Ultrasound-promoted synthesis, biological evaluation and molecular docking of novel 7-(2-chloroquinolin-4-yloxy)-4-methyl-2H-chromen-2-one derivatives

Article abstract of DOI:10.1007/s00044-012-0290-9

A series of quinoline-based coumarin derivatives have been synthesized by one pot dehydrochlorination of 2,4-dichloroquinolines (1a-g); 7-hydroxy-4-methyl-2H-chromen-2-one (2) under ultrasonic irradiation method with high regio selectivity. All the synthesized compounds were characterized through spectral data and screened against representative antibacterial and antioxidant activities. Some of the compounds are found to be equipotent or more potent than that of standard drugs. Molecular docking studies show that the binding energy value of the compounds is very less than that of standard chloroquine and amodiaquine drugs.

Full text of DOI:10.1007/s00044-012-0290-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3185–3192
DOI 10.1007/s00044-012-0290-9
ORIGINAL RESEARCH
Ultrasound-promoted synthesis, biological evaluation
and molecular docking of novel 7-(2-chloroquinolin-4-yloxy)-
4-methyl-2H-chromen-2-one derivatives
•
G. L. Balaji K. Rajesh R. Priya P. Iniyavan
•
•
•
•
R. Siva V. Vijayakumar
Received: 29 April 2012 / Accepted: 20 October 2012 / Published online: 15 November 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of quinoline-based coumarin deriva-
tives have been synthesized by one pot dehydrochlorination
of 2,4-dichloroquinolines (1a–g); 7-hydroxy-4-methyl-2H-
chromen-2-one (2) under ultrasonic irradiation method with
high regio selectivity. All the synthesized compounds were
characterized through spectral data and screened against
representative antibacterial and antioxidant activities. Some
of the compounds are found to be equipotent or more potent
than that of standard drugs. Molecular docking studies show
that the binding energy value of the compounds is very less
than that of standard chloroquine and amodiaquine drugs.
antimalarial, anti-inflammatory, antiasthmatic, antibacterial,
antihypertensive (Dube et al., 1998; Maguire et al., 1994)
and anticancer (Denny et al., 2006) and anti-HIV (Wilson
et al., 1992). Coumarin derivatives on the other hand having
wide applications as drugs and pharmaceuticals, such as
antibacterial (Appendino et al., 2004; Khan et al., 2004),
antioxidant (Nicolaides et al., 1998; Raj et al., 1998), anti-
inflammatory (Litinadj et al., 2004; Ghate et al., 2005) and
anticancer (Bhattacharyya et al., 2009). Keeping in view the
biological importance of both quinoline and coumarin in a
single molecule (Miri et al., 2011; Tabakovic et al., 1983,
1987; Emami et al., 2008), here, with which we are
reporting the synthesis of 7-(2-chloroquinolin-4-yloxy)-
4-methyl-2H-chromen-2-one derivatives and their invitro
antibacterial, antioxidant and molecular docking studies.
The idea in molecular docking is to computationally design
pharmaceuticals targeted against proteins. Docking methods
not only add insights to the biological processes at the
molecular level but also aid in the development of novel
lead compounds (drugs) that can help to combat disease.
Molecular docking algorithms seek to predict the bound
conformations of two interacting molecules, such as pro-
tein–ligand and protein–protein complexes.
Keywords 2,4-Dichloroquinoline ꢀ
Ultrasonic irradiation ꢀ Molecular docking ꢀ
Binding energy
Introduction
The quinoline scaffold is prevalent in a variety of pharma-
cologically active synthetic and natural compounds. A large
variety of quinoline derivatives have been used as
Results and discussion
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-012-0290-9) contains supplementary
material, which is available to authorized users.
Chemistry
G. L. Balaji ꢀ K. Rajesh ꢀ P. Iniyavan ꢀ V. Vijayakumar (&)
Centre for Organic and Medicinal Chemistry, VIT University,
Vellore 632 014, Tamil Nadu, India
2,4-Dichloroquinolines (2a–g) have been synthesized by the
reaction of aniline on malonic acid in excess of phosphorus
oxychloride (POCl3) (Rajesh et al., 2009). The reaction of
2a–g with 7-hydroxy-2H-chromen-2-one (1) at 60 °C
for 15 h in the presence of K2CO3 as a catalyst afford the
7-(2-chloroquinolin-4-yloxy)-4-methyl-2H-chromen-2-ones
e-mail: kvpsvijayakumar@gmail.com
R. Priya ꢀ R. Siva
Plant Biotechnology Division, School of Biosciences and
Technology, VIT University, Vellore 632014, Tamil Nadu, India
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Med Chem Res (2013) 22:3185–3192
(3a–g)with 60–80 % yield. In continuation of our earlier
interest (Balaji et al., 2012; Rajesh et al., 2012) on ultra-
sound assisted reactions, the above reaction has also been
subjected to the ultrasonic irradiation at 60 °C for 20 min,
which yield the product 3a–g with 80–94 %, and hence
ultrasound-promoted synthesis can be the better approach to
the synthesis 2-chloroquinolin-4-pyrimidine carboxylate deriva-
tives (Scheme 1).
Biological evaluation
Antimicrobial studies
As part of our interest to find the new antibacterial agents
(Venkatragavan et al., 2009, 2010, 2011; Sarveswari et al.,
2011) all the newly synthesized compounds 3a–g were
screened for their invitro antibacterial activity against
gram(?)ve and gram(-)ve bacterial strains namely Esche-
richia coli, Pseudomonas aeruginosa, Staphylococcus aur-
eus, Meloidogyne litoralis and Bacillus subtilis. Compounds
possessing methyl, methoxy and fused aryl rings such as 3c,
3d and 3g at C-8 of quinoline ring showed better activity than
their standard drug Streptomycin against Escherichia coli,
similarly compounds 3c and 3g showed better activity
against P. aeruginosa. Compound 3f with bromine at C-6
showed better activity against M. litoralis, whereas 3a with
methyl at C-6 showed better activity against S. aureus. No
compound is having good activity against B. subtilis with the
standard drug Streptomycin, respectively (Table 2).
The reactivity of the halogen atoms in the various
quinolines varied widely, but the kinetic studies indicate
that the chloro atom at C-4 of 2,4-dichloroquinolines is
about two times more reactive towards nucleophiles and
predominantly an addition elimination mechanism is
observed. The reaction of 2,4-dichloro-6-methyl quinoline
with sodium azide (1:1 molar ratio) in DMF lead to reg-
ioselective 4-azido-2-chloro-6-methylquinoline (Natarajan
et al., 2009) also confirmed the reactivity at C-4 of 2,4-
1
dichloroquinolines. H NMR, 13C NMR and mass spectra
1
confirmed the formation of 3a–g. The H NMR spectrum
of compound 3b exhibited two singlets at d 2.47, 2.87 ppm
which corresponds to the protons of methyl group at C-4 of
coumarin and C-7 of quinoline, respectively. The singlet at
d 6.31 ppm and d 6.65 ppm corresponds to the protons at
C-3 of coumarin and quinoline, respectively. A singlet at d
7.09 ppm and d 7.12 ppm corresponds to the protons at C-8
of coumarin and quinoline, respectively. A doublet at d
7.37 ppm and d 7.62 ppm corresponds to the protons at C-8
of coumarin and quinoline, respectively, and the doublet at
d 7.71 ppm and d 7.89 ppm corresponds to the protons at
C-5 of coumarin, quinoline, respectively. Its 13C NMR
spectrum shows chemical shift values at d 18.76 ppm and d
23.91 ppm corresponds to C-4 and C-7 on coumarin and
quinoline, respectively, and the chemical shift values at d
114.62, 116.21 and 118.20 ppm corresponds to C-8, C-3
and C-10 on coumarin. The chemical shift values at d
129.63, 130.94 and 142.30 ppm corresponds to the carbons
at C-8, C-6 and C-7 on quinoline. The chemical shift values
at d 160.18 and 163.78 ppm corresponds to C-4 and C-2
carbons on quinoline and coumarin, respectively. M/z
value observed at 352.1 (M ? 1) peak in ES-MS spectra
also confirms the formation of target molecule (Table 1).
DPPH radical scavenging assay
Radical scavenging activity is very important due to the
deleterious role of free radicals in foods and in biological
systems. Diverse methods are currently used to assess the
antioxidant activity. In the present study, DPPH (1,1-
diphenyl-2-picryl-hydrazil) radical-scavenging method has
been chosen to evaluate the antioxidant potential of the
compounds 3a–g. DPPH radical scavenging activity has
been determined spectrophotometrically by means of the
literature method (Farhanullah et al., 2006; Brand-
Williams et al., 1995). The percentage of inhibition was
given in Table 3 and compared with that of commercial
antioxidant (Tepe et al., 2006) butylated hydroxy toluene
(BHT). The results in percentage are expressed as the ratio
of absorbance decrease at 517 nm, and the absorbance of
DPPH solution in the absence of compounds. The observed
values given in Table 3 revealed that the radical scaveng-
ing activity of 7-(2-chloroquinolin-4-yloxy)-4-methyl-2H-
Scheme 1 Synthesis of 7-(2-
chloroquinolin-4-yloxy)-4-
methyl-2H-chromen-2-ones
(3a–g)
CH3
O
O
Ac.OH
+
Cl
CH3
O
HO
OH
HO
O
O
N
1
K2CO3, DMF
60°C, ))))
R3
R2
O
O
O
Cl
N
R1
R2
3a-g
R1
COOH
COOH
R1
R2
POCl3
5h
+
H2C
NH2
Cl
R3
R3
2 a-g
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3187
Table 1 Synthesis of 7-(2-chloroquinolin-4-yloxy)-4-methyl-2H-chromen-2-ones (3a–g)
Entry
R1
R2
R3
Product
Conventionala (D)
Ultrasounda
Time (min)
Time (h)
15
Yield (%)b
Yield (%)b
85
1
–CH3
–H
–H
77
20
Cl
N
CH3
O
O
O
CH3
Cl
CH3
O
3a
N
2
3
4
5
6
–H
–H
–H
–H
–Br
–CH3
–H
15
15
15
15
15
15
76
82
74
76
69
84
20
20
20
20
20
20
91
88
93
85
70
92
O
O
H3C
H3C
3b
Cl
CH3
N
–H
–CH3
–OCH3
–H
O
O
O
3c
Cl
CH3
O
N
H3CO
–H
O
O
3d
Cl
N
CH3
O
–H
O
O
O
3e
Cl
N
CH3
O
O
–H
–H
Br
3f
Cl
CH3
O
N
7
2-chloro benzo(h)quinoline
O
O
3g
a
Reaction was conducted under both conventional and ultrasonic methods
Isolated yields after purification
b
Molecular Docking
chromen-2-one on DPPH radicals increases with the
increase in concentration. Compounds possessing chloro,
bromo substituents at C-6 (3e, f) showed maximum activity
at a concentration of 1,000 lg/mL. The radical scavenging
activity of compounds possessing methyl at C-7 (3b)
exhibited less potent than the standard.
In silico modeling is an upcoming facade to investigate
promising therapeutics for their effective inclination as
able leads towards specific pathologies. The docking
analysis caters with the knowledge of the extent of
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Table 2 Antibacterial activity for the compounds 3a–g
S. no.
Name of species
MIC in lg/ml
Streptomycin
3a
3b
3c
3d
3e
3f
3g
1
2
3
4
5
Escherichia coli
6.25
12.5
6.25
25
12.5
100
–
–
6.25
–
6.25
6.25
–
100
12.5
100
50
–
6.25
6.25
–
Pseudomonas aeruginosa
Meloidogyne litoralis
Staphylococcus aureus
Bacillus subtilis
12.5
50
6.25
–
–
–
–
100
–
12.5
–
–
50
–
12.5
–
100
–
–
Table 3 Antioxidant activity for the compounds 3a–g by DPPH Method
S.No
Concentration (50 lg)
Concentration (100 lg)
Concentration (500 lg)
Concentration (1,000 lg)
Absorbance
Inhibition
Absorbance
Inhibition
Absorbance
Inhibition
Absorbance
Inhibition
BHT
3a
0.064
0.744
0.824
0.804
0.839
0.726
0.694
0.792
0.9213
93
19
10
12
8
0.053
0.732
0.813
0.787
0.812
0.706
0.679
0.781
94
20
11
14
11
23
26
15
0.037
0.396
0.592
0.499
0.568
0.429
0.421
0.549
96
57
35
45
38
53
54
40
0.014
0.280
0.316
0.294
0.278
0.196
0.216
0.298
98
69
65
68
69
78
76
67
3b
3c
3d
3e
21
24
14
3f
3g
Control
plausible interaction between the target of interest and the
drug under investigation. This in turn helps to procure a
primary understanding of the viability of the drug or
compound under scrutiny. The analysis etches an advan-
tage over the in vitro or in vivo analyses in being faster,
safer and having less infrastructural requirements (Garg
et al., 2010). The compounds 3a–g synthesized in the
present study revealed their respective abilities in suc-
cessful binding to the pathogen (Plasmodium falciparum)
erythrocyte membrane protein, consequently proving their
merits towards being molded as an anti malarial agent. The
Plasmodium falciparum Erythrocyte Membrane Protein-1
(PfEMP 1) structure was obtained from protein data bank
(PDB) (Hu et al., 2009). The ligands 3a–g were explored to
test their effectiveness in binding with the receptor, PfEMP
1. The Plasmodium falciparum erythrocyte membrane
protein 1 (PfEMP1) is a significant virulence factor which
expresses itself on the surface of erythrocytes infected with
the pathogen. Also, the protein is responsible for directly
mediating adhesion to a plethora of host cells (Horrocks
et al., 2005). Thus, analysing the effect of any compound
on this specific protein could therefore lead towards a
potential source by which the deleterious manifestations of
this protein can be curbed. The approach would also help
towards identifying potent lead towards developing anti-
malaria drugs. For all the compounds, 3a–g protein–ligand
docking calculations (Hu et al., 2009) were carried out on
plasmodium falciparum UCHL3 protein to compare the
ligand binding energy with standard antimalarial drugs like
amodiaquine and chloroquine (showing binding energy
value of -6.48 and -6.59 kcal/mol) and are given in
Table 4, Fig. 1. Blind docking was carried out in which the
entire receptor was scanned for probable docking sites so
as to facilitate maximum possible fits. Energy minimiza-
tion for the 2D structure (drawn by chem sketch) of each of
the isolated compounds was initiated by means of Chimera
software. In principle, amongst a variety of ligands, the
ones with the lowest binding energies are considered to be
the most potential hits (Garg et al., 2010). Therefore, the
analysis indicates towards 2-chlorobenzo(h)quinoline (3g)
that exhibits binding energy of -9.65 kcal/mol. Moreover,
the results obtained help to identify the efficacy of the
isolated novel compounds as potent antimalarial drug.
Experimental
Chemistry
The materials were purchased from Sigma–Aldrich, Merck
and were used without any additional purification. All
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3189
Table 4 Comparison of binding energy value of compounds 3a–g with standard antimalarial drugs
Chemical compound
Chloroquine
Amodiaquine
3a
3b
3c
3d
3e
3f
3g
-9.65
Binding energy value (kcal/mol)
-6.59
-6.48
-8.08
-8.64
-8.62
-7.9
-8.57
-8.36
Fig. 1 Equilibrated molecular dynamics snap shot of docked compounds 3a–g, the aminoacids pertaining to the binding site or contacting to the
ligands are shown in atom-coloured sticks, active site binding interactions are shown in dotted lines (Color figure online)
General procedure for the synthesis of 7-(2-
chloroquinolin-4-yloxy)-4-methyl-2H-chromen-2-one
derivatives (3a–g)
reactions were monitored by thin layer chromatography
(TLC). Melting points were recorded on an Elchem digital
melting point apparatus in open capillaries and are uncor-
rected. The ultrasound for the synthesis is generated with the
help of ultrasonic instrument (Make: E-chrom Tech Co. Ltd.,
Taiwan. Operating frequency: 22 kHz, Rated output power:
Conventional method
1
All the substituted 2,4-dichloroquinolines (2a–g) were pre-
pared according to the method available in literature [Rajesh
et al., 2009; Balaji et al., 2012]. To the solution of the
appropriate 2,4-dichloroquinoline (5 mmol) in 20 mL of
DMF, 7-hydroxy-2H-chromen-2-one (1) (5 mmol) and
K2CO3 (15 mmol) was added and heated at 60 °C for 15 h.
800 W). The H NMR was measured on a Bruker Avance-
400 MHz instrument at room temperature. The 1H NMR was
measured for *0.03 M solutions in CDCl3 using TMS as
internal reference. The accuracy of the 1H shifts is considered
to be 0.02 ppm. The coupling constants J are in Hertz. Mass
spectra were obtained by ESI mass spectrometry.
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Med Chem Res (2013) 22:3185–3192
After the completion of reaction, the reaction mixture poured
into ice cold water and the product was collected by filtration
and recrystallized using ethanol.
C7 of quinoline), 8.01 (d, 1H, J = 8 Hz, –H at C5 of quinoline);
ES-MS: m/z 352.0 (M?). Anal. Calcd. for C20H14ClNO3:
C, 68.28; H, 4.01; N, 3.98. Found: C, 68.23; H, 4.13; N, 3.93.
7-(2-chloro-8-methoxyquinolin-4-yloxy)-4-methyl-2H-
chromen-2-one ( 3d ) white powder; m.p. 180–182 °C;1H
NMR (400 MHz, CDCl3) d: 2.48 (s, 3H, CH3 at C4 of
coumarin), 4.09 (s, 3H, CH3 of –OCH3 at C8 of quinoline),
6.32 (s, 1H, –H at C3 of coumarin), 6.67 (s, 1H, –H at C3 of
quinoline), 7.17 (dd, 2H,J = 5.6 Hz, ArH of coumarin),
7.18 (s, 1H, –H at C8 of coumarin), 7.51 (t, 1H,J = 6.12 Hz,
–H at C6 of quinoline), 7.71 (d, 1H,J = 8.6 Hz, –H at C5 of
quinoline), 7.77 (d, 1H,J = 8.7 Hz, –H at C5 of couma-
rin);13C NMR (400 MHz, CDCl3) d: 18.76, 56.16, 106.93,
109.26, 109.99, 113.22, 114.64, 116.67, 117.91, 121.47,
126.59, 127.17, 140.66, 150.14, 151.77, 154.67, 154.78,
156.68, 160.19, 161.96; ES-MS:m/z 368.0 (M?). Anal.
Calcd. for C20H14ClNO4: C, 65.31; H, 3.84; N, 3.81. Found:
C, 65.50; H, 3.77; N, 3.68.
Ultrasonic irradiation Method
To the solution of the appropriate 2,4-dichloroquinoline
(5 mmol) in 20 mL of DMF, 7-hydroxy-2H-chromen-2-one
(5 mmol) and K2CO3 (15 mmol) was added and kept under
ultrasonic irradiation (Make: E-chrom Tech Co. Ltd., Taiwan.
Operating frequency: 22 kHz, Rated output power: 800 W) at
50 % amplitude for 20 min with five intervals each for 4 min
at 60 °C. After the completion of the reaction, the reaction
mixture poured into ice cold water and the product was col-
lected by filtration and recrystallized using ethanol. All the
synthesized compounds were characterized by 1H NMR, 13
C
NMR, ESI-MS and Elemental analysis techniques. The
spectral data of compounds 3a-g has been given below.
7-(2-Chloro-6-methylquinolin-4-yloxy)-4-methyl-2H-chro-
7-(2-chloroquinolin-4-yloxy)-4-methyl-2H-chromen-2-
one ( 3e ) white powder; m.p. 166–168 °C;1H NMR
(400 MHz, CDCl3) d: 2.49 (s, 3H, CH3 at C4 of coumarin),
6.33 (s, 1H, -H at C3 of coumarin), 6.63 (s, 1H, –H at C3 of
quinoline), 7.14 (d, 1H,J = 8.6 Hz, –H at C6 of couma-
rin), 7.23 (s, 1H, –H at C8 of coumarin),7.54 (t,
1H,J = 7.54 Hz, –H at C6 of quinoline), 7.62 (d,
1H,J = 8.6 Hz, –H at C5 of coumarin), 7.66 (t,
1H,J = 7.2 Hz, –H at C7 of quinoline), 7.72 (d,
1H,J = 8.6 Hz, –H at C8 of quinoline), 7.80 (d,
1H,J = 7.2 Hz, C5–H of quinoline); ES-MS:m/z 338.0
(M?). Anal. Calcd. for C19H12ClNO3: C, 67.56; H, 3.58;
N, 4.15. Found: C, 67.35; H, 3.69; N, 3.97.
1
men-2-one (3a) white powder; m.p. 155–157 °C; H NMR
(400 MHz, CDCl3) d: 2.49 (s, 3H, C4–CH3 of coumarin),
2.56 (s, 3H, CH3 at C6 of quinoline), 6.32 (s, 1H,
–H at C3 of coumarin), 6.61 (s, 1H, –H at C3 of quinoline), 7.13
(d, 1H, J = 8.6 Hz, –H at C6 of coumarin), 7.18 (s, 1H, –H at
C8 of coumarin), 7.62 (d, 1H, J = 8.6 Hz, –H at C7 of
quinoline), 7.71 (d, 1H, J = 8.6 Hz, –H at C5 of coumarin),
7.92 (d, 1H, J = 8.6 Hz, –H at C8 of quinoline), 8.03 (s, 1H,
–H at C5 of quinoline). ES-MS: m/z 352.0 (M?). Anal. Calcd.
for C20H14ClNO3: C, 68.28; H, 4.01; N, 3.98. Found: C,
67.97; H, 4.13; N, 3.85.
7-(2-chloro-7-methylquinolin-4-yloxy)-4-methyl-2H-chr-
omen-2-one (3b) white powder; m.p. 142–144 °C; 1H NMR
(400 MHz, CDCl3) d: 2.47 (s, 3H, C4–CH3 of coumarin),
2.87 (s, 3H, CH3 at C6 of quinoline), 6.31 (s, 1H,
–H at C3 of coumarin), 6.65 (s, 1H, –H at C3 of quinoline), 7.09
(s, 1H, –H at C8 of coumarin), 7.12 (s, 1H, –H at C8 of
quinoline), 7.37 (d, 1H, J = 10.4 Hz, –H at C6 of coumarin),
7.62 (d, 1H, J = 9.1 Hz, –H at C6 of quinoline), 7.71 (d, 1H,
J = 8 Hz, –H at C5 of coumarin), 7.89 (d, 1H, J = 8 Hz, –H
at C5 of quinoline); 13C NMR (400 MHz, CDCl3) d: 18.76,
23.91, 108.72, 114.62, 116.21, 117.56, 118.20, 120.14,
121.46, 126.55, 127.09, 129.63, 130.94, 142.30, 150.34,
151.75, 155.10, 156.94, 160.18, 163.75; ES-MS: m/z 352.0
(M?). Anal. Calcd. for C20H14ClNO3: C, 68.28; H, 4.01; N,
3.98. Found: C, 68.07; H, 4.23; N, 3.79.
7-(2-chloro-6-bromoquinolin-4-yloxy)-4-methyl-2H-chro-
1
men-2-one (3f) white powder; m.p. 160–162 °C; H NMR
(400 MHz, CDCl3) d: 2.47 (s, 3H, CH3 at C4 of coumarin),
6.40 (s, 1H, –H at C3 of coumarin), 6.61 (s, 1H, –H at C3 of
quinoline), 7.14 (d, 1H, J = 8 Hz, –H at C7 of coumarin),
7.19 (s, 1H, –H at C8 of quinoline), 7.74 (d, 1H, J = 8 Hz,
–H at C5 of coumarin), 7.86 (dd, 2H, J = 7.2 Hz, –H at C7
and –H at C8 of quinoline), 8.45 (s, 1H, –H at C5 of
quinoline); 13C NMR (400 MHz, CDCl3) d: 18.76, 106.38,
109.49, 114.89, 116.82, 118.28, 120.95, 121.38, 124.31,
126.76, 130.10, 135.04, 147.45, 151.46, 151.68, 154.99,
156.02, 160.05, 160.17; ES-MS: m/z 416.0 (M? - 1).
Anal. Calcd. for C19H11BrClNO3: C, 54.77; H, 2.66; N,
3.36. Found: C, 54.72; H, 2.76; N, 3.27.
7-(2-chloro-8-methylquinolin-4-yloxy)-4-methyl-2H-chro-
men-2-one (3c) white powder; m.p. 174–176 °C; 1H NMR
(400 MHz, CDCl3) d: 2.48 (s, 3H, CH3 at C4 of coumarin), 2.78
(s, 3H, CH3 at C8 of quinoline), 6.31 (s, 1H, –H at C3 of cou-
marin), 6.64 (s, 1H, –H at C3 of quinoline), 7.12 (d, 1H,
J = 8 Hz, ArH of coumarin), 7.16 (s, 1H, –H at C8 of couma-
rin), 7.45 (t, 1H, J = 6.8 Hz, –H at C6 of quinoline), 7.64 (d, 1H,
J = 8 Hz, –H at C5 of coumarin), 7.70 (d, 1H, J = 8 Hz, –H at
7-(2-chlorobenzo(h)quinolin-4-yloxy)-4-methyl-2H-chro-
men-2-one (3g) white powder; m.p. 208–210 °C; 1H NMR
(400 MHz, CDCl3) d: 2.50 (s, 3H, CH3 at C4 of coumarin),
6.31 (s, 1H, –H at C3 of coumarin), 6.82 (s, 1H, –H at C3 of
quinoline), 7.14 (d, 1H, J = 8.6 Hz, –H at C6 of couma-
rin), 7.20 (s, 1H, –H at C8 of coumarin), 7.75 (m, 3H, ArH
of quinoline), 7.88 (d, 1H, J = 8 Hz, –H at C6 of quino-
line), 7.94 (d, 1H, J = 10 Hz, ArH of coumarin), 8.11 (d,
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Med Chem Res (2013) 22:3185–3192
3191
1H, J = 8 Hz, ArH of benzo), 9.22 (d, 1H, J = 10 Hz,
ArH of benzo); ES-MS: m/z 388.0 (M?). Anal. Calcd. for
C23H14ClNO3: C, 71.23.77; H, 3.64; N, 3.61. Found: C,
71.01; H, 3.57; N, 3.45.
selected to perform this study was related to malarial dis-
eases. All the chemical compounds were drawn with chem.
sketch and optimized by means of chimera. The optimized
structures were converted to Mol2 file format by means of
chimera. For all the chemical compounds protein–ligand
docking calculations were carried out on plasmodium fal-
ciparum UCHL3 protein. In all cases, binding affinities
were reported (Table 4) and was compared with existing
antimalarial drugs like amodiaquine and chloroquine.
Antibacterial activity
Sterile nutrient broth was prepared and inoculated with
different species of bacteria (Escherichia coli, P. aeru-
ginosa, S. aureus, M. litoralis and B. subtilis) and incu-
bated at 37 °C for overnight. From the overnight culture,
1 % stock culture was prepared (99 mL of sterile nutrient
broth ? 1 mL of overnight culture). 25 mL of nutrient
agar was poured in sterile Petri plates and allowed to cool.
Each agar plate was inoculated with 200 lL of 1 % bac-
terial culture and spread using spreader. Using a sterile
cork borer, 6-mm diameter of holes was made in the
solidified agar plates containing 1 % of respective bacterial
culture. A total volume of 20 lL of test sample of 3a-g was
poured into the well. Streptomycin was used as a standard
drug. The minimum inhibitory concentration (MIC) values
are provided in Table 2.
Conclusion
In summary, K2CO3 proved to be an efficient catalyst to
obtain the mono-substituted 7-(2-Chloroquinolin-4-yloxy)-
4-methyl-2H-chromen-2-one with high regioselectivity
from 2,4-dichloroquinoline and 7-hydroxy-2H-chromen-2-
one. These compounds has been subjected to the antimi-
crobial screening against a panel of human pathogens that
most of the them are found to be more active than the
standard drugs, antioxidant activity for compound 3e
shows moderately 78 % of inhibition. It is worth men-
tioning that the binding energy value of synthesized com-
pounds, very less compare to standard antimalarial drugs
like chloroquine and amodiaquine.
Antioxidant activity
The synthesized compounds were used to prepare stock
using ethanol (0.3 mM). The appropriate concentrations of
the compounds were made by serial dilution in different
concentrations, i.e. 50, 100, 500 and 1,000 lg/mL of test
samples in AR grade ethanol. The samples (3 mL) of above
concentrations were mixed with 1 mL of 0.15 mM of
DPPH prepared in AR grade ethanol and incubated at room
temperature for 30 min in dark. The absorbance of the
incubated solutions and the blank (without sample) were
recorded against BHT. The absorbance was measured at
517 nm using a UV–Visible (Systronics 118 model) spec-
trophotometer. Radical-scavenging capacity (RSC) in per-
cent was calculated by the following equation:
Acknowledgments Authors are thankful to the administration, VIT
University, Vellore, India, for providing facilities to carry research
work, and also thankful to SAIF, IIT-Madras and VIT-TBI for pro-
viding NMR, Mass and IR spectral facilities respectively. Author G.L.
Balaji is thankful to the VIT University for providing Research
Associate.
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