Synthesis and antiplasmodial evaluation of novel (4-aminobutyloxy) quinolines

Article abstract of DOI:10.1016/j.bmcl.2012.10.094

A variety of 5-, 6- and 8-(4-aminobutyloxy)quinolines as novel oxygen analogues of known 4- and 8-(4-aminobutylamino)quinoline antimalarial drugs was generated from hydroxyquinolines through a three-step approach with a rhodium-catalyzed hydroformylation

Full text of DOI:10.1016/j.bmcl.2012.10.094

Bioorganic & Medicinal Chemistry Letters xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antiplasmodial evaluation of novel (4-aminobutyloxy)quinolines
Stéphanie Vandekerckhove a, Christian Müller b, , Dieter Vogt b, Carmen Lategan c, Peter J. Smith c,
a,
Kelly Chibale d, Norbert De Kimpe a, , Matthias D’hooghe
⇑
⇑
a Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
b Department of Chemical Engineering and Chemistry, Laboratory for Homogeneous Catalysis and Coordination Chemistry, Eindhoven University of Technology, 5600 MB
Eindhoven, The Netherlands
c Medical School, University of Cape Town, K45, OMB Groote Schuur Hospital, Observatory 7925, South Africa
d Department of Chemistry and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of 5-, 6- and 8-(4-aminobutyloxy)quinolines as novel oxygen analogues of known 4- and
8-(4-aminobutylamino)quinoline antimalarial drugs was generated from hydroxyquinolines through a
three-step approach with a rhodium-catalyzed hydroformylation as the key step. Antiplasmodial assays
of these new quinolines revealed micromolar potency for all representatives against a chloroquine-
sensitive strain of Plasmodium falciparum, and three compounds showed submicromolar activity against
a chloroquine-resistant strain of P. falciparum with IC50-values ranging between 150 and 680 nM.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 12 September 2012
Revised 19 October 2012
Accepted 22 October 2012
Available online xxxx
Keywords:
Quinolines
Antimalarial agents
Rh-catalyzed hydroformylation
Reductive amination
Malaria remains a major issue in health control, mostly among
African children and pregnant women, with 216 million clinical
cases and roughly 655,000 deaths worldwide in 2010.1 Quinoline
compounds, and especially the potent, inexpensive chloroquine 1
(Fig. 1), have a long history in the treatment of malaria.2,3 However,
the spread of chloroquine resistance within Plasmodium falciparum
strains has complicated medicinal treatment of malaria in the af-
fected areas. Despite the promising progress regarding the devel-
opment of live sporozoite-based vaccines4,5 and new compounds
with antimalarial activity,6 there is still an urgent need for new
antimalarial agents active against drug-resistant malaria strains.
Many important antimalarial drugs comprise a quinoline system
as the core unit, and systematic synthetic modifications of these
structures have led to a variety of antimalarial drugs and lead can-
didates with diverse substitutions around the quinoline ring.7–10
Literature reports on chloroquine analogues reveal that replace-
ment of the nitrogen atom at the 4-position of the quinoline ring
by oxygen or sulfur results in compounds with lower antimalarial
potency.9 This introduction of oxygen or sulfur was suggested to
cause a significant reduction of the quinolyl nitrogen’s basicity,
inflicting the 4-O and 4-S analogues to be monoprotic weak bases
compared to the diprotic weak basic 4-aminoquinoline derivatives.
In spite of the lower antimalarial potency of these compounds, an
improved resistance index (RI) was observed.8,9 Since the rise of
chloroquine resistance, novel drug design has been focused on di-
verse substitutions around the quinoline ring, but especially the
potency of 4-substituted (amino)quinolines has been unraveled
extensively.8–13 Other, but far less thorough studies have been per-
formed concerning the synthesis and antimalarial evaluation of 8-
substituted quinolines,6,14,15 although the elaboration of this class
has mainly been focused on the derivatization of known 8-amino-
quinoline antimalarial drugs such as pamaquine 2 and primaquine
3 (Fig. 1).14–17
In both cases the modification of the quinoline side chain has
been well examined,10,12,13,18–22 however, substitution of the ami-
no group by oxygen or sulfur equivalents has only been described
for 4-substituted quinolines so far.8,9 Given the fact that 4-O (and
4-S) analogues showed improved RI’s and toxicological advantages
compared to 4-amino derivatives,9 and knowing that the decrease
in antimalarial activity of 4-O and 4-S chloroquine derivatives cor-
relates to the decrease in basicity of the quinolyl nitrogen atom as
a result of this particular substitution pattern (i.e., para-position-
ing),9 the introduction of a functionalized alkoxy side chain at a
more remote position with respect to the quinoline nitrogen atom
might result in an overall beneficial effect with regard to the anti-
plasmodial activity of these novel structures. Thus, in the present
paper, the preparation of new 8-(4-aminobutyloxy)quinolines is
described as well as the assessment of their antiplasmodial
⇑
Corresponding authors. Tel.: +32 9 2649394; fax: +32 9 2646221.
E-mail addresses: norbert.dekimpe@UGent.be (N. De Kimpe), matthias.dhoo-
ghe@UGent.be (M. D’hooghe).
Current address: Freie Universität Berlin, Fabeckstrasse 34-36, D-14195 Berlin,
Germany
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.094
Please cite this article in press as: Vandekerckhove, S.; et al. Bioorg. Med. Chem. Lett. (2012), http://dx.doi.org/10.1016/j.bmcl.2012.10.094

2
S. Vandekerckhove et al. / Bioorg. Med. Chem. Lett. xxx (2012) xxx–xxx
MeO
MeO
N
HN
N
N
N
HN
HN
N
NH2
Cl
1
2
3
Figure 1. Structures of chloroquine, pamaquine and primaquine.
activity. In addition, the scope of this study was further extended
toward the synthesis and biological evaluation of novel 5- and 6-
(4-aminobutyloxy)quinolines as well. It should be mentioned that
the synthesis of 4-substituted quinolines can be easily accom-
plished through nucleophilic aromatic substitution starting from
4-chloroquinolines.9 Unfortunately this method is not extendable
toward the preparation of the desired quinolines bearing a func-
tionalized side chain at, for example, the 5-, 6- or 8-position, which
made a novel approach of side chain introduction necessary. The
implementation of a rhodium-catalyzed hydroformylation as the
key step in the synthesis of functionalized quinoline systems was
used and shown to be a powerful tool to accomplish this objective.
At first, a variety of allyloxyquinolines 5a–n was prepared
through O-alkylation of 5-, 6- and 8-hydroxyquinolines 4 upon
treatment with 1.5 equiv of allyl bromide or 2-methylallyl bromide
(in order to introduce structural diversity) in acetone under reflux
for 24 h in the presence of three equiv of potassium carbonate
(Scheme 1). Subsequently, the obtained quinolines 5 were evalu-
ated as substrates for a rhodium-catalyzed hydroformylation to-
ward the corresponding linear aldehydes. It should be noted that
[(2-methyl-)2-propenyloxy]quinolines have not been studied so
far as potential substrates for a catalytic hydroformylation reac-
tion. Initially, quinolines 5 were subjected to standard hydrofor-
mylation conditions, that is, applying syngas (20 bar CO/H2, 1:1)
using (acetylacetonato)dicarbonylrhodium(I) [Rh(acac)(CO)2] as a
catalyst precursor (substrate/Rh = 500/1) and xantphos (ligand/
Rh = 4) as a ligand in toluene at 80 °C (2 h preformation, 20 h
reaction).23 This method gave satisfying results for non-substituted
(2-propenyloxy)quinolines (R1 = H), but when substituted (2-pro-
penyloxy)quinolines 5 (R1 = Cl, I, Br) were used, only partial
conversion was obtained (5–75%). Elevating the reaction tempera-
ture (120 °C), changing the solvent (2-Me-THF) or prolonging the
reaction time (40–115 h) had no or a negative influence on the
conversion. The same problem arose when (2-methyl-2-propenyl-
oxy)quinolines 5 (R2 = CH3) were used as substrates, even those
bearing no additional substituents on the quinoline ring (R1 = H).
It seemed that steric hindrance prevented the catalyst to reach
the double bond in these cases. Subsequently, triphenylphosphine,
a typical monodentate ligand which is less rigid than the bidentate
xantphos, was used, but unfortunately conversion dropped even
further (5–15%), also when large quantities of the ligand were uti-
lized (20–40 equiv). The use of tris(2,4-di-tert-butylphenyl)phos-
phite,24,25 a ligand that is typically used for hydroformylation of
internal and sterically more demanding olefins,26 gave no conver-
sion at all. Other ligands known to be very selective toward the for-
mation of linear aldehydes are bidentate phosphordiamidite
ligands.27 Thus, in a final attempt, the pyrrole-containing phospho-
rdiamidite ligand DPBO (Scheme 1) was used, a ligand with a
R1
O
R2
N
N
7a-k (56-95%)
2 equiv Et2NH 2 equiv NaCNBH3
5 equiv AcOH MeOH, rt, 15 h
R2
20 bar CO/H2
Br
1.5 equiv
Rh(acac)(CO)2
DPBO-ligand
3 equiv K2CO3
R1
R1
OH
O
R2
R1
O
R2
toluene
O
H
N
acetone, Δ, 24 h
N
N
80 °C, 20-24 h
4
5a-n (57-92%)
6a-n (59-98%)
1) 1.05 equiv
2) 2 equiv NaBH4
MeOH, Δ, 1 h
4-ClC6H4CH2NH2
1.5 equiv MgSO4
CH2Cl2, Δ, 1 h
O P N
O P N
2
2
Cl
R1
O
R2
N
DPBO-ligand
HN
8a-g (48-94%)
Scheme 1. Synthesis of 4-(quinolinyloxy)butyraldehydes 6 via [(2-methyl-)2-propenyloxy]quinolines 5 and their conversion into (4-aminobutyloxy)quinolines 7 and 8.
Please cite this article in press as: Vandekerckhove, S.; et al. Bioorg. Med. Chem. Lett. (2012), http://dx.doi.org/10.1016/j.bmcl.2012.10.094

S. Vandekerckhove et al. / Bioorg. Med. Chem. Lett. xxx (2012) xxx–xxx
3
2,20-binaphthol backbone that has recently been evaluated for the
hydroformylation of styrene.28 Fortunately, the use of this DPBO-li-
gand resulted in good to excellent conversion of non-substituted
(R1 = H) as well as substituted quinolines 5 (R1 = Cl, I, Br) into the
corresponding 4-(quinolinyloxy)butyraldehydes 6 under standard
hydroformylation reaction conditions (20 bar CO/H2 (1:1), sub-
strate/Rh = 500:1, ligand/Rh = 4, toluene, 80 °C, preformation: 1 h,
reaction: 20–24 h). As expected, this ligand was selective toward
the formation of linear aldehydes, and no branched aldehydes were
formed.
This hydroformylation step proved to be a very efficient method
for the generation of a 4-oxobutyloxy side chain as an anchor point
for further derivatization, and comprises the first example of the
successful integration of homogenous catalysis within the synthe-
sis of aminoalkyloxyquinolines as potential antimalarial candi-
dates. The introduction of an aldehyde functionality within the
side chain indeed created a lot of possibilities for further synthetic
elaborations. In light of the target compounds (chloroquine and
pamaquine analogues), imination of aldehydes 6 followed by a
reduction toward the corresponding amines comprised the next
synthetic steps. In this study, diethylamine and 4-chlorobenzyl-
amine were selected as the amines to undergo condensation with
aldehydes 6. The choice for diethylamine is evident from the estab-
lished importance of the diethylamino moiety in antimalarial
agents, whereas 4-chlorobenzylamine was selected based on previ-
ous studies in which the incorporation of this group has shown to
be advantageous with respect to antiplasmodial activity.29,30
When performing the reductive amination of 4-(quinolinyloxy)
methanol under reflux for 1 h, furnishing the desired
[4-(4-chlorobenzylamino)butyloxy]quinolines 8 in moderate to
excellent yields (48–94%) (Scheme 1, Table 1).
After an initial attempt to hydroformylate compound 5f using
(acetoacetonato)dicarbonylrhodium(I) as a catalyst and xantphos
as a ligand, no aldehyde formation was observed. On the other
hand, the elevated reaction temperature (80 °C) had caused
(2-methyl-2-propenyloxy)quinoline 5f to undergo
a Claisen
rearrangement, yielding 5-chloro-7-(2-methyl-2-propenyl)quino-
lin-8-ol 9 in quantitative yield (Scheme 2). It should be noted that
no Claisen rearrangement was observed when allyl ether 5f was
heated at 80 °C in toluene for 18 h. Subsequently, compound 9
was evaluated as an alternative substrate for hydroformylation
using DPBO as the ligand. In this way, 4-(5-chloro-8-hydroxyquin-
olin-7-yl)-3-methylbutyraldehyde 10 was obtained as the sole
reaction product in 73% yield. Finally, aldehyde 10 was subjected
to reductive amination using diethylamine and sodium cyanoboro-
hydrate in methanol in the presence of acetic acid, rendering 5-
chloro-7-(4-diethylamino-2-methylbutyl)quinolin-8-ol 11 in high
yield and purity (Scheme 2).
In the next phase, the newly synthesized quinolines 7, 8 and 11
were screened for their in vitro antiplasmodial activity. All samples
were tested against
a chloroquine-sensitive (CQS) strain of
P. falciparum (D10). Subsequently, only those samples showing
promising antimalarial activity were tested against a chloro-
quine-resistant (CQR) strain of P. falciparum (Dd2) and screened
for in vitro cytotoxicity against a mammalian cell-line, Chinese
Hamster Ovarian (CHO) using the 3-(4,5-dimethylthiazol-2-yl)-
butyraldehydes
6
in
a
one-pot reaction using 2 equiv of
2,5-diphenyltetrazoliumbromide
(MTT)-assay.
Continuous
diethylamine and 2 molar equiv of sodium cyanoborohydride in
the presence of 5 equiv of acetic acid in methanol at room temper-
ature, full conversion to the desired [4-(diethylamino)
butyloxy]quinolines 7 was obtained in moderate to excellent yields
(56–95%) (Scheme 1, Table 1). However, when the primary amine
4-chlorobenzylamine was used, the same reaction conditions did
not result in full conversion to the desired amines 8, but dimeriza-
tion occurred as well and tertiary amines were formed. Fortu-
nately, this was easily overcome by performing the reductive
amination in a stepwise fashion. Firstly, aldehydes 6 were treated
with 1.05 equiv of 4-chlorobenzylamine in the presence of
1.5 equiv of magnesium sulfate in dichloromethane under reflux
for 1 h to afford the corresponding imines, which were immedi-
ately reduced utilizing 2 molar equiv of sodium borohydride in
in vitro cultures of asexual erythrocyte stages of P. falciparum were
maintained using a modified method of Trager and Jensen,31 and
quantitative assessment of antiplasmodial activity in vitro was
determined via the parasite lactate dehydrogenase assay using a
modified method described by Makler.32 The test samples were
tested in triplicate on one occasion.33 The MTT-assay was used as
a colorimetric assay for cellular growth and survival, and compares
well with other available assays.34,35 The tetrazolium salt MTT was
used to measure all growth and chemosensitivity. The test samples
were tested in triplicate on one occasion.36
The results of the biological evaluation are summarized in
Table 2. This study shows that all representatives display
micromolar potencies against the chloroquine-sensitive D10 strain
of P. falciparum, with 12 of the 19 samples having IC50-values
between 10 and 1 lM (Table 2). Interestingly, the most active com-
pounds were more potent against the chloroquine-resistant Dd2
strain of the parasite (IC50 = 150–680 nM). While 8c exhibits mod-
erate cytotoxicity (SI = 2), quinolines 7f, 8e and 8f have good to
very good selectivity indexes at the concentrations tested
(SI = 29–57). Overall, compound 11 appeared to be the most active
Table 1
Substitution pattern and yields of quinolines 7 and 8
Entry
Compound
Quinolin-5-,
6- or 8-yl
R1
R2
Yield (%)
against both parasite strains (IC50 (D10) = 1.01
0.15 M) with a SI of 5.
lM, IC50 (Dd2) =
l
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
8-yl
8-yl
8-yl
8-yl
8-yl
8-yl
8-yl
8-yl
8-yl
6-yl
5-yl
8-yl
8-yl
8-yl
8-yl
6-yl
5-yl
5-yl
H
5-Cl
5-Cl, 7-I
H
5, 7-di-Cl
2-CH3, 5-Cl, 7-Cl
5-Cl, 7-I
5,7-di-I
5,7-di-Br
H
H
5-Cl
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
CH3
CH3
CH3
H
56
57
75
89
89
60
89
61
95
91
60
53
94
48
76
58
56
84
With regard to structure–activity relationships, this assay
shows that the presence of a methyl group in the side chain or
the presence of at least one chloro atom on the quinoline core is
salutary for the antiplasmodial activity of these compounds, and
that both the diethylamino group and the 4-chlorobenzylamino
group at the terminus of the side chain can be of interest with
regard to their antimalarial properties. Based on the observations
made in this work, it can be concluded that the introduction of
substituents bearing a b-methyl group (instead of the usual
9
10
11
12
13
14
15
16
17
18
7j
7k
8a
8b
8c
8d
8e
8f
a-methyl group in known antimalarial drugs) at the less explored
H
5-, 6- or 8-positions of the quinoline nucleus might provide
promising prospects and opportunities within antimalarial drug
design. Finally, it appears that compound 11, recovered after a
Claisen rearrangement, gives the best overall results, which could
be attributed to the intramolecular hydrogen bonding between
2-CH3, 5-Cl, 7-Cl
5,7-di-I
H
H
H
H
CH3
8g
Please cite this article in press as: Vandekerckhove, S.; et al. Bioorg. Med. Chem. Lett. (2012), http://dx.doi.org/10.1016/j.bmcl.2012.10.094

4
S. Vandekerckhove et al. / Bioorg. Med. Chem. Lett. xxx (2012) xxx–xxx
Cl
Cl
20 bar CO/H2
Rh(acac)(CO)2
xanthphos
N
N
toluene
80 °C, 18 h
O
OH
5f
9 (99%)
20 bar CO/H2
Rh(acac)(CO)2
DPBO-ligand
toluene,
80 °C, 24 h
2 equiv Et2NH
5 equiv AcOH
Cl
Cl
O
H
2 equiv NaCNBH3
N
N
N
MeOH, rt, 15 h
OH
11 (81%)
OH
10 (73%)
Scheme 2. Synthesis of 5-chloro-7-(4-diethylamino-2-methylbutyl)quinolin-8-ol 11.
Table 2
IC50-values of quinolines 7, 8 and 11 tested for in vitro antimalarial activity and cytotoxicity
Entry
Compound
D10: IC50
(l
M)
Dd2: IC50
(lM)
CHO: IC50
(
lM)
SIa
RIb
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
8a
49.19
17.18
9.02
100.20
8.08
ND
ND
ND
ND
ND
0.68
ND
ND
ND
ND
ND
ND
ND
0.26
ND
>1
ND
ND
ND
ND
ND
224.46
ND
ND
ND
ND
ND
ND
ND
4.11
ND
211.45
237.35
ND
4.80
ND
0.17
ND
ND
ND
ND
ND
57
ND
ND
ND
ND
ND
ND
ND
2
ND
29
34
ND
5
ND
ND
ND
ND
ND
ND
ND
0.17
ND
ND
ND
ND
ND
ND
ND
0.11
ND
ND
ND
ND
0.15
8
3.95
12.97
13.89
8.65
6.02
10.24
9.99
5.64 (n = 6)
2.44
9.15
7.29 (n = 6)
7.01 (n = 6)
23.08
9
10
11
12
13
14
15
16
17
18
19
20
21
8b
8c
8d
8e
8f
ND
ND
0.15
0.34
ND
8g
11
CQ
Emetine
1.01 (n = 6)
0.04 (n = 28)
ND
ND
ND = not determined.
a
SI (selectivity index) = IC50 CHO/IC50 D10.
RI (resistance index) = IC50 Dd2/IC50 D10.
b
the 8-hydroxyl group and the quinoline nitrogen atom.37 It should
also be noted that calculated properties of the novel compounds
prepared in this work (molecular weight, cLogP, total polar surface
area, rotatable bonds, hydrogen bond donors, hydrogen bond
acceptors and fractional sp3 character) correspond well with those
of their commercially available analogues chloroquine 1 and pam-
aquine 2, which underlines the importance of these new structures
as templates for further elaboration and optimization.
Acknowledgments
The authors are indebted to Ghent University (BOF) for financial
support. The authors would also like to thank ir. J. Weemers (TU/e)
and ir. L. Broeckx (TU/e) for their assistance with the catalytic
hydroformylation experiments.
Supplementary data
In conclusion, the preparation of 5-, 6- and 8-(4-aminobutyloxy)
quinolines as new classes of quinoline derivatives was established
through a three-step pathway consisting of (i) O-allylation, (ii)
rhodium-catalyzed hydroformylation of the thus obtained [(2-
methyl-)2-propenyloxy]quinolines and (iii) reductive amination.
Furthermore, the biological relevance of this novel class of
compounds was demonstrated by evaluation of its in vitro anti-
plasmodial activity and cytotoxicity. Three new compounds
showed submicromolar activity against a chloroquine-resistant
strain of P. falciparum, pointing to the promising potential of these
new structures as novel antimalarial pharmacophores.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
10.094.
References and notes
1. WHO. World Malaria Report 2011.
2. Chauhan, P. M. S.; Srivastava, S. K. Curr. Med. Chem. 2001, 8, 1535.
3. Jefford, C. W. Curr. Med. Chem. 1803, 2001, 8.
4. Kumar, K. A.; Sano, G.; Boscardin, S.; Nussenzweig, R. S.; Nussenzweig, M. C.;
Zavala, F.; Nussenzweig, V. Nature 2006, 444, 937.
Please cite this article in press as: Vandekerckhove, S.; et al. Bioorg. Med. Chem. Lett. (2012), http://dx.doi.org/10.1016/j.bmcl.2012.10.094

S. Vandekerckhove et al. / Bioorg. Med. Chem. Lett. xxx (2012) xxx–xxx
5
5. Aide, P.; Dobano, C.; Sacarlal, J.; Aponte, J. J.; Mandomando, I.; Guinovart, C.;
Bassat, Q.; Renom, M.; Puyol, L.; Macete, E.; Herreros, E.; Leach, A.; Dubois, M.
C.; Demoitie, M. A.; Lievens, M.; Vekemans, J.; Loucq, C.; Ballou, W. R.; Cohen, J.;
Alonso, P. L. Vaccine 2011, 29, 6059.
6. Burrows, J. N.; Chibale, K.; Wells, T. N. C. Curr. Top. Med. Chem. 2011, 11,
1226.
25. van Leeuwen, P. W. N. M. In Catalysis by Metal Complexes; Kluwer Academic
Publishers: Dordrecht (The Netherlands), 2000. Vol. 22 (Rhodium catalyzed
hydroformylation), p 1.
26. van Leeuwen, P. W. N. M.; Roobeek, C. F. J. Organomet. Chem. 1983, 258, 343.
27. van der Slot, S. C.; Duran, J.; Luten, J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Organometallics 2002, 21, 3873.
7. Kumar, A.; Katiyar, S. B.; Agarwal, A.; Chauhan, P. M. S. Curr. Med. Chem. 2003,
10, 1137.
28. Boymans, E. H.; Janssen, M.; Müller, C.; Lutz, M.; Vogt, D. unpublished results.
29. D’hooghe, M.; Kenis, S.; Vervisch, K.; Lategan, C.; Smith, P. J.; Chibale, K.; De
Kimpe, N. Eur. J. Med. Chem. 2011, 46, 579.
30. D’hooghe, M.; Vandekerckhove, S.; Mollet, K.; Vervisch, K.; Dekeukeleire, S.;
Lehoucq, L.; Lategan, C.; Smith, P. J.; Chibale, K.; De Kimpe, N. Beilstein J. Org.
Chem. 2011, 7, 1745.
31. Trager, W.; Jensen, J. B. Science 1976, 193, 673.
32. Makler, M. T.; Ries, J. M.; Williams, J. A.; Bancroft, J. E.; Piper, R. C.; Gibbins, B.
L.; Hinrichs, D. J. Am. J. Trop. Med. Hyg. 1993, 48, 739.
33. The test samples were prepared to a 20 mg/mL stock solution in 100% DMSO.
Stock solutions were stored at ꢀ20 °C. Further dilutions were prepared in
complete medium on the day of the experiment. Samples were tested as a
suspension if not completely dissolved. Chloroquine (CQ) was used as the
reference. A full dose–response was performed for all compounds to determine
the concentration inhibiting 50% of parasite growth (IC50-value). Test samples
8. Iwaniuk, D. P.; Whetmore, E. D.; Rosa, N.; Ekoue-Kovi, K.; Alumasa, J.; de Dios,
A. C.; Roepe, P. D.; Wolf, C. Bioorg. Med. Chem. 2009, 17, 6560.
9. Natarajan, J. K.; Alumasa, J. N.; Yearick, K.; Ekoue-Kovi, K. A.; Casabianca, L. B.;
de Dios, A. C.; Wolf, C.; Roepe, P. D. J. Med. Chem. 2008, 51, 3466.
10. Yearick, K.; Ekoue-Kovi, K.; Iwaniuk, D. P.; Natarajan, J. K.; Alumasa, J.; de Dios,
A. C.; Roepe, P. D.; Wolf, C. J. Med. Chem. 1995, 2008, 51.
11. Hwang, J. Y.; Kawasuji, T.; Lowes, D. J.; Clark, J. A.; Connelly, M. C.; Zhu, F. Y.;
Guiguemde, W. A.; Sigal, M. S.; Wilson, E. B.; DeRisi, J. L.; Guy, R. K. J. Med. Chem.
2011, 54, 7084.
12. Sparatore, A.; Basilico, N.; Casagrande, M.; Parapini, S.; Taramelli, D.; Brun, R.;
Wittlin, S.; Sparatore, F. Bioorg. Med. Chem. Lett. 2008, 18, 3737.
13. Ekoue-Kovi, K.; Yearick, K.; Iwaniuk, D. P.; Natarajan, J. K.; Alumasa, J.; de Dios,
A. C.; Roepe, P. D.; Wolf, C. Bioorg. Med. Chem. 2009, 17, 270.
14. Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Eur. J. Med. Chem. 2010, 45, 3245.
15. Kaur, K.; Jain, M.; Khan, S. I.; Jacob, M. R.; Tekwani, B. L.; Singh, S.; Singh, P. P.;
Jain, R. Med. Chem. Commun. 2011, 2, 300.
were tested at a starting concentration of 100
diluted twofold in complete medium to give 10 concentrations; with the
lowest concentration being 0.2 g/mL. The same dilution technique was used
lg/mL, which was then serially
l
16. Vale, N.; Moreira, R.; Gomes, P. Eur. J. Med. Chem. 2009, 44, 937.
17. Kaur, K.; Jain, M.; Khan, S. I.; Jacob, M. R.; Tekwani, B. L.; Singh, S.; Singh, P. P.;
Jain, R. Eur. J. Med. Chem. 2012, 52, 230.
for all samples. CQ was tested at a starting concentration of 100 ng/mL against
a CQS strain. The highest concentration of solvent to which the parasites were
exposed to had no measurable effect on the parasite viability.
18. Kumar, A.; Srivastava, K.; Kumar, S. R.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med.
Chem. Lett. 2010, 20, 7059.
19. Gordey, E. E.; Yadav, P. N.; Merrin, M. P.; Davies, J.; Ward, S. A.; Woodman, G.
M. J.; Sadowy, A. L.; Smith, T. G.; Gossage, R. A. Bioorg. Med. Chem. Lett. 2011, 21,
4512.
34. Mosmann, T. J. Immunol. Methods 1983, 65, 55.
35. Rubinstein, L. V.; Shoemaker, R. H.; Paull, K. D.; Simon, R. M.; Tosini, S.; Skehan,
P.; Scudiero, D. A.; Monks, A.; Boyd, M. R. J. Natl. Cancer I 1990, 82, 1113.
36. The test samples were prepared to a 2 mg/mL stock solution in 10% DMSO and
were tested as a suspension. Test compounds were stored at ꢀ20 °C until use.
Dilutions were prepared on the day of the experiment. Emetine was used as the
reference drug in all experiments. The initial concentration of emetine was
20. Sunduru, N.; Sharma, M.; Srivastava, K.; Rajakumar, S.; Puri, S. K.; Saxena, J. K.;
Chauhan, P. M. S. Bioorg. Med. Chem. 2009, 17, 6451.
21. Kouznetsov, V. V.; Gomez-Barrio, A. Eur. J. Med. Chem. 2009, 44, 3091.
22. O’Neill, P. M.; Ward, S. A.; Berry, N. G.; Jeyadevan, J. P.; Biagini, G. A.; Asadollaly,
E.; Park, B. K.; Bray, P. G. Curr. Top. Med. Chem. 2006, 6, 479.
23. van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem. Rev.
2000, 100, 2741.
100
l
g/mL, which was serially diluted in complete medium with 10-fold
g/mL. The same
dilutions to give 6 concentrations, the lowest being 0.001
l
dilution technique was applied to all test samples. The highest concentration of
solvent to which the cells were exposed to had no measurable effect on the cell
viability. The 50% inhibitory concentration (IC50) values were obtained from
24. Kamer, P. C. J.; Reek, J. N. H.; H., J. N.; van Leeuwen, P. W. N. M. In Catalysis by
Metal Complexes; Kluwer Academic Publishers: Dordrecht (The Netherlands),
2000. Vol. 22 (Rhodium catalyzed hydroformylation), p. 35.
full dose-response curves, using a non-linear dose–response curve fitting
analysis via GraphPad Prism v.4 software.
37. Madrid, P. B.; Liou, A. P.; DeRisi, J. L.; Guy, R. K. J. Med. Chem. 2006, 49, 4535.
Please cite this article in press as: Vandekerckhove, S.; et al. Bioorg. Med. Chem. Lett. (2012), http://dx.doi.org/10.1016/j.bmcl.2012.10.094