Bioorganic & Medicinal Chemistry Letters 24 (2014) 756759

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier.com/locate/bmcl

1H-1,2,3-Triazole-tethered isatin-7-chloroquinoline
and 3-hydroxy-indole-7-chloroquinoline conjugates:
Synthesis and antimalarial evaluation
Raghu Raj a, Jiri Gut b, Philip J. Rosenthal b, Vipan Kumar a,
a
b

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India
Department of Medicine, University of California, San Francisco, CA, USA

a r t i c l e

i n f o

Article history:
Received 24 September 2013
Revised 23 December 2013
Accepted 25 December 2013
Available online 3 January 2014

a b s t r a c t
A series of 1H-1,2,3-triazole-tethered isatin-7-chloroquinoline and 3-hydroxy-indole-7-chloroquinoline
conjugates have been synthesized and evaluated for their antimalarial activity against chloroquine-resistant W2 strain of Plasmodium falciparum. The most potent of the test compound with an optimum combination of 3-hydroxy-indole ring and a n-butyl linker displayed an IC50 value of 69 nM.
2013 Elsevier Ltd. All rights reserved.

Keywords:
7-Chloroquinoline
Isatin
3-Hydroxy-indole-2-one
1H-1,2,3-Triazole
Antimalarial activity

With AIDS and tuberculosis, malaria, caused by the genus

Plasmodium, is one of the worlds deadliest diseases. It is estimated
that 216 million people were infected by malaria parasites in 2010,
with nearly all of an estimated 700,000 deaths in children infected
with Plasmodium falciparum.1 The control of malaria is challenged
by lack of an effective vaccine and the development of resistance
to most existing antimalarial drugs.2 Currently, the World Health
Organization recommends artemisinin-based combination therapy
(ACT), including an artemisinin derivative and a longer-acting partner drug, for the treatment of uncomplicated falciparum malaria.3
However, early signs of artemisinin resistance, manifested as delayed clearance of parasites after therapy in parts of southeast Asia,
is of great concern.4,5 New agents for the treatment and prevention
of malaria are greatly needed. Among the existing antimalarial
pharmacophores, the 4-aminoquinoline viz. chloroquine (CQ) was
the most widely used antimalarial for over 50 years, and the related quinoline, amodiaquine is now widely used as a component
of the ACT artesunate-amodiaquine.6 A number of recent reports
have described the synthesis of new 4-aminoquinoline analogues
with enhanced activity against CQ resistant (CQR) strains developed via synthetic modications of CQ side chains.711

Corresponding author. Tel.: +91 183 2258802x3320; fax: +91 183 2258819 20.
E-mail address: [email protected] (V. Kumar).
0960-894X/$ - see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.109

Indoles, especially 1H-indole-2,3-dione (isatin) are one of the

most prevalent heterocyclic scaffolds found in natural products,
pharmaceuticals, and agrochemicals.12 Many indole derivatives
are under development as drug candidates due to their biological
properties, which include anti-HIV,13 antiviral,14 anti-tumor,1517
antifungal,18,19 anti-angiogenic,20 anti-convulsant,21 and antiparkinsonian activity.22 The most interesting application of isatin
in organic synthesis is based on the highly reactive C-3 carbonyl
group, which upon nucleophilic addition or spiro annulation
transforms it into 2-oxoindole compounds.23 In particular, 3substituted 2-oxoindoles have been used in the synthesis of a
range of natural products and have signicant biological activities
such as progesterone receptor modulation,24 HIV inhibition,25
anticancer activity,26 antimycobacterial activity,27 and antimalarial
activity.28,29 The indoloquinolines such as cryptolepine (5-methyl5H-indolo[2,3-c]quinoline) (I), neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline, cryptotackieine) (II), isocryptolepine (5-methyl
-5H-indolo[3,2-c]quinoline, cryptosanguinolentine) (III), and the
non-natural isoneocryptolepine (5-methyl-5H-indolo[2,3-c]quinoline) (IV) have shown potent activity against CQ-resistant strains of
P. falciparum.30
Recently, molecular hybridization has emerged as a useful tool
in medicinal chemistry and drug design. The methodology involves
the rational design of drugs in which two or more different pharmacophoric units are covalently linked into a single entity to form

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R. Raj et al. / Bioorg. Med. Chem. Lett. 24 (2014) 756759

potentially dual-acting compounds.31,32 The strategy is particularly

interesting where treatment is restricted to few drugs or in cases
where discovered drugs present pharmacokinetic or pharmacodynamic restrictions.33
Our group has recently reported 1H-1,2,3-triazole tethered 7chloroquinoline-isatin conjugates with or without well modulated
alkyl chains as potential antiplasmodial agents. Our studies
showed dependence of activity on the alkyl chain length and the
substituent on the C-5 position of the isatin ring. All hybrids
without alkyl chains were inactive, and the compound with the
optimum propyl spacer (n = 3) and a chloro substituent at the
C-5 position of the isatin ring was the most potent of the test
compounds, with an IC50 for inhibition of development of cultured
P. falciparum of 1.21 lM.34 Continuing our efforts to develop
biologically relevant conjugates with therapeutic potential,35 the
present work describes the synthesis and antimalarial evaluation
of phenolic ether based 1H-1,2,3-triazole tethered isatin-7-chloroquinoline and 3-hydroxy-indole-7-chloroquinoline conjugates
with well modulated alkyl chain spacers (Fig. 1). Variation in the
nature and size of substituents in such molecular frameworks
was of interest, as this offers variable electronic, lipophilic, and steric environments that may inuence antimalarial activity. The
introduction of phenolic ether as linker in these conjugates was
based on the recent discovery of small molecule inhibitors of
multidrug resistant P. falciparum via high throughput luciferasebased assay. The phenolic cluster was shown to constitute more
than 50% of the top ChemBridge hits with activities ranging from
36 nM to 15 lM.36 The inclusion of 1H-1,2,3-triazole in the synthesized conjugates was on the basis of its stability under basic, acidic,
reductive and oxidative conditions, and additional favourable
properties including high dipole moment, capability of hydrogen
bonding, and rigidity in the binding of biomolecular targets.37
For the synthesis of desired scaffolds, the precursor (7-Chloroquinolin-4-yl)-hydrazine 2 was prepared by reuxing 4,7-dichloroquinoline 1 with hydrazine hydrate in ethanol at 110 C for 34 h
(Scheme 1).
The second precursors viz. 1H-1,2,3-triazole tethered isatins
6a6l were prepared by an initial base-assisted alkylation of isatin
3 with dibromoalkanes. The N-alkylbromoisatins 4 thus obtained
were treated with sodium azide in dry DMF at 60 C to yield the
corresponding N-alkylazido-isatins 5 in good yields. Cu-promoted
click chemistry of 5 with O-propargylated salicyaldehyde led to
the isolation of desired precursor 6 with a free aldehydic group
in excellent yields (Scheme 2).38
The reaction of 2 with 6 in dry chloroform for 510 min resulted
in the isolation of desired 1H-1,2,3-triazole-tethered isatin-7-chloroquinoline conjugates 7 as crude products, which were recrystallized with a chloroform/methanol (95:5) mixture. Treatment of the
synthesized Schiff bases 7 with sodium borohydride in methanol
resulted in the isolation of 1H-1,2,3-triazole tethered 3-hydroxyindole-7-chloroquinoline conjugates 8 formed by reduction of both
(C@N) as well as the isatin keto-carbonyl (Scheme 3). The structure

NHNH2

Cl
NH2NH2
EtOH, 110C
N

Cl

Cl
2

Scheme 1. Synthesis of (7-Chloro-quinolin-4-yl)-hydrazine 2.

Table 1
Antimalarial activity of tested compounds
Code

W2a (CQ-R)
IC50 (nM)

c log Pb

6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
Chloroquine
Artemisinin

H
H
H
F
F
F
Cl
Cl
Cl
CH3
CH3
CH3
H
H
H
F
F
F
Cl
Cl
Cl
CH3
CH3
CH3
H
H
H
F
F
F
Cl
Cl
Cl
CH3
CH3
CH3

1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3

>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
6416
118
165
119
190
288
134
263
346
141
185
163
204
128
339
69.0
112
206
164
182
350
168
320
509
326
60.0
7.00

1.362
1.684
2.254
1.861
1.685
2.007
2.577
2.184
1.802
2.124
2.694
2.301
4.791
5.113
5.683
5.290
5.114
5.436
6.006
5.613
5.231
5.553
6.123
5.730
3.412
3.734
4.304
3.911
3.735
4.057
4.627
4.234
3.852
4.174
4.744
4.351

a
b

CQ-R: Chloroquine resistant.

Calculated using Chem. Draw Ultra 10.0.

of hybrids 7 and 8 were assigned on the basis of spectral data and

analytical evidence.39,40
The test compounds were evaluated for their antimalarial
proles against the CQ resistant W2 strain of P. falciparum
(Table 1). The isatin-based triazoles 6a6l were inactive at tested

O
R
O
N

N
CHO

N
n

O
N

N
N3

R
O

OH

O
R

N
H
N

CHO

N
N

H
N

NH

Figure 1. General structure of target hybrid compounds.

Cl

NH

Cl

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R. Raj et al. / Bioorg. Med. Chem. Lett. 24 (2014) 756759

O
O
R

Br

Br

N
H

NaH, DMF,
60 C, 7-8 h

NaN3

R
O
N

DMF, 60 C
2-3 h
n

CuSO4,
Sodium ascorbate
EtOH:H2O

N
5

Br

O
n

N3

N
OHC
6

CHO

R= H, F, Cl, CH3
n=1,2,3

Scheme 2. Synthesis of isatin based triazoles 6a6l.

OH

R
2, Dry CHCl3

N
n

5-10 min., rt
N

N
N
6

NaBH4

N
O

N
CHO

Dry Methanol
5-10 min., rt

N
N

O
H
N

NH

8
N

Cl

R= H, F, Cl, CH3
n=1,2,3

NH

Cl

Scheme 3. Synthesis of 1H-1,2,3-triazole tethered isatin-7-chloroquinoline7a7l and 3-hydroxy indole-7-chloroquinoline conjugates 8a8l.

concentrations. The introduction of a 7-chloroquinoline ring

markedly improved the antimalarial proles, as evidenced by
the activity of isatin-7-chloroquinoline conjugates 7a7l with
activity ranging from 118 to 346 nM. The antimalarial proles
of test compounds showed dependence on the length of the alkyl
chain introduced as spacers, while the nature of substituents
present at the C-5 position of the isatin ring did not appear to
inuence the activity proles. Conjugates with even chain lengths
viz. n = 2 (7a, 7d, 7g, 7j) and n = 4 (7c, 7f, 7i, 7l) were comparatively more potent compared to those with odd chain lengths
n = 3 (7b, 7e, 7h, 7k).
The reduced 3-hydroxy-indole-7-chloroquinoline conjugates
viz. 8a8l had slightly improved activity compared to isatin-7chloroquinoline conjugates 7a7l, especially in the case of 8c, 8d,
8e and 8g. Compound 8c, with an optimum combination of 3-hydroxy-indole ring, butyl linker and reduced imine, showed the best
activity among the test compounds, with an IC50 value of 69 nM. As
evident from Table 1, the introduction of 7-chloroquinoline ring in
the tested compounds improved their lipophilicity values calculated by using ChemDraw ultra 10.0. However, the observed antimalarial proles do not correlate well with the calculated
lipophilicity values but most potent of the tested compounds, in
general, showed higher lipophilicity values.
In conclusion, the present manuscript describes the synthesis of
1H-1,2,3-triazole-tethered isatin-7-chloroquinoline and 3-hydroxy-indole-7-chloroquinoline conjugates along with their antimalarial evaluation against cultured chloroquine-resistant W2 strain
of P. falciparum. Antiplasmodial activity proles of tested compounds showed the dependence of activity on the length of alkyl
chain but independent of the nature of substituent present at the
C-5 position of isatin or indole ring. The synthesized conjugates
are not as potent as standard antimalarial drugs (Chloroquine
and Artemisinin); however the most potent of the test compound
displayed an activity comparable to that of chloroquine, with an
IC50 value of 69 nM. Further work to improve the activity proles
of 7-chloroquinoline-isatin conjugates via introduction of diverse
linkers such as b-aminoalcohol and bis-triazoles is currently
underway and will soon be communicated.

Acknowledgment
Financial assistance from Board of Research in Nuclear Sciences
under DAE Research Award for Young Scientist Scheme (VK) is
gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
12.109.
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38. Synthesis of 4-{1-[2-(2,3-Dioxo-2,3-dihydro-indol-1-yl)-ethyl]-1H-[1,2,3]triazol4-ylmethoxy}-benzaldehyde (6a): To the well stirred solution of 1-(2-Azidoethyl)-1H-indole-2,3-dione (1 mmol) and propargylated p-salicyaldehyde (1
mmol) in 30 mL ethanol/water (10:1) mixture was added in succession copper
sulphate (0.055 mmol) and sodium ascorbate (0.143 mmol) at room
temperature. The reaction mixture was stirred at room temperature for 2
3 h. On completion of the reaction, as monitored by TLC, water (20 mL) was
added to the reaction mixture and extracted with chloroform (2  50 mL).
Organic layers were combined, dried over anhydrous sodium sulphate and
concentrated under reduce pressure to result in a crude product which was
puried by column chromatography using ethyl acetate/hexane (80:20)
mixture to give pure 4-{1-[2-(2,3-Dioxo-2,3-dihydro-indol-1-yl)-ethyl]-1H[1,2,3]triazol-4-ylmethoxy}-benzaldehyde (6a). Orange Solid; Yield: 89%; mp
128129 C. IR (KBr) mmax: 1737, 1708, 1611 cm1; 1H NMR (300 MHz, CDCl3):
d 4.26 (t, J = 5.7Hz, 2H, NCH2); 4.73 (t, J = 6.0Hz, 2H, NCH2); 5.20 (s, 2H,
OCH2); 6.56 (d, J = 8.1Hz, 1H, ArH); 7.017.08 (m, 3H, ArH); 7.40 (t,
J = 7.8Hz, 1H, ArH); 7.55 (d, J = 7.5Hz, 1H, ArH); 7.65 (s, 1H, triazole H); 7.80 (d,
J = 6.9Hz, 2H, ArH); 9.88 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3): d ppm = 36.8,
46.9, 61.6, 110.1, 114.7, 117.8, 123.9, 124.1, 125.7, 129.9, 131.8, 138.3, 142.6,
150.1, 157.9, 163.2, 182.5, 191.1. HRMS Calculated for C20H16N4O4 [M]+
376.1172 found 376.1163; Anal. Calcd (%) for: C, 63.82; H, 4.28; N, 14.89;
Found: C, 63.76; H, 4.38; N, 14.83.
39. Synthesis of 1-[2-(4-{4-[(7-Chloro-quinolin-4-yl)-hydrazonomethyl]-phenoxymethyl}[1,2,3]triazol-1-yl)-ethyl]-1H-indole-2,3-dione (7a): A mixture of (7-Chloroquinolin-4-yl)-hydrazine 2 (1 mmol) and 6a (1 mmol) in dry CHCl3 were stirred
at room temperature for 510 min. Progress of the reaction was monitored by TLC.
The crude product got precipitated out and was recrystallized using chloroform/
methanol (95:5) mixture to yield the desired conjugates 1-[2-(4-{4-[(7-Chloroquinolin-4-yl)-hydrazonomethyl]-phenoxymethyl}-[1,2,3]triazol-1-yl)-ethyl]-1
H-indole-2,3-dione (7a). Red Solid; Yield: 85%; mp 178179 C. IR (KBr) mmax:
1742, 1612 cm1; 1H NMR (300 MHz, DMSO-d6): d 4.22 (t, J = 5.7Hz, 2H, N
CH2); 4.79 (t, J = 5.7Hz, 2H, NCH2); 5.20 (s, 2H, OCH2); 6.83 (d, J = 7.8Hz,
1H, ArH); 7.05 (t, J = 7.5Hz, 1H, ArH); 7.177.22 (m, 4H, ArH); 7.53 (dd, J = 2.1,
9.0Hz, 1H, H4, ArH); 7.62 (d, J = 1.8Hz, 1H, H5, ArH); 7.84 (d, J = 8.7Hz, 2H, ArH);
7.94 (d, J = 7.5Hz, 1H, H2, ArH); 8.30 (s, 1H, triazole H); 8.43 (d, J = 7.5Hz, 1H,
H1,ArH); 8.56 (d, J = 9.0Hz, 1H, H3, ArH); 9.85 (s, 1H, N@CH); 12.28 (s, 1H,
NH exchangeable with D2O); 13C NMR (75 MHz, CDCl3+DMSO-d6): d ppm = 35.6,
45.9, 60.2, 100.2, 108.3, 115.3, 117.4, 120.0, 121.7, 122.1, 124.8, 126.6, 127.9,
129.7, 130.2, 131.8, 136.5, 138.0, 139.4, 141.3, 142.6, 144.2, 149.1, 152.4, 162.6,
164.7, 191.1. HRMS Calculated for C29H22ClN7O3 [M]+ 551.1473 found
551.1466; Anal. Calcd (%) for: C, 63.10; H, 4.02; N, 17.76; Found: C, 63.03; H,
3.94; N, 17.66.
40. Synthesis of 1-[2-(4-{4-[N0 -(7-Chloro-quinolin-4-yl)-hydrazinomethyl]-phenoxymethyl}[1,2,3]triazol-1-yl)-ethyl]-1H-indole-2,3-dione (8a): To a well stirred solution of 7a
(1 mmol) in dry methanol, sodium borohydride (1 mmol) was added. The reaction
mixture was stirred for 510 min at room temperature. After completion of the
reaction, as monitored by TLC, water (15 mL) was added in reaction mixture and
extracted with chloroform (3  40 mL). The organic layers were combined, dried
over sodium sulphate and concentrated under reduced pressure to result in the
isolation of the crude product which after recrystallization using chloroform/
methanol (90:10) mixture affords pure product 1-[2-(4-{4-[N0 -(7-Chloro-quinolin4-yl)-hydrazinomethyl]-phenoxymethyl}-[1,2,3]triazol-1-yl)-ethyl]-1H-indole2,3-dione (8a). Red Solid; Yield: 83%; mp 210211 C. IR (KBr) mmax: 1629 cm1;
1
H NMR (300 MHz, DMSO-d6): d 3.36 (s, 1H, CH); 4.21 (t, J = 6.0Hz, 2H, N
CH2); 4.42 (d, J = 5.7Hz, 2H, NCH2); 4.65 (t, J = 6.0Hz, 2H, NCH2); 5.02 (t,
J = 5.7Hz, 1H, NH exchangeable with D2O); 5.09 (s, 2H, OCH2); 6.92 (d,
J = 8.4Hz, 2H, ArH); 7.137.24 (m, 4H, ArH); 7.41 (t, J = 7.5Hz, 1H, ArH); 7.56 (d,
J = 5.1Hz, 1H, H2, ArH); 7.63 (d, J = 7.2Hz, 1H, ArH); 7.69 (dd, J = 2.1, 9.0Hz, 1H,
H4, ArH); 7.82 (d, J = 9.0Hz, 1H, H3, ArH); 7.99 (d, J = 2.1Hz, 1H, H5, ArH); 8.22
(s, 1H, triazole H); 8.31 (s, 1H, OH exchangeable with D2O); 8.80 (d, J = 5.1Hz,
1H, H1, ArH); 13.54 (s, 1H, NH exchangeable with D2O); 13C NMR (75 MHz,
DMSO-d6): d ppm = 36.3, 42.7, 61.1, 62.2, 79.4, 102.2, 109.6, 114.5, 115.1, 119.8,
121.4, 123.1, 124.6, 126.5, 127.7, 128.3, 130.6, 132.8, 134.0, 134.5, 141.4, 142.7,
144.0, 148.9, 152.2, 156.7, 161.9. HRMS Calculated for C29H24ClN7O3 [M]+
553.1629 found 553.1637; Anal. Calcd (%) for: C, 62.87; H, 4.37; N, 17.70;
Found: C, 62.96; H, 4.44; N, 17.60.