Synthesis, stereoelectronic characterization and antiparasitic activity of new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinolines

Article abstract of DOI:10.1016/j.bmc.2009.11.010

The synthesis and full 3D structural characterization of nine new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinoline derivatives are reported. These belong to a library whose rationale for the design was the previous knowledge of the biological relevant properties of both structural moieties. From protozoan antiparasitic screening, compounds 3 demonstrated interesting activity against Trypanozoma cruzi with low cytotoxicity. Besides, most compounds were moderately active against Plasmodium falciparum. Of these, 3 and 9 can be considered as lead scaffolds for further optimization. The substituent on BS did not influence the 3D structure properties and the ¹H NMR spectra revealed the existence of an intramolecular weak hydrogen bond, C-H...O{double bond, long}S. Molecular modeling and X-ray crystallography also confirmed this finding, which is relevant to compound conformational preference.

Full text of DOI:10.1016/j.bmc.2009.11.010

Bioorganic & Medicinal Chemistry 18 (2010) 142–150
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis, stereoelectronic characterization and antiparasitic activity of new
1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinolines
Romina J. Pagliero a, Sabrina Lusvarghi a, , Adriana B. Pierini b, Reto Brun c, María R. Mazzieri a,
*
a Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
b Departamento de Química Orgánica, INFIQ, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
c Parasite Chemotherapy, Swiss Tropical Institute, CH-4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and full 3D structural characterization of nine new 1-benzenesulfonyl-2-methyl-1,2,3,4-
tetrahydroquinoline derivatives are reported. These belong to a library whose rationale for the design
was the previous knowledge of the biological relevant properties of both structural moieties. From pro-
tozoan antiparasitic screening, compounds 3 demonstrated interesting activity against Trypanozoma cruzi
with low cytotoxicity. Besides, most compounds were moderately active against Plasmodium falciparum.
Of these, 3 and 9 can be considered as lead scaffolds for further optimization. The substituent on BS did
not influence the 3D structure properties and the 1H NMR spectra revealed the existence of an intramo-
lecular weak hydrogen bond, C–Hꢀ ꢀ ꢀO@S. Molecular modeling and X-ray crystallography also confirmed
this finding, which is relevant to compound conformational preference.
Received 28 August 2009
Revised 4 November 2009
Accepted 5 November 2009
Available online 10 November 2009
Keywords:
Antiparasitic
Benzenesulfonyl
Tetrahydroquinolines
Stereoelectronic properties
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
is fatal if left untreated. In South America, a different Trypanosome
causes Chagas disease, Trypanosoma cruzi (T. cruzi). This parasite is
Approximately two million people are estimated to die each
year from parasitic diseases such as malaria, african (sleeping sick-
ness) and american trypanosomiasis (Chagas disease) and leish-
maniasis.1 Furthermore, these parasitic infections are frequently
associated with immunocompromised patients and are thus also
seen in developed countries. Malaria is the most prevalent and per-
nicious protozoan parasitic disease in humans. According to the
last WHO report,2 half of the world’s population is at risk from ma-
laria which is caused by Plasmodium parasites. Four species of
Plasmodium commonly infect humans, but two of them in partic-
ular, Plasmodium falciparum (P. falciparum) and Plasmodium vivax,
account for the majority of cases of morbidity and mortality. The
effective artemisinin-based combination therapies have resulted
in success in more than 90% of cases. However, WHO announced
recently that the emergence of artemisinin resistant parasites
could seriously undermine the global malaria control efforts thus
far achieved.2,3 Sleeping sickness is caused by the parasites Trypan-
osoma brucei rhodesiense (T.b. rhodesiense) and Trypanosoma brucei
gambiens. Only four drugs are registered for the treatment of hu-
man african trypanosomiasis and all of them have a certain level
of toxicity. However, treatment is mandatory because the disease
transmitted by bloodsucking reduviid bugs.4 The infection is an
important cause of mortality and morbidity and no vaccines or safe
and effective chemotherapeutic agents are available. A similar sit-
uation account for leishmaniasis, caused by the protozoan parasite
Leishmania.5 So, there is an urgent need for new, safe and effective
drugs against these parasitic infections, since many of those cur-
rently in use have major problems.6 Furthermore, there is a consid-
erable evidence that extended use of these drugs is leading to the
development of resistance.
As part of an ongoing lead discovery project and on the basis of
our experience in the field,7,8 we are interested in the synthesis
and screening of series of N-benzenesulfonyl derivatives of bioactive
heterocyclic compounds. One of this series is 1-benzenesulfonyl-2-
methyl-1,2,3,4-tetrahydroquinoline (BS-CH3THQ) 1–10, which is
depicted in Table 1. These new BS-CH3THQs incorporate two key
structural and biological units in their molecules: a benzenesulfonyl
(BS) and a 2-methyl-1,2,3,4-tetrahydroquinoline (CH3THQ). Indeed,
CH3THQ has shown interesting and diverse pharmacological activi-
ties such as antibacterial,9 antioxidant,9 NMDA antagonist,10
antiplatelet aggregation11 and antiarrhytmic,12 among others. On
the other hand, BS is a substituent frequently present in molecules
with biological activity. Not only is the p-aminobenzenesulfonyl
moiety a known PABA antagonist with antibacterial and antileprotic
activity, but the BS group bound to different heterocycles has led to
analogs displaying similar or better biological activities than their
precursors.13–21 Therefore, the combination of a BS and a biologically
active heterocycle, such as CH3THQ, appears to be a very promising
* Corresponding author. Tel./fax: +54 351 4334163.
E-mail addresses: mrmazzie@fcq.unc.edu.ar, maria_mazzieri@yahoo.com.ar
(M.R. Mazzieri).
Present address: Chemistry Department, Carnegie Mellon University, 4400 5th
Ave, Pittsburgh, PA, USA.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.11.010

R. J. Pagliero et al. / Bioorg. Med. Chem. 18 (2010) 142–150
143
Table 1
Synthetised BS-CH3THQs
hydrolized with HCl 4 M in acetone, affording the p-amine deriva-
tive (10) after 3 h. Crystalline and stable compounds were obtained
after work-up and purification processes as described in the exper-
imental section. All products were obtained with purity higher
than 96%.
5
4
9
3
6
7
CH3THQ
2
11
N
S
1
8
In the literature have been described many synthesis methods
for the incorporation of BS group in the anular N, most of them
include the cyclization step to obtain BS-heterocycles and also
tedious work-ups.22,23,27–30 The criteria followed for the selection
of the present method was based on its simplicity and good yield.
The procedure has also provided a facile access to derivatives of 1-
benzenesulfonyl benzotriazol.7 Furthermore, the library could be
enlarged including other nitrogenated-heterocyles and different
substitutions at BS since many benzenesulfonyl chlorides are cur-
rently commercially available. On the other hand, the simplicity
of the work-up and purification procedures would make possible
to apply this method to automation system for parallel synthesis.
NMR, FT-IR and HRMS were used to provide complete structural
characterization of 1–10. An extensive NMR analysis was performed
for both the structural characterization and future Quantitative
Structure Stereoelectronic Relationship studies. The 1H NMR spec-
trum (DMSO-d6) of 1–10 showed signals at d lower than 5 ppm that
accounted for the five aliphatic protons of the CH3THQ ring, plus
thoseoftheCH3. TheprotonsoftheCH3 grouponBS of2, 4and8were
also in that region. All the aromatic protons appeared at d values
higher than 7 ppm. Furthermore, the 13C NMR spectrum of 1–10
showed the aliphatic carbons appearing between 22–55 ppm, and
aromatic carbons between 112 and 170 ppm along with C@O signals
of 2. The complete and unambiguous 1H and 13C NMR assignments
were achieved using a combination of COSY, HSQC and HMBC exper-
iments (see Supplementary data for spectra).
2b´
O
1´
3b´
4´
O
BS
2a´
R1
3a´
R2
Yieldb
Mpc (lit.)
%Purityd
a
Compd
R1
H
R2
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
82
54
78
81
68
67
65
66
70
79
104–104.5
195–196
159–160
98.28
98.25
97.83
97.15
95.73
96.53
96.41
96.62
98.37
98.45
NHCOCH3
NO2
CH3
F
79–80 (84–85)e
121–121.5
92–92.5
Cl
Br
80–80.5
91–92
115–115.5
154–155
OCH3
H
NH2
NO2
H
10
a
Structures were proved by analytical HRMS and by 1H and 13C NMR. (1H, 13C,
COSY, HSQC, HMBC) spectrometry and FT-IR spectroscopy.
b
Isolated yields.
Uncorrected.
Measure by HPLC.
See Refs. 22,23.
c
b
e
hypothesis for drug discovery. With this in mind a major screening
for different activities is presently being carried out for the
compounds.
Our research has been focused on exploring the consequences
of a BS linkage through a N on the stereoelectronic properties of
the heterocycle for CADD applications, using either ligand-based
or structure-based molecular design methods. When a BS moiety
is bound to heterocycles through nitrogen, it has two ways of mod-
ulating its stereoelectronic properties and ultimately the biological
activity. It could intramolecularly influence the heterocyclic ring or
interact with the target through intermolecular forces.8,24 Bearing
this in mind, we synthesized ten BS-CH3THQ compounds, of which
nine are new. These ten compounds had different substituent at
the phenyl moiety (R1/R2, Table 1). The selection of them was
mainly guided by electronic considerations as defined by Hammet
The NMR spectra of 3 will be used here as example to explain
the assignment of signals to the structure (d are in ppm and J in
Hz, refer to Table 1 for atom numbering). The doublet of quartets
at dH 4.41 was assigned to H2, which directly correlated to C2 (dC
53.03) and H11 (dH 1.20). The chemical shift of H2 was consistent
with the proximity of N1, with the multiplicity being due to the
coupling with CH3 (dH 1.20, d, JH11–H2 6.5) and both enantiotopic
H3 (JH2–H3a 6.8; JH2–H3b 6.4). The two signals corresponding to both
of the H3 appeared at dH 1.30/1.85 (1J ꢁ13.3) and correlated with
C3 (dC 30.23). The same was observed with signals of the two enan-
tiotopic H4 at 1.72/2.42 (1J ꢁ15.8) which correlated with the two
H3 (JH3a–H4a 8.5; JH3b–H4a 5.2; JH3a–H4b 5.3; JH3b–H4b 6.8) and with
C4 (dC 24.46). The signal at dH 7.09 (dd, JH5–H6 7.3 and JH5–H7 1.0)
was assigned to H5, and was confirmed by HMBC experiments (3J
correlation with C4, dC 24.46) and by COSY experiments with 2J
with H6 (dH 7.16, td, JH6–H5 7.3; JH6–H77.7 and JH6–H8 0.8). The H7
signal appeared at dH 7.27 (td, JH7–H6 7.7; JH7–H8 7.8 and JH7–H5
1.0), and finally the H8 at 7.56 (dd, JH8–H7 7.8 and JH8–H6 0.8). Also,
the 3J correlations between H5, H6, H7 and H8 were also clearly ob-
served in COSY and were therefore consistent with the assignation
described. Furthermore, the analysis was supported by HMBC 3J
correlations between H5–C7, H6–C8, H7–C5 and H8–C6, thus
allowing us to assign C6 (dC 126.50), C7 (dC 127.24), C8 (dC
126.85) and C5 (dC 128.91). The two remaining signals in the pro-
ton aromatic area corresponded to the BS group; H20 appeared at
dH 7.74 and H30 at dH 8.31. Both signals showed the expected var-
iation in chemical shifts due to the substitution in the para position
of the BS.
constant, r 25
ing, such as NH2
NO2 = 0.78)) were included.
.
In this way, different groups (from electron-donat-
= ꢁ0.66) to electron-withdrawing, such as
(r
(r
In the present work we report the synthesis, 2D and 3D struc-
tural characterization and in vitro activity against protozoan para-
sites of novel BS-CH3THQ.
2. Results and discussion
2.1. Chemistry
Scheme 1 outlines the synthetic strategy for compounds 1–10.
The preparation of CH3THQ was carried out by reduction of quino-
line heterocycle as previously reported.26 The synthesis of 1–9 was
accomplished in one step with good yields (54–82% of isolated
products), by condensation of CH3THQ with the appropriate and
commercially available benzenesulfonyl chloride, under nitrogen
atmosphere. The reaction was carried out in pyridine as basic med-
ia. The sulfonylation time was around 1 h, except for 2 (3 h). The
reaction was stopped by addition of HCl 10%, which facilitated
the isolation of the product as a colored solid. Compound 10 was
achieved in two steps procedure (Scheme 1). First, the N-acety-
lsulfanyl-CH3THQ (2) was prepared, which was subsequently
On the other hand, four nonprotonated carbon signals observed
in 13C NMR were assigned as follows: 134.04 (C9), 134.37 (C10),
144.19 (C10) and 150.41 (C40). The key correlations found in HMBC
led us to an unambiguous assignment of these carbons. Com-
pounds 1, 2, 4–10 showed similar NMR spectra, with the assigna-
tions been made under the same considerations described above
for 3 (see spectra in Supplementary data).

144
R. J. Pagliero et al. / Bioorg. Med. Chem. 18 (2010) 142–150
Scheme 1. Synthesis of BS-CH3THQ. Reagents and conditions: (a) NaBH4/NiCl2ꢀ6H2O, methanol, 25 °C; (b) anhydrous pyridine, 25 °C; (c) HCl 4 M, acetone, 90 °C.
H
CH3
N
N
H
2R.
1,41Kcal/ mol
2R.
Me axial
Me equatorial
CH3
CH3
H
N
N
CH3
2S.
Me equatorial
1,42Kcal/ mol
2S.
Me axial
H
Figure 1. Four theoretical half-chair conformations of CH3THQ. Difference of
energy between the CH3 in the ax or eq position for each enantiomer is shown
under the arrows.
2.2. Computational modeling
Conformational studies of 1–10 were performed with the semi-
empirical (AM1) and DFT (B3LYP/6-31G(d)) methods as imple-
mented in GAUSSIAN 03.31 First of all, the preferred conformation of
CH3THQ was studied at the B3LYP/6-31G(d) level of theory.
CH3THQ could present either a half-chair or a half-boat conforma-
tion for each enantiomer (2R or 2S). Figure 1 shows the possible
half-chair conformers viewed down an imaginary axis toward the
heterocycle, with the CH3 group axial (ax) or equatorial (eq). The
theoretical analysis showed a maximum difference of 1.4 kcal/
mol between CH3ax and CH3eq, with the expected preferences for
the methyl group in the equatorial position (91.76%). On the other
hand, the four half-boat possible conformations were not stable. In
agreement, Charifson et al.18 were unable to find a stable boat con-
formation for tetrahydroisoquinolines.
Figure 2. Minimum structure of 1 obtained by B3LYP/6-31G(d). Angles
were scanned in the conformational search of BS-CH3THQs.
a and b
in order to inspect the positioning of sulfonyl (a angle) and phenyl
(b angle) substituents (Fig. 2). A full geometry optimization at the
B3LYP/6-31G(d) level of theory was later performed for the lowest
energy conformations found. Finally, each minimum was charac-
terized as a stationary point by vibrational frequency calculations.
For all the derivatives the number of imaginary frequencies was
zero.
The BS group was shown to be pseudo-axial for all energy-
minimized conformations. No significant difference in energy or
Once the minimum-energy conformation was found for the het-
erocycle, the BS moiety was added, and the whole molecule (BS-
CH3THQ) was minimized using AM1 semiempirical method. The
conformational search was carried out for both enantiomers (2R
or 2S) through a careful systematic scan of relevant dihedral angles
relevant geometric parameters (
a and b angles) were found be-
tween the 2R and 2S enantiomers (data not shown). Each enan-
tiomer of BS-CH3THQs has four minimum-energy conformations,

R. J. Pagliero et al. / Bioorg. Med. Chem. 18 (2010) 142–150
145
Table 2
Comparison of structures obtained by theoretical calculation and X-ray
Parameter
Theoretical calcd value
X-ray value
Torsion angle
Torsion angle b
Angle C10–N1–S
Angle N1–S–C1
Distance C6–C4
Distance C4–C4
Distance H8–O
a
65.31°
99.19°
119.34°
107.66°
6.29 Å
5.68 Å
2.27 Å
115.3°
64.92°
105.99°
116.88°
107.74°
6.84 Å
5.12 Å
2.44 Å
109°
0a
0b
0b
Angle C8–H8–O
a
Calculated with GAUSSIAN 03 at level of theory B3LYP 6-31G*.
In ORTEP representation C18 = C40 and C13 = C10.
b
2 describes some significant parameters of the geometry obtained
by theoretical calculations and X-ray crystallography.à
Another interesting observation was the presence of the signal
of H8 at a higher chemical shift (around d 7.59) than the same pro-
ton of unsubstituted CH3THQ (d 6.42), which implied a 1.17 ppm
average downfield. Also, the H8 appeared at a lower field than
the remaining H of the spin system. The same behavior was found
when NMR spectra were calculated by using a B3LYP/6-31G(d) le-
vel of theory. This unexpected unshielding of H8 may have been
caused by a dipolar interaction (hydrogen bond) with one oxygen
of the BS group. Sanchez-Viesca et al. demonstrated evidence of
C–Hꢀ ꢀ ꢀO, C–Hꢀ ꢀ ꢀN and C–Hꢀ ꢀ ꢀCl hydrogen bonds in thiazole,35 ben-
zopyridine36 and propionitriles37 derivatives by 1H NMR experi-
ments with the presence of two intramolecular weak H-bonds of
the type C–Hꢀ ꢀ ꢀO in the benzopyridine derivatives leading to a
Figure 3. ORTEP representation of the R enantiomer of 5.
two with CH3ax and two with CH3eq. For the conformers with
CH3eq the torsion angle
293–297° and between 135–137°. For
showed a minimum at 76–78°; and for
137–140°. A similar situation was found for the conformers with
CH3ax. The torsion angle showed a minimum between 293–
a
displayed the minimum between
values of 293–297°, b
135–137°, b was
a
D
d of 1.0–1.2 ppm.36 Furthermore, based on crystallographic data,
a
Desiraju et al.38,39 observed distances of 2.0–3.0 Å between Hꢀ ꢀ ꢀO,
when the H-bond C–Hꢀ ꢀ ꢀO occurred in crystals, for more than
100 analyzed structures. For BS-CH3THQ, 1–10, the calculated
geometry showed a distance of 2.28–2.39 Å between Hꢀ ꢀ ꢀO in all
minimum conformations, thus supporting the possibility of an
intramolecular H-bond between C8–Hꢀ ꢀ ꢀO. Another parameter
used by Desiraju38,39 and Taylor40 to describe the H-bond of the
type C–Hꢀ ꢀ ꢀO is the angle between these three atoms. They ob-
served by X-ray experiment that C–Hꢀ ꢀ ꢀO angles between 90–
130° corresponded to the formation of weak H-bonds. This was
true in the case of BS-CH3THQs which showed values of between
109–123°. However, it should be mentioned that the opposite ef-
fect was reported by Charifson et al.18 for the H8 of benzyltetrahy-
droquinoline, which showed a lower chemical shift than expected.
In this case, the dramatic upfield shift was explained as a conse-
quence of the position of H8 within the shielding cone of the adja-
cent phenyl group. From the conformational geometry shown by
1–10 it can be appreciated that H8 is clearly distant from the
shielding cone of the phenyl of BS moiety. The SO2 linkage con-
ferred the typical butterfly-like conformation to the com-
pounds,41,42 which was clearly different than the one from CH2
linkage.
a
295° and between 78–96°. For
had a minimum at 79–81°; for
a
a
293–295°, the torsion angle b
78–96°, b was 61–69°. The val-
ues found for these relevant angles were independent of the
substituent in BS moiety (see Supplementary data). On the other
hand, for both enantiomers, the conformers with the CH3ax were
5 kcal/mol (99.9%) more stable than those with CH3eq, showing a
higher difference of energy between both conformers (CH3eq and
CH3ax) than unsubstituted CH3THQ (1.4 kcal/mol, Fig. 1). The
DE
informed in both cases is Zero Point Corrected. Including the sol-
´
vent (DMSO) through Tomasis continuum polarized model did
not modify this energy difference.
The NMR spectral data and theoretical conformational analysis
were in agreement with the presence of the half-chair conforma-
tion with the CH3ax for 1–10. For NMR data, at room temperature,
each set of methylene protons on the piperidine ring of CH3THQ
(for 3-CH2 and 4-CH2) exhibited an AB pattern. Four distinct signals
were observed for the geminal protons H3a/H3b and H4a/H4b, indi-
cating that no conformational average was taking place. The four
signals were well resolved and the multiplicities were in agree-
ment with pseudo-axial and pseudo-equatorial positions
(2Jgem = 13.3 and 15.8 for H3a/H3b and H4a/H4b respectively; 3Jax;ax
=
2.3. Antiprotozoal activity
3
3
ce:hsp sp="0.25"/>8.6, Jax;eq = 5.4 and Jeq;eq = 6.4). The problem
of the dynamic geminal proton interchange in six member non-sat-
urated heterocyclic rings has been extensively described by Katri-
tzky et al.32 Chilmonczyk et al.33 and Amm et al.34 Moreover, the
presence of two equivalent coupling constant between the H2–H3a
and H2–H3b is fully explained if the methyl group is in an axial posi-
tion so that the H2 roughly bisects the two protons H3. The ‘V’ con-
formation of the molecule, given by the presence of the BS group in
the pseudo-axial position, makes the Meax position preferred over
Compounds 1–10 were tested against T.b. rhodesiense, T. cruzi,
Leishmania donovani, and P. falciparum as well as for cytotoxicity
against rat skeletal myoblasts (L-6). All the activity determinations
were carried out at the Screening Center of the Swiss Tropical Insti-
tute. These results are presented in Table 3.
As a general observation, all compounds exhibited low cellular
toxicity (at least more than 590-fold lower) compared to podo-
the Meeq
.
à
CCDC 744103 contains the supplementary crystallographic data for this paper.
Further confirmation of the orientation of CH3ax was made by
the X-ray crystallography analysis of the compounds (Fig. 3). Table
These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

146
R. J. Pagliero et al. / Bioorg. Med. Chem. 18 (2010) 142–150
Table 3
Antiparasitic activity of compounds 1–10 expressed as IC50 (l
M)a
T.b. rhodesiense
IC50
T. cruzi
IC50
L. donovani.
IC50
P. falciparum. K1b
IC50
Cytotoxicity. L-6
IC50
SI T. cruzic
SI P. falciparumc
Melarsoprol
0.008
Benznidazole
1.54
Miltefosine
0.25
Chloroquine
0.25
Podophyllotoxin
0.01
CH3THQ
87.25
52.86
49.79
153.14
43.99
124.62
43.50
40.09
43.85
33.06
37.20
188.73
21.26
21.45
11.44
16.61
223.74
15.98
13.78
15.89
31.94
19.73
>611.33
174.12
50.68
>271.02
22.52
167.07
18.87
21.35
>33.96
13.25
>14.53
8.31
11.03
12.10
8.43
248.61
70.03
52.02
248.28
4.90
67.57
20.46
7.36
1.32
3.29
2.42
21.70
0.29
0.30
1.28
0.53
0.37
5.85
1.78
7.32
5.28
3.58
30.00
0.44
5.58
2.43
1.10
0.5
1
2
3
4
5
6
7
8
9
10
6.65
26.74
24.93
55.81
11.79
10.34
>16.55
5.99
186.97
35.27
18.08
2.13
a
b
c
Values represent the average of four determinations (two determinations of two independent experiments); errors for individual measurements differed by less than 50%.
Resistant to chloroquine and pyrimethamine.
Selectivity Index calculated as SI = IC50L6/IC50 parasite.
phyllotoxin which was used as a reference. The antiparasitic poten-
tial of all compounds was analyzed by applying the WHO/TDR
screening activity criteria specified for each parasite.6 Four com-
pounds (3, 6, 7 and 9) showed moderate growth inhibition of P. fal-
performed. The addition of an electron-withdrawing substituent
was clearly favorable and led to the most potent analogues (3, 6, 7
and 9) while electron-donating (10) decreased the activity. In the
light of our results on molecular modeling, the substituent on BS
did not influence the 3D structure properties of 1–10. Besides, no
linear correlation could be found with any single variable such as
electronic, lipophilic or steric parameters (data not shown). So, a
combination of the electronic distribution on the phenyl group, the
size of the substituent and the lipophilicity of the compounds could
explain the differences on the antiparasitic activity.
ciparum with IC50 values around or below 10 lM. Moreover, two of
these compounds (3 and 9) had a good selectivity index (30.0 and
18.1, respectively). In line with the WHO/TDR activity criteria, all
compounds with the exception of 5 were moderately active against
T. cruzi. Compound 3 was the most active, with an IC50 of 11.4
which implies only a sevenfold reduced potency when compared
to that of benznidazole as the reference (IC50 2.13 M). Due to
the interesting antiplasmodial activity and the low cytotoxicity
(IC50 of 248 M), compound 3 represents a promising lead scaffold
lM,
l
3. Conclusions
l
for further structural optimization. Compounds 7 and 8 showed
moderate growth inhibition toward L. donovani (18.9 and
21.3 lM). Among the newly prepared derivatives, none of them
presented activity against T.b. rhodesiense (IC50 >50 lM).
We have reported on the design, synthesis and antiparasitic
activity of a small library of N-substituted benzenesulfonyl deriva-
tives of CH3THQ. The cytotoxicity on rat skeletal myoblast (L-6)
was evaluated as well. Also, a complete characterization and theo-
retical conformational analysis were carried out. Detailed NMR
investigation including 1H and 13C NMR, HSQC, HMBC data, were
consistent with structures of compounds 1–10. From spectra and
molecular modeling data we were able to conclude that the ‘V’
conformation of the molecules, given by the presence of the BS
moiety bound to the CH3THQ affected the stereoelectronic proper-
ties of the heterocycle, thus making the Meax position preferred
over the Meeq. However, the para or meta substituents on BS did
not influence the 3D structure properties of the heterocycle or
the molecules as a whole. On the other hand, computational and
NMR data were in agreement with the presence of just one chair
conformation with the CH3ax, and also with the occurrence of an
H-bond between C8–H and one of the oxygen of SO2.
The series was tested against four parasites, with moderate
activities being found. The new derivatives 1–10 demonstrated to
be selective among the four protozoan parasites. T. cruzi and P. fal-
ciparum appeared to be the most sensitive of them. In spite of the
small number of compounds in the series, some interesting inhib-
itors against T. cruzi and P. falciparum were discovered. Compounds
3 and 9 showed moderate growth inhibition of P. falciparum with
2.4. Structure–activity relationships
In general, the presence of BS moiety decreased IC50 with re-
spect to the heterocycle precursor, the only exceptions being the
compounds 3 and 5 against T.b. rhodesiense and 5 against T. cruzi.
On the other hand, the presence of different substituents on the
BS seemed to have a particular influence depending on the para-
site. Only the p-fluoro substitution (5) showed a general negative
impact on the antiparasitic activity.
Overall, the lowest IC50 values and highest potencies of the series
were towards T. cruzi. The para substitution on the BS resulted in an
increase of activity with the only exception being 2 which had
almost the same activity as 1. The substitution with a strong elec-
tron-withdrawinggroupsuchasnitroinpara(3)resultedinthemost
active compound of this series. On the other hand, meta-substitution
on the BS seemed to be unfavorable for the in vitro activity against T.
cruzi. Indeed a change of the nitro from para (3) to meta (9) reduced
the activity threefold and resulted in one of the least active analogue.
For L. donovani activity, two halogenated compounds (7 and 8)
showed moderate growth inhibition. Even though the potency was
low when compared to miltefosine, the addition of the BS substitu-
ent strongly increased the potency by about 35-fold, with respect
to the CH3THQ. The same effect was observed against P. falciparum
but less pronounced, with the addition of the BS increasing the
activityby threefoldat best. The potency of compounds 1–10 against
P. falciparum was challenging, and also some REA analysis could be
IC50 values below 10 lM and good cytotoxicity. We identified these
two compounds as being lead-candidates for antiplasmodial activ-
ity.43 On the other hand, compound 3 also presented interesting
activity against T. cruzi with only fivefold reduced potency com-
pared to benznidazole as the reference drug. Due to this moderate
antitrypanosomal activity and the low cytotoxicity (IC50
=
248 M), compound 3 represents a promising lead scaffold for
l

R. J. Pagliero et al. / Bioorg. Med. Chem. 18 (2010) 142–150
147
further structural optimization. These findings suggest that pro-
ductive criteria were used in the design strategy. Further investiga-
tions into these BS-CH3THQs structures are ongoing based on three
strategies: (1) enlarging the present series using parallel synthetic
tools, (2) QSAR studies using multiparametric regression analysis
and (3) application of CADD to identify the target proteins and
the mode of action.
solid from the reaction mixture. To eliminate the colored impuri-
ties, the compounds were dissolved in hexane/acetone 7:3 and fil-
tered through a mixture of Silica Gel 60 and active carbon. The
solvent was evaporated in vacuum and was dried over CaCl2 for
24 h. A light yellow solid resulted with a yield of 92–98%. (B) Some
derivatives seemed to discompose in silica gel. These were washed
with cold ethanol (ꢁ5 °C) to eliminate the colored impurities. The
yields were 84–86% of a pink solid. (C) All compounds were finally
recrystallized from ethanol or methanol to give 78–88% of the
products as white or yellow crystals.
4. Experimental
4.1. General considerations
4.2.3. Specific procedures and spectral data for compounds 1–10
4.2.3.1. 1-(Benzenesulfonyl)-2-methyl-1,2,3,4-tetrahydroquino-
line (1). (R1 = H; R2 = H). Purification by procedures A and C (etha-
nol). White crystals (0.71 g, 82%) mp 104.0–104.5 °C (from EtOH). IR
Melting points (mp) were determined using an electrothermal
apparatus, by microcapillary methods and are uncorrected. Infra-
red spectra were recorded on a Nicolet 5 SXC FT-IR. NMR experi-
ments were performed on a Bruker advance II 400 Hz, ultra
shield TM spectrometer at 400.16(1H) and 100.62(13C) which has
an inverse multinuclear detection sonda, digital resolution and a
variable temperature unite. Chemical shift values are reported in
ppm (d) and were taken with DMSO-d6 as a solvent (referred to
residual DMSO at 2.50 ppm for 1H and 39.5 ppm for 13C). Coupling
constants (J) are in Hz (refer to Table 1 for atom numbering). The
multiplicities of the signals are described using the following
abbreviations s = singlet, d = doublet, t = triplet, q = quartet,
sex = sextet, m = multiplet. High resolution mass spectroscopy
experiments were taken in a Micromass Q-TOF micro Hybrid
Quadrupole/Orthogonal High Resolution Time of Flight MS with
Micromass capillary HPLC (Waters Corporation).
(m
max/cmꢁ1, KBr): 3065 (CHaromatic), 2927 (CH3 asim), 1343 (SO2 asim),
1168 (SO2 sim). 1H NMR (DMSO-d6, 400.16 Hz): 7.63 (tt, 1H, 7.2 and
1.2 Hz, H40); 7.59 (d, 1H, 8.0 Hz, H8); 7.54 (d, 2H, 8.0 Hz, H20); 7.50
(dt, 2H, 7.4 and 1.2 Hz, H30); 7.3 (td, 1H, 7.8 and 1.2 Hz, H7); 7.10
(td, 1H, 7.4 and 1.1 Hz, H6); 7.08 (d, 1H, 6.8 Hz, H5); 4.3 (sex, 1H,
6.6 Hz, H2); 2.4 (m, 1H, H4b); 1.8 (m, 1H, H3b); 1.7 (m, 1H, H4a);
1.3 (m, 1H, H3a); 1.2 (d, 3H, 6.4 Hz, H11). 13C NMR (DMSO-d6,
100.62 Hz; assigned using HSQC): 139.4 (Cq-10); 135.6 (Cq-10);
134.4 (Cq-9); 134.2 (Cq-40); 130.3 (CH-30); 129.3 (CH-5); 127.6
(CH-8); 127.6 (CH-20); 127.5 (CH-7); 126.7 (CH-6); 53.0 (CH-2);
2
30.5 (CH2-3); 24.9 (CH2-4); 22.5 (CH3-11). COSY: Jgem: H3a–H3b,
3
H4a–H4b. Jvec: H2–H3a; H2–H3b; H2–H11; H3a–H4a; H3a–H4b;
3
H3b–H4b; H3b–H4a. Jortho: H6–H7; H5–H6; H7–H8; H20–H30;
4
H30–H40. Jmeta
:
H5–H7; H6–H8; H20–H40. HMBC (DMSO-d6,
All the benzenesulfonyl chlorides were purchased from Sigma–
Aldrich. The pyridine used for the synthesis was previously dis-
tilled and stored over pellets of NaOH. The 2-methyl-1,2,3,4-tetra-
f1 = 400.16 Hz, f2 = 100.62 Hz) (C?H): C11?H2, H3b; C4?H5, H3a,
H3b; C3?H2, H4a, H4b, H11; C2?H4a, H4b, H3a, H3b, H11;
C6?H8; C7?H5; C8?H6; C20?H40; C5?H7, H4a, H4b; C40?H20;
C9?H8, H6, H4a, H4b, H3a, H3b; C10?H7, H5, H2, H4a, H4b;
C10?H30. HRMS (EI) calcd mass for C16H17NO2S: 287.0980; found:
287.0988.
hydroquinoline
(CH3THQ)
was
prepared
by
catalytic
hydrogenation of 2-methyl-quinoline (Aldrich + 95%) as described
by Atsuko et al.26 Reaction progress was monitored by TLC (Silica
Gel 60 F254, Merck) visualizing with UV light. The silica gel used
in the purification of the products was Merck grade 60, 230–
400 mesh, 60A. All others reagents and solvents were used as pur-
chased from Anhedra.
4.2.3.2. 1-(4-Acetamide-benzenesulfonyl)-2-methyl-1,2,3,4-tet-
rahydroquinoline (2). (R1 = NHCOCH3; R2 = H). Purification by
procedures A and C (ethanol). White crystals (0.56 g, 54%) mp
195.0–196.5 °C (from EtOH). IR (m
max/cmꢁ1, KBr): 3352 (NH),
4.2. Experimental procedure, spectral data for compounds 1–10
3066 (CHaromatic), 2932 (CH3 asim), 2858 (CH3 sim), 1703 (CO), 1334
(SO2 asim), 1310 (CNamida), 1157 (SO2 sim). 1H NMR (DMSO-d6,
400.16 Hz): 10.3 (s, 1H, H50); 7.9 (d, 1H, 7.9 Hz, H8); 7.6 (d, 2H,
9.2 Hz, H30); 7.4 (d, 2H, 8.8 Hz, H20); 7.2 (td, 1H, 7.6 and 1.5 Hz,
H7); 7.1 (td, 1H, 7.4 and 1.6 Hz, H6); 7.0 (dd, 1H, 7.2 and 0.8 Hz,
H5); 4.3 (sex, 1H, 6.6 Hz, H2); 2.4 (m, 1H, H4b); 2.0 (s, 3H, H70);
1.8 (m, 1H, H3b); 1.7 (m, 1H, H4a); 1.3 (m, 1H, H3a); 1.2 (d, 3H,
6.8 Hz, H11). 13C NMR (DMSO-d6, 100.62 Hz; assigned using
HSQC): 170.2 (C60@O); 144.4 (Cq-40); 135.7 (Cq-10); 134.3 (Cq-
9); 133.0 (Cq-10); 129.2 (CH-5); 128.9 (CH-20); 127.5 (CH-8);
4.2.1. General procedures for the synthesis
Compounds 1–9 were synthesized by adding 4.00 mmol of an
appropriate substituted benzenesulfonyl chloride to a solution of
CH3THQ (3.00 mmol, 0.44 g, 0.43 mL) in 1.5 mL of anhydrous pyri-
dine at room temperature. The reaction mixture was vigorously
stirred at 60–80° until no more starting materials could be de-
tected by TLC (hexane/acetone 7:3). This mixture was then cooled
at ꢁ5 °C and chilled water was added to precipitate the product.
The solid was filtered off, washed exhaustively with HCl 0.01 M
and water, and dried over CaCl2 and anhydrous MgSO4. Colored
solids were obtained at yields of 70–85%.
Compound 10 was synthesized by hydrolysis of compound 2:
3 mmol (1.03 g) of 2 were dissolved in 18 mL of acetone, heated at
40 °C and 10 mL HCl 4 M was added dropwise. After that, the reac-
tion mixture was heated at 60–70° and stirred for 3 h, until no more
startingmaterial could be detected by TLC (hexane/acetone 5:5). The
mixture was cooled and a solution of NaCO3 was added to pH 9. The
acetone was evaporated in vacuum and the solid filtered off, before
being washed with water and dried over CaCl2 and anhydrous
MgSO4. A white solid was obtained at a yield of 92%.
127.5 (CH-7); 126.5 (CH-6); 119.5 (CH-30); 52.8 (CH-2); 30.5
2
(CH2-3); 25.1 (CH3-70); 24.9 (CH2-4); 22.5 (CH3-11). COSY: Jgem
:
3
H3a–H3b, H4a–H4b. Jvec: H2–H3a; H2–H3b; H2–H11; H3a–H4a;
3
H3a–H4b; H3b–H4b; H3b–H4a. Jortho: H6–H7; H5–H6; H7–H8;
4
H20–H30. Jmeta: H5–H7; H6–H8. HMBC (DMSO-d6, f1 = 400.16 Hz,
f2 = 100.62 Hz) (C?H): C11?H2; C4?H5, H3a, H3b; C3?H2,
H4a, H4b, H11; C2?H4b, H3a, H3b, H11; C30?H50, H20; C6?H8;
C7?H5; C8?H6; C5?H7, H4b; C10?H30, H20; C9?H8, H6, H4a,
H4b, H3a, H3b; C10?H7, H5, H2, H4a, H4b; C40?H20, H30, H50;
C60?H50, H70. HRMS (EI) calcd mass for C18H20N2O3S: 344.1194;
found: 344.1208.
4.2.3.3. 1-(4-Nitro-benzenesulfonyl)-2-methyl-1,2,3,4-tetrahy-
droquinoline (3). (R1 = NO2; R2 = H). Purification by procedures A
and C (ethanol). Yellow crystals (0.83 g, 78%) mp 159.0–160.0 °C
4.2.2. General procedure for purification of the derivatives
The products isolated as described previously were then puri-
fied as follows: (A) All the compounds were obtained as a colored
(from EtOH). IR (m
max/cmꢁ1, KBr): 3111 (CHaromatic), 2970, 2932

148
R. J. Pagliero et al. / Bioorg. Med. Chem. 18 (2010) 142–150
(CH3), 1527 (NO2 asim), 1347 (SO2 asim), 1308 (NO2 sim), 1166
HRMS (EI) calcd mass for
328.0781.
C16H16FNO2S: 328.0783; found:
1
(SO2 sim). H NMR (DMSO-d6, 400.16 Hz): 8.3 (d, 2H, 9.4 Hz, H30);
7.7 (d, 2H, 8,8 Hz, H20); 7.6 (d, 1H, 7.6 Hz, H8); 7.3 (td, 1H, 8.4 and
1.2 Hz, H7); 7.2 (td, 1H, 7.4 and 0.8 Hz, H6); 7,0 (d, 1H, 7.2 Hz, H5);
4.4 (sex, 1H, 6.6 Hz, H2); 2.4 (m, 1H, H4b); 1.8 (m, 1H, H3b); 1.7
(m, 1H, H4a); 1.3 (m, 1H, H3a); 1.2 (d, 3H, 5.8 Hz, H11). 13C NMR
(DMSO-d6, 100.62 Hz; assigned using HSQC): 150.4 (Cq-40); 144.2
(Cq-10); 134.4 (Cq-10); 134.0 (Cq-9); 128.9 (CH-5); 128.7 (CH-20);
4.2.3.6. 1-(4-Chloro-benzenesulfonyl)-2-methyl-1,2,3,4-tetra-
hydroquinoline (6). (R1 = Cl; R2 = H). Purification by procedures B
and C (ethanol). White crystals (0.69 g, 67%) mp 92.0–92.5 °C (from
EtOH). IR (m mCH3),
max/cmꢁ1, KBr): 3071 (CHaromatic), 2965, 2860 (
1344 (SO2 asim), 1169 (SO2 sim); 758 (CCl). 1H NMR (DMSO-d6,
400.16 Hz): 7.62 (dd, 2H, 8.80 and 2.20 Hz, H20); 7.58 (d, 1H,
8.0 Hz, H8); 7.5 (dd, 2H, 8.8 and 2.2 Hz, H30); 7.3 (td, 1H, 7.6 and
1.6 Hz, H7); 7.2 (td, 1H, 7,6 and 1,2 Hz, H6); 7.1 (d, 1H, 7.20 Hz,
H5); 4,4 (sex, 1H, 6.5 Hz, H2); 2.5 (m, 1H, H4b); 1.9 (m, 1H, H3b),
1.7 (m, 1H, H4a); 1.3 (m, 1H, H3a); 1.2 (d, 3H, 6.8 Hz, H11). 13C
NMR (DMSO-d6, 100.62 Hz; assigned using HSQC): 139.1 (Cq-10);
138.3 (Cq-40); 135.3 (Cq-10); 134.5 (Cq-9); 130.4 (CH-20); 129.6
(CH-30); 129.3 (CH-5); 127.6 (CH-7); 127.4 (CH-8); 126.8 (CH-6);
127.2 (CH-7); 126.8 (CH-8); 126.6 (CH-6); 125.1 (CH-30); 53.0 (CH-
2
2); 30.2 (CH2-3); 25.5 (CH2-4); 19.6 (CH3-11). COSY: Jgem
:
3
H3a–H3b, H4a–H4b. Jvec: H2–H3a; H2–H3b; H2–H11; H3a–H4a;
3
H3a–H4b; H3b–H4b; H3b–H4a. Jortho: H6–H7; H5–H6; H7–H8;
4
H20–H30. Jmeta: H5–H7; H6–H8. HMBC (DMSO-d6, f1 = 400.16 Hz,
f2 = 100.62 Hz) (C?H): C11?H2; C4?H5, H3a, H3b; C3?H2, H4a,
H4b, H11; C2?H4b, H4a, H3b, H11; C30?H20; C6?H8; C8?H6,
H7; C7?H5; C5?H7, H4b; C9?H8, H6, H4a, H4b, H3a, H3b;
C10?H7, H5, H2, H4a, H4b; C10?H30, H20; C40?H20, H30. HRMS
(EI) calcd mass for C12H16N2O4S: 355.0728; found: 355.0729.
53.2 (CH-2); 30.6 (CH2-3); 25.0 (CH2-4); 22.5 (CH3-11). COSY: 2Jgem
:
3
H3a–H3b, H4a–H4b. Jvec: H2–H3a; H2–H3b; H2–H11; H3a–H4a;
3
H3a–H4b; H3b–H4b; H3b–H4a. Jortho: H6–H7; H5–H6; H7–H8;
4
4.2.3.4. 1-(4-Methyl-benzenesulfonyl)-2-methyl-1,2,3,4-tetra-
hydroquinoline (4). (R1 = CH3; R2 = H). Purification by procedures
A and C (methanol). White crystals (073 g, 81%) mp 79–80 °C (from
H20–H30. Jmeta: H5–H7; H6–H8. HMBC (DMSO-d6, f1 = 400.16 Hz,
f2 = 100.62 Hz) (C?H): C11?H2, H3b; C4?H5, H3a, H3b;
C3?H2, H4a, H4b, H11; C2?H4a, H4b, H3a, H3b, H11; C6?H8,
H5; C8?H6, H7; C7?H5; C5?H7, H4b, H4a; C30?H20; C9?H8,
H6, H4a, H4b, H3a, H3b; C10?H7, H5, H2, H4a, H4b, H3a, H3b;
C40?H20, H30; C10?H30, H20. HRMS (EI) calcd mass for
C16H16ClNO2S: 344.0488; found: 344.0505.
MeOH). IR (m mCH3),
max/cmꢁ1, KBr): 3066 (CHaromatic), 2949, 2858 (
1341 (SO2 asim), 1159 (SO2 sim). 1H NMR (DMSO-d6, 400.16 Hz):
7.5 (d, 1H, 8.0 Hz, H8); 7.34 (d, 2H, 8.4 Hz, H20); 7.29 (d, 2H,
8.0 Hz, H30); 7.2 (td, 1H, 7.4 and 1.2 Hz, H7); 7.1 (td, 1H, 7,6 and
1,2 Hz, H6); 7.0 (dd, 1H, 8.0 and 0.8 Hz, H5); 4,3 (sex, 1H, 6.5 Hz,
H2); 2.4 (m, 1H, H4b); 2.3 (s, 3H, H50); 1.8 (m, 1H, H4a); 1.7 (m,
1H, H3b); 1.3 (m, 1H, H3a); 1.2 (d, 3H, 6.4 Hz, H11). 13C NMR
(DMSO-d6, 100.62 Hz; assigned using HSQC): 144.6 (Cq-40); 136.8
(Cq-10); 135.7 (Cq-10); 134.2 (Cq-9); 130.7 (CH-30); 129.3 (CH-5);
127.7 (CH-20); 127.5 (CH-7); 127.4 (CH-8); 126.6 (CH-6); 52.9
(CH-2); 30.4 (CH2-3); 24.9 (CH2-4); 22.4 (CH3-11); 22.0 (CH3-50).
4.2.3.7. 1-(4-Bromo-benzenesulfonyl)-2-methyl-1,2,3,4-tetra-
hydroquinoline (7). (R1 = Br; R2 = H). Purification by procedures
B and C (ethanol). White crystals (0.76 g, 65%) mp 80.0–80.5 °C
(from EtOH). IR (m
max/cmꢁ1, KBr): 3068 (CHaromatic), 2973, 2916
(CH3), 1344 (SO2 asim), 1168 (SO2 sim); 605 (CBr). 1H NMR (DMSO-
d6, 400.16 Hz): 7.8 (d, 2H, 8.4 Hz, H30); 7.6 (d, 1H, 8.4 Hz, H8);
7.5 (d, 2H, 8.4 Hz, H20); 7.3 (td, 1H, 7.8 and 1.0 Hz, H7); 7.2 (td,
1H, 7,4 and 0.8 Hz, H6); 7.1 (dd, 1H, 7.2 and 0.8 Hz, H5); 4,4 (sex,
1H, 6.56 Hz, H2); 2.5 (m, 1H, H4b); 1.9 (m, 1H, H3b), 1.7 (m, 1H,
H4a);; 1.3 (m, 1H, H3a); 1.2 (d, 3H, 6.8 Hz, H11). 13C NMR
(DMSO-d6, 100.62 Hz; assigned using HSQC): 138.7 (Cq-10); 135.3
(Cq-10); 134.5 (Cq-9); 133.4 (CH-30); 129.6 (CH-20); 129.4 (CH-
2
3
COSY: Jgem: H3a–H3b, H4a–H4b. Jvec: H2–H3a; H2–H3b; H2–
3
H11; H3a–H4a; H3a–H4b; H3b–H4b; H3b–H4a. Jortho: H6–H7;
4
H5–H6; H7–H8; H20–H30. Jmeta: H5–H7; H6–H8. HMBC (DMSO-
d6, f1 = 400.16 Hz, f2 = 100.62 Hz) (C?H): C50?H30; C11?H2,
H3a, H3b; C4?H5, H3a, H3b; C3?H2, H4a, H4b, H11; C2?H4b,
H3a, H11; C6?H8, H5; C8?H6; C7?H5; C5?H7, H4b, H4a;
C30?H50; C9?H8, H6, H4a, H4b, H3a, H3b; C10?H7, H5, H2,
H4a, H4b; C10?H30, H20; C40?H20, H30. HRMS (EI) calcd mass for
C17H19NO2S: 301.1136; found: 301.1135.
5); 128.2 (Cq-40); 127.7 (CH-7); 127.5 (CH-8); 126.9 (CH-6); 53.3
2
(CH-2); 30.7 (CH2-3); 25.0 (CH2-4); 22.6 (CH3-11). COSY: Jgem
:
3
H3a–H3b, H4a–H4b. Jvec: H2–H3a; H2–H3b; H2–H11; H3a–H4a;
3
H3a–H4b; H3b–H4b; H3b–H4a. Jortho: H6–H7; H5–H6; H7–H8;
4
4.2.3.5. 1-(4-Fluoro-benzenesulfonyl)-2-methyl-1,2,3,4-tetra-
hydroquinoline (5). (R1 = F; R2 = H). Purification by procedures B
and C (ethanol). White crystals (0.67 g, 68%) mp 121.0–121.5 °C
H20–H30. Jmeta: H5–H7; H6–H8. HMBC (DMSO-d6, f1 = 400.16 Hz,
f2 = 100.62 Hz) (C?H): C11?H2, H3a, H3b; C4?H5, H3a, H3b;
C3?H2, H4a, H4b, H11; C2?H4a, H4b, H3a, H3b, H11; C6?H8,
H7; C8?H6; C7?H5; C40?H20, H30; C5?H7, H4a, H4b; C9?H8,
H6, H5, H4a, H4b, H3a, H3b; C10?H7, H5, H8, H2, H4a, H4b,
H3a, H3b; C10?H30, H20. HRMS (EI) calcd mass for C16H16BrNO2S:
387.9983; found: 387.9979.
(from EtOH). IR (m
max/cmꢁ1, KBr): 3076 (CHaromatic), 2973, 2858
(CH3), 1343 (SO2 asim), 1171 (SO2 sim); 1008 (CF). 1H NMR (DMSO-
d6, 400.16 Hz): 7.59 (d, 1H, 7.6 Hz, H8); 7.56 (qt, 2H, 8.8 and
2.0 Hz, JHF(meta) = 5.2 Hz, H20); 7.4 (tt, 2H, 8.8 and 2.4 Hz,
JHF(ortho) = 9.2 Hz, H30); 7.3 (td, 1H, 7.6 and 1.2 Hz, H7); 7.2 (td,
1H, 7,4 and 1,2 Hz, H6); 7.1 (d, 1H, 7.6 Hz, H5); 4,4 (sex, 1H,
5.6 Hz, H2); 2.4 (m, 1H, H4b); 1.8 (m, 1H, H3b), 1.7 (m, 1H, H4a);
1.3 (m, 1H, H3a); 1.2 (d, 3H, 6.4 Hz, H11). 13C NMR (DMSO-d6,
4.2.3.8. 1-(4-Methoxy-benzenesulfonyl)-2-methyl-1,2,3,4-tetra-
hydroquinoline (8). (R1 = OCH3; R2 = H). Purification by proce-
dures A and C (ethanol). White crystals (0.67 g, 66%) mp 91.0–
1
100.62 Hz; assigned using HSQC): 165.0, JHF = 240.6 Hz (Cq-40);
92.0 °C (from EtOH). IR (m
max/cmꢁ1, KBr): 3066 (CHaromatic), 2970,
4
135.3, JCF = 2.89 Hz (Cq-10); 134.9 (Cq-10); 133.9 (Cq-9); 130.2,
2932 (CH3), 2840 (OCH3 asim), 1338 (SO2 asim), 1158 (SO2 sim). 1H
NMR (DMSO-d6, 400.16 Hz): 7.5 (dd, 1H, 8.4 and 0.8 Hz, H8); 7.4
(dd, 2H, 8.8 and 2.0 Hz, H20); 7.2 (td, 1H, 8.0 and 1.5 Hz, H7); 7.1
(td, 1H, 7.6 and 1.47 Hz, H6); 7.05 (dd, 1H, 7.2 and 1.2 Hz, H5);
7.01 (dd, 2H, 8.8 and 2.0 Hz, H30); 4.3 (sex, 1H, 6.4 Hz, H2); 3.8
(s, 1H, H60); 2.4 (m, 1H, H4b); 1.8 (m, 1H, H3b); 1.7 (m, 1H,
H4a); 1.3 (m, 1H, H3a); 1.2 (d, 3H, 6.4 Hz, H11). 13C NMR
(DMSO-d6, 100.62 Hz; assigned using HSQC): 163.7 (Cq-40); 135.8
(Cq-10); 134.2 (Cq-9); 131.3 (Cq-10); 129.9 (CH-20); 129.3 (CH-5);
127.5 (CH-7); 127.5 (CH-8); 126.5 (CH-6); 115.4 (CH-30); 56.7
(CH3-50); 52.8 (CH-2); 30.4 (CH2-3); 24.9 (CH2-4); 22.4 (CH3-11).
3JCF = 9.51 Hz (CH-20); 128.8 (CH-5); 127.0 (CH-7); 127.0 (CH-8);
2
126.2 (CH-6); 116.9, JCF = 22.6 Hz (CH-30); 52.6 (CH-2); 30.0
2
(CH2-3); 24.4 (CH2-4); 22.0 (CH3-11). COSY: Jgem: H3a–H3b,
3
H4a–H4b. Jvec: H2–H3a; H2–H3b; H2–H11; H3a–H4a; H3a–H4b;
H3b–H4b;H3b–H4a. 3Jortho: H6–H7;H5–H6;H7–H8; H20–H30. 4Jmeta
:
H5–H7; H6–H8. HMBC (DMSO-d6, f1 = 400.16 Hz, f2 = 100.62 Hz)
(C?H): C11?H2, H3a, H3b; C4?H5, H3a, H3b; C3?H2, H4a,
H4b, H11; C2?H4a, H4b, H3a, H3b, H11; C30?H20; C6?H8, H7;
C8?H6, H7; C7?H5; C5?H7, H4b, H4a; C9?H8, H6, H4a, H4b,
H3a, H3b; C10?H7, H5, H2, H4a, H4b; C10?H30; C40?H20, H30.

R. J. Pagliero et al. / Bioorg. Med. Chem. 18 (2010) 142–150
149
COSY: 2Jgem: H3a–H3b, H4a–H4b. 3Jvec: H2–H3a; H2–H3b; H2–H11;
mated injector system and a UV–visible detector. The column used
m which was
maintained at room temperature. A flow rate of 1.0 mL/min with
3
H3a–H4a; H3a–H4b; H3b–H4b; H3b–H4a. Jortho: H6–H7; H5–H6;
was a Water RP-C18 (50 ꢂ 3 mm) with particles of 3
l
4
H7–H8; H20–H30. Jmeta
:
H5–H7; H6–H8. HMBC (DMSO-d6,
f1 = 400.16 Hz, f2 = 100.62 Hz) (C?H): C11?H2; C4?H5, H3a,
H3b; C3?H2, H4a, H4b, H11; C2?H4a, H4b, H11; C6?H8;
C8?H6; C7?H5; C5?H7, H4b; C10?H30; C9?H8, H6, H5, H4a,
H4b, H3a; C10?H7, H5, H8, H2, H4a, H4b; C40?H20, H30. HRMS
(EI) calcd mass for C17H19NO3S: 340.0983; found: 340.0979.
methanol–water 70:30 mixtures was used as mobile phase. Detec-
tion was made at 254 nm and the injection volume was 20 lL. The
inspection of the chromatograms showed a purity of more than
96% for all the compounds (see Table 1), measured as the percent-
age of area under the sample peak. The solvent peak (methanol)
was observed at 0.578.
4.2.3.9. 1-(3-Nitro-benzenesulfonyl)-2-methyl-1,2,3,4-tetrahy-
droquinoline (9). (R1 = H; R2 = NO2). Purification by procedures A
and C (ethanol). White crystals (0.52 g, 70%) mp 115.0–115.5 °C
The melting point ranges were also measured as criteria of pur-
ity, and are reported with the spectral data in the previous section.
(from EtOH). IR (
m
max/cmꢁ1, KBr): 3111 (CHaromatic), 2970, 2932
4.2.5. Computational data of compounds 1–10
(CH3), 1531 (NO2 asim), 1352 (SO2 asim), 1352 (NO2 sim), 1170
(SO2 sim). 1H NMR (DMSO-d6, 400.16 Hz): 8.5 (ddd, 1H, 8.0, 2,4
and 1.2 Hz, H40); 8.1 (t, 1H, 2.0 Hz, H20a); 7.85 (dt,1H, 8.0 and
1.2 Hz, H20b); 7.81 (t, 1H, 7.81 Hz, H30b); 7.6 (dd, 1H, 8.4 and
1.0 Hz, H8); 7.3 (dd, 1H, 7.8 and 1.3 Hz, H7); 7.2 (td, 1H, 7.4 and
1.2 Hz, H6); 7.1 (dd, 1H, 7.2 and 0.8 Hz, H5); 4.4 (sex, 1H, 6.8 Hz,
H2); 2.4 (m, 1H, H4b); 1.8 (m, 1H, H3b); 1.6 (m, 1H, H4a); 1.3
(m, 1H, H3a); 1.2 (d, 3H, 6.4 Hz, H11). 13C NMR (DMSO-d6,
100.62 Hz; assigned using HSQC): 148.1 (Cq-30a); 140.0 (Cq-10);
134.5 (Cq-10 and Cq-9); 132.9 (C20b); 131.9 (C30b); 128.9 (CH-5);
128.3 (C40); 127.4 (CH-7); 127.1 (CH-8); 126.7 (CH-6); 121.8
(CH-20a); 51.9 (CH-2); 30.6 (CH2-3); 24.7 (CH2-4); 22.3 (CH3-11).
All the BS-CH3THQ derivatives were first minimized with the
semiempirical AM1 method. The conformational search was car-
ried out for both enantiomers (2R or 2S) through a careful system-
atic scan of the relevant dihedral angles (a and b angles) using the
‘Opt = ModRedundant’ keyword in GAUSSIAN 0331 with 36 steps of
10° each. The preference of the 2-CH3 group for the axial or equa-
torial position was also studied for both enantiomers. The potential
energy surface was explored to find the global minima by scanning
the C10–N1–S12–C10 torsion angle (
mum thus found, the N1–S12–C10–C20 torsion angle (b angle)
was scanned at fixed
. A full geometry optimization§ at the
a angle). Then, for each mini-
a
B3LYP/6-31G(d) level of theory was later performed for the lowest
energy conformations found. Finally, each minimum was character-
ized as a stationary point by vibrational frequency calculations
(‘freq = noraman’). For all the derivatives the number of imaginary
frequencies was zero. Molecular orbitals, Mülliken charges, and the
charges fitting to the electrostatic potential were calculated. The
NMR spectrum were also calculated using a B3LYP/6-31G(d) level
of theory as well as for HF/6-31G(d). In both cases the ‘nmr = giao’
method was used for the NMR calculation with no specification of
the symmetry (‘nosym’).
2
3
COSY: Jgem: H3a–H3b, H4a–H4b. Jvec: H2–H3a; H2–H3b; H2–
3
H11; H3a–H4a; H3a–H4b; H3b–H4b; H3b–H4a. Jortho: H6–H7;
4
H5–H6; H7–H8; H30b–H20b; H30b–H40. Jmeta: H5–H7; H6–H8;
H20b–H2a; H20b–H40; H20a–H40. HMBC (DMSO-d6, f1 = 400.16 Hz,
f2 = 100.62 Hz) (C?H): C11?H2; C4?H5, H3a, H3b; C3?H2,
H4a, H4b, H11; C2?H4a, H4b, H11; C20a?H40, H20b; C6H8;
C8?H6; C7?H5; C40?H20a, H20b, H30b; C5?H7; C30b?H40;
C20b?H40, H20a, H30b; C9?H8, H6, H4a, H4b, H3a, H3b;
C10?H7, H5, H2, H4a, H4b; C10?H20a, H30b; C30a?H20a, H30b.
HRMS (EI) calcd mass for C16H16N2O4S: 355.0728; found:
355.0724.
4.2.6. Antiprotozoal activity
The in vitro activities against the protozoan parasites T.b. rho-
desiense, T. cruzi, L. donovani and P. falciparum as well as cytotoxic-
ity were determined as described earlier.44 Compounds were
4.2.3.10. 1-(4-Amino-benzenosulfonyl)-2-methyl-1,2,3,4-tetra-
hydroquinoline (10). (R1 = NH2; R2 = H). Purification by proce-
dure
155.0 °C (from EtOH). IR (
(CHaromatic), 2933, 2858 (
C
(methanol). Beige crystals (0.71 g, 79%) mp 154.0–
max/cmꢁ1, KBr): 3469, 3373 (NH), 3252
CH3), 1640 (NH), 1319 (SO2 asim), 1154
measured in duplicate in the range of 0.2–300 lM. The following
m
m
substances were used as reference standards: melarsoprol (T.b.
rhodesiense), benznidazole (T. cruzi), miltefosine (L. donovani), chlo-
roquine (P. falciparum) and podophyllotoxin (cytotoxicity assay
using L-6 cells).
(SO2 sim). 1H NMR (DMSO-d6, 400.16 Hz): 7.6 (d, 1H, 8,4 Hz, H8);
7.2 (td, 1H, 7.8 and 1.6 Hz, H7); 7,11 (td, 1H, 6.4 and 0.8 Hz, H6);
7,10 (d, 2H, 7.6 Hz, H20); 7.06 (dd, 1H, 7.6 and 1.6 Hz, H5); 6.5 (d,
2H, 8.4 Hz, H30); 6.0 (s, 1H, H50); 4.3 (sex, 2H, 6.5 Hz, H2); 2,4 (m,
1H, H4b); 1.9 (m, 1H, H4a); 1.8 (m, 1H, H3b); 1.3 (m, 1H, H3a);
1.2 (d, 3H, 6.8 Hz, H11). 13C NMR (DMSO-d6, 100.62 Hz; assigned
using HSQC): 154.0 (Cq-40); 136.3 (Cq-10); 134.0 (Cq-9); 129.6
(CH-20); 129.2 (CH-5); 127.6 (CH-8); 126.1 (CH-6); 124.5 (Cq-10);
124.2 (CH-7); 113.6 (CH-30); 52.3 (CH-2); 30.1 (CH2-3); 25.0
Acknowledgments
This work was supported by SECyT-UNC (Argentina). R.J.P. and
S.L. acknowledge CONICET fellowships. Dr. Paolo Carvalho for
HRMS and X-ray. Bonetto Gloria for NMR techniques assistance.
2
3
(CH2-4); 22.3 (CH3-11). COSY: Jgem: H3a–H3b, H4a–H4b. Jvec
:
Supplementary data
H2–H3a; H2–H3b; H2–H11; H3a–H4a; H3a–H4b; H3b–H4b;
3
4
H3b–H4a. Jortho: H6–H7; H5–H6; H7–H8; H20–H30. Jmeta: H5–
H7; H6–H8. J with NH2: H30–H50; H20–H50. HMBC (DMSO-d6,
f1 = 400.16 Hz, f2 = 100.62 Hz) (C?H): C11?H2, H3a, H3b;
C4?H5, H3a, H3b; C3?H2, H4a, H4b, H11; C2?H4b, H4a, H3a,
H3b, H11; C30?H50; C10?H30, H20; C6?H8; C7?H5; C8?H6;
C5?H7, H4b, H4a; C20?H30, H50; C9?H8, H6, H7, H4a, H4b, H3a,
H3b; C10?H7, H5, H8, H6, H2, H4a, H4b; C40?H20. HRMS (EI)
calcd mass for C16H18N2O2S: 302.1089; found: 302.1073.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.11.010.
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