Synthesis and antiplasmodial evaluation of aziridine-(iso)quinoline hybrids and their ring-opening products

Article abstract of DOI:10.1039/c3md20377h

Aziridine-(iso)quinoline hybrid systems were prepared as novel synthetic intermediates en route to functionalized (iso)quinolines with potential antimalarial activity. Various quinolinecarboxaldehydes were converted into quinoline-aziridine-pyrazole, -pyridazinone or -pyrimidinone hybrids, and the three-membered azaheterocyclic moiety in these compounds was finally subjected to ring opening by either methanol or water to provide the corresponding functionalized quinolines. In addition, 5-hydroxyisoquinoline was used for the preparation of isoquinoline-aziridine chimeras, which were further transformed into a variety of functionalized isoquinolines via regioselective aziridine ring opening by various nucleophiles. Antiplasmodial evaluation of these new aziridine-(iso)quinoline hybrids and their ring-opening products revealed micromolar potency (0.22-30 μM) for all representatives against a chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum. The six most potent compounds also showed micromolar activity against a chloroquine-resistant strain of P. falciparum with IC₅₀-values ranging between 1.02 and 17.58 μM.

Full text of DOI:10.1039/c3md20377h

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CONCISE ARTICLE
Synthesis and antiplasmodial evaluation of aziridine–
(iso)quinoline hybrids and their ring-opening products†
Cite this: Med. Chem. Commun., 2013,
4, 724
a
a
a
b
´
Stephanie Vandekerckhove, Sofie De Moor, Dries Segers, Carmen de Kock,
b
c
a
a
*
*
Peter J. Smith, Kelly Chibale, Norbert De Kimpe and Matthias D'hooghe
Aziridine–(iso)quinoline hybrid systems were prepared as novel synthetic intermediates en route to
functionalized (iso)quinolines with potential antimalarial activity. Various quinolinecarboxaldehydes
were converted into quinoline–aziridine–pyrazole, –pyridazinone or –pyrimidinone hybrids, and the
three-membered azaheterocyclic moiety in these compounds was finally subjected to ring opening by
either methanol or water to provide the corresponding functionalized quinolines. In addition,
5-hydroxyisoquinoline was used for the preparation of isoquinoline–aziridine chimeras, which were
further transformed into a variety of functionalized isoquinolines via regioselective aziridine ring
opening by various nucleophiles. Antiplasmodial evaluation of these new aziridine–(iso)quinoline
hybrids and their ring-opening products revealed micromolar potency (0.22–30 mM) for all
representatives against a chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum.
The six most potent compounds also showed micromolar activity against a chloroquine-resistant strain
of P. falciparum with IC50-values ranging between 1.02 and 17.58 mM.
Received 27th December 2012
Accepted 5th February 2013
DOI: 10.1039/c3md20377h
www.rsc.org/medchemcomm
meoquine 2, quinine
3 and quinidine 4; Fig. 1) has
Introduction
unequivocally been established and has been a source of
inspiration for medicinal chemists for many years.6 As a result,
a large variety of functionalized quinolines and quinoline-
based hybrid molecules7–10 has been designed, and several
antiplasmodial quinoline drugs have been commercial-
ized.6,11,12 Although less frequently encountered as the core
structure in bioactive substances as compared to quinolines,
isoquinolines have also been associated with a range of bio-
logical activities such as anticancer, anti-inammation, anti-
diabetes, anti-HIV, etc.13–17 In addition, diverse studies have
ratied the antimalarial properties of isoquinoline derivatives,
making these systems attractive templates in antimalarial
research as well.11,17
The combination of a(n) (iso)quinoline scaffold with a
bioactive heterocyclic moiety in a hybrid system via an aziridine
linker and the study of their applications comprises an unex-
plored eld of research. As (iso)quinolines are known to be
suitable templates for the synthesis of antimalarial agents,
antimalarial evaluation of novel aziridine–(iso)quinoline
chimeras could potentially provide new leads in this eld.
Moreover, the inherent reactivity of the aziridine nucleus allows
for selective transformations of these hybrids to provide novel
functionalized (iso)quinoline derivatives.18–25 Hence, the objec-
tive of this study comprises the design, synthesis and anti-
plasmodial evaluation of a set of new aziridine–(iso)quinoline
systems and the corresponding aziridine ring-opening
products.
An emerging strategy within drug discovery programs
comprises the synthesis of novel chemical entities via combi-
nation of two biologically relevant moieties. This strategy has
recently been used in the development of, for example, new
anticancer, anti-Alzheimer, antimalarial and antiviral agents.1–5
An important motive for the application of molecular hybrid-
ization is the development of active drugs which can obviate
drug resistance by linking bioactive units into molecules that
are recognized and transported into the desired cells. However,
in addition to these biological perspectives, molecular
hybridization also allows for selective modication of the more
reactive entity within hybrid systems, thus providing an easy
access to new functionalized target compounds with biological
interest because of the conservation of the second bioactive
moiety.5
The importance of the quinoline class of compounds in the
treatment of malaria (as exemplied by chloroquine 1,
aDepartment of Sustainable Organic Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. E-mail:
matthias.dhooghe@UGent.be; norbert.dekimpe@UGent.be; Fax: +32-9-2646221; Tel:
+32-9-2649394
bMedical School, University of Cape Town, K45, OMB, Groote Schuur Hospital,
Observatory, 7925, South Africa
cDepartment of Chemistry and Institute of Infectious Disease & Molecular Medicine,
University of Cape Town, Rondebosch 7701, South Africa
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3md20377h
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Fig. 1 Important quinoline-based antimalarials.
methanol in a closed recipient to produce the desired new
{[2-(bromomethyl)aziridin-1-yl]methyl}quinolines 7 aer 30–90
min at 65 ꢀC under microwave irradiation (Scheme 1 and
Table 1). Optimization of the reaction conditions showed that
full conversion was only obtained when the reducing agent was
sequentially added (2 ꢁ 1.5 equiv., with an interval of 45 min).
This method afforded aziridines 7 in excellent yields (96–98%)
and purities (>95%, NMR). All newly synthesized {[2-(bromo-
methyl)aziridin-1-yl]methyl}quinolines 7 appeared to be rather
unstable, even when stored at low temperatures (ꢂ20 ꢀC); so
further synthetic modication of these hybrids 7 was performed
immediately through substitution with heteroaromatic nucle-
ophiles. Three nucleophiles, i.e., 5-hydroxy-1-methyl-3-(tri-
uoromethyl)pyrazole 8, 4-triuoromethyl-1H-pyrimidin-2-one
9 and 4,5-dichloro-2H-pyridazin-3-one 10, were selected because
of their known antimalarial potency,12 which could be benecial
within the concept of biological hybrid formation. To
Results and discussion
The synthetic strategy used to construct the aziridine–quinoline
chimera consists of the initial synthesis of {[2-(bromomethyl)-
aziridin-1-yl]methyl}quinolines starting from quinolinecarbox-
aldehydes. From a synthetic perspective, the 2-(bromomethyl)
aziridine core has proven to be an excellent synthon in organic
chemistry,26,27 especially toward the preparation of functional-
ized aminopropanes which in turn are known to possess a wide
variety of biological activities, for example as b-blockers, anti-
biotics, antimalarials, anti-cancer agents, etc.28–38 Condensation
of quinoline-3- and quinoline-4-carboxaldehydes 5 with 2,3-
dibromopropylamine hydrobromide in dichloromethane in the
presence of magnesium sulfate and triethylamine resulted in
the formation of dibromoimines 6 aer 15–20 min in a closed
recipient at 90 ꢀC applying microwave irradiation. These imines
6 were immediately treated with sodium borohydride in
Scheme 1 Synthesis of racemic aziridine–quinoline hybrids and their ring-opening products.
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Table 1 Substitution pattern and isolated yields of quinolines 7, 11, 12, 13, 14
and 15
opening by water at the less sterically hindered aziridine carbon
atom,43 affording the desired functionalized aminopropanes
12a,b and 15a–c (R0 ¼ H) in good yields (60–82%) aer 24 h at
room temperature in a THF–water (1/1) solvent mixture
(Scheme 1). Perilous column chromatography on silica gel was
performed in order to obtain analytically pure samples, result-
ing in low overall yields of 8–24% aer purication. To evaluate
a second approach toward the ring opening of azaheterocycles
11 and 14, the aziridine ring was activated using the Lewis acid
BF3$Et2O. Aziridine–quinoline chimeras 11 and 14 were thus
treated with 0.5 equiv. of BF3$Et2O in methanol at reux
temperature for 20 h, affording functionalized aminopropanes
12c and 15d (R0 ¼ Me) through ring opening by methanol in
good yields (74–83%). It should be noted that lower Lewis acid
loadings (<0.5 equiv.) resulted in longer reaction times and/or
lower overall yields. Once again, a tedious purication step
affected the overall yields (10–24%) of the nally obtained
products (Scheme 1 and Table 1).
Entry
Compound
Quinolin-3- or 4-yl
R
R0
Yield
1
2
3
4
5
6
7
8
7a
7b
7c
3-yl
3-yl
4-yl
3-yl
3-yl
4-yl
3-yl
3-yl
3-yl
3-yl
3-yl
3-yl
3-yl
3-yl
4-yl
3-yl
3-yl
4-yl
4-yl
H
Cl
H
H
Cl
H
—
—
—
—
—
—
H
96%
98%
96%
10%
28%
12%
11%
24%
12%
38%
45%
12%
32%
21%
34%
8%
11a
11b
11c
12a
12b
12c
12d
13a
13b
14a
14b
14c
15a
15b
15c
15d
H
Cl
Cl
OMe
H
Cl
H
Cl
H
H
H
9
CH3
CH3
—
—
—
—
—
H
10
11
12
13
14
15
16
17
18
19
Cl
H
H
H
H
CH3
9%
11%
10%
Notably, the BF3$Et2O-mediated ring opening of the azir-
idine–quinoline–pyrazole hybrid 11b under microwave irradia-
tion (MeOH, 90 ꢀC, 1 h) yielded quinoline 12c (R ¼ Cl, 12%) only
as the minor product, while the major product 12d (R ¼ OMe,
38%) was formed through replacement of chloride by methanol
accomplish the desired bromide displacement reaction, one at the 2-position of the quinoline ring. Similar reactions have
equiv. of nucleophile 8, 9 or 10 was rst treated with 2 equiv. of been reported in the literature.44
sodium hydroxide and 0.1 equiv. of sodium iodide in DMF at
A second approach toward aziridine-containing hybrids as
room temperature under inert atmosphere (N2). Aer one hour, intermediates for the synthesis of potential novel antimalarials
(aziridin-1-ylmethyl)quinolines 7 were added to the mixture and was based on the use of the isoquinoline template. As
further stirring for 60 h at room temperature afforded the mentioned above, the antiplasmodial activity of isoquinoline
desired novel quinoline–aziridine–pyrazole/pyrimidinone/pyr- derivatives has by far not been described as extensively as that of
idazinone hybrid compounds 11, 13 and 14 in moderate to good the quinoline class, although diverse literature reports have
yields (37–82%). Finally, column chromatography on silica gel mentioned their antimalarial properties.11,17 Therefore, func-
was performed to afford analytically pure samples for spectro- tionalization of the isoquinoline nucleus via molecular
scopic analysis and biological testing, although this purication hybridization was considered a new and interesting tool to
step accounted for reduced yields (10–45%) due to the strong provide an entry to new representatives of this class of
polarity of these novel compounds 11, 13 and 14 (Scheme 1). compounds. In order to achieve this objective, a reactive moiety
Literature reports show that deprotonation of pyrimidin-2-one 9 had to be introduced and, in analogy with the rst part of this
and pyridazin-3-one 10 leads to selective N-alkylation, sup- work, a strained aziridine ring was proposed.
porting the formation of N-functionalized pyrimidinones 13
As an isoquinoline source, the readily available 5-hydrox-
and pyridazinones 15.39–42 It should be noted that moderate to yisoquinoline 16 was employed. The hydroxyl group was rst
low yields were obtained aer column chromatographic puri- deprotonated using sodium hydroxide, and nucleophilic
cation (Scheme 1 and Table 1), and that the initially obtained substitution then occurred aer adding 1 equiv. of an 1-aryl-
reaction yields were considerably higher.
methyl-2-(bromomethyl)aziridine.26,27 Reaction for 2–4 h in
An interesting feature of these novel hybrid structures 11, 13 DMF at 100 C thus afforded novel 5-(aziridin-2-ylmethoxy)iso-
and 14 involves the attachment of the quinoline ring to the quinolines 17 in good yields (65–90%) (Scheme 2 and Table 2).
ꢀ
heteroaromatic moiety (pyrazole, pyrimidine or pyridazine) by
Finally, different strategies for the opening of the constrained
an aziridine linker. This small azaheterocycle represents a ring in these aziridine–isoquinoline hybrids 17 were evaluated.
useful synthon since the strained three-membered ring can be Firstly, the aziridine system in compound 17 was activated by N-
opened toward functionalized aminopropanes, a moiety which protonation using para-toluenesulfonic acid in a THF–water
has already proven its broad therapeutic relevance in the (1/1) solvent mixture. Reaction at reux for 6 h caused water to
past.28–38 Therefore, {[2-(1-methyl-3-triuoromethyl-1H-pyrazol- open the activated aziridine ring at the less substituted position,
5-yloxymethyl)aziridin-1-yl]methyl}quinolines 11 and 4,5-di- which afforded isoquinoline–aminopropanols 18 in high yields
chloro-2-[1-(quinolinylmethyl)aziridin-2-ylmethyl]-2H-pyridazin- (85–94%) (Scheme 2 and Table 2). Secondly, the aziridine ring of
3-ones 14 were selected for further elaboration and subjected to hybrids 17 was activated by complexation of the nitrogen atom
two types of regioselective ring opening. In the rst approach, with a Lewis acid (e.g., BF3$Et2O), which allowed the strained
the aziridine ring was activated by protonation with an equi- three-membered ring to be opened at the less hindered aziridine
molar mixture of para-toluenesulfonic acid followed by ring carbon atom by the solvent (methanol) aer 30 min at 90 ꢀC
726 | Med. Chem. Commun., 2013, 4, 724–730
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Scheme 2 Synthesis of racemic aziridine–isoquinoline hybrids and their ring-opening products.
under microwave conditions,43 yielding functionalized iso- addition of 1 equiv. of benzyl bromide to the aziridine–iso-
quinolines 19 in high yields (75–91%). In addition to the oxygen- quinoline chimera 17 in CH3CN, selective alkylation of the
based nucleophiles H2O and MeOH, aniline was used as a isoquinoline nitrogen atom was observed, resulting in the
nitrogen-based nucleophile to induce ring opening of aziridines formation of the isoquinolinium salt 21.17 Still containing a
17 en route to 1,2-diaminopropanes. To that end, aziridine–iso- reactive aziridine linker, this isoquinolinium bromide 21 was
quinoline hybrids 17 were dissolved in dichloromethane in the again treated with an equimolar amount of benzyl bromide in
presence of 0.5 equiv. of BF3$Et2O, aer which 1.1 equiv. of acetonitrile for 5 h at reux temperature, affording the desired
aniline was added. Reaction occurred under microwave irradia- ring-opening product, i.e., b-bromoamine 22, in excellent yield
tion (1 h at 65 ꢀC), providing new isoquinoline derivatives 20 in (98%) (Scheme 2 and Table 2). According to the literature, ring
high yields (91–92%). As reported in the literature, Lewis acid- opening of N,N-dialkylaziridinium salts by bromide proceeds at
mediated ring opening of 2-alkylaziridines by aromatic amines the more hindered aziridine carbon atom.43,45,46 It should be
occurred via a nucleophilic attack at the less substituted azir- noted that isoquinolinium salts have been reported to exhibit
idine carbon atom.43 When Yb(OTf)3 was used instead of potent antiplasmodial activities.17
BF3$Et2O, yields dropped to 68% applying the same reaction
With a small library of aziridine–(iso)quinoline chimeras
conditions, while Cu(OTf)2 did not result in conversion at all. 11a–c, 13a,b, 14a–c, 17a–h, 21 and their ring-opening products
Furthermore, aer evaluating the effect of different amounts of 12a–d, 15a–d, 18a,b,f,g, 19a,c–e,h, 20a–b, 22 in hand, anti-
Lewis acid (0.2, 0.5, 1 and 2 equiv.) on the overall reaction effi- plasmodial screening was undertaken. All samples were tested
ciency, ring opening utilizing 0.5 equiv. of BF3$Et2O was found to in triplicate against a chloroquine-sensitive (CQS) strain of
provide optimal results.
Plasmodium falciparum (NF54). Subsequently, only those
A nal method to activate the aziridine moiety in systems 17 samples showing promising antiplasmodial activity were tested
involved alkylation of the aziridine nitrogen atom. Upon against a chloroquine-resistant (CQR) strain of P. falciparum
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Table 2 Substitution pattern and isolated yields of isoquinolines 17, 18, 19, 20,
21 and 22
Table 3 IC50-values of aziridine–(iso)quinoline hybrids 11a–c, 13a,b, 14a–c,
17a–g, 21 and their ring-opening products 12a–d, 15a–d, 18a,b,f,g, 19a,c–e,
20a,b, 22 tested for in vitro antimalarial activity and cytotoxicitya
Entry
Compound
R
Yield
NF54:
Dd2:
CHO:
1
2
3
4
5
6
7
8
17a
17b
17c
17d
17e
17f
17g
17h
18a
18b
18f
18g
19a
19c
19d
19e
19h
20a
20b
21
H
4-Cl
4 F
90%
80%
75%
74%
77%
82%
84%
65%
94%
85%
89%
93%
91%
79%
82%
85%
75%
92%
91%
97%
98%
Entry Compound
IC50 (mM) IC50 (mM) IC50 (mM) SIb
RIc
1
11a
>27.60
>25.20
9.66
ND
ND
ND
15.25
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
8.46
17.58
ND
ND
ND
ND
ND
ND
ND
ND
8.21
ND
1.02
1.17
0.53
ND
ND
ND
ND
ND
181.14
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
52.27
148.19
ND
ND
ND
ND
ND
ND
ND
ND
237.03
ND
ND
ND
ND
ND
ND
ND
2-Cl
4-OMe
2,4-di-Cl
4-CF3
2-OMe
H
4-Cl
2,4-di-Cl
4-CF3
H
2
11b
3
11c
4
12a
4.73
38.28 1.23
5
12b
>24.11
17.02
>23.56
>27.75
9.12
12.73
22.75
26.85
15.29
14.99
24.52
14.49
9.99
>30.79
15.89
12.93
9.99
>27.84
>27.90
5.29
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
9.88
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
1.60
6
12c
9
7
12d
10
11
12
13
14
15
16
17
18
19
20
21
8
13a
9
13b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
14a
14b
14c
15a
15b
15c
15d
17a
17b
17c
17d
17e
17f
17g
17h
18a
18b
18f
18g
19a
19c
19d
19e
19h
20a
20b
21
22
4-F
2-Cl
4-OMe
2-OMe
H
4-Cl
—
22
—
(Dd2) and screened for in vitro cytotoxicity against a mamma-
lian cell-line, Chinese Hamster Ovarian (CHO), using the 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT)-
assay. Continuous in vitro cultures of asexual erythrocyte stages
of P. falciparum were maintained using a modied method of
Trager and Jensen.47 Quantitative assessment of antiplasmodial
activity in vitro was determined via the parasite lactate dehy-
drogenase assay using a modied method described by Makler
et al.48 The test samples were tested in triplicate on one occa-
sion.49 The MTT-assay was used to measure all growth and
survival, and compares well with other available assays.50,51 The
tetrazolium salt MTT was used to measure growth and chemo-
sensitivity. The test samples were tested in triplicate on one
occasion.52
The results of the biological evaluation are summarized in
Table 3. All compounds exhibited micromolar potencies against
a chloroquine-sensitive NF54 strain of P. falciparum, with 21 of
the 37 samples having IC50-values between 220 nM and 20 mM.
Subsequently, the activity of the six most potent compounds
was determined against a chloroquine-resistant strain of P.
6.81
21.76 2.58
22.75
>26.51
11.69
13.03
24.38
16.53
>28.37
>28.38
4.69
10.53
1.09
0.22
0.03
0.02
ND
ND
ND
ND
ND
ND
ND
ND
50.50 1.75
ND ND
47.70 0.94
205.04 5.32
ND
ND
ND
ND
ND
ND
ND
ND
51.80
45.06
ND
ND
0.40
CQ (n ¼ 14)
Artunesate (n ¼ 8)
Emetine
ND
ND
ND
21.25
ND
ND
ND
a
ND ¼ not determined; CQ ¼ chloroquine. b SI (Selectivity Index) ¼ IC50
CHO/IC50 NF54. c RI (Resistance Index) ¼ IC50 Dd2/IC50 NF54.
falciparum (Dd2), again resulting in micromolar activities with promising potential upon further investigation. Secondly, azir-
IC50-values ranging between 1.02 and 17.58 mM. Isoquinolinium idine ring opening by both water and aniline mostly results in
salts 21 and 22 in particular displayed promising in vitro activ- slightly more active compounds as compared to methanol-
ities (1.09 mM and 220 nM against a NF54 strain and 1.02 mM induced ring-opening products, although the difference is
and 1.17 mM against a Dd2 strain, respectively). These six small. Finally, both the introduction of a chloro atom at the
representatives also appear to have high selectivity indices 2-position of the quinoline ring and the choice of the hetero-
toward P. falciparum and low resistance indices, illustrating the cyclic moiety (pyrazole, pyrimidinone, pyridazinone) in quino-
potential of these compounds as novel templates in antima- line-based hybrids does not seem to have a pronounced effect
larial drug design.
on the biological activity.
From a structure–activity relationship viewpoint, a few
In conclusion, a new approach to functionalize (iso)quino-
observations can be made. Firstly, it is clear that iso- lines via molecular hybridization with a small reactive hetero-
quinolinium-based hybrids display the most potent bioactiv- cycle, i.e. a strained aziridine ring, was elaborated. With
ities, and that this class of compounds holds the most aziridines being useful synthons in organic synthesis, further
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Acknowledgements
The authors are indebted to Ghent University (BOF) for nancial 27 M. D'hooghe, A. Waterinckx and N. De Kimpe, J. Org. Chem.,
support. The University of Cape Town, South African Medical
2005, 70, 227–232.
Research Council and South African Research Chairs initiative 28 M. D'hooghe, S. Kenis, K. Vervisch, C. Lategan, P. J. Smith,
of the Department of Science and Technology administered
through the South African National Research Foundation are
gratefully acknowledged for support (KC).
K. Chibale and N. De Kimpe, Eur. J. Med. Chem., 2011, 46,
579–587.
29 M. D'hooghe, S. Vandekerckhove, K. Mollet, K. Vervisch,
S. Dekeukeleire, L. Lehoucq, C. Lategan, P. J. Smith,
K. Chibale and N. De Kimpe, Beilstein J. Org. Chem., 2011,
7, 1745–1752.
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52 The test samples were made up to a 2 mg mLꢂ1 stock
solution in 10% DMSO and were tested as a suspension.
Test compounds were stored at ꢂ20 ꢀC until use.
Dilutions were made on the day of the experiment.
Emitine was used as the reference drug in all
experiments. The initial concentration of emetine was
100 mg mLꢂ1, which was serially diluted in complete
medium with 10-fold dilutions to give 6 concentrations,
the lowest being 0.001 mg mLꢂ1. The same dilution
technique was applied to all test samples. The highest
concentration of the solvent to which the cells were
exposed to had no measurable effect on the cell viability.
The 50% inhibitory concentration (IC50) was obtained
using a non-linear dose–response curve tting analysis via
Graph Pad Prism v.4.0 soware.
49 The test samples were made up to a 20 mg mLꢂ1 stock
solution in 100% DMSO and sonicated to enhance
solubility. Samples were tested as a suspension if not
completely dissolved. Stock solutions were stored at ꢂ20
ꢀC. Further dilutions were made on the day of the
experiment. Chloroquine, artenusate and compound
MMV390048 (in-house control) were used as the reference
drugs in all experiments.
A full dose–response was
performed for all compounds to determine the
concentration of 10 mg mLꢂ1, which was then serially
diluted twofold in complete medium to give 10
730 | Med. Chem. Commun., 2013, 4, 724–730
This journal is ª The Royal Society of Chemistry 2013