4-aminoquinoline-triazine-based hybrids with improved in vitro antimalarial activity against CQ-sensitive and CQ-resistant strains of plasmodium falciparum

Article abstract of DOI:10.1111/cbdd.12108

A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4-amino-7-chloroquinolines yielded a series of new 7-chloro-4-aminoquinoline-triazine hybrids exhibiting high in vitro activity against W2 (chloroquine-resistant) and D6 (chloroquine-sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC-PK11, HepG2). Many of the compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8, 14, 16 and 29 were found to be significantly more active than chloroquine against the chloroquine-resistant strains (W2 clone) of P. falciparum.

Full text of DOI:10.1111/cbdd.12108

Received Date : 11-Aug-2012
Revised Date : 18-Dec-2012
Accepted Date : 08-Jan-2013
Article type : Research Article
4-Aminoquinoline-triazine based hybrids with improved in-vitro
antimalarial activity against CQ-sensitive and CQ-resistant strains of P.
falciparum
Sunny Manohar,1 Shabana I. Khan,2 and Diwan S. Rawat*1
1Department of Chemistry, University of Delhi, Delhi-110007, India
2National Centre for Natural Products Research, University of Mississippi, MS-38677, USA
Corresponding auther: dsrawat@chemistry.du.ac.in
Phone No: 91-11-27667465, Fax No: 91-11-27667501
Abstract: A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4-amino-7-
chloroquinolines yielded a series of new 7-chloro-4-aminoquinoline-triazine hybrids exhibiting high in vitro activity against
W2 (CQ-resistant) and D6 (CQ-sensitive) strains of P. falciparum without any toxicity against mammalian cell lines (Vero,
LLC-PK11, HepG2). Many of the compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showed excellent potency against
chloroquine sensitive and resistant strains. In particular compounds 6, 8, 14, 16 and 29 were found to be significantly more
active than chloroquine against the CQ-resistant strains (W2 clone) of P. falciparum.
Key words: Antimalarial, Plasmodium falciparum, hybrids.
Introduction
The prevalence of malaria has been documented about five thousand years back but still it has remained one of the most
lethal disease causing deaths of over one million people every year (1, 2). The drugs once considered to be safe and effective
have become useless due to the incidences of increasing reports of drug resistance, and that has put an enormous burden on
public health (3,4). Among the most commonly used drugs, chloroquine (CQ) (3) had been a drug of choice for the treatment
of malaria for nearly half a century and considered to be a wonder drug due to the fact that it was effective, easily available,
safe and inexpensive (5). The added advantage was that, it could be administered to infants and pregnant women. The
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© 2013 John Wiley & Sons A/S

problem has been complicated due to the fact that P. falciparum, the cause of the most lethal variety of malaria, has
developed resistance against chloroquine and other antimalarials. Number of isolates of P. falciparum have developed
resistance against not only CQ but against the majority of currently used antimalarials. In order to address the issue of drug
resistance several approaches that includes chloroquine resistant (CQR) reversal agents (6,7), combination therapy (8), and
use of endoperoxide based antimalarials, have been introduced (9-14). Although endoperoxides are considered to be useful
against resistant strains, but these compounds are less affordable and recently, resistance against endoperoxide-derived
antimalarials has already been reported (15). Arguably, aminoquinolines such as quinine, chloroquine (CQ), mefloquine, and
amodiaquine are among the most successful antimalarial drugs ever used (16-18), and structural modification of these
molecules has resulted many additional lead compounds with improved activity against CQR strains (19-21). SAR studies
revealed that 4-aminoquinolines carrying an aliphatic side chain with 2-3 or 10-12 carbon and the incorporation of a phenol
moiety are well tolerated and afford excellent activity-toxicity profiles (22-26). Many reports revealed that replacement of
ethyl group by isopropyl or tert-butyl groups, can furnish metabolically more stable antimalarials with enhanced lifetime and
retained activity against drug resistant strains of P. falciparum (27,28). In order to develop safe, effective, and inexpensive
antimalarials that are active against resistant strains and multiple species of Plasmodia, efforts have therefore been directed
towards the development of new CQ analogues. Towards these goals, concept of hybrid molecules have been put forward by
Meunier et al in malaria chemotherapy (29), in which two antimalarial pharmacophore are attached covalently, and it is
anticipated that these kinds of molecules may solve the problem of drug resistanc. In the past few years, number of 4-
aminoquinoline based hybrid molecules are synthesised in an attempt to solve the problem of drug resistance (29-38).
The previous studies from our laboratory (34,35), and others showed that aminoquinoline-triazine hybrids exhibit potent
antimalarial activity(39,40). In continuation to our efforts towards the development of new antimalarials (41-44), we report
herein synthesis and antimalarial activity of series of new 4-aminoquinoline-triazine based hybrids. Systematic chemical
modification in the triazine ring and linker led to the discovery of many potent antimalarial agents.
Results and discussion
Chemistry
Synthesis of substituted 4-aminoquinolines (2a-c) was achieved by aromatic nucleophillic substitution (SNAr) of 4,7-
dichloroquinoline (1) with an excess of different linear chained aliphatic diamines in neat conditions as reported in literature
(Scheme 1) (45).
Temperature controlled step wise displacement of chlorine atom from commercially available starting material cyanuric
chloride (3) was accomplished in stepwise to achieve the synthesis of target compounds (6-33) as outlined in scheme 2. In
the first step, cyanuric chloride (3) was subjected to nucleophillic substitution by piperidine or morpholine in presence of a
base at 0 oC to yield monosbustituted triazines (4a-b). These monosubstituted triazines (4a-b) on reaction with various
aliphatic and aromatic amines at room temperature provided disubstituted triazines (5a-j) in good yield. Third chlorine of
disubstituted triazines (5a-j) were then substituted by 4-aminoquinolines having varying alkyl chain lengths (2a-c) at
elevated temperature to yield final trisubstituted triazines (6-33) in moderate to excellent yields.
Antimalarial activity and cytotoxicity evaluation
The synthesized compounds (6-33) were evaluated for their in-vitro antimalarial activity against D6 clone (CQ-sensitive)
and W2 clone (CQ-resistant) of P. falciparum (table 1), while the cytotoxicity evaluation were carried against a panel of 3
mammalian cells (Vero, LLC-PK11 and HepG2) by using doxorubicin as standard drug (table 2). Selectivity index of
antimalarial activity was calculated based on the cytotoxicity to Vero cells. Out of 28 compounds synthesised in the present
study, ten compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) have shown better antimalarial activity (IC50 ranging from
0.11 to 0.42 µM) than CQ while 3 compounds (12, 26 and 32) have shown comparable activity (IC50 ranging from 0.48 to
0.49 µM) to CQ against W2 clone of P. falciparum. Four of these hybrids (17, 26, 29 and 31) have also shown potent
antimalarial activity (IC50 ranging from 0.06 to 0.10 µM) with high selective index against D6 clone of P. falciparum.
Structure activity relationship (SAR) studies of these hybrid shows that the spacer which links 4-aminoquinoline to 1,3,5-
triazine moiety plays an important role in defining the activity of these molecules. It is evident from the table 1 that
increasing the length of the linker from C2 to C4, activity of the resulting compounds increases. However, some deviations
from this trend were also observed with few compounds (7, 13, 19, 25 against D6 clone and 7, 16, 19, 31 against W2 clone).
Enhanced antimalarial activity with high selective index against W2 clone of P. falciparum has been observed for
compounds containing aromatic substitution on 1,3,5-triazine (7 out of 12 compounds are better than CQ) than their
aliphatic counterparts (2 out of 16 compounds are better than CQ). This may be attributed to greater lipophilic character
associated with aromatic compounds (table 1), which is in good agreement to our previous observation (35). It may be noted
that no obvious change in activity pattern was observed by changing the substituents (fluoro, ethyl or methoxy groups) on
phenyl ring attached to 1,3,5-triazine moiety. Most interestingly, the introduction of amino alcohols with terminal hydroxyl
groups in the 1,3,5-triazine nucleus enhances the activity of some of the compounds (26, 27, 29, 32 and 33) towards both the
strains (D6 and W2 clone) of P. falciparum with IC50 ranging from 0.10 to 0.19 µM against D6 clone and 0.28 to 0.49 µM
against W2 clone. In this series (18-33), the change of piperidine (27-33) from morpholine group (18-26) improved the
antimalarial activity of these compounds against both the strains of P. falciparum (IC50 ranging from 0.10 to 0.21 µM against
D6 clone and 0.28 to 1.17 µM against W2 clone) while the increase in the carbon chain length of aliphatic aminoalcohols
attached to 1,3,5-triazine nucleus generally increases the antimalarial activity toward W2 clone for a particular linker (C2,
C3 or C4) present between the aminoquinoline and triazine moiety. Most of the compounds were found to be non-cytotoxic
up to the highest tested concentration of 25 µM against all three cell lines (table 2) indicating their safety in mammalian
© 2013 John Wiley & Sons A/S

system. The mechanistic studies and structural modification of the lead molecules are under progress and results will be
published in due course of time.
Conclusion
In summary, systematic chemical modification of previously reported 4-aminoquinoline-triazine based hybrids led to the
discovery of more potent 4-aminoquinoline-1,3,5-triazine based hybrids with potent activity against both CQ-sensitive (D6
clone) and CQ-resistant (W2 clone) of P. falciparum. Ten compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) out of total 28
compounds synthesised have displayed better activity than chloroquine against W2 clone of P. falciparum. Introduction of
aminoalcohol side chain with free terminal hydroxyl group enhances the activity of compounds (26, 27, 29, 32 and 33)
towards both the strains of P. falciparum. The activity profile of these molecules, in particular of compounds 16 and 29, can
be beneficial for the generation of future drug candidates in malarial chemotherapy.
Acknowledgements
DSR thanks University Grants Commission [F. No. 41-202/2012(SR)], New Delhi, India and University of Delhi, Delhi,
India for financial support. SM is thankful to CSIR for the award of senior research fellowship. Thanks to USIC-CIF,
University of Delhi for analytical data. SIK is thankful to United States Department of Agriculture (USDA), Agricultural
Research Service Specific Cooperative Agreement No. 58-6408-2-0009 for partial support of this work. The authors declare
no conflict of interest.
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© 2013 John Wiley & Sons A/S

Table 1: In-vitro antimalarial activity of new 4-aminoquinoline-triazine conjugates.
Entry
n
X
R
cLogP*
P. falciparum
(D6 Clone)
P. falciparum
(W2 Clone)
IC50 (µM)
S. I.
IC50
(µM)
0.17
S. I.
6
7
8
9
10
11
12
13
14
15
16
17
18
1
2
3
1
2
3
1
2
3
1
2
3
1
O
O
O
O
O
O
O
O
O
O
O
O
O
aniline
aniline
aniline
6.36
6.77
6.88
7.39
7.79
7.91
6.52
6.92
7.04
6.29
6.69
6.81
3.54
0.29
0.44
0.29
0.47
0.40
0.39
0.24
0.43
0.24
0.25
0.16
0.07
0.49
> 86.2
> 56.8
> 170.6
> 53.1
72.0
> 64.1
> 104.1
> 58.1
> 104.1
> 100.0
> 156.2
> 357.1
> 51.0
> 147.0
> 23.8
> 198.0
> 37.3
68.5
> 138.8
> 52.0
> 75.7
> 227.2
> 42.3
> 166.6
> 35.2
> 14.7
1.05
0.25
0.67
0.42
0.18
0.48
0.33
0.11
0.59
0.15
0.71
1.70
4-ethyl aniline
4-ethyl aniline
4-ethyl aniline
4-fluoro aniline
4-fluoro aniline
4-fluoro aniline
4-methoxy aniline
4-methoxy aniline
4-methoxy aniline
19
20
2
3
O
O
4.02
4.14
0.50
0.19
> 50.0
2.06
0.59
> 12.1
> 42.3
> 131.5
21
22
23
24
1
2
3
1
O
O
O
O
3.99
4.39
4.42
3.88
0.67
0.63
0.22
0.48
> 37.3
> 39.6
> 113.6
> 52.0
1.56
1.52
0.57
1.52
> 16.0
> 16.4
> 43.8
> 16.4
25
26
27
28
29
2
3
1
2
3
O
4.39
4.50
5.52
5.92
6.04
0.51
0.09
0.14
ND
> 49.0
> 277.7
> 178.5
ND
1.12
0.49
0.40
ND
> 22.3
> 51.0
> 62.5
ND
O
CH2
CH2
CH2
0.10
> 250.0
0.28
> 89.2
30
31
32
1
3
1
CH2
CH2
CH2
5.44
6.05
5.16
0.21
0.06
0.19
> 119.0
> 858.3
> 131.5
0.83
1.17
0.49
> 30.1
> 44.0
> 51.0
33
3
CH2
5.60
0.19
> 131.5
0.42
> 59.5
Chloroquine (CQ)
Artemisinin
0.05
0.015
> 500
> 1666.6
0.43
0.014
> 58.1
>1785.7
ND: Not Determined
Selectivity index (SI): IC50 for cytotoxicity ⁄ IC50 for antimalarial activity
cLogP: Calculated by CHEMBIODRAW 11 Software, Cambridge, MA, USA.
© 2013 John Wiley & Sons A/S

Table 2: In vitro cytotoxicity of 4-aminoquinoline-triazine conjugates (6-33) to mammalian cells
Entry
6
VERO
NC
LLC-PK11
NC
HepG2
NC
7
NC
NC
NC
8
>49.5
9.9
33.2
9
NC
28.8
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
>51.5
NC
NC
>9.1
NC
8.6
NC
11.5
31.8
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
28.4
NC
40.9
1.1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
24.3
NC
NC
NC
NC
27.8
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
27.4
NC
NC
1.3
Doxorubicin
NC: Not Cytotoxic Upto 25 µM
Vero: Monkey kidney fibroblasts; LLC-PK11: Pig kidney epithelial cells and HepG2: Human hepatoma cells.
© 2013 John Wiley & Sons A/S