Synthesis, antimicrobial, and cytotoxicity studies of novel sulfur-linked quinoline-coumarin bisheterocycles

Article abstract of DOI:10.1007/s00044-013-0761-7

Abstract: A series of sulfur attached quinolines and quinoline-coumarin bisheterocycles have been synthesized by the Friedlander reaction of methyl 2-[(2,4-diaryl-3-quinolyl)sulfanyl]acetate and subsequent reaction with salicylaldehyde. These compounds were screened for their in vitro antimicrobial activity against Gram-positive, Gram-negative bacteria, and fungal pathogen. Among the 19 compounds screened, preliminary results indicated that many of the compounds demonstrated moderate to good antimicrobial activities. The cytotoxic effects against mouse fibroblasts (NIH 3T3) in vitro were evaluated for the most active compound, which displayed no toxic effects.

Full text of DOI:10.1007/s00044-013-0761-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1612–1621
DOI 10.1007/s00044-013-0761-7
ORIGINAL RESEARCH
Synthesis, antimicrobial, and cytotoxicity studies of novel
sulfur-linked quinoline–coumarin bisheterocycles
•
Nidhin Paul Shanmugam Muthusubramanian
Received: 4 April 2013 / Accepted: 22 August 2013 / Published online: 4 September 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of sulfur attached quinolines and
quinoline–coumarin bisheterocycles have been synthesized
by the Friedlander reaction of methyl 2-[(2,4-diaryl-3-
quinolyl)sulfanyl]acetate and subsequent reaction with
salicylaldehyde. These compounds were screened for their
in vitro antimicrobial activity against Gram-positive,
Gram-negative bacteria, and fungal pathogen. Among the
19 compounds screened, preliminary results indicated that
many of the compounds demonstrated moderate to good
antimicrobial activities. The cytotoxic effects against
mouse fibroblasts (NIH 3T3) in vitro were evaluated for the
most active compound, which displayed no toxic effects.
researchers to synthesize such compounds and study their
potential biological activities (Padwa et al., 1999). Quin-
oline skelton is the key structural unit in 5-lipoxygenase
inhibitors, leukotriene antagonists, and LTD4 receptor
antagonists (Musser et al., 1987). Several quinoline-based
derivatives have been found to act as antimalarial, anti-
bacterial, antiasthmatic, antihypertensive, and antiinflam-
matory drugs (Solomom et al., 2007; Chen et al., 2001).
Quinoline derivatives like protoberberins and 8-oxoberbe-
rins (Fig. 1) are known to possess antileukemic, antitumor,
and anticancer activities (Matulenko and Meyers, 1996).
The potent antitumor agents Dynamicin A and Virantmy-
cin are important natural products containing the quinoline
core (Magnus et al., 1994). Many coumarin derivatives
have been extensively investigated for their beneficial
effects such as antimicrobial, anticancer, anti-HIV, and
anticoagulant activities (Ma et al., 2008). Coumarin
derivatives are reported to act as reactive oxygen species
scavengers (Lin et al., 2008) thus protecting human body
from free radicals. The naturally occurring coumarin, um-
belliferone (Fig. 1), is found to have lipid lowering
potential (Madhavan et al., 2003).
Keywords Friedlander annulation ꢀ Quinoline ꢀ
Coumarin ꢀ Antimicrobial activity ꢀ Cytotoxicity
Introduction
Designing new compounds to fight with bacterial and
fungal pathogens has become one of the most important
areas of antibacterial research today. Quinoline skeleton is
present in several biologically active naturally occurring
alkaloids of plant origin. In addition, quinoline nucleus is
present in several pharmaceutical products prompting the
The development of hybrid molecules through the
combination of different pharmacophores may lead to
compounds with interesting biological profiles. Several
groups have reported hybrid molecules (Sashidhara et al.,
2010; Vilar et al., 2006; Song et al., 2009) by coupling
coumarins with different bioactive molecules, which are
shown to exhibit antihyperlipidemic, antioxidant, antiin-
flammatory, and antiplatelet activities. In continuation of
our work (Paul et al., 2012) on the synthesis of novel
heterocyclic molecules and drug discovery program, we
embarked on the synthesis of novel quinoline–coumarin
hybrids. The association of these two important scaffolds
through sulfur in a single molecule is hitherto unknown.
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0761-7) contains supplementary
material, which is available to authorized users.
N. Paul ꢀ S. Muthusubramanian (&)
School of Chemistry, Department of Organic Chemistry,
Madurai Kamaraj University, Madurai 625021, India
e-mail: muthumanian@gmail.com; muthumanian2001@yahoo.com
123

Med Chem Res (2014) 23:1612–1621
1613
R
Table 1 Screening of catalysts for the formation of 3a
Entry
Catalyst
Mol ( %)
Time (h)
Yield of 3a (%)
N
HO
O
O
R
1
2
3
1
2
3
4
5
7
p-TsOH
HCl
50
30
30
75
75
75
35
50
35
5
3
3
2
4
4
3
4
3
70
67
65
80
74
72
70
75
74
O
O
H2SO4
AlCl3
Umbelliferone
(Canadine)
=
1) R OCH2O
=
(Tetrahydropalmatine)
2) R OMe
ZnCl2
FeCl3
Fig. 1 Structures of bioactive quinolines and coumarins
Results and discussion
SbCl3
SnCl2ꢀ6H2O
LaCl3ꢀ7H2O
Synthesis
Isolated yield after purification by column
The route pursued for the synthesis of quinoline–coumarin
hybrids is illustrated in Scheme 1. The starting material,
methyl 2-[(2-oxo-2-arylethyl)sulfanyl]acetate 1 was pre-
pared from 2-bromo-1-phenyl-1-ethanone and methyl thi-
oglycolate by a known procedure (Vedejs et al., 1986;
Padmavathi et al., 2008). The Friedlander reaction of
The structures of quinolines 3 were established from 1H,
13C, and two dimensional NMR spectroscopic data as
illustrated for a representative example, 3b (Fig. 2). In the
1H NMR spectrum of quinoline 3b, the protons of methyl
group appear as a singlet (3.41, 3H), the respective carbon
appearing at 51.9 ppm. The ester carbonyl carbon appears
at 169.1 ppm. This ester carbonyl carbon shows HMBC
with a two hydrogen singlet at 2.81 ppm. The latter
hydrogens are having HMB connection with C-3 at
124.7 ppm and C,H-COSY relation with the carbon at
35.7 ppm. In the para methyl-substituted benzene ring, the
singlet at 2.43 ppm due to CH3 is having C,H-COSY
correlation with the carbon at 21.4 ppm and HMBC with
C-40 at 138.4 ppm. The doublet (J = 7.8 Hz) at 7.30 ppm
due to H-30 exhibits H,H-COSY correlation with H-20
doublet at 7.75 ppm (J = 7.8 Hz) and HMBC contours
with C-10 at 137.7 ppm and further shows C,H-COSY
correlation with C-30 at 128.7 ppm. The H-20 proton has
(i) C,H-COSY correlation with C-20 at 129.3 ppm and (ii)
HMB correlations with C-40 at 138.4 ppm and C-2 at
161.5 ppm. The most downfield doublet at 8.18 ppm
(J = 8.4 Hz) is ascribed to H-8 and is having C,H-COSY
correlation with C-8 at 129.4 ppm and HMBC with C-4a at
126.9 ppm. The multiplet between 7.67 and 7.71, which is
having H,H-COSY with both the doublet at 8.18 ppm and
the multiplet at 7.40–7.42 ppm is ascribed to H-7. This has
C,H-COSY correlation with C-7 at 130.0 ppm and HMBC
methyl 2-[(2-oxo-2-arylethyl)sulfanyl]acetate
1
with
2-aminobenzophenone 2 was carried out in methanol under
reflux in the presence of aluminum chloride to yield methyl
2-[(2,4-diaryl-3-quinolyl)sulfanyl]acetate, 3. Aluminum
chloride has found to be the catalyst of choice after ana-
lyzing the catalytic activity of different acids. When tested
for the formation of 3a (Table 1), the maximum yield of
80 % is found to be with anhydrous aluminum chloride
upon 2 h reflux. After completion of the reaction, the
mixture was poured into water and the solid separated was
recrystallised from ethanol-ethyl acetate mixture to get
pure quinoline derivative 3. The coumarin ring over 3 can
be generated through the ester link at the third position of
the quinoline, 3. Thus the quinoline with the methyl thio-
glycolate side chain was subsequently refluxed with equi-
molar amount of salicylaldehyde in ethanol in the presence
of piperidine. After completion of the reaction (monitored
by TLC), the mixture was poured into water and the resi-
due was subjected to column chromatography to afford
3-[(2,4-diphenyl-3-quinolyl)sulfanyl]-2H-2-chromenone 4
in good yield. This protocol is applied to get differently
substituted 3 and 4 and the results are tabulated in Table 2.
Scheme 1 Synthesis of
quinoline and quinoline–
coumarin bisheterocycle
derivatives 3 and 4
O
O
S
Ar
O
O
O
Salicylaldehyde
Piperidine
1
S
Anhy. AlCl3
Methanol
O
O
+
Methanol
S
NH2
N
Ar
3
N
Ar
O
2
4
123

1614
Med Chem Res (2014) 23:1612–1621
Table 2 Yields of 3 and 4
Entry
Ar
Yield (%)
Melting point (°C)
3
4
3
4
a
b
c
d
e
f
C6H5
80
83
84
87
81
86
83
80
85
84
81
85
87
88
89
85
84
81
79
117
79
197
242
233
273
212
210
214
211
–
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-OMeC6H4
4-NO2C6H4
4-PhC6H4
2-Naphthyl
3-ClC6H4
3-BrC6H4
3-OMeC6H4
120
142
88
135
92
g
h
i
103
97
a
-
a
j
-
85
–
a
k
-
82
–
Isolated yield after recrystallisation
a
Reaction not performed
with C-5 at 126.6 ppm. The multiplet at 7.40–7.42 ppm,
accounting for two hydrogens, is assigned to H-5 and H-6
and from the C,H-COSY spectrum, the corresponding
carbon signals are located at 126.6 and 126.7 ppm. The
carbon signal at 154.2 ppm is ascribed to C-4 from its
HMB correlation with H-5 and also with the doublet at
7.36 ppm (J = 7.5 Hz) due to H-200. Compound 3e has its
molecular ion peak [M?1] at m/e 416.1315 (calculated:
416.1242). The structure of the quinoline 3e has been
confirmed by X-ray crystallographic study of its single
crystal (Fig. 3).
In the 1H NMR spectrum of 4c, the one hydrogen singlet
at 6.78 ppm due to H-40 shows (i) C,H-COSY correlation
with the signal at 137.2 ppm assignable to C-40 and (ii)
HMBCs with C-50, C-8a0, and coumarin carbonyl C-20 at
126.5, 152.0, and 158.0 ppm, respectively (Fig. 4). The
C-50 carbon is exhibiting a C,H-COSY correlation with a
broad doublet at 7.17 ppm (J = 7.5 Hz, 1H) and is ascri-
bed to H-50. The downfield doublet at 8.21 ppm
(J = 8.4 Hz, 1H) is assigned to H-8. The H-8 proton shows
H,H-COSY with the multiplet around 7.78 ppm (H-7),
C,H-COSY correlation with the signal at 129.6 ppm (C-8),
Fig. 3 ORTEP diagram of 3e
and HMBC with C-6 at 127.4 ppm. The H-7 proton is
giving C,H-COSY contour with C-7 at 130.8 ppm and
HMBCs with C-5 and C-6 at 126.8 and 127.4 ppm,
respectively. The H,H-COSY spectrum helps to assign the
two hydrogen multiplet between 7.48 and 7.52 ppm to H-5
and H-6. The two hydrogen doublet at 7.65 ppm
(J = 8.4 Hz) is assigned as H-200 and is having H,H-COSY
relation with the doublet at 7.28 ppm (J = 8.4 Hz, 2H,
H-300), C,H-COSY correlation at 130.5 ppm and HMBCs at
134.7 and 160.4 ppm (C-1’’ and C-2 respectively). The
H-300 proton shows C,H-COSY contour with C-300 and
HMBCs with C-100 and C-400 at 134.7 and 138.8 ppm,
respectively. The molecular ion peak [M?1] of 4e
appeared at m/e 488.1315 (calculated 488.1242). The
structure of quinoline–coumarin hybrid molecule is further
confirmed by single crystal X-ray analysis of 4b (Fig. 5)
and 4g (Fig. 6).
Fig. 2 Selected HMBCs and 1H
and 13C chemical shifts of
compound 3b
7.36, d, 2H,
=
z
7.5 H
J
129.7
2.81, s, 2H,
35.7
7.40-7.42,
m,
2H
H
H
H
5
H
S
O
O
s
H
3
,
3.41
, ,
51.9
126.6
154.2
169.1
O
4
H
H
H
H
C
3
S
CH3
a
a
4
3
6
O
C
126.9 124.7
161.5
126.7
H
2
7.30, 2H,
d,
7
H
H
H
J = 7.8 Hz
8
3'
N
N
7.67-7.69, m
,
137.7
1'
8
H
128.7
1
138.4
1H,130.0
H
4'
2'
H
H
H
H
C
8.18, 1H,
d,
3
3
7.75, 2H,
d,
2.43, s, 3H,
21.4
=
Hz
J
8.4
H
=
129.3
Hz
J
7.8
129.4
123

Med Chem Res (2014) 23:1612–1621
1615
Fig. 4 Selected HMBCs and 1H
and 13C chemical shifts of
compound 4c
O
O
7.48-7.52,m, 2H
H
2'
H
5
H
H
158.0
1'
8'a
O
O
S
S
3'
4'
126.8
152.0
4
H
H
8'
7'
6
7
3
2
127.4
6.78, s, 1H
4a
8a
4'a
H
160.4
137.2
7.76 -7.80,
H
H
m, 1H,
130.5
N
H
N
134.7
5'
8
H
6'
1
H
7.17, d,
J = 7.5 Hz
126.5
138.8
Cl
8.21, d, 1H,
J = 8.4 Hz
129.6
H
H
Cl
7.65, d, 2H,
J = 8.4 Hz
H
H
130.5 7.28, d, 2H,
J = 8.4 Hz
128.1
summarized along with that of ciprofloxacin and clotrim-
azole in Table 3. The results show that most of the com-
pounds have moderate to good antibacterial and antifungal
activities (6.25–50.0 lg/ml). Compounds 3c, 3d, 3e, 3f, 3i,
3j, 3k, 4d, and 4f show moderate to good activity and have
zone of inhibition comparable to that of the standard cip-
rofloxacin (6.25 lg/ml and 28 mm) against E. coli. Against
S. aureus, compounds 3b, 3d, 3e, 3f, 3i, 3j, 3k, and 4d
showed moderate activity compared to the standard
(6.25 lg/ml and 25 mm). In the antifungal evaluation,
compounds 3b, 3d, 3f, 3i, 3j, 3k, 4d, and 4f exhibit
moderate activity compared to standard clotrimazole
(6.25 lg/ml and 28 mm) against C. albicans. Nitro, bromo,
or chloro-substituted compounds have activity comparable
to that of standard drugs.
Fig. 5 ORTEP diagram of 4b
Cytotoxicity
The cytotoxicity of the compound 3j was studied in vitro
using NIH 3T3 mouse embryonic fibroblasts cell line (NIH
3T3) by MTT assay. MTT is a yellow colored water sol-
uble tetrazolium salt. A mitochondrial enzyme in living
cells, succinate-dehydrogenase, cleaves the tetrazolium
ring, converting the MTT to an insoluble purple formazan
product that was read spectrophotometrically at 570 nm on
the basis of linear absorbance to the number of living cells
in culture. The MTT assay was validated using various
concentrations of DMSO. A dose response graph (Fig. 7)
reveals that the percentage cell viability was decreased
with increasing the concentration of 3j. However, the half
maximal inhibitory concentration (IC50) value determined
by GraphPad Prism software was found to be 456 lM for
3j. This indicates that the newly synthesized compound 3j
is not toxic to the normal fibroblasts (NIH 3T3).
Fig. 6 ORTEP diagram of 4g
Antibacterial and antifungal activity
All the synthesized compounds were evaluated for their
in vitro preliminary antibacterial activity against the Gram-
positive bacteria Staphylococcus aureus (ATCC 11632)
and Gram-negative bacteria Escherichia coli (ATCC
25922) and for their antifungal activity against Candida
albicans (ATCC 90028) by agar disk diffusion method
using ciprofloxacin and clotrimazole as reference stan-
dards, respectively. The MICs and zone of inhibition were
determined for 3a–k and 4a–h and the results are
In summary, the synthesis of quinoline and bis hetero-
cyclic compounds with quinoline and coumarin units
linked by sulfur atom has been achieved. These newly
synthesized compounds displayed good in vitro antimi-
crobial activity and the most active compound displayed
less cytotoxicity toward NIH 3T3 mouse embryonic
fibroblast cell line.
123

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Med Chem Res (2014) 23:1612–1621
Table 3 Biological activity of 3 and 4
Entry
MIC (ZI)
E. coli (25922)
S. aureus (11632)
C. albicans (90028)
3
4
3
4
3
4
a
25.0 (15)
25.0 (11)
12.5 (12)
6.25 (20)
12.5 (15)
6.25 (18)
25.0 (10)
50.0 (10)
12.5 (18)
12.5 (15)
12.5 (15)
n.t.
25.0 (13)
25.0 (13)
25.0 (12)
12.5 (18)
25.0 (12)
12.5 (15)
50.0 (\10)
50.0 (\10)
n.t.
25.0 (15)
12.5 (16)
25.0 (13)
12.5 (18)
12.5 (15)
12.5 (16)
25.0 (12)
50.0 (10)
12.5 (18)
12.5 (18)
25.0 (15)
n.t.
25.0 (12)
25.0 (10)
25.0 (12)
12.5 (18)
25.0 (16)
25.0 (15)
25.0 (10)
50.0 (\10)
n.t.
25.0 (10)
12.5 (13)
25.0 (15)
12.5 (18)
25.0 (12)
12.5 (20)
50.0 (10)
25.0 (10)
12.5 (15)
12.5 (13)
25.0 (15)
6.25 (28)
n.t.
25.0 (10)
25.0 (12)
25.0 (15)
12.5 (20)
25.0 (12)
12.5 (18)
50.0 (10)
50.0 (\10)
n.t.
b
c
d
e
f
g
h
i
j
n.t.
n.t.
n.t.
k
n.t.
n.t.
n.t.
Clotrimazole
Ciprofloxacin
6.25 (28)
6.25 (25)
The MIC values were evaluated at concentration range 1.56–50 lg/ml. Zone of inhibition in mm for 100 lg/disk of each compound
n. t. not tested
100
were obtained by crystallization from ethyl acetate. The
80
data have been submitted to CCDC. (CCDC numbers
823754, 823753, and 824666). The antimicrobial and
60
cytotoxic studies were carried out at K M C H College of
40
20
0
Pharmacy, Coimbatore, India.
General procedure for the synthesis of quinolines
(3a–3j)
-1.5
-1.0
-0.5
0.0
Log 10 concentration (mM)
A mixture of methyl 2-[(2-oxo-2 arylethyl)sulfanyl]acetate
1 (1 mmol) and 2 aminobenzophenone 2 (1 mmol) in
methanol (10 ml) was heated under reflux for 2 h with
anhydrous aluminum chloride (0.1 mmol). After comple-
tion of the reaction as evident from TLC, the mixture was
poured into ice-water (50 ml) and the resulting solid was
filtered off. The reaction mass was recrystallised from
ethanol–ethyl acetate mixture (4:1) to afford the pure
product 3. Spectroscopic data for 3 are given below.
Fig. 7 Concentration-cell viability graph for 3j
Experimental
Chemistry
All melting points reported in this work were measured in
1
open capillaries. The H and 13C NMR spectra have been
measured at 300 and 75 MHz, respectively, using Bruker
300 MHz (Avance) instrument in CDCl3 using tetrameth-
ylsilane (TMS) as internal standard. Chemical shifts are
reported as d values (ppm). All 1D and 2D NMR spectra
were obtained using standard Bruker software throughout.
Silica gel-G plates (Merck) were used for TLC analysis
with a mixture of petroleum ether (60–80 °C) and ethyl
acetate as eluant. Elemental analyses were performed on a
PerkinElmer 2400 Series II Elemental CHNS analyzer. IR
spectra were recorded on a JASCO FT IR instrument (KBr
pellet). Crystals suitable for X-ray crystallographic studies
Methyl 2-[(2,4-diphenyl-3-quinolyl)sulfanyl]acetate
(3a)
Isolated as colorless solid; IR (KBr): 3057, 3024, 2948,
1
1734 cm-1; H NMR (300 MHz, CDCl3) dH: 2.78 (s, 2H,
CH2), 3.39 (s, 3H, OCH3), 7.35 (dd, 2H, J = 7.2, 2.1 Hz,
Ar–H), 7.41–7.57 (m, 8H, Ar–H), 7.67–7.69 (m, 1H, Ar–
H), 7.85 (dd, 2H, J = 8.1, 1.5 Hz, Ar–H), 8.17 (d, 1H,
J = 8.4 Hz, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 35.7
(CH2), 51.9 (OCH3), 124.6 (Ar–C), 126.6 (Ar–C), 126.8
(Ar–C), 127.0 (Ar–C), 127.9 (Ar–C), 128.1 (Ar–C), 128.2
123

Med Chem Res (2014) 23:1612–1621
1617
(Ar–C), 128.4 (Ar–C), 129.4 (Ar–C), 129.5 (Ar–C), 129.7
(Ar–C), 130.0 (Ar–C), 137.1 (Ar–C), 140.7 (Ar–C), 147.0
(Ar–C), 154.2 (Ar–C), 161.5 (Ar–C), 169.0 (C=O). Anal.
Calcd for C24H19NO2S: C, 74.78; H, 4.97; N, 3.63 %.
Found C, 74.74; H, 4.94; N, 3.60 %.
(Ar–C), 127.1 (Ar–2C), 128.2 (Ar–C), 128.3 (Ar–C), 129.4
(Ar–C), 129.7 (Ar–C), 130.3 (Ar–C), 131.2 (Ar–C), 131.3
(Ar–C), 136.8 (Ar–C), 139.5 (Ar–C), 147.0 (Ar–C), 154.6
(Ar–C), 160.4 (Ar–C), 168.9 (C=O). Anal. Calcd for
C24H18BrNO2S: C, 62.07; H, 3.91; N, 3.02 %. Found C,
62.03; H, 3.88; N, 2.99 %.
Methyl 2-[2-(4-methylphenyl)-4-phenyl-3-quinolyl]
sulfanylacetate (3b)
Methyl 2-[2-(4-methoxyphenyl)-4-phenyl-3-quinolyl]
sulfanylacetate (3e)
Isolated as colorless solid; IR (KBr): 3057, 3025, 2948,
1
1730 cm-1; H NMR (300 MHz,CDCl3) dH: 2.43 (s, 3H,
Isolated as colorless solid; IR (KBr): 3056, 3027, 2948,
1
CH3), 2.81 (s, 2H, CH2), 3.41 (s, 3H, OCH3), 7.30 (d, 2H,
J = 7.8 Hz, H-30), 7.36 (d, 2H, J = 7.5 Hz, Ar–H),
7.41–7.42 (m, 2H, Ar–H), 7.48–7.56 (m, 3H, Ar–H), 7.69
(m, 1H, H-7), 7.75 (d, 2H, J = 7.8 Hz, H-20), 8.18 (d, 1H,
J = 8.4 Hz, H-8); 13C NMR (75 MHz, CDCl3) dC: 21.4
(Ar–CH3), 35.7 (CH2), 51.9 (OCH3), 124.7 (Ar–C), 126.6
(Ar–C), 126.7 (Ar–C), 126.9 (Ar–C), 128.1 (Ar–C), 128.2
(Ar–C), 128.7 (Ar–C), 129.3 (Ar–C), 129.4 (Ar–C), 129.7
(Ar–C), 130.0 (Ar–C), 137.1 (Ar–C), 137.7 (Ar–C), 138.4
(Ar–C), 146.9 (Ar–C), 154.2 (Ar–C), 161.5 (Ar–C), 169.1
(C=O). Anal. Calcd for C25H21NO2S: C, 75.16; H, 5.30; N,
3.51 %. Found C, 75.13; H, 5.27; N, 3.49 %.
1724 cm-1; H NMR (300 MHz, CDCl3) dH: 2.82 (s, 2H,
CH2), 3.41 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 7.02 (d, 2H,
J = 7.5 Hz, Ar–H), 7.35–7.40 (m, 4H, Ar–H), 7.49–7.52
(m, 3H, Ar–H), 7.60–7.72 (m, 1H, Ar–H), 7.84 (d, 2H,
J = 7.5 Hz, Ar–H), 8.15 (d, 1H, J = 7.8 Hz, Ar–H); 13C
NMR (75 MHz, CDCl3) dC: 35.8 (CH2), 52.0 (OCH3), 55.3
(Ar-OCH3), 113.5 (Ar–C), 124.8 (Ar–C), 126.6 (Ar–C),
126.9 (Ar–C), 128.1 (Ar–2C), 129.5, 129.7 (Ar–2C), 130.1
(Ar–C), 130.9 (Ar–C), 133.2 (Ar–C), 137.2 (Ar–C), 147.1
(Ar–C), 154.1 (Ar–C), 159.9 (Ar–C), 161.0 (Ar–C), 169.1
(C=O). Anal. Calcd for C25H21NO3S: C, 72.27; H, 5.09; N,
3.37 %. Found C, 72.24; H, 5.05; N, 3.35 %.
Methyl 2-[2-(4-chlorophenyl)-4-phenyl-3-quinolyl]
Methyl 2-[2-(4-nitrophenyl)-4-phenyl-3-quinolyl]
sulfanylacetate (3c)
sulfanylacetate (3f)
Isolated as colorless solid; IR (KBr): 3057, 3026, 2944,
1
Isolated as colorless solid; IR (KBr): 3057, 3027, 2946,
1
1726 cm-1; H NMR (300 MHz, CDCl3) dH: 2.81 (s, 2H,
1726 cm-1; H NMR (300 MHz, CDCl3) dH: 2.80 (s, 2H,
CH2), 3.41 (s, 3H, OCH3), 7.35 (dd, 2H, J = 7.5, 1.8 Hz,
Ar–H), 7.43–7.45 (m, 2H, Ar–H), 7.47 (d, 2H, J = 8.7 Hz,
Ar–H), 7.51–7.57 (m, 3H, Ar–H), 7.71–7.73 (m, 1H, Ar–
H), 7.82 (d, 2H, J = 8.7 Hz, Ar–H), 8.15 (d, 1H,
J = 8.4 Hz, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 36.0
(CH2), 52.1 (OCH3), 124.4 (Ar–C), 126.7 (Ar–C), 127.0
(Ar–C), 127.1 (Ar–C), 128.1 (Ar–C), 128.2 (Ar–C), 128.3
(Ar–C), 129.5 (Ar–C), 129.7 (Ar–C), 130.3 (Ar–C), 131.0
(Ar–C), 134.7 (Ar–C), 136.9 (Ar–C), 139.1 (Ar–C), 147.1
(Ar–C), 154.6 (Ar–C), 160.4 (Ar–C), 168.9 (C=O). Anal.
Calcd for C24H18ClNO2S: C, 68.65; H, 4.32; N, 3.34 %.
Found C, 68.61; H, 4.29; N, 3.31 %.
CH2), 3.42 (s, 3H, OCH3), 7.36–7.40 (m, 2H, Ar–H), 7.50-
7.56 (m, 5H, Ar–H), 7.74–7.78 (m, 1H, Ar–H), 7.98–8.04
(m, 2H, Ar–H), 8.22 (d, 1H, J = 7.5 Hz, Ar–H), 8.36–8.37
(m, 2H, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 36.1
(CH2), 52.2 (OCH3), 123.2 (Ar–C), 124.2 (Ar–C), 126.8
(Ar–C), 127.4 (Ar–C), 127.7 (Ar–C), 128.3 (Ar–2C), 128.6
(Ar–C), 129.4 (Ar–C), 129.7 (Ar–C), 130.9 (Ar–C), 136.3
(Ar–C), 146.7 (Ar–C), 146.8 (Ar–C), 147.7 (Ar–C), 155.3
(Ar–C), 159.5 (Ar–C), 168.6 (C=O). Anal. Calcd for
C24H18N2O4S: C, 66.96; H, 4.21; N, 6.51 %. Found C,
66.92; H, 4.18; N, 6.46 %.
Methyl 2-(2-(biphenyl-4-yl)-4-phenylquinolin-3-ylthio)
Methyl 2-[2-(4-bromophenyl)-4-phenyl-3-quinolyl]
acetate (3g)
sulfanylacetate (3d)
Isolated as colorless solid; IR (KBr): 3057, 3025, 2947,
1
Isolated as colorless solid; IR (KBr): 3057, 3028, 2944,
1
1728 cm-1; H NMR (300 MHz, CDCl3) dH: 2.74 (s, 2H,
1726 cm-1; H NMR (300 MHz, CDCl3) dH: 2.81 (s, 2H,
CH2), 3.35 (s, 3H, OCH3), 7.41–7.52 (m, 2H, Ar–H),
7.56–7.65 (m, 8H, Ar–H), 7.67–7.75 (m, 3H, Ar–H),
7.82–7.87 (m, 4H, Ar–H), 8.16 (d, 1H, J = 8.1 Hz, Ar–H);
13C NMR (75 MHz, CDCl3) dC: 35.0 (CH2), 51.9 (OCH3),
124.4 (Ar–C), 126.1 (Ar–C), 126.3 (Ar–C), 126.5 (Ar–C),
126.9 (Ar–C), 127.1 (Ar–C), 127.6 (Ar–C), 127.8 (Ar–C),
128.2 (Ar–C), 128.4 (Ar–C), 128.7 (Ar–2C), 128.9 (Ar–C),
CH2), 3.41 (s, 3H, OCH3), 7.35 (dd, 2H, J = 7.5, 2.1 Hz,
Ar–H), 7.43–7.45 (m, 2H, Ar–H), 7.52–7.57 (m, 3H, Ar–
H), 7.62 (d, 2H, J = 8.4 Hz, Ar–H), 7.69–7.72 (m, 1H, Ar–
H), 7.75 (d, 2H, J = 8.4 Hz, Ar–H), 8.15 (d, 1H,
J = 8.4 Hz, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 35.9
(CH2), 52.1 (OCH3), 123.0 (Ar–C), 124.4 (Ar–C), 126.7
123

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Med Chem Res (2014) 23:1612–1621
129.5 (Ar–C), 130.2 (Ar–C), 131.1 (Ar–C), 136.1 (Ar–C),
141.4 (Ar–C), 146.7 (Ar–C), 155.1 (Ar–C), 160.8 (Ar–C),
168.9 (C=O). Anal. Calcd for C30H23NO2S: C, 78.06; H,
5.02; N, 3.03 % Found C, 78.03; H, 4.99; N, 3.00 %.
129.7 (Ar–C), 130.4 (Ar–C), 131.5 (Ar–C), 132.4 (Ar–C),
136.7 (Ar–C), 142.5 (Ar–C), 146.9 (Ar–C), 154.6 (Ar–C),
160.1 (Ar–C), 168.8 (C=O). Anal. Calcd for
C24H18BrNO2S: C, 62.07; H, 3.91; N, 3.02 %. Found C,
62.04; H, 3.88; N, 2.98 %.
Methyl 2-[2-(2-naphthyl)-4-phenyl-3-quinolyl]
sulfanylacetate (3h)
Methyl 2-[2-(3-methoxyphenyl)-4-phenyl-3-quinolyl]
sulfanylacetate (3k)
Isolated as colorless solid; IR (KBr): 3057, 3025, 2948,
1
1728 cm-1; H NMR (300 MHz,CDCl3) dH: 2.75 (s, 2H,
Isolated as colorless solid; IR (KBr): 3056, 3027, 2948,
1
CH2), 3.31 (s, 3H, OCH3), 7.38 (dd, 2H, J = 7.5, 1.8 Hz,
Ar–H), 7.42–7.45 (m, 2H, Ar–H), 7.47–7.57 (m, 5H, Ar–
H), 7.70–7.72 (m, 1H, Ar–H), 7.87–8.00 (m, 4H, Ar–H),
8.21 (d, 1H, J = 8.4 Hz, Ar–H), 8.35 (s, 1H, Ar–H); 13C
NMR (75 MHz, CDCl3) dC: 35.9 (CH2), 51.9 (OCH3),
124.9 (Ar–C), 126.1 (Ar–C), 126.4 (Ar–C), 126.6 (Ar–C),
126.9 (Ar–C), 127.0 (Ar–C), 127.1 (Ar–C), 127.4 (Ar–C),
127.6 (Ar–C), 128.1 (Ar–C), 128.2 (Ar–C), 128.5 (Ar–C),
128.9 (Ar–C), 129.5 (Ar–C), 129.7 (Ar–C), 130.1 (Ar–C),
132.9 (Ar–C), 133.1 (Ar–C), 137.0 (Ar–C), 138.1 (Ar–C),
147.1 (Ar–C), 154.4 (Ar–C), 161.4 (Ar–C), 168.9 (C=O).
Anal. Calcd for C28H21NO2S: C, 77.21; H, 4.86; N,
3.22 %. Found C, 77.18; H, 4.83; N, 3.18 %.
1730 cm-1; H NMR (300 MHz, CDCl3) dH: 2.83 (s, 2H,
CH2), 3.42 (s, 3H, OCH3), 3,87 (s, 3H, OCH3), 7.00 (m,
1H, Ar–H), 7.35–7.43 (m, 6H, Ar–H), 7.52–7.54 (m, 4H,
Ar–H), 7.68–7.71 (m, 1H, Ar–H), 8.18 (d, 1H, J = 8.4 Hz,
Ar–H); 13C NMR (75 MHz, CDCl3) dC: 35.7 (CH2), 51.9
(OCH3), 55.2 (ArOCH3), 114.4 (Ar–C), 114.6 (Ar–C),
121.8 (Ar–C), 124.7 (Ar–C), 126.5 (Ar–C), 126.8 (Ar–C),
127.0 (Ar–C), 128.1 (Ar–C), 128.2 (Ar–C), 129.1 (Ar–C),
129.4 (Ar–C), 129.7 (Ar–C), 130.0 (Ar–C), 140.0 (Ar–C),
141.9 (Ar–C), 146.9 (Ar–C), 154.1 (Ar–C), 159.1 (Ar–C),
161.2 (Ar–C), 169.0 (C=O). Anal. Calcd for C25H21NO3S:
C, 72.27; H, 5.09; N, 3.37 %. Found C, 72.22; H, 5.05; N,
3.32 % .
Methyl 2-[2-(3-chlorophenyl)-4-phenyl-3-quinolyl]
General procedure for quinoline–coumarin
sulfanylacetate (3i)
bisheterocycle (4)
Isolated as colorless solid; IR (KBr): 3058, 3024, 2948,
1
A mixture of methyl 2-[(2,4-diaryl-3-quinolyl)sulfa-
1728 cm-1; H NMR (300 MHz, CDCl3) dH: 2.82 (s, 2H,
nyl]acetate 3 (1 mmol) salicylaldehyde (1 mmol) and
piperidine (0.1 mmol) in ethanol (10 ml) was heated under
reflux for 25 min. After completion of the reaction as
evident from TLC, the mixture was poured into ice-water
(30 ml) and the solid was filtered off and purified by wash
column using petroleum ether/ethyl acetate mixture (3:1;
v/v) as eluent to afford the pure product 4. Spectroscopic
data for 4 is given below.
CH2), 3.44 (s, 3H, OCH3), 7.36 (dd, 2H, J = 7.8, 1.5 Hz,
Ar–H), 7.42–7.47 (m, 4H, Ar–H), 7.52–7.56 (m, 3H, Ar–
H), 7.71–7.76 (m, 2H, Ar–H), 7.83 (d, 1H, J = 0.9 Hz, Ar–
H), 8.17 (d, 1H, J = 8.4 Hz, Ar–H); 13C NMR (75 MHz,
CDCl3) dC: 35.9 (CH2), 52.0 (OCH3), 124.4 (Ar–C), 126.6
(Ar–C), 127.1 (Ar–2C), 127.8 (Ar–C), 128.2 (Ar–2C),
128.5 (Ar–C), 129.2 (Ar–C), 129.5 (Ar–C), 129.6 (Ar–C),
129.7 (Ar–C), 130.3 (Ar–C), 133.8 (Ar–C), 136.7 (Ar–C),
142.4 (Ar–C), 147.0 (Ar–C), 154.5 (Ar–C), 160.2 (Ar–C),
168.8 (C=O). Anal. Calcd for C24H18ClNO2S: C, 68.65; H,
4.32; N, 3.34 %. Found C, 68.60; H, 4.28; N, 3.30 %.
3-[(2,4-Diphenyl-3-quinolyl)sulfanyl]-2H-2-chromenone
(4a)
Isolated as colorless solid; IR (KBr): 3057, 3027, 2922,
1
Methyl 2-[2-(3-bromophenyl)-4-phenyl-3-quinolyl]
1718 cm-1; H NMR (300 MHz, CDCl3) dH: 6.78 (s, 1H,
sulfanylacetate (3j)
Ar–H), 7.10–7.17 (m, 3H, Ar–H), 7.28 (d, 2H, J = 7.5 Hz,
Ar–H), 7.29–7.44 (m, 6H, Ar–H), 7.47–7.52 (m, 3H, Ar–
H), 7.68 (dd, 2H, J = 7.5, 1.8 Hz, Ar–H), 7.76 (td, 1H,
J = 8.1, 1.8 Hz, Ar–H), 8.21 (d, 1H, J = 8.4 Hz, Ar–H);
13C NMR (75 MHz, CDCl3) dC: 116.2 (Ar–C), 119.0 (Ar–
C), 122.6 (Ar–C), 124.3 (Ar–C), 126.3 (Ar–C), 126.4 (Ar–
C), 126.7 (Ar–C), 127.1 (Ar–C), 127.2 (Ar–C), 127.8 (Ar–
C), 128.1 (Ar–C), 128.4 (Ar–C), 128.5 (Ar–C), 128.9 (Ar–
C), 129.2 (Ar–C), 129.6 (Ar–C), 130.4 (Ar–C), 130.5 (Ar–
C), 136.5 (Ar–C), 136.8 (Ar–C), 140.3 (Ar–C), 147.6 (Ar–
C), 151.9 (Ar–C), 154.4 (Ar–C), 157.9 (Ar–C), 161.5
Isolated as colorless solid; IR (KBr): 3058, 3026, 2946,
1
1729 cm-1; H NMR (300 MHz, CDCl3) dH: 2.82 (s, 2H,
CH2), 3.44 (s, 3H, OCH3), 7.34–7.40 (m, 3H, Ar–H),
7.45–7.47 (m, 2H, Ar–H), 7.52–7.61 (m, 4H, Ar–H), 7.74-
7.79 (m, 2H, Ar–H), 7.98 (d, 1H, J = 1.8 Hz, Ar–H), 8.17
(d, 1H, J = 8.4 Hz, Ar–H); 13C NMR (75 MHz, CDCl3)
dC: 35.9 (CH2), 52.1 (OCH3), 122.0 (Ar–C), 124.4 (Ar–C),
126.6 (Ar–C), 127.1 (Ar–C), 127.2 (Ar–C), 128.1 (Ar–C),
128.2 (Ar–C), 128.3 (Ar–C), 129.3 (Ar–C), 129.4 (Ar–C),
123

Med Chem Res (2014) 23:1612–1621
1619
(C=O). Anal. Calcd for C30H19NO2S: C, 78.75; H, 4.19; N,
3.06 %. Found C, 78.70; H, 4.15; N, 3.04 %.
129.2 (Ar–C), 129.6 (Ar–C), 130.7 (Ar–2C), 130.8 (Ar–C),
131.1 (Ar–C), 136.3 (Ar–C), 137.3 (Ar–C), 139.2 (Ar–C),
147.5 (Ar–C), 152.0 (Ar–C), 154.6 (Ar–C), 158.0 (Ar–C),
160.4 (C=O). Anal. Calcd for C30H18BrNO2S: C, 67.17; H,
3.38; N, 2.61 %. Found C, 67.12; H, 3.34; N, 2.58 %.
3-[2-(4-Methylphenyl)-4-phenyl-3-quinolyl]sulfanyl-2H-
2-chromenone (4b)
Isolated as colorless solid; IR (KBr): 3059, 3027, 2929,
1
3-[2-(4-Methoxyphenyl)-4-phenyl-3-quinolyl]sulfanyl-
1717 cm-1; H NMR (300 MHz, CDCl3) dH: 2.25 (s, 3H,
2H-2-chromenone (4e)
CH3), 6.77 (s, 1H, Ar–H), 7.09 (d, 2H, J = 7.8 Hz, Ar–H),
7.12–7.20 (m, 3H, Ar–H), 7.33–7.49 (m, 8H, Ar–H), 7.56
(d, 2H, J = 8.1 Hz, Ar–H), 7.70–7.72 (m, 1H, Ar–H), 8.22
(d, 1H, J = 8.4 Hz, Ar–H); 13C NMR (75 MHz, CDCl3)
dC: 21.0 (Ar-CH3), 116.2 (Ar–C), 119.2 (Ar–C), 122.8
(Ar–C), 124.2 (Ar–C), 126.3 (Ar–C), 126.4 (Ar–C), 126.6
(Ar–C), 126.9 (Ar–C), 127.2 (Ar–C), 128.1 (Ar–C), 128.3
(Ar–C), 128.4 (Ar–C), 128.9 (Ar–C), 129.2 (Ar–C), 129.7
(Ar–C), 130.3 (Ar–C), 130.4 (Ar–C), 136.6 (Ar–C), 136.7
(Ar–C), 137.5 (Ar–C), 138.3 (Ar–C), 147.6 (Ar–C), 152.0
(Ar–C), 154.1 (Ar–C), 157.9 (Ar–C), 161.6 (C=O). Anal.
Calcd for C31H21NO2S: C, 78.96; H, 4.49; N, 2.97 %.
Found C, 78.93; H, 4.45; N, 2.94 %.
Isolated as colorless solid; IR (KBr): 3062, 3027, 2928,
1
1718 cm-1; H NMR (300 MHz, CDCl3) dH: 3.68 (s, 3H,
OCH3), 6.77 (s, 1H, Ar–H), 6.80 (d, 2H, J = 8.7 Hz, Ar–
H), 7.12–7.15 (m, 1H, Ar–H), 7.18 (d, 2H, J = 7.8 Hz, Ar–
H), 7.32–7.50 (m, 8H, Ar–H), 7.66 (d, 2H, J = 8.7 Hz, Ar–
H), 7.76 (ddd, 1H, J = 8.4, 5.7, 2.7 Hz, Ar–H), 8.21 (d,
1H, J = 8.4 Hz, Ar–H); 13C NMR (75 MHz, sCDCl3) dC:
55.1 (ArOCH3), 113.3 (Ar–C), 116.3 (Ar–C), 119.1 (Ar–
C), 122.6 (Ar–C), 124.4 (Ar–C), 126.3 (Ar–C), 126.4 (Ar–
C), 126.7 (Ar–C), 126.9 (Ar–C), 127.2 (Ar–C), 128.2 (Ar–
C), 128.4 (Ar–C), 129.1 (Ar–C), 129.6 (Ar–C), 130.3 (Ar–
C), 130.4 (Ar–C), 130.5 (Ar–C), 132.7 (Ar–C), 136.4 (Ar–
C), 136.6 (Ar–C), 147.6 (Ar–C), 151.9 (Ar–C), 154.5 (Ar–
C), 158.1 (Ar–C), 159.8 (Ar–C), 161.1 (C=O). Anal. Calcd
for C31H21NO3S: C, 76.37; H, 4.34; N, 2.87 %. Found C,
76.33; H, 4.30; N, 2.83 %.
3-[2-(4-Chlorophenyl)-4-phenyl-3-quinolyl]sulfanyl-2H-
2-chromenone (4c)
Isolated as colorless solid; IR (KBr): 3059, 3028, 2928,
1
1718 cm-1; H NMR (300 MHz, CDCl3) dH: 6.78 (s, 1H,
3-[2-(4-Nitrophenyl)-4-phenyl-3-quinolyl]sulfanyl-2H-
H-40), 7.17 (d, 1H, J = 7.5 Hz, H-50), 7.20 (d, 2H,
J = 6.9 Hz, Ar–H), 7.28 (d, 2H, J = 8.4 Hz, H-3’’), 7.32-
7.35 (m, 2H, Ar–H), 7.38-7.44 (m, 4H, Ar–H), 7.48–7.52
(m, 2H, Ar–H), 7.65 (d, 2H, J = 8.4 Hz, H-2’’), 7.78 (ddd,
1H, J = 8.4, 5.4, 3.0 Hz, Ar–H, H-7), 8.21 (d, 1H,
J = 8.4 Hz, H-8); 13C NMR (75 MHz, CDCl3) dC: 116.3
(Ar–C), 119.0 (Ar–C), 122.4 (Ar–C), 124.5 (Ar–C), 125.9
(Ar–C), 126.5 (Ar–C), 126.8 (Ar–C), 127.3 (Ar–C), 128.1
(Ar–C), 128.2 (Ar–2C), 128.5 (Ar–C), 129.2 (Ar–C), 129.6
(Ar–C), 130.5 (Ar–C), 130.7 (Ar–C), 130.8 (Ar–C), 134.7
(Ar–C), 136.3 (Ar–C), 137.2 (Ar–C), 138.8 (Ar–C), 147.5
(Ar–C), 152.0 (Ar–C), 154.6 (Ar–C), 158.0 (Ar–C), 160.4
(C=O). Anal. Calcd for C30H18ClNO2S: C, 73.24; H, 3.69;
N, 2.85 %. Found C, 73.19; H, 3.64; N, 2.81 %.
2-chromenone (4f)
Isolated as colorless solid; IR (KBr): 3061, 3026, 2924,
1
1715 cm-1; H NMR (300 MHz, CDCl3) dH: 6.82 (s, 1H,
Ar–H), 7.12–7.22 (m, 2H, Ar–H), 7.32–7.54 (m, 9H, Ar–
H), 7.79–7.84 (m, 1H, Ar–H), 7.93 (d, 2H, J = 8.4 Hz, Ar–
H), 8.19 (d, 2H, J = 8.4 Hz, Ar–H), 8.21 (d, 1H,
J = 8.4 Hz, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 116.4
(Ar–C), 118.8 (Ar–C), 122.1 (Ar–C), 123.0 (Ar–C), 124.7
(Ar–C), 125.4 (Ar–C), 126.5 (Ar–C), 126.7 (Ar–C), 127.5
(Ar–C), 127.8 (Ar–C), 128.3 (Ar–C), 128.6 (Ar–C), 129.2
(Ar–C), 129.7 (Ar–C), 130.3 (Ar–C), 131.0 (Ar–C), 131.1
(Ar–C), 135.9 (Ar–C), 137.9 (Ar–C), 146.7 (Ar–C), 147.5
(Ar–C), 147.6 (Ar–C), 152.1 (Ar–C), 154.7 (Ar–C), 157.9
(Ar–C), 159.3 (C=O). Anal. Calcd for C30H18N2O4S: C,
71.70; H, 3.61; N, 5.57 %. Found C, 71.67; H, 3.58; N,
5.54 %.
3-[2-(4-Bromophenyl)-4-phenyl-3-quinolyl]sulfanyl-2H-
2-chromenone (4d)
Isolated as colorless solid; IR (KBr): 3061, 3025, 2924,
1
3-(2-(Biphenyl-4-yl)-4-phenylquinolin-3-ylthio)-2H-2-
1717 cm-1; H NMR (300 MHz, CDCl3) dH: 6.78 (s, 1H,
chromenone (4g)
Ar–H), 7.17–7.22 (m, 2H, Ar–H), 7.35–7.51 (m, 11H, Ar–
H), 7.59 (d, 2H, J = 8.1 Hz, Ar–H), 7.74–7.80 (m, 1H, Ar–
H), 8.21 (d, 1H, J = 8.1 Hz, Ar–H); 13C NMR (75 MHz,
CDCl3) dC: 116.3 (Ar–C), 119.0 (Ar–C), 122.4 (Ar–C),
123.0 (Ar–C), 124.6 (Ar–C), 125.9 (Ar–C), 126.6 (Ar–C),
126.8 (Ar–C), 127.4 (Ar–2C), 128.2 (Ar–C), 128.5 (Ar–C),
Isolated as colorless solid; IR (KBr): 3058, 3025, 2927,
1
1720 cm-1; H NMR (300 MHz, CDCl3) dH; 6.83 (s, 1H,
Ar–H), 7.06–7.18 (m, 3H, Ar–H), 7.30–7.46 (m, 10H, Ar–
H), 7.48–7.52 (m, 6H, Ar–H), 7.77 (d, 2H, J = 8.1 Hz, Ar–
H), 8.24 (d, 1H, J = 8.4 Hz, Ar–H); 13C NMR (75 MHz,
123

1620
Med Chem Res (2014) 23:1612–1621
CDCl3) dC: 116.3 (Ar–C), 119.0 (Ar–C), 122.8 (Ar–C),
124.4 (Ar–C), 126.0 (Ar–C), 126.5 (Ar–C), 126.6 (Ar–C),
126.7 (Ar–C), 127.0 (Ar–C), 127.1 (Ar–C), 127.3 (Ar–C),
127.4 (Ar–C), 128.2 (Ar–C), 128.5 (Ar–C), 128.6 (Ar–C),
129.2 (Ar–C), 129.4 (Ar–C), 129.6 (Ar–C), 130.5 (Ar–C),
130.6 (Ar–C), 136.5 (Ar–C), 137.3 (Ar–C), 139.3 (Ar–C),
140.5 (Ar–C), 141.3 (Ar–C), 147.6 (Ar–C), 152.0 (Ar–C),
154.2 (Ar–C), 158.1 (Ar–C), 161.1 (C=O). Anal. Calcd for
C36H23NO2S: C, 81.03;H, 4.34; N, 2.62 %. Found C,
81.00; H, 4.30; N, 2.60 %.
bacterial and fungal growth around the disk. Averages of
three independent determinations were recorded. The mini-
mum inhibitory concentrations (MIC) of the samples were
determined by agar dilution method. MH broth was molted
and poured in sterile tubes according to National Committee
for Clinical Laboratory Standards (NCCLS, M7-A5 January
2000). Overnight culture are grown at 37 °C by Kirby–
Bauer procedure and diluted to Muller Hinton Broth.
0.01 ml of culture was added to all the test tubes containing
serial double dilution of drugs. All the tubes were incubated
at 37 °C for 18–24 h. After incubation, the OD values were
observed by spectrophotometric method. The minimum
inhibitory concentration (MIC) was noted by seeing the
lowest concentration of the drug at which there was no
visible growth.
3-[2-(2-Naphthyl)-4-phenyl-3-quinolyl]sulfanyl-2H-2-
chromenone (4h)
Isolated as colorless solid; IR (KBr): 3059, 3023, 2929,
1
1721 cm-1; H NMR (300 MHz, CDCl3) dH: 6.72 (s, 1H,
Ar–H), 6.88 (dd, 1H, J = 7.8, 1.2 Hz, Ar–H), 7.05 (d, 2H,
J = 8.4 Hz, Ar–H), 7.26–7.55 (m, 11H, Ar–H), 7.70 (d,
2H, J = 7.2 Hz, Ar–H), 7.82 (d, 2H, J = 8.4 Hz, Ar–H),
8.11 (s, 1H, Ar–H), 8.25 (d, 1H, J = 8.4 Hz, Ar–H); 13C
NMR (75 MHz, CDCl3) dC: 116.1 (Ar–C), 118.8 (Ar–C),
123.2 (Ar–C), 124.2 (Ar–C), 125.6 (Ar–C), 126.0 (Ar–C),
126.3 (Ar–C), 126.4 (Ar–C), 126.5 (Ar–C), 126.7 (Ar–C),
127.1 (Ar–C), 127.3 (Ar–C), 127.4 (Ar–C), 127.5 (Ar–C),
128.2 (Ar–2C), 128.4 (Ar–C), 128.5 (Ar–C), 129.3 (Ar–C),
129.6 (Ar–C), 130.4 (Ar–C), 130.5 (Ar–C), 132.8 (Ar–C),
133.0 (Ar–C), 136.5 (Ar–C), 137.7 (Ar–C), 137.9 (Ar–C),
147.5 (Ar–C), 152.0 (Ar––C), 154.0 (Ar–C), 158.0 (Ar–C),
161.3 (C=O). Anal. Calcd for C34H21NO2S: C, 80.45; H,
4.17; N, 2.76 %. Found C, 80.41; H, 4.12; N, 2.72 %.
Cytotoxicity
The NIH 3T3 mouse embryonic fibroblasts line (NIH 3T3)
was obtained from National Centre for Cell Science
(NCCS), Pune, and grown in Dulbeccos Modified Eagles
Medium containing 10 % fetal bovine serum (FBS). All the
cells were maintained at 37 °C, 5 % CO2, 95 % air, and
100 % relative humidity. Maintenance cultures were pas-
sage weekly, and the culture medium was changed twice a
week.
The monolayer cells were detached with trypsin–ethyle-
nediaminetetraacetic acid to make single cell suspensions
and viable cells were counted using a hemocytometer and
diluted with medium with 5 % FBS to give final density of
19105 cells/ml. One hundred microliters per well of cell
suspension were seeded into 96-well plates at plating density
of 10,000 cells/well and incubated to allow for cell attach-
ment at 37 °C, 5 % CO2, 95 % air, and 100 % relative
humidity. After 24 h, the cells were treated with serial
concentrations of the compound 3j. That was initially dis-
solved in neat dimethylsulfoxide (DMSO) and further dilu-
ted in serum-free medium to produce various concentrations.
One hundred microliters per well of each concentration was
added to plates to obtain final concentrations of 1000, 500,
250, 125, and 63 lM. The final volume in each well was
200 ll and the plates were incubated at 37 °C, 5 % CO2,
95 % air, and 100 % relative humidity for 48 h. The med-
ium containing without samples were served as control.
Triplicate was maintained for all concentrations. After 48 h,
the cells in each well were quantified by MTT assay. Briefly,
15 ll of MTT (5 mg/ml) in phosphate buffered saline (PBS)
was added to each well and incubated at 37 °C for 4 h. The
medium with MTT was then flicked off and the formed
formazan crystals were solubilized in 100 ll of DMSO and
then measured the absorbance at 570 nm using micro plate
reader. The percentage cell viability was then calculated
with respect to positive control as follows:
Antibacterial and antifungal activity
The compounds were diluted in dimethylsulfoxide (DMSO)
with required concentrations (100 lg/disk) for bioassay.
Antimicrobial activity was evaluated by screening the
compounds by standard agar disk diffusion method against a
panel of human pathogenic microorganisms: one Gram-
positive (S. aureus ATCC 11632) and one Gram-negative
(E. coli ATCC 25922) bacteria were used for the antibac-
terial assay, while for the antifungal assay C. albicans
(ATCC 90028) was used. Microorganisms were maintained
at 37 °C on Mueller–Hinton (MH) agar slants. MH agar and
sabouraud’s broth were used to evaluate antibacterial and
antifungal activity, respectively. To make a judgment of
antibacterial and antifungal potency of the synthesized
compounds, commercial antibiotics such as ciprofloxacin
(10 lg/disk) and clotrimazole (10 lg/disk) in DMSO served
as reference standards to compare inhibition of growth. The
plate containing bacterial organism were incubated at 37 °C
for 24 h and plates containing fungal organism were incu-
bated at 28 °C for 48 h. The zone of inhibition was calcu-
lated by measuring the diameter of zone of inhibition for
123

Med Chem Res (2014) 23:1612–1621
1621
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Acknowledgments The authors thank Department of Science and
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