Synthesis and antiproliferative activity of 8-hydroxyquinoline derivatives containing a 1,2,3-triazole moiety

Article abstract of DOI:10.1016/j.ejmech.2014.07.061

Twelve novel 8-hydroxyquinoline derivatives were synthesized with good yields by performing coppercatalyzed Huisgen 1,3-dipolar cycloaddition ("click" reaction) between an 8-O-alkylated-quinoline containing a terminal alkyne and various aromatic or protected sugar azides. These compounds were evaluated in vitro for their antiproliferative activity on various cancer cell types. Protected sugar derivative 16 was the most active compound in the series, exhibiting potent antiproliferative activity and high selectivity toward ovarian cancer cells (OVCAR-03, GI₅₀ < 0.25 μg mL^-1); this derivative was more active than the reference drug doxorubicin (OVCAR-03, GI₅₀ = 0.43 μg mL^-1). In structureeactivity relationship (SAR) studies, the physico-chemical parameters of the compounds were evaluated and docking calculations were performed for the a-glucosidase active site to predict the possible mechanism of action of this series of compounds.

Full text of DOI:10.1016/j.ejmech.2014.07.061

European Journal of Medicinal Chemistry 84 (2014) 595e604
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antiproliferative activity of 8-hydroxyquinoline
derivatives containing a 1,2,3-triazole moiety
Luiza B. de O. Freitas a, Thiago F. Borgati a, Rossimiriam P. de Freitas a, Ana L.T.G. Ruiz b,
b
b
c
~
Gabriela M. Marchetti , Joao E. de Carvalho , Elaine F.F. da Cunha ,
Teodorico C. Ramalho c, Rosemeire B. Alves a
Laboratorio de Síntese Organica (Labsinto), Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
,
*
a
ꢀ
^
b
~
ꢀ
Divisao de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biologicas e Agrícolas (CPQBA), Universidade Estadual de Campinas,
Campinas, CP 6171, SP 13083-970, Brazil
c
ꢀ
Laboratorio de Química Computacional, Departamento de Química, Universidade Federal de Lavras, CP 3037, Lavras, MG 37200-000, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Twelve novel 8-hydroxyquinoline derivatives were synthesized with good yields by performing copper-
catalyzed Huisgen 1,3-dipolar cycloaddition (“click” reaction) between an 8-O-alkylated-quinoline con-
taining a terminal alkyne and various aromatic or protected sugar azides. These compounds were
evaluated in vitro for their antiproliferative activity on various cancer cell types. Protected sugar deriv-
ative 16 was the most active compound in the series, exhibiting potent antiproliferative activity and high
Received 14 February 2014
Received in revised form
16 July 2014
Accepted 19 July 2014
Available online 19 July 2014
selectivity toward ovarian cancer cells (OVCAR-03, GI50 < 0.25
than the reference drug doxorubicin (OVCAR-03, GI50 ¼ 0.43
(SAR) studies, the physico-chemical parameters of the compounds were evaluated and docking calcu-
m
g mLꢀ1); this derivative was more active
g mLꢀ1). In structureeactivity relationship
m
Keywords:
8-Hydroxyquinoline
1,2,3-Triazole
“Click” reaction
Antiproliferative
lations were performed for the
this series of compounds.
a-glucosidase active site to predict the possible mechanism of action of
© 2014 Elsevier Masson SAS. All rights reserved.
1. Introduction
Triazoles, another important class of N-heterocycles, are
employed in many pharmaceutical products. In particular, 1,2,3-
triazoles are of great relevance to medicinal chemistry because
they can act as pharmacophores and linkers between two or more
substances of interest in molecular hybridization approaches [18].
In recent years, 1,2,3-triazoles have gained special attention in the
drug discovery field because of the growing use of copper-catalyzed
azide-alkyne cycloadditiondthe “click” reaction [19,20]. Com-
pounds containing a 1,2,3-triazole display a wide range of biological
activities such as cytotoxic [2,21e23], antibacterial [6,24,25], anti-
fungal [6,26,27], antimalarial [28], and trypanocidal [29,30]
activities.
A series of quinoline derivatives carrying additional aromatic
ringsdderivatives 1 [11], 2 [31] and 3 [10]dhave been reported to
possess potential anticancer activities (Fig. 1). Notably, these com-
pounds often contain halogen substituents. In some instances,
sugar moieties have been used to improve the solubility of com-
pounds or to act as key molecular recognition and communication
elements [10,32].
Cancer is an important public health concern and a significant
cause of death in the human population [1]. Despite many efforts to
fight cancer, the successful treatment of certain tumor types con-
tinues to be a challenge owing to their aggressiveness, the mech-
anisms of malignant cell metastasis, chemoresistance, and the lack
of selectivity of some drugs [2]. Therefore, the development of
novel anticancer agents that are safer and more effective by syn-
thesizing small and simple molecules is necessary.
N-Heterocyclic compounds are very important in drug design
[3e5]. Among these, quinoline and its derivatives are present in
several classes of natural and synthetic biologically active com-
pounds [6e8]. In particular, 8-hydroxyquinoline and its derivatives
are of interest because of their wide spectrum of biological activ-
ities such as cytotoxic [9e11], antifungal [12e14], antibacterial
[13e15], antifilarial [16], and HIV integrase inhibitory [17] activities.
By considering the possibility of building a single molecular
framework containing two or more heterocycles of promising
biological activity, we aimed to synthesize a series of compounds
* Corresponding author.
E-mail addresses: rosebrondi@yahoo.com.br, lubofbof@gmail.com (R.B. Alves).
http://dx.doi.org/10.1016/j.ejmech.2014.07.061
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

596
L.B. de O. Freitas et al. / European Journal of Medicinal Chemistry 84 (2014) 595e604
Fig. 1. Representative examples of biologically active quinoline derivatives.
reaction to couple 8-O-alkylated-quinoline containing terminal
alkyne moiety 7 to benzyl azide derivatives 9aei in the presence of
a Cu(I) catalyst (Scheme 1).
The required starting material, 8-O-alkylated-quinoline con-
taining a terminal alkyne moiety (7), was obtained in a good yield
(88%) by performing etherification of 8-hydroxyquinoline with 4-
pentyn-1-ol methanesulfonate under phase-transfer catalysis us-
ing tetrabutylammonium bromide (TBAB). 4-Pentyn-1-ol meth-
anesulfonate was prepared according to a previously described
method [35]. To prepare benzyl azides 9aei, the corresponding
benzyl alcohols aei were mesylated. Nucleophilic substitution re-
actions of resultant mesylates 8aei were then performed using
sodium azide in dimethyl sulfoxide (DMSO) at room temperature.
Benzyl azides 9aei were obtained in high yields (72e99%). To
obtain the 1,2,3-triazoles, solutions of alkyne 7 with each benzyl
azide derivative (9aei) in dichloromethane were treated with a
solution of copper sulfate pentahydrate (8 mol%) and sodium
ascorbate (20 mol%) in water. The reaction mixtures were stirred for
2 h, at room temperature, to exclusively obtain 1,4-disubstituted
1,2,3-triazoles 10aei with good yields (67e94%).
Fig. 2. General structures of the synthesized quinoline derivatives carrying a 1,2,3-
triazole moiety.
comprising an 8-O-alkylated-quinoline (a), a 1,2,3-triazole nucleus
(b), and an aromatic or sugar moiety (R) (Fig. 2). We chose aromatic
rings bearing different halogen substituents (F, Cl, Br, and I) or sugar
derivatives to evaluate the electronic and steric influences of these
substituents on the activities of the derivatives. Derivatization of
the hydroxyl group from 8-hydroxyquinoline by attaching a 1,2,3-
triazole has not been used previously for the purpose of evalu-
ating the biological activities of its derivatives [33,34]. The in vitro
antiproliferative activity of these new compounds was investigated
on various cancer cell types and some structureeactivity relation-
ship (SAR) studies were conducted.
We also synthesized three new analogs (15, 16, and 17)
belonging to this family of compounds, based on the 8-O-alkylated-
quinoline scaffold that contained a triazole. We added substituents
predicted to increase biological activity, such as a pyridine nucleus
[2], protected sugar group [36], or an ester group (Scheme 2) [22].
As shown in Scheme 2, 3-pyridinepropanol was first brominated
using HBr under microwave irradiation. The brominated compound
2. Results and discussion
2.1. Chemistry
In our approach for the synthesis of 8-hydroxyquinoline de-
rivatives, we developed a synthetic route that used the click
Scheme 1. Reagents and conditions: (i) TBAB, NaOH (50% w/v), Et2O/H2O, r.t., 48 h; (ii) NaAsc (20 mol%), CuSO4$5H2O (8 mol%), CH2Cl2/H2O (1:1), r.t., 2 h; (iii) MsCl, Et3N,
CH2Cl2, ꢀ40 ꢁC, 30 min; (iv) NaN3, DMSO, r.t., 15 h.

L.B. de O. Freitas et al. / European Journal of Medicinal Chemistry 84 (2014) 595e604
597
Scheme 2. Reagents and conditions: (i) HBr, microwave, 200 W, 11 min, 80 ꢁC; (ii) NaN3, DMSO, r.t., 24 h; (iii) acetone, CuSO4, H2SO4, r.t., 24 h; (iv) MsCl, Et3N, CH2Cl2, ꢀ40 ꢁC,
30 min; (v) Et3N, DMAP, CH2Cl2, 0 ꢁC e r.t. (vi) NaAsc (20 mol%), CuSO4$5H2O (8 mol%), CH2Cl2/H2O (1:1), r.t., 2 h.
was converted to 3-(3-azidopropyl)pyridine 11 by performing
nucleophilic substitution using sodium azide in DMSO at room
temperature. A three-step protocol was used to obtain 1,2:3,4-di-O-
sodium azide in DMSO at room temperature to obtain azido ester 14.
Finally, the 1,2,3-triazole derivatives 15, 16, and 17 were obtained
from 11, 12, and 14, respectively, by using the same click reaction
methodology that was applied to obtain compounds 10aei.
isopropylidene-6-azido-
a-D-galactopyranose 12 from D-galactose,
as previouslyreported [36]. Azidoester 14 was obtained in two steps.
First, benzyl alcohol derivative f and bromoacetyl bromide were
reacted in dichloromethane containing 4-dimethylaminopyridine
(DMAP) and triethylamine to generate bromo ester 13. Next,
bromo ester 13 was subjected to nucleophilic substitution by using
2.2. Antiproliferative studies
The antiproliferative activity of the tested compounds were
expressed as the concentration that produced 50% cell growth
Table 1
Antiproliferative activity (GI50 in m
g mLꢀ1) and MG MID (Log GI50) of synthesized compounds against selected human cell lines.
Compounds
Cell lines
U251
MG MID
log GI50
MCF-7
NCI-ADR/RES
786-0
0.15
22.6
195.1
2.8
25.9
7.9
8.5
5.6
>250
NCI-H460
PC-3
OVCAR-03
HaCat
0.11
>250
115.1
4.2
29.2
4.0
41.7
5.3
4.9
12.7
25
29.4
21.4
DOX
10a
10b
10c
10d
10e
10f
10g
10h
10i
15
0.039
>250
20.7
3.4
8.4
9.8
18.2
3.1
8.7
25.2
25.1
24.3
26.5
0.038
25.0
11.7
6.2
28.0
3.1
21.3
2.9
9.6
0.54
>250
49.4
11.6
25.8
5.5
42.1
2.8
2.5
10.4
12.5
28.6
4.9
<0.025
24.6
34.4
11.2
11.7
10.4
23.7
7.4
3.8
24.7
20.1
3.6
8.4
5.0
6.6
2.8
8.2
16.8
26.7
16.2
2.9
0.43
24.7
23.1
8.1
27.2
24.5
63.5
11.4
8.0
24.3
39.1
<0.25
15.1
ꢀ0.8
1.8
1.6
0.7
1.3
0.9
1.3
0.7
1.0
1.3
1.5
1.0
1.2
7.9
12.7
27.8
2.6
25.0
69.4
30.8
26.1
28.6
44.3
30.1
29.2
16
17
27.2
GI50, Growth Inhibition 50%; MG MID, mean graph midpoint; DOX, doxorubicin. Human cancer cell lines: U251 (glioma, central nervous system), MCF-7 (breast), NCI-ADR/RES
(ovarian, multidrug resistant), 786-0 (kidney), NCI-H460 (lung, non-small cell), PC-3 (prostate), and OVCAR-03 (ovarian). Normal cell line: HaCat (human keratinocytes).

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L.B. de O. Freitas et al. / European Journal of Medicinal Chemistry 84 (2014) 595e604
inhibition or a cytostatic effect (GI50, m
g mLꢀ1) for each cell line
Table 3
Reference values of the rules of Lipinski and Veber.
(Table 1). Almost all of the compounds tested inhibited cell growth
in a dose-dependent manner (Supplementary data S1). A mean
graph midpoint (MG MID, mean of log GI50) value was also calcu-
lated for each compound. Among the synthesized 1,2,3-triazoles,
the best results were obtained for derivatives 10c, 10g, 10e, 10h,
and 16, each of which had MG MID GI50 values less than or equal to
1.0 (Table 1). Derivative 10c was as effective against PC-3 cells
Comp.
cLogP
MW
PSA
HBD
HBA
nRotB
Lipinskia
Veberb
ꢂ5
ꢂ500
e
ꢂ5
ꢂ10
e
e
e
ꢂ140
ꢂ10
a
Lipinski's Rule of 5 for pharmaceuticals.
b
Veber added more criteria to Lipinski's Rule of 5.
as doxorubicin (10c GI50
GI50 ¼ 3.8
g mLꢀ1). Derivative 10h showed the best inhibitory
effect against the NCI-ADR/RES cancer cell line (GI50 ¼ 2.5
g mLꢀ1).
Protected sugar derivative 16 had the lowest GI50 value against
OVCAR-03 cells (GI50 < 0.25
g mLꢀ1), indicating that it was even
g mLꢀ1).
¼
3.6
mg
mLꢀ1
;
doxorubicin
Table 4
Predicted physicochemical properties of compounds 10aei, 15, 16 and 17.
m
m
Comp.
cLogP
MW
PSA
HBD
HBA
nRotB
m
10a
10b
10c
10d
10e
10f
10g
10h
10i
15
4.79
3.81
4.37
4.53
4.70
3.88
5.80
5.24
3.67
4.37
2.94
3.92
470.3
362.4
378.9
423.3
428.4
380.4
447.7
457.8
344.4
372.5
496.6
438.4
49.55
49.55
49.55
49.55
58.78
49.55
49.55
49.55
49.55
49.55
95.70
75.85
0
0
0
0
0
0
0
0
0
0
0
0
5
6
5
5
9
7
5
5
5
7
7
7
7
9
7
7
7
7
more active than doxorubicin (OVCAR-03, GI50 ¼ 0.43
m
Although derivative 16 had high selectivity for ovarian cancer cell
lines, it showed weak antiproliferative activity against other cancer
cell lines and HaCat cells.
Given that 10c and 10g had the best MG MID log GI50 values
among the halogenated derivatives, these results suggested that
chlorinated substituents afforded better cytostatic activity. More-
over, the presence of one or three chlorine substituents resulted in
almost the same cytostatic effect (10c and 10 g MG MID GI50 ¼ 0.7).
The addition of an ester group between the triazole ring and benzyl
derivative (compound 17) improved the antiproliferative activity
against some cell lines (PC-3, NCI-ADR/RES, and OVCAR-3), because
it contributed to an increase in cytotoxic activity when compared to
10f. However, compounds 10f and 17, both showed weak cytotoxic
effects on average (10f MG MID GI50 ¼ 1.3; 17 MG MID GI50 ¼ 1.2).
The antiproliferative activity of compounds 10g and 17 against
5
10
9
9
11
10
16
17
cLogP: calculated lipophilicity; MW: molecular weight; PSA: polar surface area;
HBD: number of hydrogen bond donor; HBA: number of hydrogen bond acceptor;
nRotB: number of rotatable bounds.
associated with orally active drugs in humans and summarized
them in the “rule-of-five” [38]. Veber and co-workers later added
additional related criteria [39]. These parameters have been widely
used as a filter for new potential drugs. Therefore, a computational
study was performed to predict the physico-chemical parameters
of the synthesized compounds to verify if the substances could
fulfill Lipinski's rule-of-five (Tables 3 and 4). These parameters
were calculated using Molinspiration, free software that can be
used to predict properties of compounds [40]. The hydrogen-
bonding capacitydthe number of hydrogen bond acceptors
(HBA)dwas estimated based on the number of nitrogen and oxy-
gen atoms in the chemical structure. The number of hydrogen bond
donors (HBD) corresponds to the sum of hydrogen atoms bound to
oxygen or nitrogen atoms [38,41]. The polar surface area (PSA) was
also calculated because it is another important property that has
been used to predict drug bioavailability. Passively absorbed mol-
ecules with PSA values >140 are thought to have low oral
bioavailability [42]. The violation of more than one of these rules
may indicate problems in the bioavailability of a potential drug.
The results (Table 4) showed that all the compounds complied
with Lipinski's rules (Table 3), with the exception of compounds
10g and 10h, which had calculated lipophilicity (cLogP) values
slightly higher than what is ideal for orally active drugs (ꢂ5), and
compound 16, which had one additional rotatable bond (nRotB)
than what is ideal. Theoretically, compounds 10aef, 10i, 15, and 17
should show good passive absorption and, thus, their differences in
bioactivity cannot be attributed to this property [43].
prostate cell lines (PC-3, 10gGI50
GI50 ¼ 2.9
g mLꢀ1) was slightly better than that of doxorubicin
(PC-3, GI50 ¼ 3.8
g mLꢀ1). Other derivatives, such as those con-
¼
2.8
mg
mLꢀ1
;
17
m
m
taining bromide (10d, MG MID GI50 ¼ 1.3), a benzyl group (10i, MG
MID GI50 ¼ 1.3), pyridine (15, MG MID GI50 ¼ 1.5), fluorine (10b, MG
MID GI50 ¼ 1.6), or iodine (10a, MG MID GI50 ¼ 1.8), did not exhibit
significant activity.
The selectivity index (SI) was calculated for each compound
(Table 2). Derivative 16 showed the highest SI value, which indi-
cated the potential use of this compound for future in vivo tests.
To reach their target sites, bioactive compounds have to cross
several barriers. Their bioavailability depends upon several pa-
rameters such as solubility, membrane permeability, as well as
active uptake and transport within the organism [37]. Lipinski and
colleagues defined the properties and molecular features that are
Table 2
Selective index (SI) for each synthesized compound.
Compounds Cell lines
U251 MCF-7 NCI-ADR/ 786-0 NCI-
PC-3
OVCAR-03
RES
H460
10a
10b
10c
10d
10e
10f
10g
10h
10i
15
e
>10.0
9.8
0.7
1.0
1.3
1.9
1.8
0.5
1.0
e
>11.1 >10.2 >10.1
>10.1
5.0
0.5
1.1
0.2
0.7
0.5
0.6
0.5
0.6
5.6
1.2
3.5
0.4
2.3
1.7
0.6
0.5
1.0
1.2
0.8
2.3
0.4
1.1
0.7
1.0
1.9
2.0
1.2
2.0
1.0
4.4
0.6
1.5
1.1
0.5
4.9
0.9
3.3
0.4
2.5
0.4
1.8
0.7
0.6
0.4
0.6
1.0
0.7
5.7
1.2
3.5
0.8
6.3
1.9
0.6
0.8
0.9
Using structureeactivity relationship (SAR) studies, phys-
icalechemical parameters were calculated for each compound.
Multiple linear regression was used to model the relationship be-
tween the independent electronic and physicochemical descriptors
and GI50 values by fitting a linear equation to the observed data. The
calculated GI50 values were obtained using the following equation:
e
0.5
0.4
0.9
0.8
0.9
11.3
0.8
16
17
1.8 >117.6
7.4 1.4
N
X
Human cell lines: U251 (glioma, CNS), MCF-7 (breast), NCI-ADR/RES (ovarian
expressing phenotype multiple drugs resistance), 786-0 (kidney), NCI-H460 (lung,
non-small cells), PC-3 (prostate) and OVCAR-03 (ovarian).
pIG50
¼
CiPi
(1)
i¼1

L.B. de O. Freitas et al. / European Journal of Medicinal Chemistry 84 (2014) 595e604
599
where Ci is the coefficient obtained from the multivariable
regression and Pi is a physicochemical property.
shows the molecular orbitals for compound 10g, which showed
antiproliferative activity that was more potent than the reference
We have used cell lines for which experimental data have been
defined for all the studied compounds. Thus, the theoretical model
proposal included the same compounds for comparison. Based on
this criterion, cell lines MCF-7 and PC-3 were selected. For the MCF-
7 cancer cell line, the following equation was obtained using an R2
value of 0.42:
drug doxorubicin (PC-3, GI50 ¼ 3.8
m
g mLꢀ1).
Although the SAR results appeared to be promising, a deeper
understanding of these results required the application of other
molecular modeling techniques such as docking calculations.
Recently, Chinthala and co-workers [46] showed the association
between a-glucosidase inhibition and the anticancer activity pro-
files of 1,2,3-triazoles derivatives towards human cancer cell lines.
In fact, glycosidase inhibitors have been studied in the field of
cancer research as agents that are able to inhibit tumor cell invasion
and migration [47,48].
To gain further insight into the bioactivity of the compounds
and SAR results, we investigated the binding mode of 8-
GI50 ¼ ꢀ0:036ðdipoleÞ þ 52:093ðHOMOÞ þ 42:457ðHOMO ꢀ 1Þ
þ 3:799ðHOMO ꢀ 2Þ ꢀ 25:855ðHOMO ꢀ 3Þ
ꢀ 34:067ðLUMOÞ ꢀ 0:002ðLog PÞ þ 19:020
(2)
The R2 value suggested a poor correlation between biological
activity and physicochemical descriptors. Therefore, those de-
scriptors are not sufficient to explain the antiproliferative activity
against the MCF-7 cell line. However, for the PC-3 cell line, an R2
greater than 0.7 (R2 ¼ 0.86) was determined for the data [44],
indicating a high correlation. This suggested that antiproliferative
activity was linked to some electronic/physicochemical properties.
Equation (3) was established for all the studied compounds
(Table 1).
hydroxyquinoline derivatives to
docking calculations. Fig. 4 shows the interaction mode between
compound 10g and -glucosidase. Compound 10g was found to be
a-glucosidase by performing
a
more active than any other inhibitor. This result is in agreement
with the antiproliferative activity reported in Table 1. In fact,
compound 10g was found to hydrogen bond to Arg643 and Arg647
of
a-glucosidase, and its benzyl group participated in an anion-
p
interaction with
a
-glucosidase Glu767, as illustrated in Fig. 4.
In addition to the orbital energy values and hydrogen bond in-
formation determined using docking calculations, HOMOeLUMO
three-dimensional structures were also examined. The obtained
data showed that the HOMO structures of all the compounds were
located in the quinoline ring and, notably, the LUMO was located on
the triazole ring and benzyl group (Fig. 3). These data were ex-
pected because the HOMO was in the electron-rich portion,
whereas the LUMO was in electron-poor region. Therefore, it is
worth mentioning that the HOMO structure was located in the
same region in all of the compounds and showed a good correlation
for the cell line PC-3. This feature clearly showed a preference for
specific reaction sites. Our docking findings showed that the tri-
azole ring and benzyl group were oriented inside the active site and
interacted strongly with Arg647 and Glu767. Thus, the LUMO
structure of the inhibitor was directed to those amino acid residues,
while the quinoline ring was oriented to the protein surface. These
results suggest that the conformational preference of 8-
hydroxyquinoline derivatives containing 1,2,3-triazole moieties is
attributable to the interaction between the LUMO (from the in-
GI50 ¼ ꢀ0:153ðdipoleÞ þ 124:604ðHOMOÞ
ꢀ 108:748ðHOMO ꢀ 1Þ þ 39:584ðHOMO ꢀ 2Þ
ꢀ 22:526ðHOMO ꢀ 3Þ ꢀ 133:758ðLUMOÞ
ꢀ 0:217ðLog PÞ þ 6:120
(3)
It should be kept in mind that negative values represent higher
antiproliferative activity values. The frontier molecular orbi-
talsdhighest occupied and lowest unoccupied molecular orbitals
(HOMO and LUMO, respectively)dgreatly affected the potency of
the compounds (Eq. (3)). Thus, positive coefficients corresponded
to unfavorable biological activity values. In order words, these
properties decreased the potencies of the studied compounds. We
have calculated the HOMO and LUMO energy values in order to
investigate the effect of electronic parameters on the anti-
proliferative activity of each compound. The HOMO has the priority
to provide electrons, while the LUMO is the first to accept electrons.
According to the frontier molecular orbital theory, the HOMO and
LUMO are two important factors that affect the bioactivity of
compounds. A small difference between the HOMO and LUMO
energy values implies high reactivity in reactions, while a large
difference implies low reactivity [45]. In addition to the energy
difference between the HOMO and LUMO, the individual positions
of these orbitals affected the reactivity of the compounds. Fig. 3
hibitor) and HOMO (from a-glucosidase Glu767).
Fig. 3. Molecular orbital surfaces of compound 10g. (a) The highest occupied molec-
Fig. 4. Docked structure of compound 10g in the
a-glucosidase active site. The resi-
ular orbital and (b) lowest unoccupied molecular orbital.
dues shown are those involved in hydrogen bonding with the inhibitor.

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L.B. de O. Freitas et al. / European Journal of Medicinal Chemistry 84 (2014) 595e604
3. Conclusions
combined organic phases were dried over anhydrous sodium sul-
fate and removed by performing distillation. The remaining residue
was purified by column chromatography on silica gel using hex-
ane:ethyl acetate (7:3) to produce pure compound 7.
We have synthesized 12 novel 8-hydroxyquinoline derivatives
in good yields by using the click reaction, coupling an 8-O-alky-
lated-quinoline containing a terminal alkyne with an aromatic
group or protected sugar azide. In general, the compounds showed
favorable physico-chemical parameters that qualify these com-
pounds to be explored as anticancer agents. These molecules were
evaluated in vitro for their antiproliferative activity on various
cancer cell types. Among the halogenated derivatives, the chlori-
nated ones showed the best overall activity, with 10c and 10g both
showing the lowest MG MID GI50 value of 0.7. Our findings also
suggest the importance of the location of the frontier orbitals
(HOMO and LUMO) in the studied compounds for their activity
toward prostate cancer cells. The HOMO of all compounds is located
on the quinoline, while the LUMO is located on the triazole ring and
benzyl group (Fig. 3). Our docking calculation data reinforce that
Pale-yellow crystals; yield 88%; m.p. 69e71 ꢁC; IR (ATR): 3174
(^CeH), 2106 (C^C), 1262 and 1082 (CeO); 1H NMR (200 MHz,
CDCl3):
d
1.99 (1H, t, J ¼ 2.6 Hz, H-50), 2.24 (2H, qn, J ¼ 6.6 Hz, H-20),
2.51 (2H, td, J ¼ 6.6 and 2.6 Hz, H-30), 4.35 (2H, t, J ¼ 6.6 Hz, H-10),
7.09 (1H, dd, J ¼ 7.2 and 1.4 Hz, H-7), 7.35e7.49 (3H, m, H-3, H-5, H-
6), 8.11 (1H, dd, J ¼ 8.4 and 1.6 Hz, H-4), 8.95 (1H, dd, J ¼ 4.2 and
1.6 Hz, H-2); 13C NMR (50 MHz, CDCl3):
d
15.51 (C-30), 27.94 (C-20),
67.39 (C-10), 69.12 (C-50), 83.63 (C-40), 108.98 (C-7), 119.76 (C-5),
121.65 (C-3), 126.82 (C-6), 129.59 (C-10), 136.14 (C-4), 140.28 (C-9),
149.31 (C-2), 154.69 (C-8).
4.3. General procedure for the synthesis of benzyl mesylates (8aei)
the binding orientation of the inhibitors in the active site of
a
-
Each benzyl alcohol derivative (1.00 mmol) was combined with
glucosidase is likely governed by the interaction between the
HOMO and LUMO orbitals. Additional accurate theoretical calcu-
lations and experimental techniques are now in progress in order to
garner a deeper understanding of the antiproliferative activity of
this series of compounds. Protected sugar derivative 16 was the
most active against and highly selective for ovarian cancer cells
dichloromethane (5 mL) and triethylamine (280 mL, 2.01 mmol) in a
50-mL round-bottom flask. The mixture was cooled to ꢀ40 ꢁC, and
methanesulfonyl chloride (110 mL, 1.40 mmol) was added to the
mixture while being stirred vigorously. After 30 min at ꢀ40 ꢁC, the
reaction mixture was washed with a 1% HCl solution (3 ꢃ 10 mL)
and a saturated aqueous NaHCO3 solution (3 ꢃ 5 mL). The organic
layer was dried (Na2SO4), filtered and the solvent was removed in
vacuo to produce high yields (90e100%) of pure benzyl mesylates
8aei.
(OVCAR-03, GI50 < 0.25
these cells than doxorubicin (OVCAR-03, GI50 ¼ 0.43
m
g mLꢀ1), showing greater activity against
m
g mLꢀ1). The
high antiproliferative activity and selectivity of compound 16 has
driven efforts to synthesize other analogs containing sugar moi-
eties that can be further studied with respect to their anticancer
activity and mechanisms of action.
4.3.1. 4-Iodobenzyl methanesulfonate (8a)
Colorless oil; yield 90%; 1H NMR (200 MHz, CDCl3):
d 2.94 (3H, s,
CH3), 5.14 (2H, s, C-7), 7.13 (2H, d, J ¼ 8.4 Hz, H-2, H-6), 7.70 (2H, d,
4. Materials and methods
J ¼ 8.4 Hz, H-3, H-5); 13C NMR (50 MHz, CDCl3):
d 38.23 (CH3), 70.64
(C-7), 95.38 (C-4), 130.47 (C-2, C-6), 133.13 (C-1), 137.98 (C-3 and C-
5).
4.1. Reagents and equipment
Commercially available reagents were purchased from Sigma-
eAldrich and used without further purification. The solvents were
purified by distillation. The melting points were determined on a
Büchi apparatus and were uncorrected. Column chromatography
was performed on Silica Gel 60 (70e230 mesh, Merck). The prog-
ress of the reactions was monitored by thin-layer chromatography
using Merck silica plates (GF254). 1H and 13C NMR spectra were
recorded using a Bruker AVANCE DRX 200 MHz or 400 MHz
spectrometer by using tetramethylsilane as an internal standard.
4.4. General procedure for the synthesis of benzyl azides (9aei)
Benzyl mesylate (0.77 mmol), DMSO (5 mL), and sodium azide
(0.200 g, 3.08 mmol) were added to a 50-mL round-bottom flask.
The reaction mixture was stirred at room temperature for 15 h.
Dichloromethane (15 mL) was then added and the resulting
mixture was washed with brine (3 ꢃ 10 mL). The organic phase was
dried (Na2SO4) and distilled. This procedure produced good yields
(72e99%) of pure benzyl azides 9aei.
The results are presented as the chemical shift d in ppm, number of
protons, multiplicity, J values in Hertz, proton position, and carbon
position. Multiplicities are abbreviated as follows: s, singlet; brs,
broad signal; d, doublet; dd, double doublet; t, triplet; m, multiplet;
qn, quintet; and td, triple doublet. Infrared spectra were recorded
on a PerkineElmer Spectrum One SP-IR Spectrometer. The micro-
wave reactor used was a CEM Discover. High-resolution mass
spectra were recorded using an LC-MS Bruker Daltonics Micro
electrospray ionization-time-of-flight mass spectrometer (solvent:
MeOH/H2O, 1:1).
4.4.1. 1-(Azidomethyl)-4-iodobenzene (9a)
Colorless oil; yield 85%; IR (ATR): 2109 (N]Nþ]Nꢀ); 1H NMR
(200 MHz, CDCl3):
d
4.29 (2H, s, H-7), 7.07 (2H, d, J ¼ 8.4 Hz, H-2, H-
6), 7.72 (2H, d, J ¼ 8.4 Hz, H-3, H-5); 13C NMR (50 MHz, CDCl3):
d
54.16 (C-7), 94.08 (C-4), 130.02 (C-2, C-6), 135.07 (C-1), 137.94 (C-
3, C-5).
4.4.2. Synthesis of 3-(3-azidopropyl)pyridine (11)
3-Pyridine-propanol (0.400 g, 2.92 mmol) and HBr 47% (w/w
aq., 4 mL, 34.60 mmol) were added to a 50-mL round-bottom flask.
The mixture was irradiated with microwaves for 11 min at 80 ꢁC
(200 W, atmospheric pressure). After the reaction mixture was
cooled to room temperature, it was neutralized using a saturated
solution of NaHCO3. The resultant solution was extracted with
dichloromethane (3 ꢃ 15 mL). The organic layer was dried (Na2SO4)
and filtered, and the solvent was removed in vacuo to produce the
crude product (3-(3-bromopropyl)pyridine), a yellow oil. The crude
product was immediately subjected to nucleophilic substitution
with NaN3. A stock solution of NaN3 (0.5 mol/L) in DMSO was
prepared by stirring the solution for 24 h at 25 ꢁC. A portion of the
4.2. Synthesis
4.2.1. Synthesis of 8-(pent-4-ynyloxy)quinoline (7)
Diethyl ether (12 mL), 8-hydroxyquinoline (2.76 mmol), 4-
pentyn-1-ol methanesulfonate (3.30 mmol), and TBAB
(0.82 mmol) were added to a 50-mL round-bottom flask. To this
solution, 10 mL of an aqueous 50% NaOH (w/v) solution was added.
The reaction mixture was stirred for 48 h at room temperature.
After 48 h, 30 mL of water was added to the reaction mixture,
followed by extraction with dichloromethane (3 ꢃ 25 mL). The

L.B. de O. Freitas et al. / European Journal of Medicinal Chemistry 84 (2014) 595e604
601
NaN3 solution (8 mL, containing 4.00 mmol of NaN3) and 3-(3-
bromopropyl)pyridine (0.525 mg, 2.62 mmol) were added to a
50-mL round-bottom flask equipped with a magnetic stir bar. The
mixture was stirred for 24 h at room temperature. After the reac-
tion was complete, 3 mL of cold water was added, and the mixture
was stirred for 5 min. The reaction was then quenched using H2O
(50 mL) and stirred for an additional 5 min. Next, the mixture was
extracted with dichloromethane (3 ꢃ 30 mL), and the resultant
combined organic extracts were washed with H2O (2 ꢃ 50 mL) and
brine (3 ꢃ 50 mL). The organic layer was dried (Na2SO4) and
filtered, and the solvent was removed in vacuo to produce pure 3-
(3-azidopropyl)pyridine 11.
water was added to the reaction mixture, followed by extraction
with CH2Cl2 (3 ꢃ 8 mL). The organic layer was dried (Na2SO4),
filtered, and then removed under reduced pressure to produce the
crude product. The crude product was purified by column chro-
matography on silica gel using EtOAc, and eluted using EtOAc:-
MeOH (9:1e8:2) to obtain pure compounds 10aei, 15, 16, and 17.
4.5.1. 8-(3-(1-(4-Iodobenzyl)-1H-1,2,3-triazol-4-yl)propoxy)
quinoline (10a)
Yellow-white solid; m.p. 108e109 ꢁC; yield 86%; IR (ATR): 1108
(CeO); 1H NMR (200 MHz, CDCl3):
d
2.32e2.42 (2H, m, H-20), 3.01
(2H, t, J ¼ 7.4 Hz, H-30), 4.28 (2H, t, J ¼ 7.4 Hz, H-10), 5.40 (2H, s, H-
100), 6.94 (2H, d, J ¼ 8.3 Hz, H-300, H-700), 7.04 (1H, dd, J ¼ 7.0 and
2.2 Hz, H-7), 7.37e7.48 (4H, m, H-3, H-5, H-6, H-50), 7.65 (2H, d,
J ¼ 8.3 Hz, H-400, H-600), 8.15 (1H, dd, J ¼ 8.2 and 1.4 Hz, H-4),
Colorless oil; yield 64%; 1H NMR (200 MHz, CDCl3):
d 1.89 (2H,
qn, J ¼ 7.4 Hz, H-8), 2.70 (2H, t, J ¼ 7.4 Hz, H-7), 3.30 (2H, t,
J ¼ 7.4 Hz, H-9), 7.19e7.25 (1H, m, H-5), 7.50 (1H, d, J ¼ 7.8 Hz, H-4),
8.45 (2H, s, H-2, H-6); 13C NMR (50 MHz, CDCl3):
d 30.04 (C-7 or C-
8.91e8.93 (1H, m, H-2); 13C NMR (50 MHz, CDCl3):
d
22.50 (C-30),
28.59 (C-20), 53.53 (C-100), 68.06 (C-10), 94.52 (C-500), 109.12 (C-7),
119.77 (C-5), 121.47 (C-3, C-50), 127.01 (C-6), 129.84 (C-10, C-300, C-
700), 134.71 (C-200), 136.42 (C-4), 138.29 (C-400, C-600), 140.12 (C-9),
148.05 (C-40), 149.20 (C-2), 154.62 (C-8); HRMS (ESI) m/z: [MþH]þ
calcd for C21H19IN4O, 471.0681; found, 471.0676.
8), 30.26 (C-8 or C-7), 50.56 (C-9), 123.61 (C-5), 136.15 (C-3, C-4),
147.69 (C-6), 149.86 (C-2).
4.4.3. Synthesis of 3,4-difluorobenzyl 2-bromoacetate (13)
(3,4-Difluorophenyl)methanol (1.39 mmol), DMAP(0.139mmol),
triethylamine (195
were combined in a 15-mL round-bottom flask. Before the addition
of bromoacetyl bromide (120 L, 1.39 mmol), the reaction mixture
mL, 1.39 mmol), and dichloromethane (2 mL)
4.5.2. 8-(3-(1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)propoxy)
quinoline (10b)
m
was cooled to 0 ꢁC while being stirred vigorously. The mixture was
maintained at 0 ꢁC for 20 min, followed by 30 min at room tem-
perature. Next, 5 mL of cold water was added to the reaction mixture
and it was then extracted with dichloromethane (3 ꢃ 8 mL). The
organic layer was dried (Na2SO4), filtered, and the solvent was
removed in vacuo to produce the crude product. The crude product
was purified by column chromatography on silica gel using hex-
ane:ethyl acetate (8:2) to obtain pure compound 13.
Yellow solid; yield 86%; m.p. 81-73 ꢁC; IR (ATR): 1221 (CeF),
1260 and 1103 (CeO); 1H NMR (400 MHz, CDCl3):
d 2.34 (2H, brs, H-
20), 2.95 (2H, brs, H-30), 4.23 (2H, brs, H-10), 5.36 (2H, s, H-100),
6.89e6.98 (3H, m, H-7, H-400, H-600), 7.10e7.16 (2H, m, H-300, H-700),
7.30e7.35 (4H, m, H-3, H-5, H-6, H-50), 8.06 (1H, sl, H-4), 8.86 (1H,
sl, H-2); 13C NMR (50 MHz, CDCl3): 22.28 (C-30), 28.37 (C-20), 53.11
d
(C-100), 67.86 (C-10), 108.80 (C-7), 115.89 (d, J ¼ 21.6 Hz, C-400, C-600),
119.71 (C-5), 121.16 (C-3, C-50), 126.74 (C-6), 129.72 (d, J ¼ 8.2 Hz, C-
300, C-700, C-10), 130.77 (d, J ¼ 2.8 Hz, C-200), 135.86 (C-4), 140.32 (C-
9), 147.76 (C-40), 149.09 (C-2), 154.63 (C-8), 162.62 (d, J ¼ 246.3 Hz,
C-500); HRMS (ESI) m/z: [MþH]þ calcd for C21H19FN4O, 363.1621;
found, 363.1616.
Pale yellow oil; yield 99%; IR (ATR): 1738 (C]O), 1277 (CeF); 1H
NMR (200 MHz, CDCl3):
d
3.88 (2H, s, H-20), 5.14 (2H, s, H-1),
7.11e7.27 (3H, m, H-3, H-6, H-7); 13C NMR (50 MHz, CDCl3):
d 25.67
(C-20), 66.65 (C-1), 117.66 (d, J ¼ 17.0 Hz, C-3, C-6), 124.77 (d,
J ¼ 3.5 Hz, H-7), 132.21 (d, J ¼ 4.6 Hz, C-2), 148.10e153.17 (m, C-4, C-
5), 167.06 (C-10).
4.5.3. 8-(3-(1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)propoxy)
quinoline (10c)
4.4.4. Synthesis of 3,4-difluorobenzyl 2-azidoacetate (14)
Yellow wax; yield 81%; IR (ATR): 1260 and 1105 (CeO); 1H NMR
3,4-Difluorobenzyl 2-bromoacetate (13) (1.51 mmol), sodium
azide (4.53 mmol), and DMSO (3 mL) were added to a 15-mL round-
bottom flask. The reaction mixture was stirred at room temperature
for 24 h. Dichloromethane (15 mL) was added and the resulting
mixture was washed with brine (3 ꢃ 10 mL). The organic layer was
dried (Na2SO4), filtered, and concentrated under reduced pressure
to produce the crude product. The crude product was purified by
column chromatography on silica gel using hexane:ethyl acetate
(1:1) to obtain pure compound 14.
(400 MHz, CDCl3):
d
2.39 (2H, brs, H-20), 3.01 (2H, t, J ¼ 6.8 Hz, H-30),
4.28 (2H, brs, H-10), 5.42 (2H, s, H-100), 7.03e7.05 (1H, m, H-7),
7.12e7.14 (2H, m, H-300, H-700), 7.27e7.29 (2H, m, H-400, H-600),
7.36e7.44 (4H, m, H-3, H-5, H-6, H-50), 8.13 (1H, d, J ¼ 6.0 Hz, H-4),
8.91 (1H, brs, H-2); 13C NMR (50 MHz, CDCl3):
d
22.46 (C-30), 28.52
(C-20), 53.31 (C-100), 68.05 (C-10), 109.04 (C-7), 119.77 (C-5), 121.37
(C-3 or C-50), 121.66 (C-3 or C-50), 126.90 (C-6), 129.31 and 129.59
(C-10, C-300, C-400, C-600, C-700),133.54 (C-500), 134.68 (C-200), 136.14 (C-
4),140.37 (C-9),147.99 (C-40), 149.24 (C-2),154.70 (C-8); HRMS (ESI)
m/z: [MþH]þ calcd for C21H19ClN4O, 379.1326 (35Cl), 381.1296
Pale yellow oil; yield 80%; IR (ATR): 2105 (N]Nþ]Nꢀ), 1746
(C]O), 1288 (CeF); 1H NMR (200 MHz, CDCl3): 3.92 (2H, s, H-20),
d
(
37Cl); found, 379.1332 (35Cl), 381.1315 (37Cl).
5.17 (2H, s, H-1), 7.11e7.25 (3H, m, H-3, H-6, H-7); 13C NMR
(50 MHz, CDCl3):
50.37 (C-20), 66.23 (C-1), 117.49e117.92 (m, C-3,
d
C-6), 124.81e125,00 (m, C-7), 132.01e132.20 (m, C-2),
147.72e153.31 (m, C-4, C-5), 168.20 (C-10).
4.5.4. 8-(3-(1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)propoxy)
quinoline (10d)
Yellow oil; yield 85%; IR (ATR): 1260 and 1105 (CeO); 1H NMR
4.5. General procedure for the synthesis of compounds (10aei, 15,
16 and 17)
(400 MHz, CDCl3):
d
2.38 (2H, qn, J ¼ 6.8 Hz, H-20), 3.01 (2H, t,
J ¼ 6.8 Hz, H-30), 4.28 (2H, t, J ¼ 6.8 Hz, H-10), 5.41 (2H, s, H-100),
7.03e7.08 (3H, m, H-7, H-300, H-700), 7.29e7.44 (6H, m, H-3, H-5, H-6,
H-50, H-400, H-600), 8.14 (1H, d, J ¼ 8.0 Hz, H-4), 8.92 (1H, brs, H-2);
Each of the azide compounds (9aei, 11, 12, or 14) (1.00 equiv.)
and 8-(pent-4-ynyloxy)quinoline (7) (1.00 equiv.) were dissolved in
CH2Cl2. To this solution, a freshly prepared solution of CuSO4$5H2O
(0.08 equiv.) and sodium ascorbate (0.20 equiv.) in H2O was added
while being stirred vigorously. The reaction mixture was stirred for
2 h at room temperature. After the reaction was complete, 5 mL of
13C NMR (50 MHz, CDCl3): 22.45 (C-30), 28.55 (C-20), 53.35 (C-100),
d
68.06 (C-10), 109.15 (C-7), 119.74 (C-5), 121.44 (C-3 or C-50), 121.66
(C-3 or C-50), 122.79 (C-500), 126.98 (C-6), 129.62 (C-10, C-300, C-700),
132.26 (C-400, C-600), 134.06 (C-200), 136.39 (C-4), 140.04 (C-9), 147.98
(C-40), 149.09 (C-2), 154.56 (C-8); HRMS (ESI) m/z: [MþH]þ calcd for

602
L.B. de O. Freitas et al. / European Journal of Medicinal Chemistry 84 (2014) 595e604
C21H19BrN4O, 423.0821 (79Br), 425.0800 (81Br); found, 423.0820
79Br), 425.0806 (81Br).
459.0410 (81Br or 37Cl), 461.0381 (81Br and 37Cl); found, 457.0428
(
79Br and 35Cl), 459.0408 (81Br or 37Cl), 461.0382 (81Br and 37Cl).
(
4.5.5. 8-(3-(1-(4-(Trifluoromethoxy)benzyl)-1H-1,2,3-triazol-4-yl)
propoxy)quinoline (10e)
4.5.9. 8-(3-(1-Benzyl-1H-1,2,3-triazol-4-yl)propoxy)quinoline (10i)
Yellow solid; yield 92%; m.p. 63e65 ꢁC; IR (ATR): 1258 and 1105
White solid; yield 72%; m.p. 104e105 ꢁC; IR (ATR): 1263 (CeF),
(CeO); 1H NMR (200 MHz, CDCl3):
d
2.34e2.40 (2H, m, H-20), 2.98
1263 and 1107 (CeO); 1H NMR (200 MHz, CDCl3):
d 2.33 (2H, qn,
(2H, t, J ¼ 6.4 Hz, H-30), 4.26 (2H, t, J ¼ 6.4 Hz, H-10), 5.43 (2H, s, H-
100), 6.99e7.04 (1H, m, H-7), 7.16e7.24 (2H, m, H-300, H-700),
7.28e7.43 (7H, m, H-3, H-5, H-6, H-50, H-400, H-500, H-600), 8.09 (1H, d,
J ¼ 8.0 Hz, H-4), 8.90 (1H, brs, H-2); 13C NMR (50 MHz, CDCl3):
J ¼ 6.8 Hz, H-20), 2.95 (2H, t, J ¼ 6.8 Hz, H-30), 4.22 (2H, t, J ¼ 6.8 Hz,
H-10), 5.39 (2H, s, H-100), 6.95e6.98 (1H, m, H-7), 7.07e7.19 (4H, m,
H-300, H-400, H-600, H-700), 7.27e7.39 (4H, m, H-3, H-5, H-6, H-50), 8.03
(1H, d, J ¼ 8.2 Hz, H-4), 8.85 (1H, brs, H-2); 13C NMR (50 MHz,
d
22.19 (C-30), 28.34 (C-20), 53.75 (C-100), 67.79 (C-10), 108.80 (C-7),
CDCl3): d
22.35 (C-30), 28.38 (C-20), 52.98 (C-100), 67.88 (C-10), 108.85
119.47 (C-5), 121.17 (C-3, C-50), 126.69 (C-6, C-500), 127.72 (C-300, C-
700), 128.37 and 128.83 (C-10, C-400, C-600), 134.79 (C-200), 135.96 (C-
4),139.90 (C-9),147.47 (C-40),148.83 (C-2),154.39 (C-8); HRMS (ESI)
m/z: [MþH]þ calcd for C21H20N4O, 345.1715; found, 345.1711.
(C-7), 119.60 (C-5), 120.33 (q, J ¼ 255.7 Hz, CF3), 121.36 and 121.51
(C-3, C-50, C-400, C-600), 126.70 (C-6), 129.30 (C-10, C-300, C-700), 133.69
(C-200), 135.95 (C-4), 140.21 (C-9), 147.86 (C-40), 149.14 (C-2, C-500),
154.54 (C-8); HRMS (ESI) m/z: [MþH]þ calcd for C22H19F3N4O2,
429.1538; found, 429.1534.
4.5.10. 8-(3-(1-(3-(Pyridin-3-yl)propyl)-1H-1,2,3-triazol-4-yl)
propoxy)quinoline (15)
4.5.6. 8-(3-(1-(3,4-Difluorobenzyl)-1H-1,2,3-triazol-4-yl)propoxy)
quinoline (10f)
Yellow solid; yield 67%; m.p. 82e83 ꢁC; IR (ATR): 1261 and 1105
(CeO); 1H NMR (200 MHz, CDCl3):
d
2.19 (2H, qn, J ¼ 7.0 Hz, H-20),
Beige solid; yield 89%; m.p. 90e91 ꢁC; IR (ATR): 1210 (CeF), 1259
2.42 (2H, qn, J ¼ 7.0 Hz, H-200), 2.69 (2H, t, J ¼ 7.0 Hz, H-30), 3.04 (2H,
t, J ¼ 7.0 Hz, H-300), 4.32 (4H, t, J ¼ 7.0 Hz, H-10, H-100), 7.07 (1H, dd,
J ¼ 7.2 and 1.8 Hz, H-7), 7.26e7.51 (6H, m, H-3, H-5, H-6, H-50, H-800,
H-900), 8.12e8.16 (1H, m, H-4), 8.56 (2H, ls, H-500, H-700), 8.95 (1H, ls,
and 1103 (CeO); 1H NMR (400 MHz, CDCl3):
d 2.40 (2H, qn,
J ¼ 7.2 Hz, H-20), 3.02 (2H, t, J ¼ 7.2 Hz, H-30), 4.29 (2H, t, J ¼ 7.2 Hz,
H-10), 5.41 (2H, s, H-100), 6.93e6.95 (1H, m, H-7), 7.02e7.11 (3H, m,
H-300, H-600, H-700), 7.37e7.45 (4H, m, H-3, H-5, H-6, H-50), 8.14 (1H,
d, J ¼ 8.4 Hz, H-4), 8.93 (1H, brs, H-2); 13C NMR (50 MHz, CDCl3):
H-2); 13C NMR (50 MHz, CDCl3):
d
22.44 (C-30), 28.56 (C-20), 29.79
(C-200), 31.42 (C-300), 49.21 (C-100), 68.05 (C-10), 108.98 (C-7), 119.69
(C-5), 121.37 (C-3, C-50), 126.86 (C-6, C-800), 129.60 (C-10), 135.96
and 136.14 (C-4, C-400, C-900), 140.21 (C-9), 147.47 (C-40, C-700), 149.66
(C-2, C-500), 154.61 (C-8); HRMS (ESI) m/z: [MþH]þ calcd for
d
22.01 (C-30), 28.16 (C-20), 52.33 (C-100), 67.52 (C-10), 108.59 (C-7),
116.65 (d, J ¼ 17.8 Hz, C-300),117.46 (d, J ¼ 17.4 Hz, C-600),119.33 (C-5),
121.27 (C-3, C-50), 123.78 (dd, J ¼ 6.2 and 3.6 Hz, C-700), 126.47 (C-6),
129.14 (C-10), 131.42e131.60 (m, C-200), 135.74 (C-4), 139.79 (C-9),
147.55 (C-40),148.75 (C-2),147.36e152.48 (m, C-400 and C-500),154.19
(C-8); HRMS (ESI) m/z: [MþH]þ calcd for C21H18F2N4O, 381.1527;
found, 381.1522.
C22H23N5O, 374.1981; found, 374.1983.
4.5.11. 8-(3-(1-1,2:3,4-di-O-isopropylidene-6-a-D-galactopyranosyl-
1H-1,2,3-triazol-4-yl) propoxy)quinoline (16)
White solid; yield 72%; m.p. 123e124 ꢁC; IR (ATR): 1255, 1103
4.5.7. 8-(3-(1-(2,4,6-Trichlorobenzyl)-1H-1,2,3-triazol-4-yl)propoxy)
quinoline (10g)
and 1078 (CeO); 1H NMR (200 MHz, CDCl3):
d 1.28, 1.34, 1.37 and
1.49 (s, 12H, 4ꢃ CH3), 2.39e2.46 (2H, m, H-20), 3.02 (2H, t, J ¼ 7.2 Hz,
H-30), 4.15e4.18 (2H, m, H-400, H-500), 4.27e4.36 (3H, m, H-10, H-200),
4.45 (1H, d, J ¼ 8.0 Hz, H-600), 4.55e4.64 (2H, m, H-300, H-600), 5.49
(1H, d, J ¼ 4.8 Hz, H-100), 7.07 (1H, dd, J ¼ 7.2 and 1.6 Hz, H-7),
7.38e7.44 (3H, m, H-3, H-5, H-6), 7.57 (1H, s, H-50), 8.12 (1H, dd,
J ¼ 4.2 and 1.6 Hz, H-4), 8.95 (1H, dd, J ¼ 8.2 and 1.6 Hz, H-2); 13C
Greenewhite solid; yield 73%; m.p. 86e88 ꢁC; IR (ATR): 1073
(CeCl), 1260 and 1106 (CeO); 1H NMR (200 MHz, CDCl3):
d
2.28e2.35 (2H, m, H-20), 2.93 (2H, t, J ¼ 6.4 Hz, H-30), 4.18 (2H, t,
J ¼ 6.4 Hz, H-10), 5.63 (2H, s, H-100), 6.93e6.96 (1H, m, H-7),
7.25e7.34 (6H, m, H-3, H-5, H-6, H-50, H-400, H-600), 8.04 (1H, d,
J ¼ 8.0 Hz, H-4), 8.85 (1H, brs, H-2); 13C NMR (50 MHz, CDCl3):
22.05 (C-30), 28.25 (C-20), 48.20 (C-100), 67.60 (C-10), 108.74 (C-7),
NMR (50 MHz, CDCl3):
d
22.46 (C-30), 24.50, 24.97, 26.02 and 26.07
d
(4ꢃ CH3), 28.66 (C-20), 50.41 (C-600), 67.37 (C-500), 68.09 (C-10), 70.41,
70.82 and 71.23 (C-200, C-300, C-400), 96.31 (C-100), 108.96 (C-7), 109.09
and 109.89 (2ꢃ C(CH3)2), 119.63 (C-5), 121.61 (C-3), 122.53 (C-50),
126.80 (C-6), 129.57 (C-10), 135.98 (C-4), 140.49 (C-9), 147.00 (C-40),
149.37 (C-2), 154.83 (C-8); HRMS (ESI) m/z: [MþH]þ calcd for
119.46 (C-5), 121.40 (C-3, C-50), 126.61 (C-6), 128.65 (C-400, C-600),
128.83 (C-500 or C-10), 129.32 (C-10 or C-500), 135.86 (C-200, C-4),
137.02 (C-300, C-700), 140.12 (C-9), 147.00 (C-40), 149.09 (C-2), 154.46
(C-8); HRMS (ESI) m/z: [MþH]þ calcd for C21H17Cl3N4O, 447.0546
(3ꢃ 35Cl), 449.0517 (2ꢃ 35Cl þ 1ꢃ 37Cl), 451.0487 (2ꢃ 37Cl þ 1ꢃ
35Cl); found, 447.0541 (3ꢃ 35Cl), 449.0509 (2ꢃ 35Cl þ 1ꢃ 37Cl),
451.0499 (2ꢃ 37Cl þ 1ꢃ 35Cl).
C26H32N4O6, 497.2400; found, 497.2398.
4.5.12. 3,4-Difluorobenzyl 2-(4-(3-(quinolin-8-yloxy)propyl)-1H-
1,2,3-triazol-1-yl)acetate (17)
4.5.8. 8-(3-(1-(5-Bromo-2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)
propoxy)quinoline (10h)
White solid; yield 80%; m.p. 104e105 ꢁC; IR (ATR): 1754 (C]O),
Yellow oil; yield 94%; IR (ATR): 1259 and 1105 (CeO); 1H NMR
1261 and 1108 (CeO); 1H NMR (200 MHz, CDCl3):
d 2.37e2.44 (2H,
(200 MHz, CDCl3):
d
2.42 (2H, qn, J ¼ 6.8 Hz, H-20), 3.05 (2H, t,
m, H-20), 3.02 (2H, t, J ¼ 6.8 Hz, H-30), 4.30 (2H, t, J ¼ 6.8 Hz, H-10),
5.09 (2H, s, H-60), 5.17 (2H, s, H-100), 7.03e7.16 (4H, m, H-7, H-300, H-
600, H-700), 7.39e7.61 (3H, m, H-3, H-5, H-6), 7.61 (1H, s, H-50),
8.09e8.13 (1H, m, H-4), 8.91 (1H, brs, H-2); 13C NMR (50 MHz,
J ¼ 6.8 Hz, H-30), 4.30 (2H, t, J ¼ 6.8 Hz, H-10), 5.55 (2H, s, H-100),
7.04e7.07 (1H, m, H-7), 7.20e7.29 (2H, m, H-500, H-600), 7.36e7.49
(4H, m, H-3, H-5, H-6, H-50), 7.49 (1H, s, H-300), 8.14 (1H, d,
J ¼ 8.2 Hz, H-4), 8.93 (1H, brs, H-2); 13C NMR (50 MHz, CDCl3):
CDCl3):
d
22.41 (C-30), 28.44 (C-20), 50.68 (C-60), 66.41 (C-100), 67.99
d
22.48 (C-30), 28.54 (C-20), 50.83 (C-100), 68.02 (C-10), 109.09 (C-7),
(C-10), 108.99 (C-7), 117.59 (d, J ¼ 17.4 Hz, C-300, C-600), 119.65 (C-5),
121.57 (C-3), 122.82 (C-50), 124.76 (dd, J ¼ 6.0 and 3.9 Hz, C-700),
126.82 (C-6), 129.52 (C-10), 131.53e131.72 (m, C-200), 136.09 (C-4),
140.19 (C-9), 147.80 (C-40) 147.56e152.88 (m, C-400, C-500), 149.12 (C-
2), 154.57 (C-8), 166.26 (C-70); HRMS (ESI) m/z: [MþH]þ calcd for
119.72 (C-5), 121.22 (C-3 or C-50), 121.67 (C-3 or C-50), 121.89 (C-400),
126.99 (C-6), 129.62 (C-10), 131.28 (C-500), 132.24 (C-700), 132.84 (C-
300 or C-600), 133.15 (C-300 or C-600), 134.78 (C-200), 136.34 (C-4), 140.08
(C-9), 147.95 (C-40), 149.15 (C-2), 154.57 (C-8); HRMS (ESI) m/z:
[MþH]þ calcd for C21H18BrClN4O, 457.0431
(
79Br and 35Cl),
C23H20F2N4O3, 439.1582; found, 439.1584.

L.B. de O. Freitas et al. / European Journal of Medicinal Chemistry 84 (2014) 595e604
603
4.6. Antiproliferative assay
basis set DN*. The final structures were again optimized until a
gradient of 10ꢀ8 kcal molꢀ1 Åꢀ1 was obtained. No imaginary fre-
quencies were found for the optimized geometries. These opti-
mized geometries were used in all subsequent calculations. MP2
single-point energy calculations were computed using the 6-
311G(d,p) basis set. The orbital energies from these methods were
fitted to a linear model with experimental antiproliferative activity
values. The determination coefficients and other statistical pa-
rameters were analyzed using the Molegro Virtual Docker (MVD)
[53]. The molecular obritals figures were generated by the Gaussian
View 2.1 package72 using a contour value of 0.020. In order to
clarify the binding mode between ligand and enzyme, docking
calculations were performed for the studied compounds in the
The obtained 1,2,3-triazoles were each evaluated for their
in vitro antiproliferative activity against HaCat cells (human kera-
tinocytes), a normal human normal cell line, as well as seven hu-
man cancer cell lines: U251 (glioma, CNS), MCF-7 (breast), NCI-
ADR/RES (ovarian, multidrug resistant), 786-0 (kidney), NCI-H460
(lung, non-small cell), PC-3 (prostate), and OVCAR-03 (ovarian).
The cancer cell lines were kindly provided by the United States
National Cancer Institute (Frederick, MA, USA), while the HaCat cell
line was kindly donated by Dr. Ricardo Della Coletta (FOP, UNI-
CAMP). Stock cultures were grown in 5 mL of RPMI-1640 (Gibco
BRL) supplemented with 5% fetal bovine serum (Gibco BRL). A
penicillin (1000 U mLꢀ1):streptomycin (1000
(1 mL Lꢀ1 RPMI) was added to the experimental cultures.
Cells were placed in 96-well plates (100 L cells/well) and were
exposed to different concentrations of compounds 10aei, 15, 16,
and 17 (0.25, 2.5, 25, and 250
g mLꢀ1) in DMSO/RPMI (0.1% v/v) at
m
g mLꢀ1) mixture
active site of
was obtained from the Protein Data Bank (PDB code: 3L4Y) [54].
The docking calculation of the ligands inside -glucosidase active
a-glucosidase. The crystal structure of a-glucosidase
m
a
site was performed using MVD software [53]. This program is able
to predict the most likely conformation by which a given ligand will
bind to a macromolecule.
m
37 ꢁC and 5% CO2 for 48 h. The final DMSO concentration did not
affect cell viability. Next, the cells were fixed with aqueous solution
of trichloroacetic acid (50%, v/v) and cell proliferation was
measured by performing spectrometry (540 nm) on the cellular
protein content using a sulforhodamine B assay [45]. All experi-
ments were performed in triplicate. Doxorubicin (0.025e
Conflict of interest
The authors have declared no conflict of interest.
25 m
g mLꢀ1) was used as a positive control. Measurements were
Acknowledgments
obtained at three time points for both the compound-free (C) and
the tested (T) cells: time zero (To), the beginning of incubation, and
48 h post-incubation. Cell proliferation was calculated according to
the equation: 100 ꢃ [(T ꢀ To)/C ꢀ To]. A cytostatic effect was
observed when T ꢄ To, whereas a cytocidal effect occurred when
T < To. Based on the concentrationeresponse curve for each cell
line, a GI50 value (the concentration that caused 50% cell growth
inhibition or a cytostatic effect) was determined by non-linear
regression analysis using Origin 8.0® software (OriginLab Corpo-
ration). Furthermore, a mean graph midpoint (MG MID, mean of log
GI50) was calculated for the GI50 values obtained for each sample,
using MS Excel software. MG MID displays an averaged activity
parameter over all cell lines. The selectivity index (SI) was deter-
mined according to the equation: IS ¼ HaCat cell GI50/cancer cell
GI50. SI values greater than two were considered significant [49,50].
This research was supported by grants from CNPq (Conselho
ꢀ
Nacional de Desenvolvimento Científico e Tecnologico), CAPES
~
(Coordenaçao de Aperfeiçoamento de Pessoal de Nível Superior),
~
ꢁ
FAPEMIG (Fundaçao de Amparo a Pesquisa do estado de Minas
ꢀ
Gerais) and PRPq (Pro-Reitoria de Pesquisa da Universidade Federal
de Minas Gerais).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.07.061.
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