Targeting Asexual and Sexual Blood Stages of the Human Malaria Parasite P. falciparum with 7-Chloroquinoline-Based 1,2,3-Triazoles

Article abstract of DOI:10.1002/cmdc.201800728

Novel 4-amino-7-chloroquinoline-based 1,2,3-triazole hybrids were synthesised in good yields by Cu^I-catalysed Huisgen 1,3-dipolar cycloaddition reactions of 2-azido-N-(7-chloroquinolin-4-ylaminoalkyl)acetamides with various terminal alkynes. Th

Full text of DOI:10.1002/cmdc.201800728

Accepted Article
Title: Targeting Asexual and Sexual Blood Stages of Human Malaria
Parasite P. falciparum with 7-Chloroquinoline based [1,2,3]-
Triazoles
Authors: Mahendra Nath, Ishan Wadi, Davinder Prasad, Neha Batra,
Kumkum Srivastava, Anupkumar R. Anvikar, and Neena
Valecha
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Targeting Asexual and Sexual Blood Stages of Human Malaria
Parasite P. falciparum with 7-Chloroquinoline Based [1,2,3]-
Triazoles
Ishan Wadi,[a] Davinder Prasad,[a] Neha Batra,[a] Kumkum Srivastava,[b] Anupkumar R. Anvikar,[c]
Neena Valecha,[c] Mahendra Nath*[a]
Abstract: Novel 4-amino-7-chloroquinoline based [1,2,3]-triazole
hybrids were synthesized in good yields via Cu[I] catalysed Huisgen
1,3-dipolar cycloaddition reaction of 2-azido-N-(7-chloroquinolin-4-
ylaminoalkyl)acetamides with various terminal alkynes. These new
hybrids were screened in vitro against asexual blood stages of
chloroquine sensitive 3D7 strain of P. falciparum. The most active
compounds were further screened against asexual and sexual
stages (gametocytes) of chloroquine resistant RKL-9 strain of P.
falciparum. Although all compounds were less potent than
chloroquine against 3D7 strain, the three best compounds 8a, 8b
and 9c were appreciably more active than chloroquine against the
RKL-9 strain, displaying IC50 values of <100 nM, with 8b showing an
IC50 of 2.94 nM. Further, the lead compounds were gametocytocidal
with IC50 values in the micromolar range, and were observed to
induce morphological deformations in mature gametocytes. Most
compounds demonstrated little or no cytotoxicity and exhibited good
selectivity indices. These most active compounds represent
promising candidates for further evaluation of their schizonticidal and
gametocytocidal potential.
compounded by absence of an effective transmission blocking
drug with good safety profile for glucose-6-phosphate
a
dehydrogenase (G6PD) deficient individuals.[3] Therefore,
development of safe and effective antimalarial drugs including
the ones with transmission blocking potential is extremely crucial
to tackle the ongoing threat of drug resistance and to curb
malaria transmission.[4] In order to widen the scope of treatment
and support malaria elimination program of the World Health
Organization, developing antimalarial drugs having broader
therapeutic potential which can simultaneously target both
asexual blood stages that cause disease symptoms and
gametocytes, stages responsible for transmission is beneficial.
Historically, the most targeted pathway for antimalarial drug
development is detoxification of heme and formation of
hemozoin.[5] A number of highly effective 4-aminoquinoline
antimalarial drugs such as CQ and amodiaquine (AQ) function
by targeting this pathway. Structure-activity studies of 4-
aminoquinolines have suggested that the presence of chlorine
group at seventh position and amino group at terminal position is
required for antimalarial activity of quinolines and their potency
is enhanced by the presence of a basic side chain attached to
the amino group such as in CQ.[6-8] Further modification of this
basic side chain has led to improvised antimalarials with high
potency against P. falciparum.[9] Moreover, studies on 4-
aminoquinoline analogues also resulted in generation of
promising lead compounds[10-12] and several candidates are in
preclinical development or clinical trials.[13] Considering safety
and efficacy of 4-aminoquinoline based drugs and remarkable
success of CQ in the past, 4-aminoquinoline base is
pharmaceutically suitable for use as a scaffold to develop new
Introduction
Malaria is a tropical parasitological disease that remains one of
the biggest global health challenges despite the availability of
effective tools. Severe malaria caused by P. falciparum is the
major cause of mortality and morbidity worldwide especially in
sub-Saharan Africa.[1] Antimalarial drugs have long been a
mainstay in our fight against this deadly disease, whether as
chemo-prophylactic agents or in the treatment regimen.
However, our malaria elimination efforts have been jeopardized
by the continuous emergence of resistance to common
antimalarial drugs including chloroquine (CQ), sulfadoxine-
pyrimethamine and recently artemisinin.[2] This problem is further
antimalarial drug candidates.
However, synthesis of compounds solely based on this 4-
aminoquinoline moiety might exhibit similar cross resistance
susceptibility patterns as shared by other established 4-
aminoquinolines such as CQ and AQ and might illicit drug
resistance responses earlier in areas with reported CQ
resistance. Therefore, in order to broaden the structural diversity
of the compounds with the additional objective of intensifying
biological activity, covalently linked hybrids were created with
another pharmacologically significant class of compounds
known as [1,2,3]-triazoles, appended with 7-chloro-4-
aminoquinoline base. These [1,2,3]-triazoles, exhibit myriad of
biological activities including antifungal,[14] antibacterial[15] and
antitubercular activities.[16] Apart from just being a passive linker,
the triazoles can also act as important constituent of antimalarial
compounds[17] because they themselves are lipophilic nitrogen
[a]
I. Wadi, Dr. D. Prasad, Dr. N. Batra, Prof. M. Nath
Department of Chemistry, University of Delhi, Delhi 110007, India
*Corresponding author. Tel.: +91 11 27667794 Extn. 186.
E-mail: mnath@chemistry.du.ac.in
[b]
[c]
Dr. K. Srivastava
Parasitology Division, Central Drug Research Institute, Lucknow,
226031, Uttar Pradesh, India
Dr. A. R. Anvikar, Dr. N. Valecha
ICMR-National Institute of Malaria Research, Dwarka, New Delhi,
110077, India
Supporting information for this article is given via a link at
the end of the document.
1
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10.1002/cmdc.201800728
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Figure 1. Prototypes and IC50 values of quinoline and triazole based hybrids reported by Singh et al.[19] (A), Raj et al.[20] (B and C), Pereira et al.[21] (D to F), Rawat
et al.[22] (G and H), Hamann et al.[23] (I to J), Guantai et al.[24] (K to M) and Boechat et al.[25] (N to Q). For the nature of R in the prototypes and other details, please
refer to the respective references.
containing heterocycles that tend to accumulate into the food
vacuole of the parasite, a property also expressed by CQ.[18]
Prototypes of reported quinoline based triazole hybrids (A to Q)
synthesized by other investigators along with their antimalarial
activity in terms of IC50 are depicted in Figure 1. [1,2,3]-Triazole
tethered 7-chloroquinoline and β-lactam bifunctional hybrids
where [1,2,3]-triazole acted as a linker between β-lactam ring
(connected at 4th position of triazole via amino methyl group) and
7-chloroquinoline moiety, demonstrated IC50 values in the range
of 1.9 µM to >10 µM for chloroquine resistant W2 strain of P.
falciparum (Figure 1; structure A).[19] Enhanced potency of
[1,2,3]-triazole tethered 7-chloroquinoline-isatin hybrids (Figure
1; structure C) was observed when [1,2,3]-triazole is linked to 7-
chloroquinoline skeleton by an aliphatic amine linker as
compared to the hybrids where the [1,2,3]-triazole is covalently
bonded to 7-chloroquinoline base (Figure 1; structure B).[20] The
2
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most potent molecule, 5-chloro-1-{1-[3-(7-chloroquinolin-4-yl-
amino)-propyl]-1H-[1,2,3]-triazol-4-ylmethyl}-1H-indole-2,3-dione
demonstrated an IC50 of 1.21 µM against W2 strain of P.
cycloaddition reaction of 2-azido-N-(7-chloroquinolin-4-ylamino-
alkyl)acetamide (4a-d) and terminal alkynes (5 and 6a-e) in
tBuOH:H2O (1:1) mixture containing catalytic amount of copper
sulfate and sodium ascorbate at ambient temperature (Scheme-
1). For making the target molecules, initially alkynes (6a-e) were
prepared in one step by reacting substituted phenols with
propargyl bromide in presence of K2CO3 in DMF at room
temperature for 8-10 hours.[26,27] The desired azides (4a-d) were
synthesized in three steps. Firstly, N’-(7-chloroquinolin-4-
falciparum.[20]
Further,
synthesis
via
copper-catalysed
cycloaddition reaction was carried out to yield hybrids with
[1,2,3]-triazole moiety (containing different substituents) directly
attached to 7-chloroquinoline base. These compounds displayed
potency in the range of 9.6 µM to >166 µM against W2 strain of
P. falciparum (Figure-1; structures D to F).[21] Rawat et al.
evaluated antiplasmodial activity of 4-amino-7-chloroquinoline-
[1,2,3]-triazole and 4-amino-7-chloroquinoline-[1,2,3]-triazole-
triazine hybrids (Figure 1; structures G and H) where triazole
moiety is appended to the 7-chloro-4-aminoquinoline base by an
aliphatic linker. Here, IC50 values for 4-amino-7-chloroquinoline-
[1,2,3]-triazole and 4-amino-7-chloroquinoline-[1,2,3]-triazole-
triazine hybrids were reported to be in range (0.65 µM to 7.24
µM) and (0.58 µM to 5.25 µM) for CQ sensitive D6 strain,
respectively and (1.12 µM to 11.52 µM) and (0.73 µM to 5.97
µM) for CQ resistant W2 strain, respectively.[22] The concept of
triazole as a linker between two moieties was further escalated
to synthesis of compounds with mefloquine (Figure 1; structures
I and J) instead of the standard 7-chloroquinoline and IC50
values were reported to be in range (1.00 µM to 31.8 µM) for
NF54 strain of P. falciparum.[23] Guantai and co-workers
developed antimalarial compounds (Figure 1; structures K to M)
where [1,2,3]-triazoles acted as a linker between a chalcone
functionality (connected at 4th position of triazole via ether
linkage) and 7-chloroquinoline moiety with IC50 values between
(0.04 µM to 19 µM) for CQ sensitive D10 strain and (0.09 µM to
>20 µM) for CQ resistant W2 strain of P. falciparum.[24] Moreover,
7-chloro-4-(1H-1,2,3-triazol-1-yl)quinolines (Figure 1; structures
N to Q) with different substituents at 4th position of 1,2,3-triazole
ring were synthesized and half maximal inhibitory concentration
was reported to be in range (1.4 µM to 130 µM) against CQ
resistant W2 strain of P. falciparum.[25] In majority of these
studies, 1,2,3-triazole moiety is either covalently bonded to the
quinoline scaffold, without any linker.[19-21, 23-25] or it is appended
with 7-chloroquinoline through an aliphatic aminoalkyl chain.[20,22]
Fascinated by the previously reported work, and in consensus
with our aim to develop novel antimalarials based on quinoline-
triazole scaffold, we have designed hybrid compounds in such a
way that [1,2,3]-triazole group is linked to 7-chloroquinoline by
an aliphatic diamine linker juxtaposed to a carbonyl group
(quinoline-NH-R-NH-carbonyl-triazole, where R is an aliphatic
group) (Scheme 1). The advantage that hybrid molecules
possess, is the ability to surpass the threat of drug resistance
due to the presence of multiple pharmacophores and hence
multiple mechanism of actions. In the advent of new antimalarial
drugs, our aim was to obtain novel chemical entities with two
‘biologically privileged’ pharmacophores, coupled into a single
molecular framework that can act at more than one target site to
intensify the antimalarial activity. We herein report synthesis,
characterization and antimalarial activity evaluation of a panel of
novel 4-amino-7-chloroquinoline based [1,2,3]-triazole hybrids.
yl)alkanediamines
(2a-d)
were
obtained
by
heating
alkanediamines with 4,7-dichloroquinoline (1) at 130oC for 7-8
hours according to the literature procedure.[28,29] In subsequent
step, the free amino group of N’-(7-chloroquinolin-4-yl)alkane-
diamines (2a-d) was coupled with chloroacetyl chloride in DMF
at ambient temperature to afford the compounds (3a-d) which on
heating with sodium azide in methanol at reflux temperature for
7-8 hours afford desired precursors (4a-d) in almost quantitative
yields. Finally, the synthesis of desired compounds (7, 8a-b, 9a-
e, 10a-b and 11a-b) was accomplished in good to excellent
yields via Cu(I)-catalysed Huisgen [2+3] cycloaddition reaction
between 2-azido-N-(7-chloroquinolin-4-ylaminoalkyl)acetamides
(4a-d) and terminal alkynes (5 and 6a-e) in the presence of a
catalytic amount of copper sulfate and sodium ascorbate in 50%
aqueous t-butanol at ambient temperature (Scheme 1). The
structures of all the compounds were established on the basis of
spectral analysis and their characterization data are presented in
the experimental section.
O
Cl
NH2
NH
O
HN
HN
N
Cl
n
n
NH2
Cl
H2N
Cl
n
a
b
Cl
N
Cl
Cl
N
1
2a-d
3a-d
c
O
N3
NH
HN
n
5
O
N
N
d
Cl
N
N
NH
HN
N
n
4a-d
Cl
R
O
7
d
6a-e
R
O
O
N
N
N
NH
HN
N
n
Cl
8a-b, 9a-e,
10a-b, 11a-b
Scheme 1. Synthesis of 7-chloroquinoline based [1,2,3]-triazole hybrids 7, 8a-
b, 9a-e, 10a-b, 11a-b: a) 130oC, 7-8 h, 83-91%; b) DMF, RT, 5-6 h, 78-96%; c)
NaN3, MeOH, reflux, 7-8 h, 79-91%; d) CuSO4, sodium ascorbate, tBuOH/H2O
(1:1), RT, 8 h, 76-88%.
The IR spectrum of a representative compound 9e has shown
four characteristic absorption peaks at 3274, 1686, 1656 and
1599 cm-1 corresponding to the stretching frequency of NH, C=O,
CHO and C=N. In proton NMR of 9e, four characteristic peaks
were observed at δ 9.86, 8.21, 5.28 and 5.12 ppm which
correspond to the protons of CHO, triazole, CH2O and CH2CO
groups, respectively. The mass spectral analysis gave further
evidence for the formation of N-[3-(7-chloroquinolin-4-
ylamino)propyl]-2-[4-(4-formylphenoxymethyl)-[1,2,3]-triazol-1-
yl]acetamide (9e) by showing a [M + H]+ ion peak at m/z 479 for
Results and Discussion
Synthesis
A new series of 4-amino-7-chloroquinoline based [1,2,3]-triazole
hybrids were synthesized via Cu(I) catalyzed Huisgen [2+3]
3
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10.1002/cmdc.201800728
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the molecular formula C24H23ClN6O3. The remaining compounds
were similarly characterized and their characterization data are
presented in the experimental section.
value 75.01 nM. The respective dose-response curves are given
in Figure S1 (ESI).
The activity results revealed that the replacement of halogen
moiety (from chlorine to bromine) at para position of phenoxy
group remarkably increases the potency of the compound
against CQ resistant P. falciparum by ~25 fold (IC50 2.94 nM vs
75.01 nM). Moreover, an ethyl side chain (instead of propyl side
chain) attached to 4-amino-7-chloroquinoline increases
antimalarial potency by ~5 folds (IC50 2.94 nM vs 16.01 nM).
Although compound 8a, 8b and 9c bear structural similarity with
CQ due to the presence of 7-chloroquinoline moiety but the
potency data demonstrates that, none of them show any
significant signs of cross resistance with CQ thereby
demonstrating comparatively higher potency as compared to CQ
(IC50 (CQ) 114.4 nM) against CQ resistant P. falciparum.
Collectively, compounds 8a, 8b and 9c demonstrated greater
potency as compared to CQ against CQ resistant P. falciparum
and the fact that they also proved effective against CQ sensitive
P. falciparum makes them potential candidates to be developed
further as schizonticidal antimalarials.
Antimalarial activity against asexual stages of CQ sensitive
strain (3D7) of P. falciparum and structure activity
relationships
Initial screening for antimalarial activity of these 7-
chloroquinoline-triazole hybrids was performed using a Malaria
SYBR Green-I Fluorescence (MSF) assay. All twelve
compounds demonstrated antimalarial activity in nanomolar
range (38.75 to 910.14 nM) against 3D7 strain of P. falciparum.
Out of the tested compounds, three most potent compounds 8a,
8b and 9c demonstrated IC50 values of 39.98 nM, 40.00 nM and
38.75 nM, respectively (Table 1). In general, the in vitro
screening results revealed that the antimalarial activity of these
hybrid molecules decreases with increase in the length of
aliphatic diamino-linker which connects both [1,2,3]-triazole and
7-chloroquinoline scaffolds. In addition, the presence of a
halogen at p-position of the phenoxy group within the series
having same spacer is very crucial for the antimalarial activity of
the synthesized compounds with exception to compound 9c.
Overall, the molecules having lipophilic substituents such as Cl,
Br and CH3 at p-position of phenoxy ring are found to be more
active as compared to those having either unsubstituted
phenoxy substituent or a p-substituted phenoxy ring with more
hydrophilic formyl substituent (Table 1).
Antimalarial activity against gametocytes
For carrying out the drug sensitivity experiments, mature
gametocytes were produced from the same field isolate (RKL-9)
which was previously used for measuring the asexual stage
antimalarial activity. The compounds, 8a, 8b and 9c were clearly
found to target mature gametocytes and induce morphological
deformations in them in a dose dependent manner. Compound
8b showed maximum potency with IC50 (NM) (Normal
Morphology) of 8.50 µM and was considered as most active out
of three tested compounds. Other tested compounds, 8a and 9c
also targeted gametocytes with IC50 (NM) as 10.71 µM and
12.03 µM, respectively. IC50 (NM) and IC50 (Total) values for the
tested compounds are mentioned in Table 1. The respective
dose-response curves are given in Figure S2 (ESI). Microscopic
images of morphological deformations induced by treatment with
Selectivity assays
The selectivity of 12 new compounds for P. falciparum (3D7) as
compared to VERO cells was determined using MTT assay with
selectivity index (SI) defined as ratio of CC50 and IC50 values
(Table 1). In general, majority of compounds showed no signs of
any significant toxicity. Compound 11a showed least selectivity
index while compound 8a demonstrated highest selectivity index
amongst all compounds. On the basis of collective analysis of
potency against CQ sensitive strain (3D7) of P. falciparum and
toxicity data, three compounds 8a, 8b and 9c which showed
promising selectivity profile were also tested against asexual
stages of CQ resistant P. falciparum as well as against sexual
stages whose details are mentioned in subsequent sections.
these
hybrids
along
with
microscopic
images
of
healthy/untreated gametocytes are given in Figure S3 (ESI).
Conclusions
In summary, 4-amino-7-chloroquinoline based [1,2,3]-triazole
hybrids were synthesized via a click chemistry approach and
were screened for their potential antiplasmodial activity. All the
compounds demonstrated promising activity in nanomolar range
against CQ sensitive strain (3D7) of P. falciparum. Three hybrids
(8a, 8b and 9c) were also found to be active against CQ
resistant field isolate of P. falciparum (RKL-9) and proved to be
more potent than CQ, suggesting minimum possibility of any
cross resistance with CQ. Furthermore, these compounds also
demonstrated potency against mature gametocytes which is
suggestive of their potential transmission blocking activity.
These compounds also exhibited no evidence of significant
cytotoxicity against mammalian cell line (VERO). Overall, the
promising schizonticidal and gametocytocidal activity displayed
by the best of the quinoline-triazole hybrids described here
encourage further studies on identifying newer hybrids,
especially as most quinoline-based schizonticidal drugs are
relatively inactive against mature gametocytes.[38] Collectively,
Antimalarial activity against asexual stages of CQ resistant
field isolate (RKL-9) and structure activity relationships
Since CQ resistance has spread its wings globally[30] especially
in P. falciparum, and almost all malaria prone areas are
gradually becoming CQ resistant, it was imperative to see
whether these compounds were showing any signs of cross
resistance with CQ since they also possess the same 7-
chloroquinoline moiety. Therefore, antimalarial activity of
selected compounds namely 8a, 8b and 9c was evaluated
against CQ resistant field isolate collected from one of the most
malaria endemic areas of India (Rourkela, Odisha). Compounds
8a, 8b and 9c exhibited <100 nM IC50 against CQ resistant field
isolate (RKL-9) of P. falciparum (Table 1). Out of these three
compounds, compound 8b was found to be most potent as
evident from its lowest IC50 value of 2.94 nM followed by 9c with
IC50 of 16.01 nM. Compound 8a was found least active with IC50
4
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Table 1. In vitro antimalarial activity and cytotoxicity evaluation of 4-amino-7-chloroquinoline based [1,2,3]-triazoles.
Compds.
R
n
Asexual stage
RKL-9
Gametocyte stage
RKL-9
Cytotoxicity
VERO
3D7
[a]
[c]
IC50
IC50 NM[b]
(95% CI)
IC50 Total[b]
(95% CI)
CC50
SI[d]
[a]
IC50
(95% CI)
7
-
2
1
137.10
39.98
-
-
-
41.53
86.75
304.78
75.01
10.71
20.87
8a
Cl
2223.72
(60.53 to 92.96)
(7.70 to 14.88)
(17.30 to 25.16)
2.94
8.50
19.80
8b
9a
40.00
28.86
723.477
Br
1
(1.96 to 4.43)
(6.76 to 10.67)
(15.06 to 26.02)
179.56
90.02
-
-
-
-
-
-
78.21
40.58
437.81
453.68
H
2
2
Cl
9b
9c
16.01
12.03
21.91
38.75
27.06
713.62
Br
2
(10.84 to 23.65)
(10.05 to 14.3)
(17.79 to 26.98)
91.94
910.14
92.77
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
75.49
>208
12.18
10.87
5.02
828.12
>236.47
132.42
130.52
19.08
CH3
CHO
Cl
2
2
3
3
5
5
9d
9e
10a
10b
11a
11b
83.55
CH3
Cl
263.12
307.29
7.41
24.19
Br
114.4
CQ
5.8
-
-
112.44
>20000
-
-
(77.70 to 168.4)
[a]IC50 values are in nanomolar (nM) concentration. [b]IC50 values are in micromolar (μM) concentration. [c]CC50 values are in micromolar (μM) concentration. [d]SI
(CC50/IC50) of 3D7 strain. CC50 = Concentration of test compound inhibiting 50% growth of VERO cells. CI = Confidence Interval. NM = Normal Morphology. SI =
Selectivity Index.
General procedure for the synthesis of compounds 3a-d. To a well
stirred solution of N1-(7-chloro-quinolin-4-yl)-alkanediamines (2a-d; 1.0
mmol) in N,N-dimethylformamide (10 mL), chloroacetyl chloride (4.0
mmol) was added and the reaction mixture was stirred at ambient
temperature for 4-5 hours. After the completion of the reaction as
indicated by TLC, the reaction mixture was diluted with water (40 mL)
and the pH of the solution was adjusted to 10 by using 10% aqueous
NaOH solution. The resulting solution was then extracted with ethyl
acetate (60 mL×3 times). The ethyl acetate layer was washed with water
(40 mL×3 times) and the organic layers were combined, dried over
anhydrous Na2SO4 and evaporated under vacuum to furnish the products
(3a-d) in good yields. These compounds were obtained in a sufficiently
pure form and were used as such for further reactions without any
purification.
these results indicate that the new hybrids with carbonyl group
juxtaposed to alkylamino linker connecting 4-amino-7-
chloroquinoline base and [1,2,3]-triazole may have the potential
to be considered as prototypes for the development of next
generation antimalarials.
Experimental Section
Materials and methods
All the chemicals were purchased from Sigma-Aldrich unless otherwise
mentioned and used without any further purification. Thin layer
chromatography (TLC) was performed on silica gel 60 F254 pre-coated
aluminium plates from Merck and spots were developed either under UV
light or in iodine chamber. The 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded in DMSO-d6 on Jeol ECX-400P (400 MHz)
NMR spectrometer. The coupling constants (J) are reported in Hertz (Hz).
IR spectra were recorded on a Perkin Elmer IR spectrometer and
absorption maxima (υmax) are given in cm-1. Mass spectra were recorded
on Waters Micromass LCT ESI-MS spectrometer in positive ionization
mode. Elemental analyses were determined on Elementar Analysen
systeme GmbH VarioEL V3.00. The melting points were determined in
open capillary tubes on Buchi melting point apparatus and are
uncorrected. N1-(7-chloro-quinolin-4-yl)-alkanediamines (2a-d) were
prepared according to the literature methods and their characterization
data were matched with the reported data.[28,29]
2-Chloro-N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-acetamide
(3a).
Dark brown solid; yield: 92%; mp: 160C; IR (Nujol): νmax=3361 (NH),
3194 (NH), 1649 (C=O), 1584 (C=N), 1455, 1222, 1138, 897, 871, 849,
808, 762, 722 cm-1; 1H NMR (400 MHz, [D6]DMSO): δ=8.43 (d, J=5.13
Hz, 1H, quinoline H-2), 8.42-8.39 (m, 1H, NH), 8.32 (d, J = 8.05 Hz, 1H,
quinoline H-5), 7.97 (s, 1H, quinoline H-8), 7.49-7.39 (m, 2H, quinoline H-
6 and NH), 6.61 (d, J = 5.86 Hz, 1H, quinoline H-3), 4.13 (s, 2H, CH2Cl),
3.42-3.27 (m, 4H, 2CH2) ppm; MS (ESI) m/z: 298 [M+H]+.
2-Chloro-N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-acetamide (3b).
Off white solid; yield: 96%; mp: >200C; IR (Nujol): νmax=3349 (NH), 3177
(NH), 1681 (C=O), 1613, 1582 (C=N), 1463, 1455, 1376, 1337, 1298,
1282, 1241, 1215, 1198, 1141, 1078, 1053, 935, 902, 854, 816, 799, 759,
722 cm-1; 1H NMR (400 MHz, [D6]DMSO): δ=8.40 (d, J=5.86 Hz, 1H,
quinoline H-2), 8.37 (d, J=5.13 Hz, 1H, NH), 8.29 (d, J=9.52 Hz, 1H,
5
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10.1002/cmdc.201800728
ChemMedChem
FULL PAPER
quinoline H-5), 7.79 (d, J=2.20 Hz, 1H, quinoline H-8), 7.48-7.46 (m, 2H,
quinoline H-6 and NH), 6.49 (d, J=5.13 Hz, 1H, quinoline H-3), 4.07 (s,
2H, CH2Cl), 3.31 (q, J=6.59 Hz, 2H, CH2), 3.23 (q, J=6.59 Hz, 2H, CH2),
1.86-1.80 (m, 2H, CH2) ppm; 13C NMR (100 MHz, [D6]DMSO): δ=166.04,
151.09, 150.47, 139.06, 133.79, 126.68, 124.30, 124.23, 117.28, 98.63,
42.67, 40.11, 36.85, 27.50 ppm; MS (ESI) m/z: 312 [M+H]+.
1255, 1208, 1141, 1083, 998, 917, 901, 853, 814, 793, 761, 722, 644 cm-
1; 1H NMR (400 MHz, [D6]DMSO): δ=8.36 (d, J=5.13 Hz, 1H, quinoline H-
2), 8.25 (d, J=8.79 Hz, 1H, quinoline H-5), 8.11 (t, J=5.13 Hz, 1H, NH),
7.76 (d, J=2.20 Hz, 1H, quinoline H-8), 7.41 (dd, J1=8.79 Hz, J2=2.20 Hz,
1H, quinoline H-6), 7.30 (t, J=5.13 Hz, 1H, NH), 6.44 (d, J=5.86 Hz, 1H,
quinoline H-3), 3.78 (s, 2H, CH2N3), 3.25 (q, J=6.59 Hz, 2H, CH2), 3.14 (q,
J=6.59 Hz, 2H, CH2), 1.66-1.60 (m, 2H, CH2), 1.56-1.50 (m, 2H, CH2)
ppm; 13C NMR (100 MHz, [D6]DMSO): δ=167.20, 151.91, 150.12, 149.08,
133.43, 127.46, 124.12, 124.03, 117.47, 98.68, 50.85, 42.04, 38.39,
26.69, 25.17 ppm; MS (ESI) m/z: 333 [M+H]+.
2-Chloro-N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-acetamide
(3c).
Dark brown solid; yield: 90%; mp: >200C; IR (Nujol): νmax=3352 (NH),
3187 (NH), 1678 (C=O), 1576 (C=N), 1455, 1377, 1336, 1284, 1235,
1205, 1141, 1078, 954, 900, 849, 803, 722 cm-1; 1H NMR (400 MHz,
[D6]DMSO): δ=8.36 (d, J=5.13 Hz, 1H, quinoline H-2), 8.32-8.30 (m, 2H,
NH and quinoline H-5), 7.76 (s, 1H, quinoline H-8), 7.52 (d, J=4.39 Hz,
1H, NH), 7.43-7.40 (m, 1H, quinoline H-6), 6.45 (d, J=5.13 Hz, 1H,
quinoline H-3), 4.03 (s, 2H, CH2Cl), 3.26 (q, J=5.86 Hz, 2H, CH2), 3.13 (q,
J=5.86 Hz, 2H, CH2), 1.67-1.50 (m, 4H, 2CH2) ppm; MS (ESI) m/z: 326
[M+H]+.
2-Azido-N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-acetamide
(4d).
Dark brown solid; yield: 88%; mp: 124C; IR (Nujol): νmax=3369 (NH),
3191 (NH), 2105 (N3), 1681 (C=O), 1609, 1576 (C=N), 1534, 1463, 1376,
1327, 1284, 1250, 1167, 1134, 1078, 905, 870, 854, 815, 798, 722 cm-1;
1H NMR (400 MHz, [D6]DMSO): δ=8.40 (d, J=5.13 Hz, 1H, quinoline H-2),
8.31 (d, J=8.79 Hz, 1H, quinoline H-5), 8.13 (t, J=5.13 Hz, 1H, NH), 7.80
(d, J=2.20 Hz, 1H, quinoline H-8), 7.44 (dd, J1=8.79 Hz, J2=2.20 Hz, 1H,
quinoline H-6), 7.36 (brs, 1H, NH), 6.45 (d, J=5.13 Hz, 1H, quinoline H-3),
3.81 (s, 2H, CH2N3), 3.28-3.23 (m, 2H, CH2), 3.13-3.08 (m, 2H, CH2),
1.68-1.62 (m, 2H, CH2), 1.48-1.30 (m, 6H, 3CH2) ppm; 13C NMR (100
MHz, [D6]DMSO): δ=167.04, 151.64, 150.22, 148.82, 133.47, 127.22,
124.15, 123.99, 117.40, 98.54, 50.83, 42.36, 38.59, 28.94, 27.71, 26.32,
26.16 ppm; MS (ESI) m/z: 361 [M+H]+.
2-Chloro-N-[6-(7-chloro-quinolin-4-ylamino)-hexyl]-acetamide (3d).
Dark brown solid; yield: 78%; mp: >200C; IR (Nujol): νmax=3352 (NH),
3189 (NH), 1675 (C=O), 1587 (C=N), 1474, 1452, 1379, 1342, 1299,
1
1280, 1235, 1205, 1184, 942, 732 cm-1; H NMR (400 MHz, [D6]DMSO):
δ=8.40 (d, J=5.13 Hz, 1H, quinoline H-2), 8.39 (d, J=5.13 Hz, 1H, NH),
8.34 (d, J=8.05 Hz, 1H, quinoline H-5), 7.77 (s, 1H, quinoline H-8), 7.51-
7.41 (m, 2H, quinoline H-6 and NH), 6.54 (d, J=5.13 Hz, 1H, quinoline H-
3), 4.09 (s, 2H, CH2Cl), 3.32-3.28 (m, 2H, CH2), 3.11-3.06 (m, 2H, CH2),
1.70-1.66 (m, 2H, CH2), 1.52-1.34 (m, 6H, 3CH2) ppm; MS (ESI) m/z: 354
[M+H]+.
General procedure for the synthesis of compounds 7, 8a-b, 9a-e,
10a-b and 11a-b. To a solution of azide (4a-d; 3.0 mmol) in 50% t-
butanol in water (20 mL), alkyne (5 or 6a-e; 3.5 mmol), CuSO4.5H2O (1.0
mmol) and sodium ascorbate (2.2 mmol) were added. The reaction
mixture was stirred at room temperature for 8 hours. After the completion
of reaction as indicated by TLC, the reaction mixture was diluted with
water (80 mL) and the product was extracted with ethyl acetate (60 mL×3
times). The ethyl acetate layers were combined, dried over anhydrous
Na2SO4 and evaporated under vacuum. Thus, the crude product
obtained was stirred in diethyl ether (60 mL) at room temperature for 2
hours. The solid was then filtered, washed well with Et2O and dried under
vacuum to obtain the pure product in good to excellent yields.
General procedure for the synthesis of compounds 4a-d. To a well
stirred solution of compound (3a-d; 1.0 mmol) in MeOH (60 mL), sodium
azide (6.0 mmol) was added and the resulting solution was refluxed for 7-
8 hours. After the completion of the reaction, the solvent was evaporated
under vacuum to dryness. Thus, the residue obtained was dissolved in
ethyl acetate (80 mL). The resulting ethyl acetate solution was washed
with water (40 mL×3 times), dried over anhydrous Na2SO4 and
evaporated under vacuum to furnish the desired products (4a-d) in good
yields. The products (4a-d) were obtained in sufficiently pure form and
used as such for next step without any further purification.
N-(3-(7-Chloroquinolin-4-ylamino)propyl)-2-(4-phenyl-1H-1,2,3-
triazol-1-yl)acetamide (7). Pale yellow solid; yield: 87%; mp: >200C; IR
(Nujol): νmax=3273 (NH), 1654 (C=O), 1583 (C=N), 1455, 1377, 1079,
976, 846, 805, 762, 721, 689 cm-1; 1H NMR (400 MHz, [D6]DMSO):
δ=8.47 (brs, 3H, NH, quinoline H-2 and quinoline H-5), 8.22 (s, 1H,
triazole H), 7.81-7.76 (m, 3H, ArH and quinoline H-8), 7.41-7.29 (m, 5H,
ArH, quinoline H-6 and NH), 6.47 (s, 1H, quinoline H-3), 5.11 (s, 2H,
CH2CO), 3.45-3.22 (m, 4H, 2CH2), 1.86-1.80 (m, 2H, CH2); MS (ESI)
m/z: 421 [M + H]+.
2-Azido-N-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-acetamide
(4a).
Yellow solid; yield: 79%; mp: 154C; IR (Nujol): νmax=3368 (NH), 2113
(N3), 1663 (C=O), 1581 (C=N), 1543, 1459, 1376, 1276, 1224, 1139,
1077, 899, 872, 849, 795, 760, 721 cm-1; 1H NMR (400 MHz, [D6]DMSO):
δ=8.40 (d, J=5.13 Hz, 1H, quinoline H-2), 8.35 (brs, 1H, NH), 8.18 (d,
J=8.79 Hz, 1H, quinoline H-5), 7.78 (d, J=2.20 Hz, 1H, quinoline H-8),
7.44 (d, J=9.52 Hz, 1H, quinoline H-6), 7.39-7.38 (m, 1H, NH), 6.54 (d,
J=5.13 Hz, 1H, quinoline H-3), 3.86 (s, 2H, CH2N3), 3.37-3.35 (m, 4H,
2CH2) ppm; 13C NMR (100 MHz, [D6]DMSO): δ=167.86, 151.93, 150.01,
149.07, 133.44, 127.53, 124.14, 123.94, 117.44, 98.62, 50.92, 41.85,
37.35 ppm; MS (ESI) m/z: 305 [M+H]+.
2-[4-(4-Chloro-phenoxymethyl)-[1,2,3]triazol-1-yl]-N-[2-(7-chloro-
quinolin-4-ylamino)-ethyl]-acetamide (8a). White solid; yield: 85%; mp:
190C; IR (Nujol): νmax=3385 (NH), 3272 (NH), 1660 (C=O), 1574 (C=N),
1455, 1377, 1239, 1170, 1137, 1077, 1041, 903, 880, 855, 812, 787, 722,
1
652 cm-1; H NMR (400 MHz, [D6]DMSO): δ=8.58 (s, 1H, quinoline H-2),
2-Azido-N-[3-(7-chloro-quinolin-4-ylamino)-propyl]-acetamide (4b).
Light brown solid; yield: 84%; mp: 164C; IR (Nujol): νmax= 3359 (NH),
3186 (NH), 2102 (N3), 1693 (C=O), 1611, 1583 (C=N), 1546, 1456, 1425,
1374, 1337, 1280, 1253, 1216, 1141, 1079, 1054, 937, 901, 856, 814,
798, 757, 721, 644 cm-1; 1H NMR (400 MHz, [D6]DMSO): δ=8.38 (d,
J=5.13 Hz, 1H, quinoline H-2), 8.25 (d, J=9.52 Hz, 1H, quinoline H-5),
8.24 (brs, 1H, NH), 7.78 (s, 1H, quinoline H-8), 7.42 (d, J=8.79 Hz, 1H,
quinoline H-6), 7.34 (s, 1H, NH), 6.44 (d, J=5.13 Hz, 1H, quinoline H-3),
3.84 (s, 2H, CH2N3), 3.29-3.23 (m, 4H, 2CH2), 1.84-1.81 (m, 2H, CH2)
ppm; 13C-NMR (100 MHz, [D6]DMSO): δ=170.19, 154.43, 152.99, 151.58,
136.39, 130.07, 126.94, 126.86, 120.24, 101.46, 53.76, 42.84, 39.50,
30.48 ppm; MS (ESI) m/z: 319 [M+H]+.
8.43 (brs, 1H, NH), 8.21 (s, 1H, quinoline H-5), 8.19 (s, 1H, triazole H),
7.81 (s, 1H, quinoline H-8), 7.47(d, J=8.79 Hz, 1H, quinoline H-6), 7.40 (s,
1H, NH), 7.35 (d, J=8.79 Hz, 2H, ArH), 7.08 (d, J=8.79 Hz, 2H, ArH),
6.57 (d, J=4.39 Hz, 1H, quinoline H-3), 5.16 (s, 2H, CH2O), 5.15 (s, 2H,
CH2CO), 3.40-3.37 (m, 4H, 2 CH2) ppm; 13C NMR (100 MHz, [D6]DMSO):
δ=165.97, 156.90, 151.93, 150.01, 149.07, 142.14, 133.46, 129.25,
127.54, 126.21, 124.53, 124.18, 123.98, 123.86, 116.46, 98.67, 61.28,
51.64, 41.73, 37.46 ppm; MS (ESI) m/z: 471 [M + H]+. Anal. calcd for
C22H20Cl2N6O2.0.2H2O: C, 55.64; H, 4.33; N, 17.69, found: C, 55.57; H,
4.45; N, 17.57.
2-[4-(4-Bromo-phenoxymethyl)-[1,2,3]triazol-1-yl]-N-[2-(7-chloro-
quinolin-4-ylamino)-ethyl]-acetamide (8b). Dirty white solid; yield:
87%; mp: 184C; IR (Nujol): νmax=3387 (NH), 3273 (NH), 1654 (C=O),
1582 (C=N), 1458, 1376, 1237, 1172, 1139, 1054, 811, 721 cm-1; 1H
2-Azido-N-[4-(7-chloro-quinolin-4-ylamino)-butyl]-acetamide (4c). Off
white solid; yield: 91%; mp: 168C; IR (Nujol): νmax=3376 (NH), 3184
(NH), 2120 (N3), 1667 (C=O), 1586 (C=N), 1463, 1455, 1373, 1335, 1283,
6
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10.1002/cmdc.201800728
ChemMedChem
FULL PAPER
NMR (400 MHz, [D6]DMSO): δ=8.58 (s, 1H, quinoline H-2), 8.43 (brs, 1H,
NH), 8.21 (d, J=8.79 Hz, 1H, quinoline H-5), 8.19 (s, 1H, triazole H), 7.81
(s, 1H, quinoline H-8), 7.48-7.45 (m, 4H, ArH, quinoline H-6 and NH),
7.04 (d, J=8.79 Hz, 2H, ArH), 6.58 (brs, 1H, quinoline H-3), 5.16 (s, 2H,
CH2O), 5.15 (s, 2H, CH2CO), 3.43-3.40 (m, 4H, 2CH2) ppm; 13C NMR
(100 MHz, [D6]DMSO): δ=165.98, 157.34, 151.72, 150.11, 142.13,
133.54, 132.15, 132.03, 131.97, 127.43, 126.23, 124.25, 124.05, 117.01,
112.27, 98.87, 61.21, 51.64, 39.91, 39.29 ppm; MS (ESI) m/z: 516
[M+H]+. Anal. calcd for C22H20ClBrN6O2.0.6 H2O: C, 50.18; H, 4.06; N,
15.96, found: C, 50.18; H, 3.92; N, 15.64.
NH), 7.09 (d, J=8.05 Hz, 2H, ArH), 6.92 (d, J=8.79 Hz, 2H, ArH), 6.66
(brs, 1H, quinoline H-3), 5.13 (s, 2H, CH2O), 5.10 (s, 2H, CH2CO), 3.30-
3.25 (m, 4H, 2CH2), 2.23 (s, 3H, CH3), 1.86-1.83 (m, 2H, CH2) ppm; MS
(ESI) m/z: 465 [M+H]+. Anal. calcd for C24H25ClN6O2.H2O: C, 59.69; H,
5.63; N, 17.40, found: C, 59.77; H, 5.91; N, 17.09.
N-(3-(7-chloroquinolin-4-ylamino)propyl)-2-(4-((4-formylphenoxy)-
methyl)-1H-1,2,3-triazol-1-yl)acetamide (9e). Pale yellow solid; yield:
88%; mp: 182C; IR (Nujol): νmax=3274 (NH), 1686 (C=O), 1656 (CHO),
1599 (C=N), 1508, 1459, 1376, 1262, 1217, 1162, 1141, 1052, 1032, 999,
944, 902, 827, 765, 721 cm-1; 1H NMR (400 MHz, [D6]DMSO): δ=9.86 (s,
1H, CHO), 8.44-8.42 (m, 2H, quinoline H-2 and NH), 8.25 (d, J=9.52 Hz,
1H, quinoline H-5), 8.21 (s, 1H, triazole H), 7.87 (d, J=8.79 Hz, 2H, ArH),
7.77 (s, 1H, quinoline H-8), 7.45 (d, J=8.79 Hz, 1H, quinoline H-6), 7.35 (t,
J=5.13 Hz, 1H, NH), 7.24 (d, J=8.79 Hz, 2H, ArH), 6.49 (d, J=4.39 Hz, 1H,
quinoline H-3), 5.28 (s, 2H, CH2O), 5.12 (s, 2H, CH2CO), 3.26-3.21 (m,
4H, 2CH2), 1.86-1.81 (m, 2H, CH2) ppm; MS (ESI) m/z: 479 [M+H]+.
N-[3-(7-Chloro-quinolin-4-ylamino)-propyl]-2-(4-phenoxymethyl-
[1,2,3]triazol-1-yl)-acetamide (9a). Pale yellow solid; yield: 78%; mp:
174C; IR (Nujol): νmax=3369 (NH), 1693 (C=O), 1574 (C=N), 1539, 1488,
1455, 1377, 1332, 1281, 1241, 1177, 1141, 1118, 1098, 1079, 1058,
1036, 942, 893, 864, 848, 820, 797, 767, 751, 722, 691, 644, 621 cm-1;
1H NMR (400 MHz, [D6]DMSO): δ=8.47 (brs, 2H, quinoline H-2 and NH),
8.27 (d, J=8.05 Hz, 1H, quinoline H-5), 8.18 (s, 1H, triazole H), 7.80 (s,
1H, quinoline H-8), 7.45 (d, J=8.79 Hz, 1H, quinoline H-6), 7.32 (brs, 1H,
NH), 7.29 (d, J=7.32 Hz, 2H, ArH), 7.04 (d, J=8.79 Hz, 2H, ArH), 6.95 (t,
J=7.32, 1H, ArH), 6.50 (brs, 1H, quinoline H-3), 5.14 (s, 2H, CH2O), 5.13
(s, 2H, CH2CO), 3.32 (t, J=6.59 Hz, 2H, CH2), 3.25 (t, J=6.59 Hz, 2H,
CH2), 1.86-1.83 (m, 2H, CH2) ppm; MS (ESI) m/z: 451 [M+H]+. Anal.
calcd for C23H23ClN6O2.0.8 H2O.0.1C4H10O: C, 59.45; H, 5.46; N, 17.78,
found: C, 59.41; H, 5.54; N, 17.44.
2-[4-(4-Chloro-phenoxymethyl)-[1,2,3]triazol-1-yl]-N-[4-(7-chloro-
quinolin-4-ylamino)-butyl]-acetamide (10a). Pale yellow solid; yield:
76%; mp: 198C; IR (Nujol): νmax=3278 (NH), 1654 (C=O), 1611, 1582
(C=N), 1489, 1463, 1377, 1283, 1243, 1217, 1170, 1139, 1093, 1056,
1033, 1005, 899, 851, 819, 803, 765, 722, 644 cm-1; 1H NMR (400 MHz,
[D6]DMSO): δ=8.41-8.38 (m, 3H, quinoline H-2, H-5 and NH), 8.18 (s, 1H,
triazole H), 7.85 (s, 1H, quinoline H-8), 7.45 (d, J=9.52 Hz, 1H, quinoline
H-6), 7.38 (s, 1H, NH), 7.34 (d, J=8.05 Hz, 2H, ArH), 7.07 (d, J=8.79 Hz,
2H, ArH), 6.56 (s, 1H, quinoline H-3), 5.15 (s, 2H, CH2O), 5.10 (s, 2H,
CH2CO), 3.28-3.27 (m, 2H, CH2), 3.20-3.17 (m, 2H, CH2), 1.68-1.66 (m,
2H, CH2), 1.58-1.54 (m, 2H, CH2) ppm; 13C NMR (100 MHz, [D6]DMSO):
δ=165.23, 156.90, 151.76, 150.12, 144.51, 142.08, 133.45, 129.26,
127.52, 127.42, 126.24, 124.53, 124.19, 124.10, 116.47, 98.21, 61.26,
51.64, 42.03, 38.52, 26.61, 25.16 ppm; MS (ESI) m/z: 500 [M+H]+. Anal.
calcd for C24H24Cl2N6O2.1.4 H2O: C, 54.95; H, 5.15; N, 16.02, found: C,
55.15; H, 4.93; N, 15.63.
2-[4-(4-Chloro-phenoxymethyl)-[1,2,3]triazol-1-yl]-N-[3-(7-chloro-
quinolin-4-ylamino)-propyl]-acetamide (9b). Pale yellow solid; yield:
82%; mp: 192C; IR (Nujol): νmax=3379 (NH), 1678 (C=O), 1570 (C=N),
1542, 1518, 1469, 1365, 1329, 1285, 1255, 1182, 1158, 1065, 946, 896,
1
877, 848, 820, 799 cm-1; H NMR (400 MHz, [D6]DMSO): δ=8.47 (s, 1H,
quinoline H-2), 8.42 (brs, 1H, NH), 8.26 (d, J=8.79 Hz, 1H, quinoline H-5),
8.19 (s, 1H, triazole H), 7.80 (s, 1H, quinoline H-8), 7.45 (d, J=8.79 Hz,
1H, quinoline H-6), 7.35 (s, 1H, NH), 7.33-7.31 (m, 2H, ArH), 7.08 (d,
J=9.52 Hz, 2H, ArH), 6.49 (d, J=4.39 Hz, 1H, quinoline H-3), 5.16 (s, 2H,
CH2O), 5.14 (s, 2H, CH2CO), 3.32 (t, J=6.59 Hz, 2H, CH2), 3.25 (t,
J=6.59 Hz, 2H, CH2), 1.88-1.81 (m, 2H, CH2) ppm; 13C NMR (100 MHz,
[D6]DMSO): δ=165.44, 156.90, 151.93, 150.03, 149.06, 142.11, 133.43,
129.25, 127.51, 126.25, 124.53, 124.11, 124.08, 117.48, 116.47, 98.78,
61.27, 51.69, 39.91, 36.83, 27.63 ppm; MS (ESI) m/z: 486 [M+H]+. Anal.
calcd for C23H22Cl2N6O2.0.89 H2O: C, 55.10; H, 4.78; N, 16.76, found: C,
54.93; H, 4.45; N, 16.42.
N-[4-(7-Chloro-quinolin-4-ylamino)-butyl]-2-(4-p-tolyloxymethyl-
[1,2,3]triazol-1-yl)-acetamide (10b). White solid; yield: 82%; mp: 202C;
IR (Nujol): νmax=3300 (NH), 1651 (C=O), 1612, 1584 (C=N), 1543, 1508,
1463, 1455, 1377, 1330, 1252, 1235, 1211, 1171, 1138, 1081, 1059,
1035, 1007, 901, 876, 853, 818, 803, 766, 721, 645 cm-1; 1H NMR (400
MHz, [D6]DMSO): δ=8.37 (brs, 2H, NH and quinoline H-2), 8.27 (d,
J=7.32 Hz, 1H, quinoline H-5), 8.13 (s, 1H, triazole H), 7.78 (s, 1H,
quinoline H-8), 7.42 (d, J=8.79 Hz, 1H, quinoline H-6), 7.31 (s, 1H, NH),
7.07 (d, J=8.05 Hz, 2H, ArH), 6.90 (d, J=8.05 Hz, 2H, ArH), 6.47 (s, 1H,
quinoline H-3), 5.08 (s, 4H, CH2O and CH2CO), 3.27-3.25 (m, 2H, CH2),
3.17-3.15 (m, 2H, CH2), 2.21 (s, 3H, CH3), 1.66-1.54 (m, 4H, CH2) ppm;
13C NMR (100 MHz, [D6]DMSO): δ=165.24, 155.95, 151.82, 150.01,
142.55, 133.34, 129.82, 129.69, 129.44, 125.99, 124.16, 124.02, 114.46,
114.29, 98.52, 60.94, 51.62, 42.00, 38.51, 26.61, 25.16, 20.07 ppm; MS
(ESI) m/z: 479 [M+H]+.
2-[4-(4-Bromo-phenoxymethyl)-[1,2,3]triazol-1-yl]-N-[3-(7-chloro-
quinolin-4-ylamino)-propyl]-acetamide (9c). Pale yellow solid; yield:
77%; mp: 202C; IR (Nujol): νmax=3364 (NH), 1688 (C=O), 1574 (C=N),
1538, 1463, 1455, 1377, 1332, 1300, 1281, 1242, 1171, 1141, 1118,
1099, 1074, 1045, 1028, 945, 894, 871, 848, 823, 797, 766, 722, 643,
621 cm-1; 1H NMR (400 MHz, [D6]DMSO): δ=8.45 (d, J=5.13 Hz, 1H,
quinoline H-2), 8.43 (s, 1H, NH), 8.26 (d, J=8.79 Hz, 1H, quinoline H-5),
8.18 (s, 1H, triazole H), 7.79 (s, 1H, quinoline H-8), 7.46 (dd, J1=6.59 Hz,
J2=2.20 Hz, 2H, ArH), 7.45-7.44 (m, 1H, quinoline H-6), 7.31 (t, J=5.13
Hz, 1H, NH), 7.03 (dd, J1=7.69 Hz, J2=2.20 Hz, 2H, ArH), 6.49 (d, J=4.39,
Hz, 1H, quinoline H-3), 5.15 (s, 2H, CH2O), 5.12 (s, 2H, CH2CO), 3.31 (t,
J=6.59 Hz, 2H, CH2), 3.24 (t, J=6.59 Hz, 2H, CH2), 1.87-1.80 (m, 2H,
CH2) ppm; 13C NMR (100 MHz, [D6]DMSO): δ=168.10, 160.00, 154.49,
152.69, 150.23, 149.55, 144.75, 136.11, 134.87, 130.15, 128.91, 126.79,
126.75, 119.67, 114.93, 98.55, 63.87, 54.35, 42.77, 39.50, 30.29 ppm;
MS (ESI) m/z: 530 [M+H]+. Anal. calcd for C23H22ClBrN6O2.0.3 H2O: C,
51.61; H, 4.26; N, 15.70, found: C, 51.73; H, 4.53; N, 15.38.
2-[4-(4-Chloro-phenoxymethyl)-[1,2,3]triazol-1-yl]-N-[6-(7-chloro-
quinolin-4-ylamino)-hexyl]-acetamide (11a). White solid; yield: 79%;
mp: 116C; IR (Nujol): νmax=3284 (NH), 1654 (C=O), 1581 (C=N), 1458,
1376, 1280, 1243, 1168, 1138, 1094, 1056, 1004, 899, 848, 821, 722,
643 cm-1; 1H NMR (400 MHz, [D6]DMSO): δ=8.35-8.32 (m, 2H, quinoline
H-2 and NH), 8.25 (d, J=8.79 Hz, 1H, quinoline H-5), 8.15 (s, 1H, triazole
H), 7.76 (s, 1H, quinoline H-8), 7.41 (dd, J1=9.15 Hz, J2=2.20 Hz, 1H,
quinoline H-6), 7.32-7.29 (m, 3H, ArH and NH), 7.04 (dd, J1=7.32 Hz,
J2=20 Hz, 2H, ArH), 6.44 (d, J=5.13 Hz, 1H, quinoline H-3), 5.12 (s, 2H,
CH2O), 5.07 (s, 2H, CH2CO), 3.23 (q, J=6.59 Hz, 2H, CH2), 3.08 (q,
J=6.59 Hz, 2H, CH2), 1.65-1.61 (m, 2H, CH2), 1.44-1.31 (m, 6H, 3CH2)
ppm; 13C NMR (100 MHz, [D6]DMSO): δ=162.28, 159.50, 154.03, 148.96,
147.30, 146.10, 139.21, 126.39, 124.50, 123.37, 121.67, 121.28, 121.18,
114.57, 113.60, 95.77, 58.40, 48.78, 39.50, 35.89, 26.04, 24.87, 23.46,
23.30 ppm; MS (ESI) m/z: 528 [M+H]+. Anal. calcd for C26H28Cl2N6O2.0.7
H2O: C, 57.82; H, 5.49; N, 15.56, found: C, 57.82; H, 5.56; N, 15.27.
N-[3-(7-Chloro-quinolin-4-ylamino)-propyl]-2-(4-p-tolyloxymethyl-
[1,2,3]triazol-1-yl)-acetamide (9d). Light brown solid; yield: 79%; mp:
196C; IR (Nujol): νmax=3371 (NH), 1689 (C=O), 1576 (C=N), 1540, 1513,
1455, 1377, 1332, 1282, 1247, 1175, 1141, 1059, 944, 895, 874, 849,
822, 798, 765, 722 cm-1; 1H NMR (400 MHz, [D6]DMSO): δ=8.46 (brs, 2H,
quinoline H-2 and H-5), 8.17 (s, 1H, triazole H), 7.95-7.87 (brs, 2H, NH
and quinoline H-8), 7.45 (d, J=8.79 Hz, 1H, quinoline H-6), 7.38 (s, 1H,
7
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10.1002/cmdc.201800728
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2-[4-(4-Bromo-phenoxymethyl)-[1,2,3]triazol-1-yl]-N-[6-(7-chloro-
quinolin-4-ylamino)-hexyl]-acetamide (11b). White solid; yield: 82%;
mp: 186C; IR (Nujol): νmax=3281 (NH), 1655 (C=O), 1611, 1581 (C=N),
1462, 1377, 1282, 1244, 1170, 1140, 1074, 1055, 1032, 1001, 898, 848,
reader. The half maximal inhibitory concentration values (IC50) for each
compound were determined using nonlinear regression analysis of dose-
response curves generated using pre-programmed excel spread sheet
after two independent experiments.
1
818, 722 cm-1; H NMR (400 MHz, [D6]DMSO): δ=8.36-8.33 (m, 2H, NH
and quinoline H-2), 8.26 (d, J=8.79 Hz, 1H, quinoline H-5), 8.16 (s, 1H,
triazole H), 7.76 (s, 1H, quinoline H-8), 7.44-7.42 (m, 3H, ArH and
quinoline H-6), 7.31 (s, 1H, NH), 7.00 (d, J=8.05 Hz, 2H, ArH), 6.44 (d,
J=4.39 Hz, 1H, quinoline H-3), 5.12 (s, 2H, CH2O), 5.07 (s, 2H, CH2CO),
3.24-3.22 (m, 2H, CH2), 3.09-3.08 (m, 2H, CH2), 1.63-1.34 (m, 8H, 4CH2)
ppm; 13C NMR (100 MHz, [D6]DMSO): δ=165.54, 157.75, 152.19, 150.59,
149.33, 142.45, 133.86, 132.55, 127.75, 126.64, 124.56, 124.46, 117.84,
117.42, 112.66, 99.03, 61.62, 52.06, 42.77, 39.16, 29.32, 28.14, 26.74,
26.57 ppm; MS (ESI) m/z: 572 [M+H]+.
Evaluation of antimalarial activity against chloroquine resistant P.
falciparum: Selected compounds which showed promising activity
against 3D7 were further tested for their antimalarial potential against CQ
resistant field isolate (RKL-9) of P. falciparum using
a Schizont
Maturation Inhibition assay (SMI).[35-37] Briefly, for carrying out dose
response evaluation, two fold dilutions of test compounds in desired
concentrations were prepared in 96 well microtiter plates. Inhibition
experiments were typically carried out at a final concentration of 4 µM.
Sorbitol-synchronized parasites with 1% parasitaemia (>90% rings) were
added in each well during the start of experiment. 100 nM DHA
(Dihydroartemisinin) and 0.5% DMSO (v/v) were used as positive and
negative (vehicle) control, respectively. Separate wells without any test
compounds/drugs were used to monitor uninhibited growth. Microtiter
plates were incubated at 37ºC in the presence of 5% CO2 for 22-36 hours,
till >10% schizont maturation (schizonts with 4 or more merozoites) in
untreated wells is observed. After the end of incubation period, thin
smears were prepared from each well and stained with 10% Giemsa for
20 minutes. Schizont maturation was assessed by counting number of
schizonts per 200 asexual parasites. Schizont maturation data collected
for each treated well was compared with data obtained from untreated
control wells and collectively used to calculate the percentage inhibition.
Percentage inhibition data was plotted against log of concentration using
a non-linear regression analysis with four parameter log dose with
variable slope to compute IC50 values and 95% confidence intervals
(Table 1) using Graphpad prism 6. Compounds were tested in triplicates
in three separate occasions.
Biological assays
Culture adaptation and in vitro cultivation of asexual stages. P.
falciparum cryo-preserved strains (CQ sensitive-3D7 and CQ resistant-
RKL9, a field isolate collected from Rourkela, India) were revived
according to standard protocols and introduced in culture with the
objective of adaptation to in vitro conditions. Asexual stages were
cultivated by following the procedures of Trager and Jensen[31,32] with
minor modifications. The parasites were cultivated in RPMI-1640 medium
(GIBCO) (with glutamine) containing 25 mM HEPES, 2g/L D-glucose, 2
g/L sodium bicarbonate, 40 μg/ml gentamicin sulfate supplemented with
10% heat inactivated AB+ human serum. A+ human blood at 10%
haematocrit was used as a source of host erythrocytes. Cultures were
maintained at 37ºC in a CO2 incubator in the presence of 5% CO2.
Synchronous parasites at ring stages were obtained by treatment with
5% sorbitol (w/v) as per requirement.
Gametocytocidal assays and data analysis: Gametocytocidal drug
assays were carried out in three independent experiments and potency
evaluation performed as described elsewhere.[33] Briefly, gametocytes
with majority of late stages were harvested on the day of experiment and
thorough systematic morphological examination was performed by light
microscopy before carrying out the screening experiments. Test plates
were prepared by plating two fold dilutions of the drugs in duplicates to
achieve the concentrations upto 50 µM for test compounds and
incubated with blood containing 2-3% mature gametocytes. Control wells
were also prepared containing gametocytes with drug free media for
evaluation of untreated inhibition. Also, 0.5% DMSO and 10 µM
methylene blue were used as vehicle (negative) and positive controls,
respectively. Plates were incubated at 37°C for 48 hours in presence of
5% CO2.[38] After incubation period, thin smears were prepared, stained
with 10% Giemsa and examined under a 100x oil immersion objective.[39]
Five thousand erythrocytes from each smear were counted to examine
the gametocytaemia and gametocyte morphology at each concentration.
Late stage gametocytes (Stage IV and V) observed were morphologically
categorized into two groups, 1) Normal Morphology (NM) group
containing healthy gametocytes and 2) Altered Morphology (AM) group
In vitro production of gametocytes: The detailed procedures for
gametocyte production is described elsewhere.[33] Briefly, on the day of
setting up the gametocyte culture (day 0), asexual culture was sorbitol-
synchronized to get >90% ring stages and parasitaemia was lowered to
0.5% by addition of fresh erythrocytes (10% haematocrit). These
parasites were daily replenished with complete RPMI-1640 media
supplemented with hypoxanthine (50 µg/mL) and kept devoid of fresh
erythrocytes throughout the period of culture maintenance. Haematocrit
was reduced to 5% on day 8 and 50 mM N-Acetyl-Glucosamine (NAG)
was added on days 9-12 to eliminate asexual stages and enrich for
gametocytes. On day 14 onwards, a gametocyte culture with a majority
of mature gametocytes (stages IV and V) was obtained and used for
evaluating the sensitivity of compounds.
Selection of most potent compounds using Malaria SYBR-green-I
based Fluorescent (MSF) Assay: All twelve quinoline-triazole hybrids
were initially screened for their antimalarial activity using Malaria SYBR
green-I based Fluorescence assay[34] to select most potent compounds
for a detailed investigation. Appropriate stock solutions of compounds
and standard drug CQ were prepared in DMSO (final DMSO
concentrations <0.5% v/v) and water respectively and stored at -20ºC
until use. Appropriate working solutions were made afresh on the day of
the experiment with complete culture medium. Two fold serial dilutions of
test samples were prepared in triplicates in 96 well microtiter plates and
incubated with 1% parasitized red blood cell suspension having 0.8-1%
parasitaemia (>90% rings, sorbitol synchronized). Positive control and
negative control wells were also prepared without the test compounds,
with 1% parasitized and non-parasitized erythrocyte suspension,
respectively. Unused parasite culture was kept separately without any
drug for monitoring the parasite growth. Plates were incubated at 37ºC
for 72 hours in presence of 5% CO2 and air mixture. After incubation
period, 100 µl of lysis buffer (Tris, EDTA, Saponin, Triton X-100, 2x
concentration of SYBR-Green I (Invitrogen) in water) was added to each
well and incubated in dark for one hour at 37ºC. The plates were
examined at 485±20 nm of excitation and 530±20 nm of emission for
Relative Fluorescence Units (RFUs) per well using the fluorescence plate
containing
morphologically
deformed/unhealthy
gametocytes.
Gametocytaemia for each concentration was expressed as percentage
inhibition compared to drug-free control which was plotted against log of
concentration using a non-linear regression analysis (four parameter log
dose with variable slope) to compute IC50 values and 95% confidence
intervals. Dose-response curves expressed as percentage inhibition vs.
logarithm of drug concentration were generated by Graphpad prism 6.
IC50 values were also calculated in two categories. In the first category,
only gametocytes bearing normal morphology were included and the
activity was labelled as IC50 (NM). In the second category, gametocytes
with both normal and altered morphology were included and IC50 is
designated as IC50 (Total).
Cytotoxicity studies: Cytotoxicity studies were carried out against
VERO cells (C 1008; Monkey Kidney Fibroblast) using MTT cell viability
assay by following the published protocols with minor modifications.[40]
8
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10.1002/cmdc.201800728
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FULL PAPER
Briefly, the desired concentration ranges of compounds were plated in 96
well microtiter plate after serially diluting the compound solutions. Cells
were seeded with the compound dilutions and incubated at 37°C in the
presence of 5% CO2 for 72 hours. MTT (5mg/ml) (3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide) reagent was added to each well
and plates were incubated in the dark for 4 hours. The by-product (dark
blue formazan) formed by viable cells was dissolved in DMSO and
absorbance was recorded at 550 nm using ELISA reader. 50% cytotoxic
concentration (CC50) was determined using nonlinear regression analysis.
Selectivity indices (SI) were calculated for each compound using IC50
values obtained for 3D7 strain of P. falciparum, as follows:
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푆퐼 = CC50
⁄
퐼퐶50
Acknowledgements
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The authors would like to thank the staff of Malaria Parasite
Bank, ICMR-National Institute of Malaria Research, Dwarka for
providing the technical help. IW, DP and NB are thankful to
UGC/CSIR for providing the Senior Research Fellowships.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: 7-chloroquinolines • [1,2,3]-triazole hybrids •
Plasmodium falciparum • antimalarial activity • dual-stage
antimalarials • gametocyte • synthesis
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9
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FULL PAPER
Entry for the Table of Contents
R
H
N
N
N
N
HN
N
O
n
O
Cl
n = 1, 2, 3, 5
R = H, Cl, Br, CH3, CHO
(IC50 = 38.75 - 910.14 nM)
Dual stage antimalarials: Novel hybrids based on 4-amino-7-chloroquinoline and [1,2,3]-triazole scaffolds were synthesized and
evaluated for their antiplasmodial activity against asexual blood stages and gametocytes of P. falciparum. Majority of the compounds
displayed <100 nM IC50 values against CQ sensitive strain (3D7) and exhibited no significant signs of cytotoxicity against mammalian
cell line (VERO). Three best compounds were appreciably more active (IC50 values <100 nM) than chloroquine against CQ resistant
field isolate RKL-9 and also demonstrated potency against mature gametocytes.
10
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