Design, synthesis and characterization of quinoline-pyrimidine linked calix[4]arene scaffolds as anti-malarial agents

Article abstract of DOI:10.1007/s10847-015-0581-0

In this paper, we report a series of quinolinepyrimidine linked calix[4]arene derivatives functionalized with 8-amino quinoline, 5-amino quinoline, 8-hydroxy quinoline, 2-amino pyrimidine and 4-amino 3-methyl quinoline. The synthesized compounds were purified and characterized by elemental analysis, FT-IR,¹H NMR and ESI-MS and screened for their anti-malarial activity against plasmodium falciparum strains. Two synthesized compounds with 8-hydroxy quinoline and 2-amino pyrimidine substituents showed good antimalarial activity with IC₅₀ 0.073 and 0.043 μg/ml respectively which is comparable with the standard drug chloroquine. The present study provides valuable information for developing calix[4]arene conjugates quinoline-pyrimidine based derivatives as an effective antimalarial agents. Graphical Abstract In this paper, we report a series of quinoline-pyrimidine linked calix [4]arenes derivatives functionalised with 8-amino quinoline, 5-amino quinoline, 8-hydroxy quinoline, 2-amino pyrimidine and 4-amino 3-methyl quinoline and screened for antimalarial activity. Two synthesized compounds with 8-hydroxy quinoline and 2-amino pyrimidine substituents showed good antimalarial activity with IC₅₀ 0.073 and 0.043 μg/mL respectively, which is comparable with the standard drug chloroquine. The present study provides valuable information for developing calix[4]arene conjugates quinoline-pyrimidine derivatives.

Full text of DOI:10.1007/s10847-015-0581-0

J Incl Phenom Macrocycl Chem
DOI 10.1007/s10847-015-0581-0
SHORT COMMUNICATION
Design, synthesis and characterization of quinoline–pyrimidine
linked calix[4]arene scaffolds as anti-malarial agents
1
1
2
1
Rahul B. Shah
•
Nikunj N. Valand
•
Pinkesh G. Sutariya
•
Shobhana K. Menon
Received: 7 September 2015 / Accepted: 10 November 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract In this paper, we report a series of quinoline-
pyrimidine linked calix[4]arene derivatives functionalized
with 8-amino quinoline, 5-amino quinoline, 8-hydroxy
quinoline, 2-amino pyrimidine and 4-amino 3-methyl
quinoline. The synthesized compounds were purified and
present study provides valuable information for developing
calix[4]arene conjugates quinoline-pyrimidine derivatives.
1
characterized by elemental analysis, FT-IR, H NMR and
ESI-MS and screened for their anti-malarial activity
against plasmodium falciparum strains. Two synthesized
compounds with 8-hydroxy quinoline and 2-amino
pyrimidine substituents showed good antimalarial activity
with IC50 0.073 and 0.043 lg/ml respectively which is
comparable with the standard drug chloroquine. The pre-
sent study provides valuable information for developing
calix[4]arene conjugates quinoline-pyrimidine based
derivatives as an effective antimalarial agents.
Graphical Abstract In this paper, we report a series of
quinoline-pyrimidine linked calix [4]arenes derivatives
functionalised with 8-amino quinoline, 5-amino quinoline,
Keywords Calix[4]arene Á Quinoline Á Pyrimidine Á
Plasmodium falciparum strains Á Anti-malarial activity
8
3
-hydroxy quinoline, 2- amino pyrimidine and 4-amino
-methyl quinoline and screened for antimalarial activity.
Two synthesized compounds with 8-hydroxy quinoline and
-amino pyrimidine substituents showed good antimalarial
Introduction
2
activity with IC50 0.073 and 0.043 lg/mL respectively,
which is comparable with the standarddrug chloroquine. The
Calixarenes, with their unique three-dimensional surface,
are one of the best known host molecules along with
cyclodextrins, cucurbiturils, cryptands, and crown ethers. By
their availability and easy functionalization at either the
upper or lower rim of the molecular skeleton among potential
building blocks, calixarenes have become important recep-
tors in synthesis and applications as supramolecular plat-
forms for molecular recognition, sensing and self-assembly,
catalysis, nanotechnology and drug discovery.
Electronic supplementary material The online version of this
article (doi:10.1007/s10847-015-0581-0) contains supplementary
material, which is available to authorized users.
&
Shobhana K. Menon
shobhanamenon07@gmail.com
1
2
Department of Chemistry, University School of Sciences,
Gujarat University, Ahmedabad, Gujarat 380009, India
It is well known that the toxicity is a barrier to the
discovery and development of potent drug molecules. Most
calixarene derivatives showed low or no toxicity in the
Bhavans Shree I. L. Pandya Arts-Science College, Gujarat
University, Dakor 388225, India
123

J Incl Phenom Macrocycl Chem
animal models [1]. Calixarenes have shown antiviral [2]
antibacterial [3], antifungal, antitubercular [4] and anti-
cancer activities [5-7]. In 2009, F a´ tima et al. [8] has
reviewed the use of calixarenes as new chemical entitiesof
distinct biological activities or as host for bioactive guest
molecules.
novel triazine–pyrimidine hybrids have been synthesized
and evaluated for their in vitro antimalarial activity [18].
Pandey and co-workers synthesized a novel series of
tetrazole derivatives of 4-aminoquinoline and screened for
their antimalarial activities against both chloroquine-sen-
sitive (3D7) and chloroquine-resistant (K1) strains of
Plasmodium falciparum as well as for cytotoxicity against
VERO cell lines [19]
Malaria is a parasitic infection of the red blood cells,
transmitted by the female anopheles mosquito through
biting and transfer of plasmodium parasites by saliva.
According to the WHO, over 198 million people world-
wide live under the threat of malaria infection and in 2009,
nearly 584,000 people lost their lives to the disease [9, 10].
Malaria is caused by infection with four species of the
family Plasmodium; plasmodium falciparum (Pf), Plas-
modium malariae (Pm), Plasmodium ovale (Po) and
Plasmodium vivax (Pv) of which Pf is responsible for the
most severe and fatal form of the disease. Most of the drugs
currently used in the treatment of malaria target either the
haem detoxification system (e.g. chloroquine and meflo-
quine) or the biosynthesis of nucleotide bases by inhibiting
dihydrofolate reductase (DHFR) or dihydropteroate
reductase (DHPR) (e.g. pyrimethamine/sulfadoxine). The
primary chemotherapeutic drugs, such as chloroquine (CQ)
and pyrimethamine, are of little or no use because the
malarial parasite developed resistance against them [11].
Recent reports of resistance to artemisinin, the only
effective antimalarial drug at present, have become the
cause of concern [12, 13]. Therefore, it is important to
search for new antimalarial drugs and also to test the
efficacies of some of the old drugs whose antimalarial
potential has not been verified in depth.
Recently our research group reported [20, 21] calixarene
based thiadiazole-oxadiazole derivatives and calix[4]re-
sorcinarene with curcumin interactions and their biological
evaluations, which showed excellent anti-microbial, anti-
tubercular and anti-oxidant activities. However, since no
work has been reported on the antimalarial activities, in the
present investigation we functionalized calix[4]arene with
8-amino quinoline, 5-amino quinoline, 8-hydroxy quino-
line, 2-amino pyrimidine and 4-amino 3-methyl quinoline
at the lower rim to study the antimalarial activity against P.
falciparum strain.
Experimental
Chemical and reagents
All the chemicals and reagents used are of analytical grade
of BDH, Aldrich and Merck unless and otherwise specified.
Apparatus
Melting points were taken on Opti-Melt (Automated
melting point system). The FTIR spectra were recorded on
It is well known that quinoline-based molecules are
effective anti malarials; in fact the readily available and
inexpensive chloroquine, mefloquine and quinine are all
quinoline derivatives. Recently, Solomon et al. [14]
reported the synthesis of a new series of side-chain modi-
fied 4-aminoquinolines which were found active against P.
falciparumin vitro and P. yoelli in vivo. These analogs
form a complex with hematin and inhibit the b-hematin
formation, suggesting that this class of compounds act on a
heme polymerization target. Twenty-four new 4-amino-
quinoline–pyrimidine hybrids containing a terminal ali-
phatic amino-alcohol chain were also synthesized and
assessed for their antimalarial activity against chloroquine-
sensitive (D ) andchloroquine-resistant (W ) strains of
-
1
Bruker TENSOR-27 in the range of 4000–400 cm using
KBr pellet. GmbH Vario Micro cube elemental analyzer
1
was used for elemental analysis. H NMR spectra was
scanned on 400 MHz FT-NMR Bruker Avance—400 in
the range of 0.5–15 ppm using internal standard tetram-
ethylsilane (TMS) and DMSO-d as a solvent. ESI Mass
6
spectra were taken on a Shimadzu GCMS-QP 2000A.
Synthesis of compound A: microwave synthesis
of p-tert butyl calix[4]arene
A mixture of p-tert-butyl phenol (4.0 g, 0.0266 mol)
sodium hydroxide (NaOH) (1 g) and formaldehyde(1.8 ml,
0.0641 mol) solution was taken in an open vessel and was
irradiated with 100 W power in a microwave synthesizer
discover(CEM) by stirring for 3 min. Cooling for 10 min,
resulted yellow solid mass. Added, 4 ml of toluene and
30 ml of diphenyl ether to this yellow solid, again irradi-
ated with microwave power of 100 W for 5 min with
stirring and obtained a dark brown solution. Further, this
solution was added into 75 ml of ethyl acetate and kept for
6
2
Plasmodium falciparum [15].
Ferroquine is a derivative of chloroquine that have
shown promising potential as new generation antimalarial
agents of clinical interest [16]. A series of new 4-amidino
quinoline (4-AMQ) and 10-amidinobenzonaphthyridine
(
10-AMB) derivatives were synthesized and displayed high
activity in vitro and in vivo against D , W and C strains
6
2
235
of Plasmodium falciparum(Pf clones) [17]. A series of
1
23

J Incl Phenom Macrocycl Chem
2
h. Finally, white precipitate was obtained which was
4-dimethylaminopyridine (DMAP) were added into the
reaction mixture. This reaction mixture was stirred at room
temperature for 48 h. The reaction progress was monitored
by TLC using mixture of chloroform:methanol (7:3). After
the completion of reaction, solvent was evaporated. The
crude product was then wash with 1 N HCl followed by
filtered and washed with ethyl acetate and finally dried.
Yield, 3.5 g (96 %). Elemental analysis for C H O
4 56 4
4
calcd. C; 81.44 %, H; 8.70 %, Found: C; 81.11 %, H;
1
8
.261 %. HNMR: (DMSO, 400 MHZ) dH: 1.18 (36H,
tbutyl, s), 3. 81 (8H, ArCH Ar, s), 7.12 (8H, Ar–H, s),
2
9
.71(4H, Ar–OH, s), ESI–MS (m/z) 648 (M?1).
NaHCO for the removal of unreacted quinoline and pyrim-
3
idine compounds and unreacted compound C. The product
was then crystalized with dichloromethane, solubility: sol-
uble in CHCl , CH Cl , CH CN and insoluble in H O.
Synthesis of compound B
3
2
2
3
2
In a solution of p-tert-butylcalix[4]arene (A) (1.296 g,
2
mmol) in freshly distilledacetone (80 mL), ethylbromo
Compound D1
acetate (0.764 g, 4. 5 mmol) and K CO (0.345 g, 2.5 mmol)
3
2
were added and the reaction mixture was heated at 57 °C for
0 h under inert atmosphere. The solution was then allowed
Yield 78 %, mp [ 280 °C. Anal. calc: C H N O : C,
8
8 88 8 8
2
76.28; H, 6.40; N, 8.09; O, 9.24 % Found: C, 75.88; H,
1
-
to cool to room temperature and evaporated to dryness by
rotary evaporation. The residue was then triturated three
times with methanol (25 mL each time) and filtered off the
white solid. The desired white solid was kept in high vacuum
overnight. Yield: 1.124 g, (71 %). Elemental analysis for
C H O calcd: C, 77.55; H, 8.68. Found: C, 77.35; H, 8.42.
6.12; N, 7.90; O, 10.10 % FT-IR (KBr)t: 3180 cm
-
1
-1
1
(–NH), 3320 cm
(–CH), 1710 cm
(–C=O).
H
NMR(DMSO-d ) 1.31 (s, C(CH ) , 36H), 3.82 (s, Ar–
6 3 12
CH –Ar, 8H), 7.67 (s, Ar–H, 8H), 4.09 (s, –OCH , 8H),
2
2
8.22 (s, –NH, 4H), 8.10 (s, Ar–H, 4H), 8.06 (s, Ar–H, 4H),
7.88 (s, Ar–H, 4H), 7.38 (s, Ar–H, 4H), 7.32 (s, Ar–H, 4H),
7.40(s, Ar–H, 4H), ESI–MS: (m/z) 1386 (M?1).
6
0 80 8
-
1
1
FT-IR, (KBr pellet)/cm
400 MHz, DMSO): d 7.03 (s, 4H, Ar–H), 6.81 (s, 4H, Ar–
H), 4.73 (s, 4H, –OCH CO), 4.43 (d, 4H, ArCH Ar), 3.85 (s,
1759 (–C=O); H NMR
(
Compound D2
2
2
6
H, –CH ), 3.32 (d, 4H, ArCH Ar), 1.27 (s, 36H, –C(CH ) ),
3 2 3 3
ESI MS (m/z): 929.23 (M?1).
Yield 79 %, mp [ 290 °C. Anal. calc: C H N O : C,
8
8 88 8 8
7
6.28; H, 6.40; N, 8.09; O, 9.24 % Found: C, 75.88; H,
1
-
Synthesis of compound C
6.12; N, 7.90; O, 10.10 % FT-IR (KBr)t: 3180 cm
-
1
-1
1
(–NH), 3320 cm
(–CH), 1710 cm
(–C=O).
H
A solution of B (0.794 g, 0.799 mmol) and KOH (0.6 g,
0.69 mmol) in a mixture of THF (10 ml), methanol
20 ml) and water (10 mL) was heated at reflux for 15 h.
NMR(DMSO-d ) 1.31 (s, C(CH ) , 36H), 3.81 (s, Ar–
6 3 12
1
CH –Ar, 8H), 7.14 (s, Ar–H, 8H), 4.68 (s, –OCH , 8H),
2 2
(
10.02 (s, –NH, 4H), 8.99 (d, Ar–H, 4H), 8.73(d, Ar–H, 4H),
8.59 (d, Ar–H, 4H), 7.87 (d, Ar–H, 4H), 7.84(d, Ar–H, 4H),
7.71 (d, Ar–H, 4H), ESI–MS: (m/z) 1386 (M?1).
The solution was then allowed to cool to room temperature
and evaporated to dryness by rotary evaporation. The
residue was dissolved in EtOAc (150 ml), and the solution
was washed thrice with 20 % HCl (60 ml each time). After
that this solution was washed thrice by water (100 ml each
time). The organic layer was separated, dried over MgSO4
and evaporated in vacuum to give compound C as white
solid. Yield: 0.762 g, (90 %). Elemental analysis for
C H O calcd: C, 70.89; H, 7.32. Found: C, 70.33; H,
Compound D3
Yield 69 %, mp [ 290 °C. Anal. calc: C H N O : C,
88
84 4 12
76.06; H, 6.09; N, 4.03; O, 13.82 % Found: C, 76.00; H,
-
1
6.12; N, 4.08; O, 13.80 % FT-IR (KBr)t: 3320 cm (–
-
1
-1
1
CH), 1710 cm
(–C=O) 1730 cm
(–COO).
H
5
2 64 12
-
1
-1
1
7
.17. FT-IR: 3434 cm (–OH), 1742 cm (–C=O); H
NMR(DMSO-d ) 1.31 (s, C(CH ) , 36H), 3.81 (s, Ar–
6 3 12
NMR (400 MHz, DMSO): d 7.06 (s, 4H, Ar), 6.95 (s, 4H,
Ar–H), 4.68 (s, 4H, –OCH CO), 4.15 (d, 8H, ArCH Ar),
CH –Ar, 8H), 7.14 (s, Ar–H, 8H), 5.15 (s, –OCH , 8H),
2 2
8.87 (d, Ar–H, 4H), 8.43(d, Ar–H, 4H), 7.95 (d, Ar–H, 4H),
7.81 (d, Ar–H, 4H), 7.44(d, Ar–H, 4H), 7.19 (d, Ar–H, 4H),
ESI–MS: (m/z) 1389 (M?1).
2
2
1
.25 (s, 36H, C (CH ) ). ESI MS (m/z): found 881 (M?1).
3 3
Synthesis of compound D
Compound D4
A mixture of compound C (1 g, 1.13 mmol) and different
quinoline and pyrimidine moiety (X) (0.6 g) were dissolved
in anhydrous dichloromethane (20–25 ml) and stirred this
Yield 86 %, mp [ 260 °C. Anal. calc: C H N O : C,
6
8 76 12 8
68.67; H, 6.44; N, 14.13; O, 10.76 % Found: C, 68.61; H,
-1
0
solution for 15 min. Then N,N -dicyclohexylcarbodiimide
6.51; N, 14.18; O, 10.70 % FT-IR (KBr)t: 3180 cm (–
-
1
-1
1
(
DCC) (0.93 g, 0.004 mol) and catalytic amount of
NH), 3320 cm
(–CH), 1710 cm
(–C=O).
H
123

J Incl Phenom Macrocycl Chem
NMR(DMSO-d ) 1.31 (s, C(CH ) , 36H), 3.81 (s, Ar–
6 3 12
the quinoline–pyrimidine moieties (D1–D5), conjugates at
the lower rim of calix[4]arene in the presence of DCC and
DMAP in dichloromethane which gave the desired
calix[4]arene conjugates quinoline–pyrimidine scaffolds
CH –Ar, 8H), 7.14 (s, Ar–H, 8H), 4.63 (s, –OCH , 8H),
2
2
1
0.30 (s, –NH, 4H), 8.58 (s, Ar–H, 8H), 7.17(d, Ar–H, 4H),
ESI–MS: (m/z) 1190 (M?1).
(
D1–D5) in excellent yields. The structure of final
derivatives were determined on the basis of several spectral
1
analysis viz., FT-IR, H-NMR and Mass. The spectro-
Compound D5
Yield 82 %, mp [ 290 °C. Anal. calc: C H N O : C,
scopic data are in good arrangement with the proposed
structures.
9
2 96 8 8
7
6
3
6.64; H, 6.71; N, 7.77; O, 8.88 % Found: C, 76.61; H,
-
1
.76; N, 7.69; O, 8.94 % FT-IR (KBr)t: 3180 cm (–NH),
-
1
-1
-1
320 cm
1
(–CH), 1710 cm
(–C=O), 1370 cm
(–
In vitro antimalarial activity
CH ). H NMR(DMSO-d ) 1.31 (s, C(CH ) , 36H), 3.81
3
6
3 12
(
s, Ar–CH –Ar, 8H), 7.14 (s, Ar–H, 8H), 4.63 (s, –OCH ,
2
In this research work, we have identified the p-hydroxy and
amino substituents on the D-series ring having good anti-
malarial activity. Analysis of the in vitro antimalarial data
reveals that good activity can be achieved by the intro-
duction of a hydroxy group in quinoline analogues (D3) in
the 8-position and amino group pyrimidine analogues (D4)
in the 2-position. The six-membered ring containing two
nitrogen analogue (D4) was much more effective. While a
clear trend is seen in the amino group based quinoline
compound (D2) in the 5-position provide optimum activity.
In contrast, 8 and 4- amino quinoline analogues of D1 and
D5 resulted in a complete less in antimalarial activity
compared to standard drugs against P. falciparum strain.
The IC50 values are calculated from experiments carried
out in triplicate. Among the tested compounds, compounds
D3 and D4 showed an IC50 values of 0.073 and 0.043 lg/
ml respectively. Moreover, compounds D2 and D5 have an
IC valuesof 0.098 and 0.42 lg/ml respectively (Table 1;
2
8
4
4
H), 9.92 (s, –NH, 4H), 8.77 (s, Ar–H, 4H), 8.06(d, Ar–H,
H), 7.93 (d, Ar–H, 4H), 7.81 (d, Ar–H, 4H), 7.48(d, Ar–H,
H), 1.96 (s, –CH , 12H), ESI–MS: (m/z) 1442 (M?1).
3
In vitro antimalarial assay
The novel synthesized calix[4]arene conjugates quinoline
and pyrimidine based derivatives (D1–D5) were evaluated
for their antimalarial activity against the P. falciparum
in vitro assay according to the reported procedure in the
literature [22]. Briefly, The cultures of P. falciparum strain
weremaintained in medium RPMI1640 supplemented with
2
5 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethane-
sulfonic acid), 1 % D-glucose, 0.23 % sodium bicarbonate
and 10 % heat inactivated human serum. For carrying out
the assay, an initial ring stage parasitaemia of 0.8 to 1.5 %
at 3 % haematocrit in a total volume of 200 ll of medium
RPMI-1640 was determined by Jaswant Singh Bhat-
tacharya (JSB) staining to assess the percent parasitaemia
5
0
Fig. 2).
The quinoline and pyrimidine analogues D3 and D4 are
(
rings) and uniformly maintained with 50 % RBCs. A
well known antimalarial agents; their mechanism of action
is to inhibit hemazoin (b-hematin) formation by the
malarial parasites. Here, the difference in the IC50 values
can be recognized to features such as hydroxy as well as
amino group’s position, ring size and substitutions on the
ring at distal amino groups.
stock solution of 5 mg/ml of each of the test samples was
prepared in DMSO and subsequent dilutions were prepared
with culture medium. The diluted samples in 20 ll volume
were added to the test wells so as to obtain final concen-
trations (at fivefold dilutions) ranging between 0.4 and
1
00 lg/ml in duplicate well containing parasitized cell
One of the major goals of this study is to synthesize a
potent, safe and long-acting antimalarial compound to
replace chloroquine as malaria prophylactic drug. Among
the D1–D5 analogs, compounds D3 and D4 showed good
in vitro antimalarial activities against P. falciparum strains
(Table 1; Fig. 2). Regarding structure activity relationship
(SAR), antimalarial activity data suggested that the com-
pounds with 8-hydroxy quinoline and 2-amino pyrimidine
based calix[4]arene derivatives are more potent than the
other compounds. These results indicates that 2- amino
pyrimidine with additional nitrogen atom in the ring sig-
nificants increase the p-deficiency there by increasing the
electronegativity, which has a remarkable effect on the
preparation. The culture plates were incubated at 37 °C in a
candle jar. After 36–40 h incubation, thin blood smears
from each well were prepared and stained with JSB stain.
The test concentration which inhibited the complete mat-
uration into schizonts was recorded as the minimum inhi-
bitory concentrations (MIC). Chloroquine and quinine
were used as the reference drugs.
Results and discussion
The synthesis of hydroxy and amino series was carried out
in 4 steps from commercially available starting materials as
well as all quinoline–pyrimidine moieties (see Fig. 1). All
antimalarial activity. Further, -NH group substitution at
2
2-position in phenyl ring will increase the electronegativity
1
23

J Incl Phenom Macrocycl Chem
Fig. 1 Scheme of synthesis of
quinoline–pyrimidine based
calix[4]arene derivatives
2
K CO3
,KI
Ethylbromo acetate,
Anhydrous acetone,
4
8 h
O
O
O
O
OH
OH OH
HO
A
O
OC H
2 5
O
O
O
OC H
OC H
2 5
H
2
5
OC2
5
B
THF-Methanol,
KOH,
o
2
5 C
X
DCC, DMAP,
DCM,
o
O
25 C
O
O
X
O
O
O
O
O
O
O
O
X
X
O
X
O
D
OH O
OH
O
OH
OH
O
NH2
C
N
N
D1
D3 OH
N
8
-amino quinoline 8-hydroxy quinoline
X
=
N
CH3
N
NH2
N
NH2
D5
-amino 3-methyl quinoline
4
NH2
D4
D2
5
-amino quinoline
2-amino pyrimidine
Antimalarial activity
Table 1 Antimalarial activity of calix[4]arene conjugates quinolone-
pyrimidine based derivatives (D1–D5)
1
0
.8
a
0.6
Sr.
No.
Compounds
(IC50 lg/ml)
0
0
.4
.2
0
1
2
3
4
5
6
7
D1
0.85
D2
0.098
0.073
0.043
0.42
D3
Compounds
D4
Fig. 2 Antimalarial activity of compounds D1–D5 with standard
drugs
D5
Chloroquine
Quinine
0.02
0.268
there by increasing the antimalarial activity of the com-
4-amino 3-methyl quinoline (D5) may significantly
degrade activity against P. falciparum strain due to steric
factor. The substitution of electron donating group -OH at
pound (D4) compared to the –NH substituted quinoline
2
derivatives, D1, D2 and D5. Large substituents like
123

J Incl Phenom Macrocycl Chem
the 8-position of quinoline also showed an enhancement in
the antimalarial activity due to increase in the electroneg-
ativity of the quinoline scaffold.
7. Yousaf, A., Hamid, S.A., Bunnori, N.M., Ishola, A.A.: Applica-
tions of calixarenes in cancer chemotherapy: facts and perspec-
tives. Drug Des. Dev. Ther. 9, 2831–2838 (2015)
8
. de F a´ tima, A., Fernandes, S.A., Sabino, A.A.: Calixarenes as new
platforms for drug design. Curr. Drug Discov. Technol. 6,
1
51–170 (2009)
. World Malaria Report 2014: World Health Organization, Geneva
2014)
9
Conclusion
(
1
0. World Malaria Report 2013: World Health Organization, Geneva
(2013)
11. Rosario, V.E.: Genetics of chloroquine resistance in malaria
The present study is on a series of calix[4]arene conjugates
quinoline- pyrimidine based derivatives that have been
successfully synthesized and screened for antimalarial
activity. Two of the synthesized compounds, 5, 11, 17, 23
tetra tert butyl-25, 26, 27, 28 tetra (8- hydroxy quinolate)
calix[4]arene (D3) and 5, 11, 17, 23 tetra tert butyl-25, 26,
parasites. Nature 261, 585–586 (1976)
1
2. Dondorp, A.M., Nosten, F., Yi, P., Das, D., Phyo, A.P., Tarning,
J., Lwin, K.M., Ariey, F., Hanpithakpong, W., Lee, S.J., Ring-
wald, P., Silamut, K., Imwong, M., Chotivanich, K., Lim, P.,
Herdman, T., An, S.S., Yeung, S., Singhasivanon, P., Day, N.P.,
Lindegardh, N., Socheat, D., White, N.J.: Artemisinin resistance
in Plasmodium falciparum malaria. N. Engl. J. Med. 361,
27, 28 tetra (2- amino pyrimidine) calix[4]arene (D4),
showed good antimalarial activity against P. falciparum
4
55–467 (2009)
strain. The results indicates that 8-hydroxy quinoline and
13. Noedl, H., Se, Y., Schaecher, K., Smith, B.L., Socheat, D.,
Fukuda, M.M.: Evidence of artemisinin-resistant malaria in
Western Cambodia. N. Engl. J. Med. 359, 2619–2620 (2008)
2
-amino pyrimidine substituted compounds exhibited good
antimalarial activity with IC50 0.073 and IC50 0.043 lg/ml
respectively which was comparable with the standard drug
chloroquine. Thus the present study provides valuable
information for developing calix[4]arene conjugates
quinoline-pyrimidine based derivatives as an effective
antimalarial agents.
1
4. Solomon, V.R., Haq, W., Srivastava, K., Puri, S.K., Katti, S.B.:
Synthesis and antimalarial activity of side chain modified
4-aminoquinoline derivatives. J. Med. Chem. 50(2), 394–398
(2007)
1
5. Tripathi, M., Khan, S.I., Thakur, A., Ponnan, P., Rawat, D.S.:
4-Aminoquinoline-pyrimidine-aminoalkanols: synthesis, in vitro
antimalarial activity, docking studies and ADME predictions.
New J. Chem. 39, 3474–3483 (2015)
Acknowledgments Nikunj N. Valand would like to acknowledge
financial assistance from DST-New Delhi as Innovation in Science
Pursuit for Inspire Research (INSPIRE) fellowship. The authors also
acknowledge Microcare Laboratory, Surat for the antimalarial activity
studies.
16. Wani, W.A., Jameel, E., Baig, U., Mumtazuddin, S., Hun, L.T.:
Ferroquine and its derivatives: new generation of antimalarial
agents. Eur. J. Med. Chem. 101, 534–551 (2015)
17. Korotchenko, V., Sathunuru, R., Gerena, L., Caridha, D., Li, Q.,
Deitrick, M.K., Smith, P.L., Lin, A.J.: Antimalarial activity of
4-amidinoquinoline and 10-amidinobenzonaphthyridine deriva-
tives. J. Med. Chem. 58(8), 3411–3431 (2015)
1
8. Kumar, D., Khan, S.I., Ponnan, P., Rawat, D.S.: Triazine-
pyrimidine based molecular hybrids: synthesis, docking studies
and evaluation of antimalarial activity. New J. Chem. 38,
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