics developed for the synthesis of aspartyl protease
inhibitors.
Fig. 3. X-ray crystal structure of compound 8e. Ellipsoyds at 50% of probability.
Fig. 2. Hydroxyethylamine and hydroxyethylsulfonamide derivatives with antimalarial
activity.
for thioether moiety and study their influence on antimalarial
activity. So, the thioetherhydroxyethylsulfonamides were synthe-
sized and evaluated for their in vitro antimalarial activity against
P. falciparum. The clone W2 was used for the test, as described in
our previous work [18aec], and activity compared to that lopinavir
and saquinavir, used in parallel as control in each test.
2. Results and discussion
2.1. Chemistry
The target compounds 8aej were synthesized according to
Scheme 1, using the previous studies carried out in our laboratory.
The hydroxyethylamine transition-state core of intermediates 4
and 5 were prepared by selective ring-opening of (2S,3S)Boc-
phenylalanine epoxide
1 with 2-mercaptopyridine 2 and 2-
mercaptopyrimidine 3, respectively, in excellent yields at room
temperature (Scheme 1). It is noteworthy that when these reactions
were carried out refluxing methanol for long reaction times (24 h),
it has been also identified the formation of the by-product (4S,5R)-
4-benzyl-5-(hydroxymethyl)-1,3-oxazolidin-2-one 9. This comp-
ound could be easily synthesized from reaction of epoxide 1 at
reflux of methanol and its mesylate derivative 10 was characterized
by X-ray diffraction (Scheme 2) [19]. In a subsequent step the
intermediates 4,5 were deprotected using TFA/CH2Cl2 mixture and
the 3-amino-4-phenyl-1-thioetherazine-butan-2-oles 6,7 were
coupled with appropriate benzenesulfonyl chlorides in triethyl-
amine (TEA) with dimethylformamide (DMF) as catalyst, at room
temperature, to afford the thioetherhydroxyethylsulfonamides
8aej in good yields (Table 1), as described in the general procedure.
Spectral data of all compounds (1H NMR, 13C NMR and ESI-MS)
are in full agreement with the proposed structures. 2D-NMR
techniques (COSY, HSQC and HMBC) helped us to assign the correct
Scheme 1. Reaction conditions: i: MeOH, TEA, r.t., 2 h; ii: TFA/CH2Cl2 (1:3), r.t., 8 h; iii:
ArSO2Cl, AcOEt, TEA, DMF, r.t., 8 h.
Scheme 2. Reaction conditions: i: MeOH, 68 ꢀC, 24 h; ii: MsCl, TEA, r.t., 2 h.
Previously, we have been reported the in vitro activity of
hydroxyethylamine [18a] and aminohydroxyethylsulfonamide
[18b,c] derivatives against P. falciparum (Fig. 2). Our studies showed
that the aminohydroxyethylsulfonamides showed better antima-
larial activity than the hydroxyethylamines and in the course of our
investigation on protease inhibitors-based compounds [18], the
aim of this work was to explore the replacement of amino moiety
Table 2
Selected bond lengths, bond angles and torsion angles for compound 8e.
Atoms Bond
lengths
(Å)
Atoms
Bond
angles
(ꢀ)
Atoms
Torsion
angles
(ꢀ)
Table 1
Yields and selected physical properties of thioetherhydroxyethylsulfonamides 8aej.
Compound
X
R
m.p. (ꢀC)a
Yield (%)b
ESI-MS (m/z) (%)
C1eC2 1.528 (3) O1eS1eO2
C2eC3 1.525 (3) C2eN1eS1
120.21 (14) C4eS2eC17eN2
126.33 (13) S1eN1eC2eC3 ꢁ107.18 (18)
26.0 (2)
8a
8b
8c
8d
8e
8f
8g
8h
8i
CH
CH
CH
CH
CH
N
N
N
N
N
NO2
CH3
Br
OCH3
F
NO2
CH3
Br
OCH3
F
89e90
77
79
81
62
65
75
72
77
60
72
483.1 (Mþ þ Na, 52%)
451.0 (Mþ þ Na, 100%)
494.8 (Mþ þ H, 100%)
466.8 (Mþ þ Na, 100%)
450.1 (Mþ þ Na, 100%)
483.0 (Mþ þ Na, 100%)
467.9 (Mþ þ K, 100%)
533.9 (Mþ þ K, 100%)
484.0 (Mþ þ K, 100%)
472.0 (Mþ þ K, 100%)
C3eC4 1.509 (3) C2eC1eC11 115.43 (18) C10eS1eN1eC2 ꢁ84.65 (19)
145e147
195e196
101e103
148e149
140e142
111e113
116e118
92e93
C4eS2 1.798 (2) C1eC2eC3
C3eO3 1.417 (3) C2eC3eC4
110.09 (16) O3eC3eC2eN1 ꢁ171.32 (15)
111.94 (16) O3eC3eC4eS2 55.9 (2)
N1eC2 1.454 (3) C4eS2eC17 102.44 (12) C11eC1eC2eC3 ꢁ179.64 (18)
C1eC11 1.489 (3) N2eC17eS2 119.40 (17) C11eC1eC2eN1
S1eN1 1.587 (16) C17eN2eC21 118.10 (2)
ꢁ59.1 (2)
S1eO1 1.434 (2) O3eC3eC4
S1eO2 1.417 (18) N1eC2eC3
C7eF1 1.347 (3) O3eC3eC2
S2eC17 1.754 (3) N1eS1eC10 108.35 (10)
N2eC17 1.330 (3) N1eC2eC3 108.86 (16)
111.77 (18)
108.86 (16)
109.41 (16)
8j
112e114
a
Melting points are uncorrected.
Yields of isolated compounds.
b

5690
W.T. Vellasco Junior et al. / European Journal of Medicinal Chemistry 46 (2011) 5688e5693
Fig. 4. Crystal packing for compound 8e.
Table 3
arrangement, acting as receiver or hydrogen donor in those inter-
Hydrogen-bond geometry (Åꢀ) for 8e.
actions, whereas the sulfonamide group shows a hydrogen donor
character, as discussed elsewhere [22]. Geometric parameters
associated to those bonds are shown in Table 2. The intramolecular
hydrogen bond (O3eH3/N2) (Table 3) is responsible by the
observed pyridine ring conformation, leading to a torsion angle of
26.2ꢀ among C4eS2eC17eN2 atoms. In solid state, the molecules
DeH/A
DeH
H/A
D/A
DeH/A
O3eH3/N2
N1eH6/O3a
0.82
0.86
1.87
1.98
2.679 (2)
2.792 (2)
167
158
Symmetry codes:
a
ꢁx, yꢁ1/2, ꢁzþ1.
are also stabilized by
p/p interaction (stacking) between the 4-
halidebenzenosulfonamide and the adjacent phenyl rings, with
centroid distance of 3.71 Å, characteristic for this kind of inter-
molecular interaction [20].
signals of the compounds. For the hydroxyethylamine core, protons
H1 and H4 were both showed as two double-doublets, being H4
protons more shielded than the H1 protons. The two multiplets in
the 1H NMR spectra in the range of 3.97 to 3.56 ppm were assigned
to the H2 and H3 protons. On aromatic region we assigned all the
phenyl, pyridinic and pyrimidinic signals. For all compounds
we could also assign the two doublets referred to the benzene-
sulfonamidic hydrogens. The 13C NMR spectra exhibited the C2
(CeNH) signals at 74.0e71.6 ppm and C3 (CeOH) at 59.1e60.7 ppm.
The CH2 signals for C1 and C4 appeared at 33.1e36.8 ppm.
Prismatic colorless crystals of compound 8e were obtained by
slow ethanol evaporation at room temperature. Asymmetric unit is
shown in Fig. 3. Main functional groups are linked to an aliphatic
chain formed by C1, C2, C3 and C4 atoms. The substituents of C2 are
benzyl and 4-fluoro-benzenesulfonamide groups and for C3,
a hydroxyl group, confirming the structure elucidated by NMR. C2
and C3 are chiral atoms showing S configuration. Selected bond
lengths and angles listed in Table 2 are typical when compared with
those previously reported for sulfonamide groups [20,21].
2.2. Biological activity
In order to investigate the potential antimalarial activity of these
novel thioether derivatives, six of them (4, 5, 8a, 8b, 8f and 8h) were
evaluated in vitro against P. falciparum W2 clone, which is
chloroquine-resistant and mefloquine sensitive. The P. falciparum
blood parasites were maintained in continuous cultures of human
erythrocytes, at 37 ꢀC using the candle jar method and the anti-
malarial activity of the compounds was assessed by the hypoxan-
thine [3H]-incorporation assay [23] with slight modifications [24].
Saquinavir and lopinavir were used as standard drugs. The
concentrations that induce 50% inhibition of cell growth (IC50) are
reported in Table 4.
Results showed that the thioetherhydroxyethylsulfonamide 8f
displayed a moderate antimalarial activity with an IC50 value of
Crystalline structure of the compound 8e is stabilized by
hydrogen bonds network along the b axis (Fig. 4), which one of
them is intramolecular, between alcohol hydrogen and pyridinic
nitrogen (O3eH3/N2), the other one is intermolecular between
the sulfonamide hydrogen and the alcohol oxygen (N1eH6/O3).
Alcohol group has an important contribution to the structural
15 mg/mL (31.7 mM). The IC50 value in the micromolar concentration
range is comparable to IC50 observed for some hydroxyethylamine
derivatives previously synthesized for us [18aec]. For compounds
8a, 8b, 8h and the precursors 4 and 5, the IC50 values were higher
than 50 mg/mL, thus considered inactive against P. falciparum. We
also explored the antimalarial activity of oxazolidinone 9, however
this compound did not show activity at the maximum concentra-
Table 4
tion tested (IC50 > 50 mg/mL).
Antimalarial activity expressed by IC50 of compounds for inhibiting the growth of
P. falciparum (strain W2) and cytotoxicity to HepG2 and to BGM cells.
An important observation was the low cytotoxicity of all
compounds tested. The in vitro toxicity activity of these compounds
was evaluated against HepG2 (human hepatoma) and BGM (kidney
epithelial) cell lines in different concentrations using MTT cell
viability assay. The results were expressed as lethal dose for 50% of
Compound
IC50
m
g/mL
LD50 HEPG2
g/mL)b
LD50 BGM
g/mL)b
(m
M)a ꢂ S.D.
(
m
(m
4
5
8a
8b
8f
8h
9
31.7 ꢂ 1.0 (84.7)
>200
197
>200
170
>50.0
the cells and the LD50 values were higher than 99 mg/mL, as shown
in Table 4, indicating that these compounds had low toxicity.
>50.0
>50.0
>200
191 ꢂ 4
>200
101 ꢂ 9
>200
360 ꢂ 20
e
>200
192 ꢂ 6
>200
99 ꢂ 14
>200
383 ꢂ 12
e
15.0 ꢂ 1 (31.7)
25.0 (50.7)
>50.0
0.085 ꢂ 0.01 (0.26)
7.0 (10.4)
1.7 (2.7)
3. Conclusion
Chloroquine
Saquinavir
Lopinavir
A new series of thioetherhydroxyethylsulfonamides was easily
synthesized in good yields from commercially available materials.
The structures of compounds were identified and characterized by
1H and 13C NMR and in one of them by X-ray diffraction (8e). Some
compounds were evaluated for their in vitro antimalarial activities
e
e
S.D.: Standard deviation of three different assays.
a
IC50 represents the inhibitory concentration of 50% of parasite growth.
LD50 represents the lethal dose of 50% of cells.
b

W.T. Vellasco Junior et al. / European Journal of Medicinal Chemistry 46 (2011) 5688e5693
5691
and compound 8f displayed moderate activity against P. falciparum
4.3. General procedure for the preparation of thioetherhydroxyethyl-
sulfonamides 8aej
W2 clone. In addition, this class of compounds has showed no
significant toxic effects in vitro to human HepG2 and BGM cells.
These preliminary results encourage further investigation on
hydroxyethylsulfonamide derivatives aiming at the discovery of
more potent antimalarial compounds.
Trifluoroacetic acid (1.5 mL, 20 mmol) was added to a solution of
the compound 4 or 5 (2 mmol) in CH2Cl2 (6 mL). The mixture was
stirred for 8 h at room temperature and the solvent was removed in
high vacuum. The residue dissolved in EtOAc (20 mL) was washed
with 5% NaHCO3 aqueous solution, water, brine and dried over
MgSO4. The solvent was removed to afford the corresponding free
amines 6 or 7 which were used in the next step. The amines were
dissolved in EtOAc (10 mL) and then TEA (2.2 mmol) and N,N-dime-
thylformamide (0.2 mmol) were added. The system was stirred for
30 min over nitrogenous atmosphere and arenesulfonyl chloride
(2.0 mmol) was added portion wise. The mixture was stirred over 8 h
andwashedwith5%HClaqueoussolution, water, brineanddriedover
MgSO4. The solvent was removed in high vacuum and the products
8a-j were obtained in good yields after recrystallization in hexane.
4. Experimental protocols
4.1. General
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. Diffraction data for compound 8e [25] was obtained on
an Enraf-Nonius Kappa-CCD diffractometer at room temperature
(298 K). The crystal structures were solved by direct methods using
SHELXS-97 and they were refined by full-matrix least-squares on F2
using SHELXL-97 [26]. All non-hydrogen atoms were refined using
anisotropic displacement parameters. The CeH hydrogen atoms
were positioned stereochemically and refined with fixed individual
displacement parameters [Uiso(H) ¼ 1.2Ueq (C2sp) or 1.5Ueq (Cs3p)]
using a riding model. The melting points were determined on
a Buchi Melting Point B-545 and are uncorrected. 1H and 13C NMR
spectra were recorded on a Bruker DRX 400 spectrometer (1H at
400.14 MHz and 13C at 100.61 MHz) and on a Bruker Avance 500
spectrometer (1H at 500.13 MHz and 13C at 125.75 MHz) in DMSO-
d6 containing TMS as in internal standard. The ESI-MS analyses
were performed on a LC/MS micromass ZMD using Electrospray
Ionization technique on positive ion mode. Samples were intro-
duced by the standard direct insertion probe method. The IR
spectra were performed in a spectrophotometer Nicolet-Nexus 670
with KBr.
4.3.1. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyridin-2-ylthio)butan-2-
yl)-4-nitrobenzenesulfonamide (8a)
IR (cmꢁ1 KBr): 3414 (OH); 3109 (NH); 1530 and 1390 (NO2);
1323 and 1154 (O]S]O); 678 (CeS). 1H NMR (DMSO-d6,
400 MHz):
d
8.37 (dd, 1H, 3J ¼ 4.9, 4J ¼ 0.8; H21); 8.23 (d, 1H,
3J ¼ 11.2; NH); 8.03 (d, 2H, 3J ¼ 8.9; H5 and H9); 7.63 (dt, 1H,
3J ¼ 8.0; 4J ¼ 1.8; H19); 7.60 (dd, 2H; 3J ¼ 8.9; H6 and H8); 7.30 (d,
1H; 3J ¼ 8.1; H18); 7.10 (ddd, 1H, 3J ¼ 7.2; 3J ¼ 4.9; 4J ¼ 0.8; H20);
7.00e6.95 (m, 5H; Ph); 5.49 (d, 1H, 3J ¼ 5.8; OH); 3.67e3.63 (m, 1H;
H2); 3.60e3.56 (m, 1H; H3); 3.40 (dd, 1H, 2J ¼ 13.6, 3J ¼ 5.4; H1b);
3.10 (dd,1H, 2J ¼ 13.6; 3J ¼ 7.5; H1a); 2.88 (dd,1H, 2J ¼ 14.0; 3J ¼ 3.4;
H4b); 2.54 (dd, 1H, 2J ¼ 14.0; 3J ¼ 9.9; H4a). 13C NMR (DMSO-d6,
100 MHz): d 158.5 (C17); 149.6 (C7); 149.1 (C10); 147.7 (C21); 138.8
(C11); 137.0 (C19); 129.7 (C13 and C15); 128.3 (C5 and C9); 127.7
(C12 and C16); 126.0 (C14); 124.4 (C6 and C8); 122.3 (C18); 120.2
(C20); 72.7 (C2); 60.1 (C3); 35.1 (C4); 33.6 (C1).
4.2. General procedure for the synthesis of compounds 4,5
4.3.2. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyridin-2-ylthio)butan-
2-yl)-4-methylbenzenesulfonamide (8b)
Mercaptoazines 2 or 3 (1.5 mmol), TEA (1.6 mmol) and epoxide 1
(1.6 mmol) were dissolved in methanol (10 mL) and stirred at room
temperature for 2 h. After this period, the solvent was removed by
evaporation and the crude product was purified by crystallization
IR (cmꢁ1 KBr): 3289 (OH); 3195 (NH); 1340 and 1161 (O]S]O);
678 (CeS). 1H NMR (DMSO-d6, 400 MHz):
d
8.35 (dd, 1H, 3J ¼ 4.9;
4J ¼ 0.8; H21); 7.61 (dt, 1H, 3J ¼ 7.9; 4J ¼ 1.8; H19); 7.47 (d, 2H,
3J ¼ 8.9; H5 and H9); 7.28 (d,1H, 3J ¼ 8.1; H18); 7.11e7.07 (m, 3H; Ph
and H20); 7.02e7.00 (m, 2H; Ph); 6.78 (d, 2H, 3J ¼ 8.9; H6 and H8);
3.81 (s, 3H; OCH3); 3.80e3.76 (m, 1H; H2); 3.64e3.59 (m, 1H; H3);
3.41 (dd,1H, 3J ¼ 14.2; 3J ¼ 4.7; H1b); 3.12 (dd,1H, 3J ¼ 14.2; 3J ¼ 7.6;
H1a); 2.94 (dd, 1H, 2J ¼ 13.9; 3J ¼ 4.5; H4b); 2.63 (dd, 1H, 2J ¼ 14.0;
3J ¼ 8.7; H4a).
in methanol/water (7:3) to give the intermediates
respectively.
4 or 5,
4.2.1. Selected data for compound 4
Yield 98%. m.p. 99e101 ꢀC. EM-ESI (m/z) 397.2 (Mþ þ Na, 100%).
IR (cmꢁ1 KBr): 3356 (OH); 2979 (NH); 1686 (C]O); 659 (CeS). 1H
NMR (DMSO-d6, 400 MHz): 8.39 (d, 1H, 3J ¼ 4.2); 7.62 (dt, 1H,
3J ¼ 8.0, 4J ¼ 1.8); 7.29 (d, 1H, 3J ¼ 9.5); 7.25e7.22 (m, 2H); 7.18e7.14
(m, 3H); 7.09 (ddd, 1H, 3J ¼ 7.3, 3J ¼ 5.0, 4J ¼ 0.7); 6.70 (d, 1H,
3J ¼ 8.8); 5.37 (d, 1H, 3J ¼ 5.8); 3.66e3.58 (m, 2H); 3.51 (dd, 1H,
2J ¼ 13.5, 3J ¼ 3.4); 3.08e3.01 (m, 2H); 2.57 (dd, 1H, 2J ¼ 13.7,
3J ¼ 10.2); 1.26 (s, 9H). 13C NMR (DMSO-d6, 100 MHz): 158.7; 155.2;
149.1; 139.5; 136.5; 129.1 (2C); 127.8 (2C); 125.6; 121.7; 119.5; 77.4;
72.4; 56.2; 35.6; 34.1; 28.1.
13C NMR (DMSO-d6, 100 MHz):
d 164.0 (C7); 160.5 (C17); 150.2
(C21); 139.4 (C10); 138.1 (C19); 134.3 (C11); 130.7 (C13 and C15);
129.9 (C5 and C9); 129.3 (C12 and C16); 127.3 (C14); 123.7 (C18);
121.2 (C20); 115.2 (C6 and C8); 74.3 (C2); 60.4 (C3); 56.2 (OCH3);
36.8 (C4); 35.2 (C1).
4.3.3. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyridin-2-ylthio)butan-
2-yl)-4-bromobenzenesulfonamide (8c)
IR (cmꢁ1 KBr): 3438 (OH); 3168 (NH); 1325 and 1159 (O]S]O);
4.2.2. Selected data for compound 5
641 (CeS).1H NMR (DMSO-d6, 400 MHz):
d
8.60 (d, 1H, 3J ¼ 5.2;
Yield 95%. m.p. 98e100 ꢀC. EM-ESI (m/z) 398.2 (Mþ þ Na, 52%).
IR (cmꢁ1 KBr): 3358 (OH); 3030 (NH); 1686 (C]O); 640 (CeS). 1H
NMR (DMSO-d6, 400 MHz): 8.59 (d, 2H, 3J ¼ 4.8); 7.18 (t, 1H,
3J ¼ 4.7); 7.19e7.13 (m, 5H); 6.70 (d, 1H, 3J ¼ 8.7); 5.33 (d, 1H,
3J ¼ 6.0); 3.66e3.58 (m, 2H); 3.52 (dd, 1H, 2J ¼ 13.6, 3J ¼ 3.2); 3.08
(dd,1H, 2J ¼ 13.6, 3J ¼ 8.0); 3.03 (dd,1H, 2J ¼ 13.5, 3J ¼ 2.6); 2.56 (dd,
1H, 2J ¼ 13.7, 3J ¼ 10.0); 1,26 (s, 9H). 13C NMR (DMSO-d6, 100 MHz):
171.4; 157.6 (2C); 155.3; 139.5; 129.1 (2C); 127.9 (2C); 125.7; 117.0;
77.5; 72.1; 56.3; 35.8; 35.0; 28.2.
H21); 7.62 (dt, 1H, 3J ¼ 7.6; 4J ¼ 1.6; H19); 7.99 (d, 1H, 3J ¼ 8.4; H18);
7.72 (d, 2H, 3J ¼ 8.8; H5 and H9); 7.70e7.66 (m, 1H; H20); 7.58 (d,
2H, 3J ¼ 8.4; H6 and H8); 7.11e7.07 (m, 1H; Ph); 7.01 (t, 2H, 3J ¼ 7.2;
Ph); 6.95 (d, 2H, 3J ¼ 7.2; Ph); 3.95e3.90 (m, 1H; H2); 3.71 (dd, 1H;
2J ¼ 14.0; 3J ¼ 3.2; H1b); 3.68e3.64 (m, 1H; H3); 3.57 (dd, 1H,
2J ¼ 14.0; 3J ¼ 8.0; H1a); 3.05 (dd, 1H, 2J ¼ 14.0; 3J ¼ 3.2; H4b); 2.52
(dd, 1H, 2J ¼ 14.0; 3J ¼ 10.0; H4a).
13C NMR (DMSO-d6, 100 MHz):
d
158.0 (C17); 148.0 (C21); 147.6
(C10); 141.1 (C11); 138.5 (C19); 131.9 (C5 and C9); 130.8 (C6 and C8);

5692
W.T. Vellasco Junior et al. / European Journal of Medicinal Chemistry 46 (2011) 5688e5693
129.4 (C13 and C15); 128.0 (C12 and C16); 125.9 (C7); 125.7 (C14);
122.8 (C18); 120.5 (C20); 72.2 (C2); 59.6 (C3); 35.2 (C4); 34.0 (C1).
4.3.8. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyrimidin-2-ylthio)
butan-2-yl)-4-bromobenzenesulfonamide (8h)
IR (cmꢁ1 KBr): 3327 (OH); 2924 (NH); 1383 and 1159 (O]S]O);
4.3.4. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyridin-2-ylthio)butan-
2-yl)-4-methoxybenzenesulfonamide (8d)
698 (CeS).1H NMR (DMSO-d6, 400 MHz):
d
8.62 (d, 2H, 3J ¼ 4.9; H19
and H21); 7.95 (d, 1H, 3J ¼ 8.4; NH); 7.45 (d, 2H, 3J ¼ 8.6; H5 and
H9); 7.34 (d, 2H, 3J ¼ 8.6, H6 and H8); 7.22 (t, 1H, 3J ¼ 4.9, H20);
7.09e7.06 (m, 3H; Ph); 7.03e7.01 (m, 2H; Ph); 3.66e3.63 (m, 1H;
H2); 3.54e3.50 (m, 1H; H3); 3.37 (dd, 1H, 2J ¼ 13.7; 3J ¼ 5.2; H1b);
3.05 (dd, 1H, 2J ¼ 13.7; 3J ¼ 8.0; H1a); 2.87 (dd, 1H, 2J ¼ 14.0;
3J ¼ 3.9; H4b); 2.54 (dd, 1H, 2J ¼ 14.0; 3J ¼ 9.4; H4a).
IR (cmꢁ1 KBr): 3296 (OH); 2933 (NH); 1326 and 1153 (O]S]O);
679 (CeS).1H NMR (DMSO-d6, 400 MHz):
d
8.35 (dd, 1H, 3J ¼ 4.9;
4J ¼ 0.8; H21); 7.61 (dt, 1H, 3J ¼ 7.9; 4J ¼ 1.8; H19); 7.47 (d, 2H,
3J ¼ 8.9; H5 and H9); 7.28 (d, 1H, 3J ¼ 8.1; H18); 7.11e7.07 (m, 3H; Ph
and H20); 7.02e7.00 (m, 2H; Ph); 6.78 (d, 2H, 3J ¼ 8.9; H6 and H8);
3.81 (s, 3H; OCH3); 3.80e3.76 (m, 1H; H2); 3.64e3.59 (m, 1H; H3);
3.41 (dd,1H, 2J ¼ 14.2; 3J ¼ 4.7; H1b); 3.12 (dd,1H, 2J ¼ 14.2; 3J ¼ 7.6;
H1a); 2.94 (dd, 1H, 2J ¼ 13.9; 3J ¼ 4.5; H4b); 2.63 (dd, 1H, 2J ¼ 14.0;
3J ¼ 8.7; H4a).
13C NMR (DMSO-d6, 100 MHz):
d 170.9 (C17); 157.6 (C19 and
C21); 141.0 (C10); 138.3 (C11); 131.7 (C6 and C8); 129.2 (C5 and C9);
127.9 (C13 and C15); 127.8 (C12 and C16); 125.7 (C7); 125.4 (C14);
117.1 (C20); 71.6 (C2); 59.4 (C3); 35.0 (C4); 34.1 (C1).
13C NMR (DMSO-d6, 100 MHz):
d 164.0 (C7); 160.5 (C17); 150.2
(C21); 139.4 (C10); 138.1 (C19); 134.3 (C11); 130.7 (C13 and C15);
129.9 (C5 and C9); 129.3 (C12 and C16); 127.3 (C14); 123.7 (C18);
121.2 (C20); 115.2 (C6 and C8); 74.3 (C2); 60.4 (C3); 56.2 (OCH3);
36.8 (C4); 35.2 (C1).
4.3.9. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyrimidin-2-ylthio)
butan-2-yl)-4-methoxybenzenesulfonamide (8i)
IR (cmꢁ1 KBr): 3298 (OH); 3023 (NH); 1384 and 1158 (O]S]O);
656 (CeS). 1H NMR (DMSO-d6, 400 MHz):
d
8.54 (d, 2H, 3J ¼ 4.9;
H19 and H21); 7.47 (d, 2H, 3J ¼ 8.9; H5 and H9); 7.13 (t, 1H, 3J ¼ 4.9;
H20); 7.10e7.08 (m, 3H; Ph); 7.04e7.01 (m, 2H; Ph); 6.78 (d, 2H,
J ¼ 8.9, H6 and H8) 3.87e3.83 (m, 1H; H2); 3.82 (s, 3H; OCH3);
3.65e3.61 (m, 1H; H3); 3.43 (dd, 1H, 2J ¼ 14.0; 3J ¼ 5.1; H1b); 3.13
(dd, 1H, 2J ¼ 14.1; 3J ¼ 7.8; H1a); 2.94 (dd, 1H, 2J ¼ 14.1; 3J ¼ 4.7;
H4b); 2.62 (dd, 1H, 2J ¼ 14.0; 3J ¼ 8.7; H4a).
4.3.5. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyridin-2-ylthio)butan-
2-yl)-4-fluorobenzenesulfonamide (8e)
IR (cmꢁ1 KBr): 3290 (OH); 2927 (NH); 1330 and 1159 (O]S]O);
1084 (CeF); 693 (CeS).1H NMR (DMSO-d6, 500 MHz):
d 8.36 (d, 1H,
3J ¼ 4.5; H21); 7.62 (dt, 1H, 3J ¼ 8.0; 4J ¼ 2.0; H19); 7.52 (dd, 2H,
3J ¼ 9.0; 4J ¼ 5.0; H5 and H9); 7.31 (d, 1H, 3J ¼ 8.0; H18); 7.12e7.09
(m, 1H; H20); 7.08e7.06 (m, 3H; Ph); 7.02e6.98 (m, 2H; Ph); 6.97 (t,
2H, 3J ¼ 9.0; H6 and H8); 3.83e3.80 (m, 1H; H2); 3.68e3.64 (m, 1H;
H3); 3.45 (dd, 1H; 2J ¼ 14.0; 3J ¼ 5.0; H1b); 3.17 (dd, 1H, 2J ¼ 14.0;
3J ¼ 7.5; H1a); 2.98 (dd, 1H, 2J ¼ 14.5; 3J ¼ 4.5; H4b); 2.61 (dd, 1H,
13C NMR (DMSO-d6, 100 MHz):
d 173.1 (C17); 163.9 (C7); 158.7
(C19 and C21); 139.4 (C11); 134.1 (C10); 130.5 (C13 and C15); 129.8
(C12 and C16); 129.3 (C5 and C9); 127.2 (C14); 118.1 (C20); 115.1 (C6
and C8); 73.7 (C2); 60.3 (C3); 56.1 (OCH3); 36.5 (C4); 35.4 (C1).
2J ¼ 14.0; 3J ¼ 9.5; H4a).
4.3.10. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyrimidin-2-ylthio)
butan-2-yl)-4-fluorobenzenesulfonamide (8j)
1
13C NMR (DMSO-d6, 125 MHz):
d
165.0 (C17); 161.7 (d, JC-
¼ 247.6; C7); 158.0 (C11); 148.9 (C21); 138.1 (d, 4JCeF ¼ 3.3; C10);
IR (cmꢁ1 KBr): 3449 (OH); 3167 (NH); 1381 and 1155 (O]S]O);
F
136.4 (C19); 129.0 (C13 and C15); 128.6 (d, 3JCeF ¼ 9.8; C5 and C9);
127.6 (C12 and C16); 125.5 (C14); 121.7 (C18); 119.5 (C20); 115.5 (d,
2JCeF ¼ 22.1; C6 and C8); 71.7 (C2); 59.1 (C3); 34.9 (C4); 33.1 (C1).
1091 (CeF); 676 (CeS). 1H NMR (DMSO-d6, 400 MHz):
d 8.55 (d, 2H,
3J ¼ 4.9; H19 and H21); 7.52 (dd, 2H, 3J ¼ 8.9; 4J ¼ 5.1; H5 and H9);
7.14 (t, 1H, 3J ¼ 4.9; H20); 7.08e7.07 (m, 3H; Ph); 7.03e7.01 (m, 2H;
Ph); 6.96 (t, 2H, 3J ¼ 8.7, H6 and H8) 3.90e3.86 (m, 1H; H2);
3.69e3.64 (m, 1H; H3); 3.47 (dd, 1H, 3J ¼ 14.0; 3J ¼ 5.2; H1b); 3.17
(dd, 1H, 2J ¼ 14.1; 3J ¼ 7.8; H1a); 2.97 (dd, 1H, 2J ¼ 14.0; 3J ¼ 4.1;
H4b); 2.61 (dd, 1H, 2J ¼ 14.0; 3J ¼ 9.5; H4a).
4.3.6. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyrimidin-2-ylthio)
butan-2-yl)-4-nitrobenzenesulfonamide (8f)
IR (cmꢁ1 KBr): 3300 (OH); 3105 (NH); 1524 and 1347 (NO2);
1383 and 1163 (O]S]O); 695 (CeS).1H NMR (DMSO-d6, 400 MHz):
13C NMR (DMSO-d6, 100 MHz):
d 173.1 (C17); 165.8 (d,
d
8.60 (d, 2H, 3J ¼ 4.9; H19 and H21); 8.05 (d, 2H, 3J ¼ 8.8; H5 and
1JCeF ¼ 248; C7); 158.7 (C10, C19 and C21); 139.5 (C11); 130.5 (C13
H9); 7.20 (t,1H, 3J ¼ 4.9; H20); 7.01e6.96 (m, 5H; Ph); 3.71e3.67 (m,
1H; H2); 3.60e3.55 (m, 1H; H3); 3.42 (dd, 1H, 2J ¼ 13.7; 3J ¼ 5.1;
H1b); 3.08 (dd, 1H, 2J ¼ 13.7; 3J ¼ 7.9; H1a); 2.90 (dd, 1H, 2J ¼ 14.0;
3J ¼ 3.5; H4b); 2.55 (dd, 1H, 2J ¼ 14.0; 3J ¼ 9.8; H4a).
and C15); 130.4 (d, JCeF ¼ 8.9; C5 and C9); 129.3 (C12 and C16);
3
2
127.2 (C14); 118.2 (C20); 116.8 (d, JCeF ¼ 23.1; C6 and C8); 74.0
(C2); 60.7 (C3); 36.5 (C4); 35.4 (C1).
13C NMR (DMSO-d6, 100 MHz):
d
170.9 (C17); 165.6 (C7); 157.6
4.4. Antimalarial assay
(C19 and C21); 147.3 (C10); 138.3 (C11); 129.2 (C13 and C15); 128.0
(C5 and C9); 127.2 (C12 and C16); 125.6 (C14); 124.0 (C6 and C8);
117.1 (C20); 71.9 (C2); 59.8 (C3); 34.8 (C4); 34.1 (C1).
Parasites were cultured with human erythrocytes (blood group
Oþ) at 5% hematocrit in RPMI 1640 supplemented with 10% human
plasma as previously described [18aec]. Test compounds have been
dissolved in ethanol prior to in vitro tests. The antiparasitic effects
of the molecules was measured by the [3H]-hypoxanthine incor-
poration assay [23] with slight modifications [24]. Briefly, tropho-
zoite stages in sorbitol-synchronized blood, were cultured at 2%
parasitaemia and 2.5% hematocrit, in the presence of the test
compounds (at various concentrations), diluted with culture
medium (RPMI 1640) without hypoxanthine; a chloroquine control
(as a reference antimalarial drug) was used in each experiment.
Inhibition of parasite growth was evaluated through the levels of
[3H]-hypoxanthine incorporation plotted to generate dos-
4.3.7. N-((2S,3S)-3-hydroxy-1-phenyl-4-(pyrimidin-2-ylthio)
butan-2-yl)-4-methylbenzenesulfonamide (8g)
IR (cmꢁ1 KBr): 3304 (OH); 3059 (NH); 1381 and 1155 (O]S]O);
666 (CeS).1H NMR (DMSO-d6, 400 MHz):
d
8.54 (d, 2H, 3J ¼ 4.9; H19
and H21); 7.42 (d, 2H, 3J ¼ 8.2; H5 and H9); 7.13 (t, 1H, 3J ¼ 4.9;
H20); 7.09e7.07 (m, 5H; Ph, H6 and H8); 7.03e7.00 (m, 2H; Ph);
3.86e3.82 (m, 1H; H2); 3.67e3.63 (m, 1H; H3); 3.44 (dd, 1H,
2J ¼ 14.1; 3J ¼ 5.1; H1b); 3.13 (dd, 1H, 2J ¼ 14.1; 3J ¼ 7.9; H1a); 2.93
(dd, 1H, 2J ¼ 14.0; 3J ¼ 4.6; H4b); 2.61 (dd, 1H, 2J ¼ 14.0; 3J ¼ 8.7;
H4a); 2.33 (s, 3H; CH3).
13C NMR (DMSO-d6, 100 MHz):
d
170.9 (C17); 157.7 (C19 and
eeresponse curves. The half-maximal inhibitory response (IC50)
C21); 141.8 (C10); 138.9 (C11); 138.5 (C7); 129.3 (C6 and C8); 129.2
(C13 and C15); 127.9 (C5 and C9); 126.1 (C12 and C16); 125.8 (C14);
117.2 (C20); 73.8 (C2); 60.5 (C3); 36.6 (C4); 35.5 (C1); 21.6 (CH3).
compared with parasite growth in the drug-free controls was
estimated by curve fitting using a software program [Microcal,
Origin Software, Inc. (Northampton, MA, USA)].

W.T. Vellasco Junior et al. / European Journal of Medicinal Chemistry 46 (2011) 5688e5693
5693
[7] (a) A. Brik, C.-H. Wong, Org. Biomol. Chem. 1 (2003) 5e14;
(b) A.K. Ghosh, G. Bilcer, G. Schiltz, Synthesis (2001) 2203e2229.
4.5. Citotoxicity assay
[8] N. Trudel, R. Garg, N. Messier, S. Sundar, M. Ouellette, M.J. Tremblay, J. Infect.
Dis 198 (2008) 1292e1299.
Eachcompound was tested invitroagainst two different celllines,
HepG2 (a human hepatoma cell line) and BGM (a kidney epithelial
cell line from green monkey) using cells maintained in RPMI 1640
medium supplemented with 10% heat-inactivated fetal calf serum
and antibiotics-gentamicin, 40 mg/L (complete medium), in 75 cm2
sterile culture flasks (Corning, USA), in an atmosphere of 5% CO2 in
air at 37 ꢀC. The culture medium was changed every 2e3 days. The
cells were used from confluent monolayers, trypsinized, washed
with culture medium, then resuspended in complete medium,
distributed in flat-bottomed 96-well plate (5 ꢃ 103 cells/well), and
incubated for 18 h at 37 ꢀC, for cell adherence. The cell viability was
assessed by the MTTassay, after incubationwith the test compounds
[9] L.R. Marcin, M.A. Higgins, F.C. Zusi, Y. Zhang, M.F. Dee, M.F. Parker,
J.K. Muckelbauer, D.M. Camac, P.E. Morin, V. Ramamurthy, A.J. Tebben,
K.A. Lentz, J.E. Grace, J.A. Marcinkeviciene, L.M. Kopcho, C.R. Burton,
D.M. Barten, J.H. Toyn, J.E. Meredith, C.F. Albright, J.J. Bronson, J.E. Macor,
L.A. Thompson, Bioorg. Med. Chem. Lett. 21 (2011) 537e541.
[10] M. Altenkämper, B. Bechem, J. Perruchon, S. Heinrich, A. Mädel, R. Ortmann,
H.-M. Dahse, E. Freunscht, Y. Wang, J. Rath, A. Stich, M. Hitzler, P. Chiba,
M. Lanzer, M. Schlitzer, Bioorg. Med. Chem. 17 (2009) 7690e7697.
[11] A. Scozzafava, T. Owa, A. Mastrolorenzo, C.T. Supuran, Curr. Med. Chem. 10
(2003) 925e953.
[12] I. Argyropoulou, A. Geronikaki, P. Vivini, F. Zani, Arkivoc (2009) 89e102.
[13] L. Bouissane, S. El Kazzouli, S. Léonce, B. Pfeiffer, E.M. Rakib, M. Khouili, Bioorg.
Med. Chem. 14 (2006) 1078e1088.
[14] Y.A. Al-Soud, H.H. Al-Sa’doni, B. Saeed, I.H. Jaber, M.O. Beni-Khalid, N.A. Al-
Masoudi, T. Abdul-Kadir, P. La Colla, B. Busonera, T. Sanna, R. Loddo, Arkivoc
(2008) 225e238.
[15] S.M. Sondhi, A.D. Dwivedi, J. Singh, P.P. Gupta, Indian J. Chem. B. Org. 49
(2010) 1076e1082.
[16] D. Vullo, B. Steffansen, B. Brodin, C.T. Supuran, A. Scozzafava, C.U. Nielsen,
Bioorg. Med. Chem. 14 (2006) 2418e2427.
[17] G. Melagraki, A. Afantitis, H. Sarimveis, O. Igglessi-Markopoulou, C.T. Supuran,
Bioorg. Med. Chem. 14 (2006) 1108e1114.
[18] (a) W. Cunico, C.R.B. Gomes, M. Moreth, D.P. Manhanini, I.H. Figueiredo,
C. Penido, M.G.M.O. Henriques, F.P. Varotti, A.U. Krettli, Eur. J. Med. Chem. 44
(2009) 1363e1368;
[27]. Briefly, the cell cultures (180
mL in RPMI complete medium
supplemented in a flat-bottomed 96-well plate) were incubated
with 20
m
L of the test compounds in different concentrations
g/mL) for 24 h, in 5% CO2 atmosphere at 37 ꢀC. This was
L of MTT (SigmaeAldrich) solution
(5 mg/mL) to each well, following another 3 h incubation after which
the supernatant was carefully removed and addition of 100 L DMSO
(1000e1
m
followed by the addition of 20
m
m
with thorough mixing. The optical density (background) was
determined on an ELISA reader at 570 and 630 nm. Cell viability was
expressed as the percentage of control absorbance obtained in
untreated cells after subtracting the absorbance from the appro-
priate background. Lastly, the minimum lethal dose for 50% of the
cells (LD50) was determined as previously described [28].
(b) W. Cunico, C.R.B. Gomes, V. Facchinetti, M. Moreth, C. Penido,
M.G.M.O. Henriques, F.P. Varotti, L.G. Krettli, A.U. Krettli, F.S. da Silva,
E.R. Caffarena, C.S. de Magalhães, Eur. J. Med. Chem. 44 (2009) 3816e3820;
(c) W. Cunico, M.L.G. Ferreira, T.G. Ferreira, C. Penido, M.G.M.O. Henriques,
L.G. Krettli, F.P. Varotti, A.U. Krettli, Lett. Drug Des. Discov. 5 (2008) 178e181;
(d) W. Cunico, C.R.B. Gomes, M.L.G. Ferreira, T.G. Ferreira, D. Cardinot,
M.V.N. de Souza, M.C.S. Lourenço, Eur. J. Med. Chem. 46 (2011) 974e978.
[19] W. Cunico, C.R.B. Gomes, E.R.T. Tiekink, W.T. Vellasco Junior, J.L. Wardell,
S.M.S.V. Wardell, Acta Cryst. E66 (2010) o267eo268.
Acknowledgments
[20] D. Bouchouk, E. Colacino, L. Toupet, N. Aouf, J. Martinez, G. Dewynter, Tetra-
hedron Lett. 50 (2009) 1100e1104.
The authors thank FAPERJ, Farmanguinhos/Fiocruz, FAPEMIG
and CNPq/MCT-DECIT (Project 575746/2008-4), for financial
support. Fellowships granted to W.T.V.J. by CAPES and G.P.G, A.U.K.
and W.C. by CNPq. We also thank LDRX-UFF.
[21] Z.-Q. Hu, C.-F. Chen, Tetrahedron 62 (2006) 3446e3454.
[22] J.M. Langenhan, J.D. Fisk, S.H. Gellman, Org. Lett. 3 (2001) 2559e2562.
[23] R.E. Desjardins, C.J. Canfield, J.D. Haynes, J.D. Chulay, Antimicrob. Agents
Chemother. 16 (1979) 710e718.
[24] M. Zalis, L. Pang, M.S. Silveira, W.K. Milhous, D.F. Wirth, Am. J. Trop. Med. Hyg.
58 (1998) 630e637.
[25] X-ray crystal data for 8e: CCDC 773177; Empirical formula: C21H21FN2O3S2;
References
Crystal System: Monoclinic; Space Group: P21; Unit cell dimensions:
ꢀ
a
¼
11.955 (2),
b
¼
7.7703 (16),
c
¼
12.073 (2) Å,
b
¼
110.89 (3)
,
[1] A.U. Krettli, Expert Opin. Drug Discov. 4 (2009) 95e108.
[2] G.H. Coombs, D.E. Goldberg, M. Klemba, C. Berry, J. Kay, J.C. Mottram, Trends
Parasitol. 17 (2001) 532e537.
[3] K. Ersmark, B. Samuelsson, A. Hallberg, Med. Res. Rev. 26 (2006) 626e666.
[4] C. Boss, S. Richard-Bildstein, T. Weller, W. Fischli, S. Meyer, C. Binkert, Curr.
Med. Chem. 10 (2003) 883e907.
Volume ¼ 1047.8 (4) Å3; Z ¼ 2; D ¼ 1.371 g cmꢁ3
;
m
(MoKa) ¼ 0.29; Color:
colorless; Habit: prism; Crystal size: 0.56 ꢃ 0.22 ꢃ 0.16 mm; Temperature:
293 (2) K; F(000) ¼ 452; Reflections collected ¼ 21,225; R(int) ¼ 3.2%; Theta
range for data collection 3e27.5ꢀ; No. reflections: 3810; No. reflections
observed: 4597; No. parameters: 263; R1 obs ¼ 3.5%; wR2 obs ¼ 7.85%; R1
all
¼
4.8%; wR2 all
¼
8.65%; GooF
¼
1.06; Drmax
¼
0.16 e$Åꢁ3
;
[5] S. Parikh, J. Gut, E. Istvan, D.E. Goldberg, D.V. Havlir, P.J. Rosenthal, Antimicrob.
Agents Chemother. 49 (2005) 2983e2985.
Drmin ¼ ꢁ0.14 e$Åꢁ3
.
[26] G.M. Sheldrik, SHELX-97. University of Göttingen, Germany, 1997.
[6] K.T. Andrews, D.P. Fairlie, P.K. Madala, J. Ray, D.M. Wyatt, P.M. Hilton,
L.A.Melville, L. Beattie, D.L. Gardioner, R.C. Reid, M.J.Stoermer, T. Skinner-Adams,
C. Berry, J.S. McCarthy, Antimicrob. Agents Chemother. 50 (2006) 639e648.
[27] F. Denizot, R. Lang, J. Immunol. Methods 89 (1986) 271e277.
[28] M.C. de Madureira, A.P. Martins, M. Gomes, J. Paiva, A.P. da Cunha, V. do
Rosário, J. Ethnopharmacol. 81 (2002) 23e29.