In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine

Article abstract of DOI:10.1016/j.bmc.2015.06.044

The synthesis and in vitro evaluation of novel triazole-linked chloroquinoline derivatives as potential antiplasmodial agents against Plasmodium falciparum is reported. The 15 synthesized target compounds were obtained by means of a copper(I)-mediated click reaction between a variety of 1,2- and 1,3-azidoamines and 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine in moderate to good yields (53-85%). The compounds were screened for antiplasmodial activity against NF54 chloroquine-sensitive and Dd2 chloroquine-resistant strains, alongside chloroquine and artesunate as reference compounds. Six of the test compounds revealed a 3-5 fold increase in antiplasmodial activity against chloroquine-resistant strain Dd2 compared to chloroquine. Among the six compounds with good antiplasmodial activity, a reduced cross-resistance relative to artesunate (>3 fold in comparison to chloroquine) was observed, mainly in derivatives that incorporated chloroquine-resistance reversing pharmacophores. A general trend for reduced chloroquine cross-resistance was also detected among 12 out of the 15 compounds tested.

Full text of DOI:10.1016/j.bmc.2015.06.044

Accepted Manuscript
In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives
synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine
Lebusetsa Taleli, Carmen de Kock, Peter J. Smith, Stephen C. Pelly, Margaret
A.L. Blackie, Willem A.L. van Otterlo
PII:
S0968-0896(15)00538-6
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.06.044
BMC 12400
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 May 2015
10 June 2015
20 June 2015
Please cite this article as: Taleli, L., Kock, C.d., Smith, P.J., Pelly, S.C., Blackie, M.A.L., van Otterlo, W.A.L., In
vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives synthesized from 7-chloro-N-(prop-2-
yn-1-yl)quinolin-4-amine, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.
2015.06.044
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Graphical Abstract
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In vitro antiplasmodial activity of triazole-
linked chloroquinoline derivatives
synthesized from 7-chloro-N-(prop-2-yn-1-
yl)quinolin-4-amine
Leave this area blank for abstract info.
Lebusetsa Taleli,a Carmen de Kock,b Peter J. Smith,b Stephen C. Pelly,a Margaret A. L. Blackiea and Willem A.
a
L. van Otterloa∗ Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1,
Matieland 7602, South Africa bDivision of Pharmacology, Department of Medicine, University of Cape Town,
Observatory 7925, South Africa

Bioorganic & Medicinal Chemistry
journal homepage: www.els evier.com
In vitro antiplasmodial activity of triazole-linked chloroquinoline derivatives
synthesized from 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine
Lebusetsa Taleli,a Carmen de Kock,b Peter J. Smith,b Stephen C. Pelly,a Margaret A. L. Blackiea and
Willem. A. L. van Otterloa∗
a Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa
b Division of Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa
ARTICLE INFO
ABSTRACT
Article history:
Received
The synthesis and in vitro evaluation of novel triazole-linked chloroquinoline derivatives as
potential antiplasmodial agents against Plasmodium falciparum is reported. The 15 synthesized
target compounds were obtained by means of a copper(I)-mediated click reaction between a
variety of 1,2- and 1,3-azidoamines and 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine in
moderate to good yields (53−85%). The compounds were screened for antiplasmodial activity
against NF54 chloroquine-sensitive and Dd2 chloroquine-resistant strains, alongside chloroquine
and artesunate as reference compounds. Six of the test compounds revealed a 3−5 fold increase
in antiplasmodial activity against chloroquine-resistant strain Dd2 compared to chloroquine.
Among the six compounds with good antiplasmodial activity, a reduced cross-resistance relative
to artesunate (>3 fold in comparison to chloroquine) was observed, mainly in derivatives that
incorporated chloroquine-resistance reversing pharmacophores. A general trend for reduced
chloroquine cross-resistance was also detected among 12 out of the 15 compounds tested.
Received in revised form
Accepted
Available online
Keywords:
Antiplasmodial
4-aminoquinoline
CuAAC click chemistry
Triazole linkers
Resistance reversal
2009 Elsevier Ltd. All rights reserved
.
———
∗
Corresponding author. Tel.: +27-021-808-3344; fax: +27-021-808-3360; e-mail: wvo@sun.ac.za

1. Introduction
For several decades, the challenge of emerging multidrug
resistant strains of Plasmodium falciparum and its mosquito
vector has been partially managed by the provision of
chemotherapeutic regimens and insecticide-treated nets to the
people at risk of endemic malaria. Despite significant progress,
there are still ~109 countries where malaria is endemic, of which
99 have on-going malaria transmission challenges.1 Because of
the rapid emergence of resistance the use of combinations of
existing antimalarial drugs is almost ubiquitous. Nonetheless,
systematic research efforts to identify the next generation of
antimalarial drugs remain a pressing need.
Figure 2 A hybridized CQ compound with chemosensitizing effects in
CQ-resistant P. falciparum strains.13
In this regard, researchers have demonstrated that the 4-
aminoquinoline core can be used as a template for the discovery
of novel agents.2, 3 Compounds such as chloroquine (CQ) have
With these points in mind, we proposed the synthesis of short-
chain chloroquinoline derivatives, coupled to various small
heterocyclic and/or aryl amine functionalities through a triazole
linker. We have recently explored triazole-linked quinoline
derivatives against P. falciparum and found these compounds to
have moderate activity.19, 20 It was thus decided to re-examine the
7-chloro-4-aminoquinoline nucleus, a haematin-binding core
recognized for potent antiplasmodial activity, due to its
association with haem and the prevention of toxic haematin
sequestration.3, 21
thus remained inspirational
for
alternative malaria
chemotherapies [Fig. 1 (a)].4, 5 Of importance is that this class of
compound derives its popularity from decent safety profiles,
efficacy and cost effective syntheses.5, 6 In terms of compounds
from this class, clinical candidates such AQ-13 (b),7 amodiaquine
(c),8 and GSK369796 (d),8 and many more have been
demonstrated as effective antimalarial agents against numerous
CQ-resistant P. falciparum strains.8, 9a
The use of a triazole-linker, a privileged pharmacophore in a
large number of bioactive agents,22 afforded an opportunity to
link various functional groups by way of click chemistry.
Moreover, triazoles have been shown to possess metabolic
stability which makes them ideal lipophilic-linkers.22 It should be
noted that several synthetic approaches to triazole-linked 7-
chloroquinoline antimalarials have been documented.23-27 The
synthesis of the largest set of triazole-quinoline prototypes have
been carried out by click reactions between 4-azido-7-
chloroquinoline and alkyne moieties, resulting in structures with
the generic structure (e) [as in Figure 3].24, 25, 28-30 Alternatively,
small libraries of molecules have been generated with the triazole
portion on a side chain originating from the 4-amino-7-
chloroquinoline scaffold. This is exemplified by the generic
structure (f) [Fig. 3] and this template has been recently utilized
by the groups of Egan,26 Andrews and Poulsen27 Unfortunately,
the bioactivities of compounds with the general structure (e) have
to date been rather modest, most probably because there is no 4-
amino functionality on the quinoline nucleus, which appears to
strongly influence the haematin binding ability of these
N
HN
3
HN
N
N
3
N
Cl
Cl
(a)
AQ-13
Chloroquine (
)
CQ
(b)
NH
OH
N
HN
N
OH
HN
N
Cl
(c)
Cl
Amodiaquine
(d)
GSK369796
Figure 1: Quinoline-based antimalarial agents
compounds, as well as their ability to accumulate in the food
vacuole of the parasite.2,
25, 31
A number of investigations aimed at the reversal of CQ-
resistance in P. falciparum isolates have involved the covalent
linking of privileged 4-aminoquinoline scaffolds with CQ
modulating agents.10-12 In this area, several hybridized CQ
molecules (see Fig. 2) that act as chemosensitizers for P.
falciparum, have been investigated; however, only a few of these
compounds have reached clinical trials.13-14 Among these
compounds, hybrids that are composed of the chloroquinoline
scaffold and dibenzyl or bulky distal aryl amine groups have
On the other hand, a number of
compounds with the general structure (f) have shown improved
antimalarial activity against drug resistant P. falciparum parasite
strains.26, In view of the influence of the side chain amino
27
26
groups on antiplasmodial activity,2, together with the above
discussed factors; we prepared 7-chloro-N-(prop-2-yn-1-
yl)quinolin-4-amine 1 (Scheme 1) and generated a small library
of compounds by click chemistry of this compound and varied
1,2- and 1,3-azidoamines. Subsequently, their antimalarial
activity against P. falciparum was determined.
been shown to be promising sensitizers and resistance reversing
agents.15,
16
In some instances, hybrids with distal amine
functional groups have also been associated with the ability to
induce sensitivity and increase drug accumulation in CQ-resistant
parasite to levels similar, or close to those of CQ-sensitive
strains.11 Earlier studies have however shown that short chain
N,N-dialkylamine analogues tend to undergo in vivo dealkylation
which also affects their activity and cross-resistance properties.9b,
17
While the bulkier distal amine groups have proven to enhance
in vivo efficacy, small heterocyclic rings have been demonstrated
to possess metabolic stability and significantly improve
antimalarial activity.18
Figure 3 Triazole-linked choroquinoline antiplasmodial agents.

2. Results and discussion
2.1. Chemistry
Starting from a commercially available 4,7-dichloroquinoline,
nucleophilic substitution at the C(4)-position was carried out
under inert conditions using propargyl amine and catalytic p-
toluene sulfonic acid in dioxane, to afford 7-chloro-N-(prop-2-
yn-1-yl)quinolin-4-amine (1) in 63% yield as depicted in Scheme
1.
Scheme 3 Preparation of dibenzo-fused amino azide building block.
In terms of the click reactions, compounds (5b–5i′) were
obtained in moderate to good yields (53–85%) using anhydrous
Cu(I) in THF for 0.5–1.5 h (see Scheme 4). The desired products
were highly polar and often their extraction from aqueous
saturated ammonium chloride solution resulted in low yields.
Therefore, removal of excess CuI was achieved by filtration
through celite after dilution of the reaction mixture with
dichloromethane. Silica gel column purifications were then
performed to separate desired compounds (5b–5i′) from any
unreacted compound 1.
Scheme 1 Synthesis of 4-aminoquinoline alkyne precursor 1.
The aliphatic azides connected to variable carbon spacers
were then synthesized from propane-1,3-diol and ethane-1,2-diol
(see reaction Scheme 2). The diols were firstly converted into
their corresponding bis-mesylate compounds using mesyl
chloride and trimethylamine to obtain compounds 2a and 2a′
(94% and 99%, respectively).32 The bis-mesylate compounds
were then treated with sodium azide in acetonitrile to obtain
azidoamine mesylates 3a and 3a′ in moderate yields (42% and
46%, respectively). Finally, selected secondary amines were
coupled to compounds 3a and 3a′ in an SN2 reaction to afford the
desired amino azides (4b–4h′) in yields of 34–73%.
Scheme 4 Click synthesis of 7-chloroquinoline derivatives.
All the compounds (5b–5i′) were characterized by NMR, IR
and high resolution mass spectroscopy, providing spectral data in
agreement with the postulated structures. In addition, the
regioselective formation of the triazoles was unambiguously
confirmed by the application of gHSQCAD and gHMBC NMR
spectroscopic experiments.34
2.2. In vitro antiplasmodial activity
The antiplasmodial activity of compounds 5b–5i' was
evaluated against strains of P. falciparum NF54 (CQ susceptible)
and Dd2 (CQ resistant), using CQ and artesunate as positive
controls (see Table 1 and Figure 4). The resistance factor (RI)
for each compound was subsequently calculated (see Table 1
Table 1 and Figure 4).18
Among the 15 triazole-linked chloroquinoline derivatives
under study, 10 compounds displayed a moderate to good 50%
growth inhibition of CQ-resistant Dd2 at a concentration range of
51–261 nM (refer to Table 1 and Figure 4). Of these, six
compounds (5b, 5c, 5d, 5g', 5h and 5i') possessed increased
antiplasmodial activity at 100 nM (50.8–78.6 nM range) against
Dd2, when compared to CQ (245 nM). It must be noted that these
compounds were 3–5 fold more active than CQ; however, they
were still 2–3 fold less active compared to the gold standard
artesunate. It is noteworthy that this activity was more or less
equivalent to the CQ reference drug against CQ-susceptible
NF54 P. falciparum strain.
Scheme 2 Preparation of amine azide building blocks (see experimental
section for more details).
Following unsuccessful attempts to prepare sterically hindered
dibenzo-fused amine azide analogues from 3a and 3a′, amino
azide 4i′ was prepared from commercially available 10,11-
dihydro-5H-dibenzo[b,f]azepine and 1-bromo-3-chloropropane
starting materials by consecutive nucleophilic displacement of
the halogens (shown on Scheme 3). The first step of the reaction
sequence33 afforded intermediate 3i′, which was separated from
the 5-allyl byproduct (3i) by means of chromatography. In the
second step, azidation was carried out on 3i′ with excess sodium
azide in a 1:1 DMSO-C6H6 solvent mixture to afford compound
4i′ in a reasonable 61% yield.

Table 1 Antimalarial activity of test compounds 5b−5i' [see Figure 4
below] against NF54 and Dd2 P. falciparum strains.
reported a marginal improvement of antimalarial profile between
mono- and bis-1,2,3-triazole tethered 7-chloroquinolines against
CQ resistant W2.28 This slight increase in antiplasmodial activity
was thought to be a result of the bis-triazole linker motif or
enhanced binding of haem to the bis-7-chloroquinoline
compounds.28 Recently, studies on triazole-chloroquinoline
hybrids have, however, strongly highlighted the dependence of
activity upon the alkyl side chain rather than a triazole linker.25-27
The latter developments support proposals that quinoline
scaffolds and variations in chain length are the core features
responsible for activity, while the triazole-linker provides
structural variations which could be responsible for
circumventing CQ resistance. Although a direct comparison
between the antiplasmodial activities of various triazole-
chloroquinoline derivatives is impractical due to variations in
study approaches (different P. falciparum strains and assay
methods), it appears that in the cases where a triazole group is
tethered directly to the 4-position of quinolone core, it is the loss
of the amino functionality on the quinoline which appears to
affect basicity, haem interactions and subsequent potency.2, 25, 31
The side chain amino group also impacts the effect of resistance
reversing activity as reflected in previously published work.26, 35
Keeping in mind that the 4-aminoquinoline core is a known
privileged antimalarial scaffold with potent haemozoin inhibition
properties,2 the scaffold used in this manuscript maintains these
favorable properties while affording the opportunity to vary the
side chains in a divergent manner with a variety of amino azides.
Figure 4 General structure of triazole-based test compounds*
IC50 (nM)
Dd2
245 5
RI
Dd2/NF54
20
Compound*
n†
n/a
n/a
2
NF54
CQ
Artesunate
5b
12.1 0.4
< 5.2 0.5
10.2 2.4
8.9 1.6
24.2 3.1
51.6 6.8
4.6
5.1
5b′
3
123
1
14
5c
2
16.2 5.1
18.4 3.0
9.8 1.1
69.3 22.7
149 28
4.3
5c′
3
8.1
5d
2
53.5 3.3
5330 268
1763 121
261 13
5.5
5d′
3
1977 142
1303 217
77.7 4.7
380 66
2.7
5e
2
1.4
3. Conclusion
5e′
3
3.3
Fifteen N-[(1H-1,2,3-triazol-4-yl)methyl]-7-chloroquinolin-4-
amine derivatives have been synthesized by applying a copper-
mediated click strategy to the 7-chloro-N-(prop-2-yn-1-
yl)quinolin-4-amine scaffold and a variety of 1,2- and 1,3-
aminoazides. The compounds were tested in terms of their ability
to in vitro inhibit NF54 and Dd2 P. falciparum strains and
preliminary evaluations indicate that some members of this novel
class of compounds (5b, 5c, 5d, 5g', 5h and 5i') have the ability
(3–5 fold) to overcome CQ resistance when compared to CQ. We
believe that these new CQ derivatives offer a fresh approach for
the synthesis and identification of novel compounds with activity
against CQ resistant P. falciparum strains. Our future work
intends to explore other isomeric triazole linkers, and to perform
additional biological assessment of these lead compounds.
5f
2
492 82
1.3
5f′
3
165 42
305 15
1.8
5g
2
151
4
216 42
1.4
5g′
3
15.0 3.1
140 11
50.8 4.5
78.6 26.9
2241 158
74.1 6.1
3.4
5h
2
0.6
5h′
3
114
4
20
5i′
3
64.3 5.0
1.2
* The NR1R2 portions of the chemical structures shown in Figure 4 are
graphically shown in Scheme 2. In addition, the full structures are provided
in the supporting information as Table S1; †ethyl/propyl side chain spacer.
4. Experimental
Interestingly, antiplasmodial activity was observed for
triazole-linked chloroquinoline analogues that contained small N-
heterocyclic (5b, 5c and 5d) and bulky N-aryl amine (5g', 5h and
5i') side chain groups. In general, analogues with smaller amines
on the lateral side chain demonstrated an overall increase in
activity towards the CQ sensitive NF54 strain, when compared to
their bulkier N-aryl amine counterparts. However, there was no
evident trend against the CQ resistant Dd2 strain in this regard.
4.1. General
Unless otherwise indicated, air- and moisture-sensitive
reactions were carried out in oven dried glassware with
anhydrous solvents distilled prior to use under a positive pressure
of nitrogen gas. Organic solvents were evaporated on Büchi
rotary evaporator equipped with diaphragm vacuum pump.
Analytical grade reagents were used as received from
commercial sources. Preparative column chromatography was
carried out on a silica gel 60 (70–230 mesh ASTM), Fluka. Thin
layer chromatography (TLC) was performed using pre-coated
60F aluminium silica gel plates with 254 nm fluorescent
indicator from Merck. Developed TLC plates were viewed under
ultra violet light or by treatment with an appropriate stain such as
iodine, KMnO4, while aliphatic azides were visualized after a
contrast Rehumann’s purple colour was developed with
ninhydrin following a TLC Staudinger azide reduction protocol.38
Twelve of the compounds tested showed reduced cross-
resistance, with a resistance index factor in the range 0.6–8.1
compared to 20 for CQ. Chloroquinoline derivatives
incorporating known CQ resistance reversing pharmacophores35-
37
(5f–5i') generally had improved resistance factors when
compared to artesunate (4.6), with the exception of 5h'. The
observed resistance index of the three most active compounds
(compound 5g', 5h and 5i') was between 0.6–3.4.
20
In line with our earlier investigations,19,
this study has
illustrated that another class of triazole-linked 7-chloroquinoline
compounds based on the 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-
amine scaffold, was able to overcome a CQ resistant P.
falciparum strain. It should be noted that Kumar and co-workers
The melting points were determined on a variable heat
Gallenkamp apparatus (temperature range 20–350 °C) equipped
with a laboratory thermometer, and are uncorrected. NMR

4.2.3. Preparation of azido mesylate spacers (3a
and 3a′)
spectra were obtained from Varian Unity Inova spectrometers
1
with H frequency of 300 MHz or 400 MHz, and 13C frequency
of 75 MHz or 150 MHz. All spectra were obtained on a 5 mm
dual broad band PFG probe with a probe temperature of 25 °C
and the solvents that were used are indicated in the text. Data for
1H NMR spectra are reported as follows: chemical shifts (δ, ppm)
relative to internal solvent peaks, integration, multiplicity
abbreviation were as singlet (s), (doublet), triplet (t), quartet (q),
doublet of doublets (dd), doublet of triplet (dt), multiplet (m), and
coupling constants (J, Hz). Data for 13C NMR spectra are
reported in chemical shifts (δ, ppm) relative to residual solvent
peak. High resolution mass spectra were recorded on electrospray
ionisation in positive mode (ESI+) using a quadrupole MALDI-
TOF LC-MS instrument. The recorded mass values are within
5 ppm. Fingerprint identification of functional groups was
achieved using wavenumbers (υ, cm-1) on Nexus infra-red Pc
spectrometer equipped with a DTGS KBr detector.
Both compounds 3a and 3a′ were prepared according to a
published method.32 Starting with 2a (10 g, 46 mmol), 3a was
obtained as a colourless oil (3.2 g, 42% yield) and the NMR
spectra data obtained matched the literature values.32 1H and 13C
NMR (300 MHz, CDCl3) δ 4.28 (br t, J = 7.7 Hz, 2H), 3.53 (br t,
J = 6.5 Hz, 2H), 3.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
66.4, 48.9, 36.8.
In a similar manner, compound 3a′ was obtained as a
1
colourless oil (5.0 g, 46% yield) from 2a′ (14 g, 60 mmol). H
and 13C NMR spectroscopic data was found to be in agreement
with literature data.40 1H NMR (300 MHz, CDCl3) δ 4.34 (t, J =
6.0 Hz, 2H), 3.50 (t, J = 6.5 Hz, 2H), 3.05 (s, 3H), 2.07–1.98 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 66.5, 47.4, 37.4, 28.7.
It should be noted that during the synthesis of 3a and 3a’ the
corresponding bis-azide-containing by-products were also
observed on TLC (as less polar spots) [see reference 39 for the
staining procedure utilized]. However, after chromatoraphic
isolation of a desired product, no attempt was made to
concentrate or characterise these byproducts due to their potential
hazardous nature.
4.2. Synthesis
4.2.1. 7-Chloro-N-(prop-2-yn-1-yl)quinolin-4-amine (1)
In a Schlenk reaction tube, a solution of 4,7-dichloroquinoline
(0.50 g, 2.5 mmol) and a catalytic amount of anhydrous pTsOH
(43 mg, 0.25 mmol) in 1,4-dioxane (0.5 mL) was stirred at 50 °C
for 30 min. To this emulsion, propargyl amine (0.38 mL, 5.5
mmol) was added and the reaction was continued for 18–24 h at
85 °C. The reaction was then cooled to RT and was diluted with
CH2Cl2 (20 mL) and washed with 10% aqueous NaHCO3 (3 × 20
mL). The organic extract was dried over MgSO4, filtered, and
concentrated under reduced pressure to obtain a pale yellow
solid. Purification of crude was performed on a silica gel column
(Hex/EtOAc; 6:4) giving 1 (0.33 g, 63% yield) as off-white solid
4.2.4. Preparation of amine azides (4b–4e′)
Compounds 4b–4e′ were synthesized using the same literature
procedure,32 with the exception of 4c and 4c′ which were
prepared using an alternative literature procedure.41 The former
reactions were performed using the 3a or 3a′ intermediates at 0.5
g scale. In brief, to 3a (3.0 mmol) and K2CO3 (1.3 g, 9.1 mmol)
in MeCN (15 mL) was added the corresponding amine (HNR2,
2.6 mmol). The resulting mixture was then heated at reflux
overnight. After filtration and chromatographic separation on a
silica gel column (Hex/EtOAc; 2:3), the desired products were
obtained as colourless to yellow oils (characterizations follow).
1
(mp: 186–190 °C). IR υmax 3461, 3089, 2947, 2161, 1573; H
NMR (300 MHz, DMSO) δ 8.49 (d, J = 5.4 Hz, 1H), 8.19 (d, J =
9.0 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.80–7.72 (m, 1H), 7.49
(dd, J = 9.0, 2.3 Hz, 1H), 6.59 (d, J = 5.4 Hz, 1H), 4.14 (dd, J =
5.7, 2.3 Hz, 2H), 3.19 (t, J = 2.3 Hz, 1H); 13C NMR (75 MHz,
DMSO) δ 152.3, 149.7, 149.4, 134.0, 128.0, 125.0, 124.3, 118.0,
100.3, 80.9, 74.2, 32.0; HRMS [M + H]+ calculated for
C12H9ClN2 was 217.0533, found 217.0529.
4.2.4.1. 1-(2-Azidoethyl)piperidine (4b)
Compound 4b was obtained as a pale yellow oil (0.27 g, 72%
yield). The NMR spectroscopic data for 4b was found to be in
agreement with the data reported in the literature.42 1H NMR (300
MHz, CDCl3) δ 3.34 (t, J = 6.3 Hz, 2H), 2.55 (t, J = 6.3 Hz, 2H),
2.43 (br t, J = 6.2 Hz, 4H), 1.64–1.54 (m, 4H), 1.48-1.38 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 57.8, 54.6 (2C), 48.4, 25.7
(2C), 24.3.
4.2.2. Representative procedure for the synthesis of
sulfonyl esters (2a and 2a′)
Synthesis 2a and 2a′ was carried out using a previously
described literature method using THF solvent.32 Starting with
ethane-1,2-diol (4.5 mL, 80 mmol) solution in THF (200 mL),
mesyl chloride (7.6 mL, 96 mmol) was added in a drop-wise
manner over ca. 15 min. The reaction was stirred in an ice bath
for 1 h, warmed to RT and stirring was continued for another 3 h.
A white precipitate formed which was removed by filtration and
the solvent removed by evaporation under reduced pressure, to
afford 2a as a colourless oil (16.6 g, 94% yield) following a silica
4.2.4.2. 1-(3-Azidopropyl)piperidine (4b′)
Compound 4b′ was obtained as a pale yellow oil (0.27 g, 70%
yield). The NMR spectroscopic data was found to match that of
reported data.43 1H NMR (300 MHz, CDCl3) δ 3.33 (t, J = 6.8 Hz,
2H), 2.56–2.47 (m, 6H), 1.84–1.73 (m, 2H), 1.64–1.53 (m, 4H),
1.48–1.39 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 56.2, 54.6
(2C), 49.8, 26.4, 26.0 (2C), 24.4.
1
gel column purification using 20% EtOAc/Hex eluent. H NMR
and 13C NMR spectra data for 2a were found to match the values
reported in the literature.32 1H NMR (400 MHz, CDCl3) δ 4.47 (s,
4H), 3.08 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 66.6 (2C), 37.9
(2C).
4.2.4.3. 1-(2-Azidoethyl)pyrrolidine (4c)
Compounds 4c and 4c′ were synthesized by adapting the
literature method.41 Compound 4c was obtained as a pale yellow
oil (0.20 g, 64%). The NMR spectroscopic data for 4c was
consistent with the same compound previously reported.44 1H
NMR (300 MHz, CDCl3) δ 3.38 (t, J = 6.4 Hz, 2H), 2.67 (t, J =
6.4 Hz, 2H), 2.56–2.52 (m, 4H), 1.81–1.75 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 54.9, 54.2 (2C), 50.2, 23.5 (2C).
In a similar manner, compound 2a′ was obtained as a
colourless oil (14.7 g, 99% yield) and spectroscopic data was
found to be consistent with the literature values.39 1H NMR (300
MHz, CDCl3) δ 4.36 (t, J = 7.2 Hz, 4H), 3.04 (s, 6H), 2.19 (p, J =
7.6, 4.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 65.5 (2C), 37.7
(2C), 29.2.

4.2.4. 4. 1-(3-Azidopropyl)pyrrolidine (4c′)
4.2.5.2. N-(3-Azidopropyl)-N-methylaniline (4f′)
Compound 4c′ was afforded as pale yellow oil (0.26 g, 73%
yield). IR υmax 2961, 2789, 2093, 1456, 1276, 1147; H NMR
(300 MHz, CDCl3) δ 3.31 (t, J = 6.6 Hz, 2H), 2.51–2.42 (m, 6H),
1.80–1.70 (m, 6H); 13C NMR (150 MHz, CDCl3) δ 56.8 (2C),
55.9, 52.4, 31.0, 26.1(2C); HRMS [M + H]+ calculated for
C7H14N4 was 155.1297, found 155.1297.
Compound 4f′ was obtained as a pale yellow oil (0.13 g, 37%
yield) and purified as in 4f above. IR υmax 3056, 2945, 2875,
2092, 1588, 1492, 1243; H NMR (300 MHz, CDCl3) δ 7.32–
7.21 (m, 2H), 6.79–6.71 (m, 3H), 3.45 (t, J = 6.5 Hz, 2H), 3.40 (t,
J = 6.5 Hz, 2H), 2.97 (s, 3H), 1.95–1.84 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 149.1, 129.3 (2C), 116.5, 112.2 (2C), 49.8, 49.2,
38.5, 26.3; HRMS [M + H]+ was 191.1294 calculated for
C10H14N4, found 191.1294.
1
1
4.2.4. 5. 2-Azido-N, N-diethylenamine (4d)
Compound 4d was obtained as colourless oil (0.19 g, 48%).
The NMR spectrum was found to be similar to one reported in
the literature.45 1H NMR (300 MHz, CDCl3) δ 3.29 (t, J = 6.4 Hz,
2H), 2.65 (t, J = 6.4 Hz, 2H), 2.56 (q, J = 7.2 Hz, 4H), 1.04 (t, J =
7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 52.4, 49.7, 47.5 (2C),
12.0 (2C).
4.2.5.3. 2-Azido-N-benzyl-N-methylethanamine
(4g).
Benzylamine azide compounds 4g–4h′ were synthesized using
a literature procedure.48 Compound 4g was obtained as a
colourless oil (0.16 g, 41% yield). IR υmax 2947, 2791, 2092,
1
1453, 1253; H NMR (300 MHz, CDCl3) δ 7.41–7.23 (m, 5H),
4.2.4. 6. 3-Azido-N, N-diethylpropan-1-amine (4d′)
Compound 4d′ was afforded as a colourless oil (0.13 g, 36%
3.59 (s, 2H), 3.36 (t, J = 6.1 Hz, 2H), 2.67 (t, J = 6.1 Hz, 2H),
2.29 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 138.6, 128.9 (2C),
128.3 (2C), 127.1, 62.5, 56.2, 48.9, 42.2; HRMS [M + H]+
calculated for C10H14N4 was 191.1297, found 191.1300.
1
yield). IR υmax 2942, 2097, 1343, 1169; H NMR (300 MHz,
CDCl3) δ 3.34 (t, J = 6.8 Hz, 2H), 2.58–2.47 (m, 6H), 1.79–1.67
(m, 2H), 1.03 (t, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
49.8 (2C), 46.9 (2C), 26.7, 11.8 (2C); HRMS [M + H]+
calculated for C7H16N4 was157.1454, found 157.1446.
4.2.5.4. 3-Azido-N-benzyl-N-methylpropan-1-amine
(4g′).
Compound 4g′ was obtained as a colourless oil (0.18 g, 47%
yield). IR υmax 3096, 3059, 2937, 2873, 2090, 1598, 1503, 1258;
1H NMR (300 MHz, CDCl3) δ 7.38–7.22 (m, 5H), 3.51 (s, 2H),
3.37 (t, J = 6.9 Hz, 2H), 2.48 (t, J = 6.9 Hz, 2H), 2.21 (s, 3H),
1.86–1.75 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 139.0, 128.9
(2C), 128.2 (2C), 126.9, 62.4, 54.2, 49.5, 42.0, 25.5; HRMS [M +
H]+ calculated for C11H16N4 was 205.1454, found 205.1457.
4.2.4. 7. 4-(2-Azidoethyl)morpholine (4e)
Compound 4e was obtained as a colourless oil (0.27 g, 69%
yield) and the 1H and 13C NMR spectrum corresponded to
published data.46 1H NMR (300 MHz, CDCl3) δ 3.78–3.69 (m,
4H), 3.35 (br t, J = 6.4 Hz, 2H), 2.63–2.57 (m, 2H), 2.55–2.47
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 66.9 (2C), 57.6, 53.6
(2C), 47.9.
4.2.5.5. 2-Azido-N,N-dibenzylethanamine (4h)
4.2.4. 8. 4-(3-Azidopropyl)morpholine (4e′)
Compound 4h was obtained as a colourless oil that slowly
solidified into an off-white solid at room temperature (0.33 g,
61% yield, mp: 36–38 °C). IR υmax 3021, 2947, 2796, 2089,
Compound 4e′ was obtained as a colourless oil (0.27 g, 68%
yield). The 1H and 13C NMR spectrum was in agreement with the
published data.43 1H NMR (300 MHz, CDCl3) δ 3.76–3.67 (m,
4H), 3.35 (t, J = 6.7 Hz, 2H), 2.50–2.32 (m, 6H), 1.82–1.72 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 66.9 (2C), 55.6, 53.6 (2C),
47.5, 25.9.
1
1493, 1449, 1294; H NMR (300 MHz, CDCl3) δ 7.47–7.25 (m,
10H), 3.67 (s, 4H), 3.28 (t, J = 6.1 Hz, 2H), 2.74 (t, J = 6.1 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 139.0 (2C), 128.8 (4C), 128.4
(4C), 127.1 (2C), 58.9 (2C), 53.0, 49.3; HRMS [M + H]+
calculated for C16H18N4 was 267.1610, found 267.1610.
4.2.5. Preparation of azido phenyl/benzylamine
moieties (4f–4h′)
4.2.5.6. 3-Azido-N,N-dibenzylpropan-1-amine (4h′)
Compound 4h′ was obtained as a pale yellow oil (0.30 g, 57%
Azido phenylamines 4f and 4f′ were prepared from 3a and 3a′
by adapting a previously described literature procedure and a
representative procedure is described below.47 In a round-
bottomed flask, a catalytic amount of KI (38 mg, 0.23 mmol) was
added to a mixture of 3a (0.50 g, 3.0 mmol) and K2CO3 (1.3 g,
9.1 mol) in MeCN (15 mL). N-Methylaniline (0.20 g, 1.9 mmol)
was then added and the reaction was heated at reflux for 72 h.
The K2CO3 was then filtered off, the filtrate washed with
saturated brine (20 mL) and the product was extracted into
CH2Cl2 (3 × 20 mL). The organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure to
obtain the following products after purification as described
below:
1
yield). IR υmax 3021, 2947, 2796, 2089, 1490, 1449, 1294; H
NMR (400 MHz, CDCl3) δ 7.37–7.22 (m, 10H), 3.58 (s, 3H),
3.31 (t, J = 7.0 Hz, 2H), 2.53 (t, J = 6.8 Hz, 2H), 1.82–1.72 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 139.4 (2C), 128.5 (4C), 128.3
(4C), 127.1 (2C), 58.5 (2C), 50.6, 49.6, 26.6; HRMS [M + H]+
calculated for C17H20N4 was 281.1767, found 281.1775.
4.2.6. Synthesis
dihydro-5H-dibenzo[b,f]azepine (4i')
of
5-(3-Azidopropyl)-10,11-
Synthesis of compound 4i′ was carried out in two separate
steps, starting from commercially available 10,11-dihydro-5H-
dibenzo[b,f]azepine that was coupled with 1-bromo-3-
chloropropane using a modified procedure reported by DePue,33
followed by azidation to afford the desired product. Under inert
conditions, 10,11-dihydro-5H-dibenzo[b,f]azepine (0.25 g, 1.3
mmol) was dissolved in a mixture of benzene-THF (1:4, 10 mL)
in a Schlenk vessel and then nBuLi (1.7 M in hexane, 0.76 mL,
1.3 mmol) was added in a drop-wise fashion over 30 min at 0 °C.
The reaction mixture was allowed to warm to RT and 1-bromo-3-
chloropropane (0.16 mL, 55 mmol) was added, and the reaction
was stirred for an additional 3.5 h. The light brown solution was
then concentrated in vacuo to obtain a crude product (0.15 g)
4.2.5. 1. N-(2-Azidoethyl)-N-methylaniline (4f)
Compound 4f was obtained as a pale yellow oil (0.12 g, 34%
yield) following purification on a silica gel column using hexane
1
eluant. IR υmax 2947, 2791, 2092, 1453, 1253; H NMR (300
MHz, CDCl3) δ 7.33–7.23 (m, 2H), 6.81–6.71 (m, 3H), 3.60–3.54
(m, 2H), 3.51–3.44 (m, 2H), 3.03 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 148.9, 129.3 (2C), 116.3, 111.9 (2C), 52.0, 49.8, 38.7;
HRMS [M + H]+ calculated for C9H12N4 was 177.1142, found
177.1142.

from which an intermediate 3i′ was isolated from 3i on a silica
gel column using hexane mobile phase (see characterization
below).
(t, J = 6.2 Hz, 2H), 2.48–2.36 (m, 4H), 1.57–1.45 (m, 4H), 1.46–
1.38 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 150.3, 148.4, 147.7,
143.0, 134.2, 127.4, 124.6, 121.2, 120.4, 116.2, 98.4, 54.0, 53.3
(2C), 47.3, 38.0, 26.1, 24.6 (2C); HRMS [M + H]+ calculated for
C19H23ClN6 was 371.1752, found 371.1751.
4.2.6. 1. 5-allyl-10,11-dihydro-5H-
dibenzo[b,f]azepine (3i)
4.2.7.2. 7-Chloro-N-({1-[3-(piperidin-1-yl)propyl]-
1H-1, 2,3-triazol-4-yl}methyl)quinolin-4-amine (5b')
Compound 3i was obtained as a colourless oil (70 mg, 23%
yield. The NMR data was in agreement with the published data.49
1H NMR (300 MHz, CDCl3) δ 7.21–7.03 (m, 6H), 7.00–6.89 (m,
2H), 5.82 (tdd, J = 5.7Hz, 17.3, 10.3 Hz, 1H), 5.28 (dd, J = 17.3,
1.6 Hz, 1H), 5.12 (dd, J = 10.3, 1.5 Hz, 1H), 4.45–4.41 (m, 2H),
3.20 (s, 4H); 13C NMR (75 MHz, CDCl3) δ 148.0 (2C), 135.6,
134.1, 129.7 (2), 126.2(2), 122.4 (2C), 120.4 (2C), 117.1 (2C),
54.4, 32.4 (2C).
Compound 5b′ was obtained as a pale yellow solid (23 mg,
79% yield, mp: 133–135 °C). IR υmax 3489, 2922, 1461, 1260,
1
1022; H NMR (300 MHz, CDCl3) δ 8.53 (d, J = 5.4 Hz, 1H),
7.94 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H),
7.33 (dd, J = 8.9, 2.1 Hz, 1H), 6.48 (d, J = 5.4 Hz, 1H), 6.08 (br
s, 1H), 4.64 (2s, 2H overlapping), 4.42 (t, J = 6.9 Hz, 2H), 2.35–
2.14 (m, 6H), 2.11–2.00 (m, 2H), 1.58–1.47 (m, 4H), 1.46–1.34
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 152.1, 149.6, 149.1,
144.0, 135.3, 128.7, 125.7, 122.4, 121.6, 117.5, 99.6, 55.3, 54.6
(2C), 48.6, 39.1, 27.6, 26.2 (2C), 24.5; HRMS [M + H]+
calculated for C20H25ClN6 was 385.1876, found 385.1895.
4.2.6. 2. 5-(3-Chloropropyl)-10,11-dihydro-5H-
dibenzo[b,f]azepine (3i')
Compound 3i′ was obtained as a pale yellow solid (84 mg,
24% yield, mp: 43–45 °C). IR υmax 3056, 2953, 1587, 1492,
1
1364, 1265, 747, 693; H NMR (300 MHz, CDCl3) δ 7.25–7.05
4.2.7.3. 7-Chloro-N-({1-[2-(pyrrolidin-1-yl)ethyl]-
1H-1, 2,3-triazol-4-yl}methyl)quinolin-4-amine (5c)
(m, 6H), 7.01–6.94 (m, 2H), 3.94 (t, J = 6.5 Hz, 2H), 3.60 (t, J =
6.5 Hz, 2H), 3.20 (s, 4H), 2.13–203 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 147.0 (2C), 133.3 (2C), 128.9 (2C), 125.4 (2C), 121.7
(2), 118.8 (2C), 46.5, 41.9, 31.1 (2C), 29.6; HRMS [M + H]+
calculated for C17H18ClN was 272.1207, found 272.1215.
Compound 5c was obtained as a pale yellow solid (18 mg,
67% yield, mp: 117–119 °C). IR υmax 3409, 2923, 1699, 1518,
1451; 1H NMR (300 MHz, CDCl3) δ 8.52 (br s, 1H), 7.95 (s, 1H),
7.81 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H), 7.35 (dd, J = 8.9, 2.1 Hz,
1H), 6.54 (d, J = 5.4 Hz, 1H), 6.17 (s, 1H), 4.65 (s, 2H), 4.50 (t, J
= 6.4 Hz, 2H), 2.98 (t, J = 6.4 Hz, 2H), 2.60–2.51 (m, 4H), 1.83–
1.74 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 151.4, 149.3,
148.2, 143.5, 135.4, 128.0, 125.8, 122.5, 121.7, 117.1, 99.5, 55.7,
54.1 (2C), 49.7, 39.0, 23.6 (2C); HRMS [M + H]+ calculated for
C18H21ClN6 was 357.1595, found 357.1581.
4.2.6. 3. 5-(3-Azidopropyl)-10,11-dihydro-5H-
dibenzo[b,f]azepine (4i')
In a round-bottomed flask, compound 3i′ (70 mg, 0.26 mmol)
was dissolved in benzene (2.5 mL) and a solution of NaN3 (25
mg, 0.39 mmol) in DMSO (2.5 mL) was transferred into the
reaction flask via a syringe. The reaction was then stirred at 100
°C for 48 h until TLC showed the starting material had been
consumed. The reaction mixture was then diluted with distilled
water (15 mL) and product was extracted into CH2Cl2 (3 × 15
mL). The organic solvent was dried over MgSO4 and the
evaporated in vacuo to afford 4i′ (61%, 44 mg) as a pale yellow
4.2.7.4. 7-Chloro-N-({1-[3-(pyrrolidin-1-
yl)propyl]-1H-1,2,3-triazol-4-yl}methyl)quinolin-4-
amine (5c')
Compound 5c′ was obtained as a pale yellow solid (18 mg,
63% yield, mp: 115–117 °C). IR υmax 3493, 2977, 1740, 1388,
1
oil. IR υmax 2921, 2843, 2091, 1592, 1485, 1229; H NMR (300
1
1217; H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 5.3 Hz, 1H),
MHz, CDCl3) δ 7.23–7.06 (m, 6H), 7.02–6.92 (m, 2H), 3.86 (t, J
= 6.7 Hz, 2H), 3.36 (t, J = 6.7 Hz, 2H), 3.19 (s, 4H), 1.94–184
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.0 (2C), 134.3 (2C),
130.0 (2C), 126.5 (2C), 122.8 (2C), 119.8 (2C), 49.6, 47.5, 32.2
(2C), 27.2; HRMS [M + H]+ calculated for C17H18N4 was
272.1610, found 279.1619.
7.97 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.60 (s, 1H),
7.37 (dd, J = 8.9, 1.6 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H), 6.02 (br
s, 1H), 4.65 (2s, 2H overlapping), 4.44 (t, J = 6.4 Hz, 2H), 2.39–
2.26 (m, 4H), 2.18–2.01 (m, 2H), 1.64–1.41 (m, 4H), 1.49–1.41
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 151.1, 149.3, 149.1,
143.8, 135.1, 128.8, 125.6, 122.0, 121.2, 116.5, 99.5, 54.0 (2C),
52.3, 48.5, 39.2, 29.4, 23.5 (2C); HRMS [M + H]+ calculated for
C19H23ClN6 was 371.1752, found 371.1751.
4.2.7. General procedure for the preparation of
triazole-linked chloroquinoline derivatives (5b–5i′)
Triazole-linked compounds were synthesized using a CuAAC
click reaction adapted from the literature.50 In a 2.5 mL round-
bottomed flask, compound 1 (20 mg, 0.092 mmol) and CuI (17
mg, 0.089 mmol) were mixed in anhydrous THF (0.5 mL). The
appropriate amino alkyl azide (0.11 mmol) was then added and
the reaction mixture was stirred for 30–90 min. at RT, until the
starting material was consumed. The reaction mixture was then
diluted with CH2Cl2 (3 mL), filtered through celite and purified
on a silica gel column by means of a gradient elution with 50%
EtOAc:Hex to 10% MeOH:Me2CO mobile phase.
4.2.7.5. 7-Chloro-N-({1-[2-(diethylamino)ethyl]-
1H-1, 2,3-triazol-4-yl}methyl)quinolin-4-amine (5d)
Compound 5d was obtained as a pale yellow solid (19 mg,
70% yield, mp: 83–85 °C). IR υmax 3493, 3054, 2976, 1581,
1495, 1365, 1265; 1H NMR (300 MHz, CDCl3) δ 8.52 (br s, 1H),
7.94 (s, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.70 (s, 1H), 7.34 (d, J =
9.0 Hz, 1H), 6.50 (d, J = 5.2 Hz, 1H), 5.95 (br s, 1H), 4.63 (s,
2H), 4.39 (t, J = 6.2 Hz, 2H), 2.85 (t, J = 6.1 Hz, 2H), 2.52 (q, J =
6.9 Hz, 4H), 0.92 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 151.7, 149.4, 148.8, 143.2, 135.4, 128.4, 125.7, 122.6, 121.3,
117.3, 99.5, 52.9, 49.2, 47.3 (2C), 39.0, 11.8 (2C); HRMS [M +
H]+ calculated for C18H23ClN6 was 359.1752, found 359.1758.
4.2.7. 1. 7-Chloro-N-({1-[2-(piperidin-1-yl)ethyl]-
1H-1,2,3-triazol-4-yl}methyl)quinolin-4-amine (5b)
Compound 5b was obtained as a pale yellow solid (22 mg,
76% yield, mp: 132–134 °C). IR υmax 3145, 2925, 1576, 1451,
4.2.7.6. 7-Chloro-N-({1-[3-(diethylamino)propyl]-
1H-1, 2,3-triazol-4-yl}methyl)quinolin-4-amine (5d')
1
1370; H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.2 Hz, 1H),
7.96 (d, J = 2.1 Hz, 1H), 7.77 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H),
7.38 (dd, J = 6.8, 2.0 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 5.95 (br
s, 1H), 4.63 (2s, 2H overlapping), 4.45 (t, J = 6.2 Hz, 2H), 2.75
Compound 5d′ was obtained as a pale yellow solid (17 mg,
61% yield, mp: 82–84 °C). IR υmax 3493, 3080, 2852, 1513,

1459,1336, 1216; 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 5.4
Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.61
(s, 1H), 7.39 (dd, J = 8.9, 2.2 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H),
5.92 (s, 1H), 4.66 (s, 2H), 4.45 (t, J = 6.9 Hz, 2H), 2.55 (q, J =
7.2 Hz, 4H), 2.47 (t, J = 6.9 Hz, 2H), 2.15–2.06 (m, 2H), 1.00 (t,
J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 152.1, 149.7,
149.5, 144.2, 135.6, 129.1, 126.2, 122.6, 121.8, 117.8, 100.2,
50.2, 49.4, 47.7 (2C), 40.1, 28.9, 12.5 (2C). HRMS [M + H]+
calculated for C19H25ClN6 was 373.1908, found 373.1904.
128.9 (2C), 126.4, 122.5, 122.2, 117.8, 113.4 (2C), 100.2, 50.2,
49.0, 39.7, 39.3, 30.4; HRMS [M + H]+ calculated for
C22H23ClN6 was 407.1752, found 407.1743.
4.2.7.11. 7-Chloro-N-[(1-{2-
[benzyl(methyl)amino]ethyl}-1H-1, 2,3-triazol-4-
yl)methyl] quinolin-4-amine (5g)
Compound 5g was obtained as an off-white solid (22 mg, 69%
yield, mp: 133–135 °C). IR υmax 3444, 3317, 3144, 2932, 2847,
1
1579, 1448, 1367, 1220; H NMR (300 MHz, CDCl3) δ 8.45 (br
4.2.7. 7. 7-Chloro-N-{[1-(2-morpholinoethyl)-1H-
1,2,3-triazol-4-yl]methyl}quinolin-4-amine (5e)
s, 1H), 7.88 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.53 (s, 1H), 7.27
(d, J = 7.6 Hz, 1H), 7.26–7.02 (m, 5H), 6.44 (d, J = 5.2 Hz, 1H),
5.92 (br s, 1H), 4.56 (2s, 2H overlapping), 4.37 (t, J = 6.1 Hz,
2H), 3.45 (s, 2H), 2.78 (t, J = 6.1 Hz, 2H), 2.29 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 151.5, 149.6, 148.6, 143.6, 138.2 (2C),
135.2, 128.8 (2C), 128.3(2C), 127.3, 125.7, 122.3, 122.4, 117.2,
99.4, 62.4, 56.4, 48.4, 42.2, 39.0; HRMS [M + H]+ calculated for
C22H23ClN6 was 407.1752, found 407.1744.
Compound 5e was obtained as a pale yellow solid (21 mg,
74% yield, mp: 158–160 °C). IR υmax 3485, 2921, 2849, 1581,
1460, 1374, 1260; 1H NMR (300 MHz, CDCl3) δ 8.53 (br s, 1H),
7.95 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H),
7.32 (dd, J = 8.9, 2.0 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 6.07 (br
s, 1H), 4.64 (2s, 2H), 4.46 (t, J = 6.9 Hz, 2H), 3.66 (t, J = 4.8 Hz,
4H), 2.81 (t, J = 4.6 Hz, 4H), 2.50–2.45 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 151.4, 149.5, 148.7, 143.7, 135.3, 128.3, 125.7,
122.3, 121.4, 117.2, 99.6, 66.8 (2C), 57.8, 53.5 (2C), 47.4, 39.0;
HRMS [M + H]+ calculated for C18H21ClN6O was 373.1544,
found 373.1537.
4.2.7.12. 7-Chloro-N-[(1-{3-
[benzyl(methyl)amino]propyl}-1H-1,2,3-triazol-4-
yl)methyl]quinolin-4-amine (5g')
Compound 5g′ was obtained as an off-white solid (21 mg,
65% yield, mp: 132–134 °C). IR υmax 3444, 3317, 2932, 1579,
4.2.7. 8. 7-Chloro-N-{[1-(3-morpholinopropyl)-1H-
1,2,3-triazol-4-yl]methyl}quinolin-4-amine (5e')
1
1448, 1367, 1220, 1137; H NMR (300 MHz, CDCl3) δ 8.56 (br
s, 1H), 7.98 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.42–7.18 (m, 7H),
6.51 (s, 1H), 5.95 (br s, 1H), 4.58 (s, 2H), 4.43 (t, J = 6.8 Hz,
2H), 3.46 (s, 2H), 2.35 (t, J = 6.4 Hz, 2H), 2.22 (s, 3H), 2.09–
2.04 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 151.1, 149.8, 148.0,
143.4, 138.8, 135.5, 129.1 (2C), 128.3 (2C), 127.9, 127.2, 125.8,
122.2, 121.5, 117.1, 99.4, 62.7, 53.0, 48.1, 42.2, 38.9, 27.8;
HRMS [M + H]+ calculated for C23H25ClN6 was 421.1908, found
421.1905.
Compound 5e′ was obtained as a pale yellow solid (25 mg,
85% yield, mp: 153–155 °C). IR υmax 3338, 2929, 1576, 1450,
1370; 1H NMR (300 MHz, CDCl3) δ 8.53 (br s, 1H), 7.97 (d, J =
2.0 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.55 (s, 1H), 7.37 (dd, J =
8.9, 2.0 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 5.97 (s, 1H), 4.66 (2s,
2H overlapping), 4.45 (t, J = 6.9 Hz, 2H), 3.70–3.63 (m, 4H),
2.40–2.36 (m, 4H), 2.40 (t, J = 6.8 Hz, 2H overlapping), 2.13–
2.04 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 150.4, 149.5, 147.5,
142.8, 134.2, 127.2, 124.6, 121.5, 120.5, 116.3, 98.8, 65.9 (2C),
53.8 (2C), 52.5, 47.2, 37.9, 25.9; HRMS [M + H]+ calculated for
C19H23ClN6O was 387.1701, found 387.1707.
4.2.7.13. 7-Chloro-N-({1-[2-(dibenzylamino)ethyl]-
1H-1, 2,3-triazol-4-yl}methyl)quinolin-4-amine (5h)
Compound 5h was obtained as a yellow solid (20 mg, 54%
yield, mp: 115–118 °C). IR υmax 3493, 3004, 2970, 1740, 1368,
4.2.7. 9. 7-Chloro-N-[(1-{2-[phenyl(methyl)amino]
ethyl}-1H-1, 2,3-triazol-4-yl)methyl]quinolin-4-
amine (5f)
1
1217, 1054; H NMR (300 MHz, CDCl3) δ 8.55 (br s, 1H), 7.98
(s, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.41–7.17 (m, 10H), 6.89 (s,
1H), 6.48 (d, J = 5.4 Hz, 1H), 5.98 (br s, 2H), 4.50 (s, 2H), 4.35
(t, J = 6.1 Hz, 2H), 3.57 (s, 4H), 2.46 (t, J = 6.3 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 151.3, 150.1, 149.2, 143.8, 140.1 (2C),
136.1, 129.8 (4C), 129.1 (2C), 128.9 (4C), 127.9, 126.4, 122.8,
122.1, 117.7, 100.0, 59.5 (2C), 50.4, 48.7, 39.5; HRMS [M + H]+
calculated for C28H27ClN6 was 483.2065, found 483.2063.
Compound 5f was obtained as an off-white solid (25 mg, 85%
yield, mp: 167–169 °C). IR υmax 3493, 2970, 1740, 1368, 1217;
1H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 5.3 Hz, 1H), 7.99 (d, J
= 2.1 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.40 (s, 1H overlapping),
7.39 (dd, J = 8.7, 2.2 Hz, 1H ovelapping), 7.26–7.12 (m, 2H),
6.81–6.70 (m, 1H), 6.59–6.54 (m, 2H), 6.46 (d, J = 5.4 Hz, 1H),
5.65 (br s, 1H), 4.63–4.52 (m, 4H), 3.84 (t, J = 5.9 Hz, 2H), 2.78
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.0, 149.1, 148.2, 144.1,
135.1, 129.4 (2C) , 128.8 (2C), 125.6, 122.8, 121.1, 117.6, 117.2,
112.3 (2C), 99.5, 53.1, 48.0, 38.9, 38.6; HRMS [M + H]+
calculated for C21H21ClN6 was 393.1595, found 393.1595.
4.2.7.14. 7-Chloro-N-({1-[3-
(dibenzylamino)propyl]-1H-1, 2,3-triazol-4-
yl}methyl)quinolin-4-amine (5h')
Compound 5h′ was obtained as a yellow solid (24 mg, 63%
yield, mp: 114–115 °C). IR υmax 3484, 3206, 2994, 2931, 1580,
1543, 1431, 1365; 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 4.8
Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.39–
7.22 (m, 11H), 6.79 (s, 1H), 6.47 (d, J = 5.4 Hz, 1H), 5.96 (br s,
1H), 4.49 (2s, 2H overlapping), 4.35 (t, J = 6.8 Hz, 2H), 3.56 (s,
4H), 2.46 (t, J = 6.2 Hz, 2H), 2.10–2.00 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 151.8, 149.3, 148.9, 143.2, 139.4 (2C), 135.2,
129.1 (4C), 128.7 (2C), 128.4 (4C), 127.2, 125.7, 121.9, 121.2,
117.2, 99.4, 58.8 (2C), 49.7, 48.0, 38.9, 28.1; HRMS [M + H]+
calculated for C29H29ClN6 was 497.2221, found 497.2214.
4.2.7. 10. 7-Chloro-N-[(1-{3-[phenyl(methyl)amino]
propyl}-1H-1,2,3-triazol-4-yl)methyl]quinolin-4-
amine (5f′)
Compound 5f′ was obtained as an off-white solid (17 mg,
53% yield, mp: 163–165 °C). IR υmax 3452, 2932, 1576, 1450,
1
1366, 1220; H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 5.4 Hz,
1H), 7.94 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.47 (s,
1H), 7.33 (dd, J = 9.0, 2.1 Hz, 1H), 7.24–7.15 (m, 2H), 6.78–6.67
(m, 1H), 6.65 (d, J = 8.0 Hz, 2H), 6.49 (d, J = 5.4 Hz, 1H), 6.09
(br s, 1H) 4.63 (br s, 2H), 4.38 (t, J = 7.0 Hz, 2H), 3.37 (t, J = 6.9
Hz, 2H), 2.89 (s, 3H), 2.28–2.16 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 152.1, 150.3, 149.8, 149.2, 144.7, 136.0, 130.0 (2C),

4.2.7. 15. 7-Chloro-N-({1-[2-(10,11-dihydro-5H-
dibenzo[b,f]azepin-5-yl)ethyl]-1H-1,2,3-triazol-4-
yl}methyl)quinolin-4-amine (5i')
4. Tilley, L.; Loria, P.; Foley, M. In Antimalarial
chemotherapy:Mechanisms of action, resistance, and new
directions in drug discovery; Rosenthal, P. J., Ed.; Humana Press:
Totowa N.Y., 2001, 87.
Compound 5i′ was obtained as a pale yellow solid (24 mg,
64% yield, mp: 67–69 °C). IR υmax 3484, 3371, 3147, 2927,
5. Muregi, F. W.; Kirira, P. G.; Ishih, A. Curr. Med. Chem. 2011, 18,
113.
1
2851, 1576, 1544, 1258, 1058; H NMR (300 MHz, CDCl3) δ
8.50 (d, J = 5.4 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 9.0
Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.35 (s, 1H) 7.16–6.90 (m,
8H), 6.44 (d, J = 5.5 Hz, 1H), 5.98 (br s, 1H) 4.57 (2s, 2H
overlapping), 4.35 (t, J = 6.9 Hz, 2H), 3.77 (t, J = 6.4 Hz, 2H),
3.18 (s, 4H), 2.26–2.16 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
151.1, 150.6, 147.6, 143.8, 135.4, 134.1 (2C), 130.1(2C), 129.5,
128.0, 126.6 (2C), 125.7, 123.1 (2C), 121.9, 121.4, 121.0, 119.7
(2C), 117.0, 99.3, 48.1, 46.9, 38.9, 32.1 (2C), 28.3; HRMS [M +
H]+ calculated for C29H27ClN6 was 495.2065, found 495.2067.
6. Kouznetsov, V. V.; Gómez-Barrio, A. Eur. J. Med. Chem. 2009,
44, 3091.
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Tenaglia, A. N.; Mushatt, D. M.; Dreisbach, A. W.; Lertora, J. J.;
Krogstad, D. J. PLoS Clin. Trials 2007, 2, e6.
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N.; Winstanley, P. A.; Mukhtar, A.; Bonar-Law, R.; Hindley, S.;
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4.3. Cell culture and antiplasmodial activity measurements
The antimalarial activity of compounds 5b–5i′ was tested and
determined in triplicate on two separate occasions against
chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2)
strains of P. falciparum. Continuous in vitro cultures of asexual
erythrocyte stages of P. falciparum were maintained using a
modified method of Trager and Jensen.51 Quantitative assessment
of antiplasmodial activity in vitro was determined via the parasite
lactate dehydrogenase assay (pLDH) using a modified method
essentially described by Makler et al.52
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 on the day of the experiment. CQ
diphosphate (Sigma) and artesunate (Sigma) were used as the
reference drugs in all experiments. The concentration inhibiting
50% of parasite growth (IC50 value) for each compound was
determined from a full-dose response curve. The test samples
were tested at a starting concentration of 100 µg/mL, which was
then serially diluted 2-fold in complete medium to give 10
concentrations, with the lowest concentration being 0.20 µg/mL.
Reference drugs were tested at 100 ng/mL starting concentration
of 100 ng/mL. Several compounds were also tested at a starting
concentration of 1000 µg/mL. The highest concentration of
solvent to which the parasites were exposed to had no measurable
effect on the parasite viability (data not included). The IC50
values were obtained using non-linear dose-response curve fitting
analysis via Graph Pad Prism v.4.0 software.
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5. Acknowledgements
The authors thank the Group of Organic and Medicinal
Chemistry, Central Analytical Facility Stellenbosch, Stellenbosch
University and the National Research Foundation (NRF South
Africa) for financial support. We also thank the Centre for High
Performance Computing (CHPC) for providing access to
Accelrys Discovery Studio. We gratefully acknowledge the
assistance of reviewers in pointing out references 26 and 27, of
relevance to our work and this manuscript.
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