Camphorsulfonic acid catalysed facile tandem double Friedlander annulation protocol for the synthesis of phenoxy linked bisquinoline derivatives and discovery of antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2011.12.119

A series of phenoxy linked bisquinoline derivatives were synthesised from the Friedlander annulation of 2-(4-acetylphenoxy)-1-aryl-1-ethanones with 2-aminobenzophenone in good yields using (±)-camphor-10-sulfonic acid (CSA) as the catalyst. These compound

Full text of DOI:10.1016/j.bmcl.2011.12.119

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1643–1648
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Camphorsulfonic acid catalysed facile tandem double Friedlander
annulation protocol for the synthesis of phenoxy linked bisquinoline
derivatives and discovery of antitubercular agents
Nidhin Paul a, Muthuchamy Murugavel a, Shanmugam Muthusubramanian a, , Dharmarajan Sriram b
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science – Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2011
Revised 1 December 2011
Accepted 26 December 2011
Available online 10 January 2012
A series of phenoxy linked bisquinoline derivatives were synthesised from the Friedlander annulation of
2-(4-acetylphenoxy)-1-aryl-1-ethanones with 2-aminobenzophenone in good yields using ( )-camphor-
10-sulfonic acid (CSA) as the catalyst. These compounds were screened for their in vitro activity against
Mycobacterium tuberculosis H37Rv (MTB) and among the 23 compounds screened, 2-(3-bromophenyl)-
6-chloro-3-[4-(6-chloro-4-phenyl-2-quinolyl)phenoxy]-4-phenylquinoline (3q) and 2-(4-bromophe-
nyl)-6-chloro-3-[4-(6-chloro-4-phenyl-2-quinolyl)phenoxy]-4-phenylquinoline (3o) were found to be
the most active compounds with MIC of 1.1 and 2.2 lM against MTB. The cytotoxic effects against mouse
fibroblasts (NIH 3T3) in vitro were evaluated for 3o and 3q, which displayed no toxic effects against mouse
fibroblast cell line NIH 3T3.
Keywords:
Double Friedlander annulation
Bisquinoline
( )-Camphor-10-sulfonic acid (CSA)
Antimycobacterial activity
Mycobacterium tuberculosis
Ó 2011 Elsevier Ltd. All rights reserved.
The control of tuberculosis (TB) remains one of the most serious
challenges of human health. World Health Organization has esti-
mated that nearly a third of the world population is now infected
with Mycobacterium tuberculosis and 5–10% of the infected individ-
uals will develop active TB disease during their life time.1 There are
also approximately 400,000 new annual cases of TB caused by mul-
ti-drug-resistant strains (MDR) that are resistant to isoniazid (INH)
and rifampicin (RMP).2,3 HIV positive patients are more susceptible
to MTB with a 50-fold risk increase over HIV negative patients.4 Re-
cently, the emergence of multi-drug resistant (MDR) strains and
the global HIV pandemic have amplified the incidence of TB and
have created an urgent need for alternative drug treatments for
M. tuberculosis infection.5 At present the most widely used TB
treatment regimen DOTS (directly observed therapy short-course)
requires taking isoniazid, pyrazinamide and rifampicin for two
months followed by an additional four months of treatment with
isoniazid and rifampicin alone.6,7
an antimalarial,11 talnetant, a potential NK3 receptor antagonist
developed by GSK,12 irinotecan, an anticancer drug13 and
TAK-603, an antirheumatic drug14 (Fig. 1). The biological activity
of quinoline compounds has also been found in the form of antitu-
mor activity,15 antimicrobial and antioxidant,16 antiplasmodial
activity,17 HIV-1 Tat–TAR interaction inhibitors18 and selective
PDE4 (phosphodiesterase) inhibitors.19 Bisquinolines are com-
pounds with two quinoline nuclei bound by a covalent aliphatic
or aromatic link and this skeleton occurs in very few natural com-
pounds and pharmacologically active drugs displaying antimalarial
activity.20 The core ring of the natural bisquinoline alkaloid has
emerged as a model for synthetic drug design.21 Bisquinoline alka-
loids and their derivatives have been given special attention due to
their antimalarial and anticancer activities through the bis-interca-
lation formation22,23 with the DNA double helix.24–26 In addition,
the bisquinoline systems display very interesting biological
activities such as in vitro antileishmanial, antimicrobial (a panel
of pathogenic bacteria and fungi), cytotoxicity, b-hematin inhibi-
tory and methemoglobin (MetHb) formation activities.27 They also
act as antifilarial agent,28 triple-helix DNA intercalators and antag-
onists of immunostimulatory CpG-oligodeoxynucleotides.29 It is
pertinent to note that many recently reported monoquinolines
were screened against TB.30 The diarylquinoline drug TMC207
(Fig. 1) is in phase 2 clinical trials and is very promising against
MDR-TB.31 Recently Mital et al. reported that the bisquinolines,
Compounds containing a quinoline skeleton have been found
applications as pharmaceuticals and agrochemicals, as well as
being general synthetic building blocks.8,9 Quinoline is a ubiqui-
tous sub-structure found in various biologically active natural
products10 and is also found in various drugs such as mefloquine,
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: muthumanian2001@yahoo.com (S. Muthusubramanian).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.119

1644
N. Paul et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1643–1648
4-amino substituted 2,8-bis(trifluoromethyl)quinoline derivatives
(Fig. 1), have been found to have moderate anti-TB activity against
Mycobacterium tuberculosis (MTB) strain H37Rv.32
Ph
Et
NH
OH
HO
O
N
H
H
In this context, as a continuation of our previous work on the
discovery of novel heterocyclic compounds and their antimicrobial
activities,33 we decided to focus our attention on the synthesis and
preliminary biological evaluation against MTB of mono and
bisquinolines. To the best of our knowledge the bisquinolines have
not been screened as antitubercular agents, either as a core or
incorporated as substituent in other base structures. Herein, we
describe the synthesis and the in vitro activity against
N
CF3
N
CF3
Mefloquine
Talnetant
OMe
OMe
N
N
Et
N
M. tuberculosis strain H37Rv of
a novel structural class of
N
O
bisquinolines.
O
MeO
MeO
N
N
Our initial experiments were focused on the Friedlander
reaction of 2-(4-acetylphenoxy)-1-aryl-1-ethanones 1 with 2-ami-
nobenzophenone 2 (1:2) using different catalysts under reflux in
water–ethanol (1:1) solvent system, and the results are listed in
Table 1 (Scheme 1). It was found that ( )-camphor-10-sulfonic acid
(CSA) showed better catalytic activity among other catalysts such
as p-toluenesulfonic acid, mineral acids, FeCl3, SbCl3, ZnCl2,
SnCl2ꢀ6H2O, LaCl3ꢀ7H2O and AlCl3. Over the past few years,
( )-camphor-10-sulfonic acid (CSA) is emerging as a powerful non-
toxic, inexpensive, eco-friendly, readily available, economical and
water soluble Bronsted acid catalyst for various organic transfor-
mations.34 When 15 mol % ( )-camphor-10-sulfonic acid was used,
the reaction proceeded smoothly and gave the product 3c in 85%
yield (Table 1). Moreover, we found that the yields were obviously
affected by the amount of camphor-10-sulfonic acid loaded. When
O
N
N
CO2Et
O
Et
TAK-603
Irinotecan
HO
O
(CH2)n
Me
Me
NH
N
HN
N
OH
OMe
TMC 207
Br
F3C
CF3
N
N
CF3
CF3
2,8-bis[(trifluoromethyl)-4-amino-quinolines]
n = 2, 3, 4, 5, 7, 9
Figure 1. Chemical structures of mono and bisquinoline drugs.
Table 1
Catalyst screening for the synthesis of 3c in water–ethanol medium
Ph
O
O
O
N
O
Ph
+
N
NH2
Cl
Ac
Ph
Cl
1c
2
3c
Entry
Catalyst
Mol %
Time (h)
Yield of 3ca (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
p-TsOH
HCl
H2SO4
AlCl3
ZnCl2
50
30
30
75
75
75
35
50
35
15
5
5
5
5
6
6
6
4
4
3
2.5
4
3
3
67
54
53
28
34
22
30
35
24
85
34
57
84
FeCl3
SbCl3
SnCl2ꢀ6H2O
LaCl3ꢀ7H2O
( )-CSA
( )-CSA
( )-CSA
( )-CSA
10
20
a
Isolated yield after purification by column chromatography.The optimized condition is given in bold.
O
O
Ar
Ph
Ph
( )-CSA
1
Ac
O
O
Ar
R
R
(15 mol%)
+
N
+
R
O
Ac
water+ethanol,
reflux, 2.5 h
Ar
N
N
R
Ph
NH2
4
3
Ph
2
Ar = C6H5, 4-MeC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeOC6H4, 1-Naphthyl,
2-Naphthyl, 4-PhC6H4, 3-ClC6H4, 3-BrC6H4 3-MeOC6H4 : R = H, Cl
Scheme 1. Synthesis of phenoxy linked bisquinoline derivatives.

N. Paul et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1643–1648
1645
5 mol %, 10 mol % and 20 mol % of camphor ( )-CSA were used, the
yields were 34%, 57%, and 84%, respectively (Table 1). After opti-
mizing the reaction conditions, different bisquinolines 3a–k
(74–87%) have been obtained using this protocol (Table 2). Only
traces of monoquinolines have been noticed in the NMR spectra
of crude reaction products. However, when the reaction of 1 with
5-chloro-2-aminobenzophenone was effected under same reaction
condition, considerable amount of monoquinolines 4l–q (6–11%)
were isolated, along with the major bisquinolines 3l–q (76–83%)
(Table 2).
The structures of the phenoxy linked bisquinolines, 3 were
established from 1H, 13C and 2D NMR spectroscopic data as illus-
trated for a representative example 3n.35 In the 1H NMR spectrum
of 3n, the p-chloro substituted aryl ring H-20 proton appears as
doublet at 7.96 ppm with J = 8.4 Hz, which shows (i) H,H-COSY
with the doublet at 7.33 ppm (J = 8.4 Hz), [H-30 protons], (ii) C,H-
COSY with the signal at 130.6 ppm assignable to C-20 and (iii)
HMBC with carbon signals at 131.4, 135.4 and 153.7 ppm ascrib-
able to C-10, C-40 and C-2 respectively (Fig. 2). Further, H-30 shows
C,H-COSY with the signal at 128.6 ppm and HMBC with carbon
signal at 135.4 ppm. The quinoline H-7 proton appears as doublet
of doublet at 7.67 ppm with J = 9.0 and 1.8 Hz, which shows
H,H-COSY with doublet at 8.17 ppm (J = 9.0 Hz, H-8), C,H-COSY
with the signal at 128.7 ppm and HMBC with C-5 at 131.2 ppm.
The doublet of H-8 proton shows HMBC with ipso C-4a at
131.9 ppm, C-6 at 133.2 ppm and C-7 at 128.7 ppm. The doublet
at 7.59 is ascribable to H-5 and is having C,H-COSY correlation with
the signal at 131.2 ppm and HMBC with C-6 at 133.2 ppm and C-8a
at 147.0 ppm. The H-200 proton of phenoxy ring appears as doublet
at 6.62 ppm (J = 8.7 Hz) and gives: (i) H,H-COSY with the doublet at
7.86 ppm (J = 8.7 Hz), [H-300 protons] (ii) C,H-COSY with the signal
at 115.7 ppm and (iii) HMBC with ipso C-100 at 158.8 ppm. The H-300
proton shows C,H-COSY with carbon signal at 129.3 ppm and
HMBC with C-400 at 132.8 ppm and C-100 at 158.8 ppm. The second
quinoline ring is having a singlet at 7.63 ppm which is gives (i) C,H-
COSY with the signal at 119.5 ppm assignable to C-3000 and (ii)
HMBC with carbon signals at 126.2, 137.6 and 156.0 ppm ascrib-
able to C-4a000, C-4000 and C-2000 respectively. H-8000 proton appears
as a doublet at 8.05 ppm with J = 9.0 Hz, which shows H,H-COSY
with doublet of doublet at 7.61 ppm (J = 9.0, 2.1 Hz, H-7000) and
HMBC with C-4a000 at 126.2 ppm and C-6000 at 132.1 ppm. The struc-
tures of the monoquinolines, 4 were also established from 1H, 13C
and 2D NMR spectroscopic data as illustrated for a representative
example 4n. In the spectrum of 4n,35 the doublet at 8.17 ppm with
coupling constant 9.0 Hz is ascribable to H-8 and is having (i) H,H-
COSY with the doublet of doublet at 7.67 ppm (J = 9.0, 1.8 Hz), [H-7
proton], (ii) C,H-COSY with the signal at 131.3 ppm assignable to C-
8 and (iii) HMBC with carbon signals at 130.3 and 133.4 ppm
(Fig. 3) ascribable to C-7 and C-6, respectively. Further the doublet
of doublet at 7.67 ppm is giving (i) C, H-COSY with the signal at
130.3 ppm and (ii) HMBC with C-5 at 124.6 ppm and C-8a at
144.7 ppm. The doublet at 7.57 ppm with a coupling constant
1.8 Hz is ascribable to H-5 and is giving C,H-COSY correlation with
the carbon signal at 124.6 ppm and HMBC with signals at 133.4,
140.3 and 144.7 ppm ascribable to C-6, C-4 and C-8a respectively.
The H-20 proton of p-chloro substituted aryl ring shows doublet at
7.91 ppm with J = 8.7 Hz, which has (i) H,H-COSY with the doublet
at 7.33 ppm (J = 8.7 Hz), [H-30 protons], (ii) C,H-COSY with the sig-
nal at 130.6 ppm assignable to C-20 and (iii) HMBC with carbon sig-
nal at 135.5 ppm ascribable to C-10. The doublet at 7.33 is giving
C,H-COSY correlation with the signal at 128.4 ppm assignable to
C-30 and HMBC with carbon signals at 130.6, 135.2 and 135.5
assignable to C-20, C-40 and C-10, respectively. The acetyl methyl
hydrogens exhibit a singlet at 2.44 ppm with the corresponding
carbon signal at 26.3 ppm. These hydrogens have HMBC connec-
tions with the signal at 131.9 ppm ascribable to C-400. The doublet
at 6.53 ppm with a coupling constant 9.0 Hz is due to H-200 and is
having (i) H,H-COSY with the doublet at 7.64 ppm (J = 9.0 Hz),
[H-300 proton], (ii) C,H-COSY correlation with the signal at
115.2 ppm assignable to C-200 and (iii) HMBC with carbon signals
at 131.9 and 161.0 ppm ascribable to C-400 and C-100 respectively.
The doublet at 7.64 ppm is giving C,H-COSY correlation with car-
bon at 130.2 ppm and HMBC with C-100 and carbonyl carbon at
196.5 ppm. The mass spectra for the compounds 3o and 4o have
Table 2
Yield and antimycobacterial activities of mono and bisquinolines
Compound
Ar
R
Yielda (%)
MIC (MTB) (lM)
3
4
3
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
C6H5
4-MeC6H4
4-ClC6H4
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
81
80
85
85
87
76
74
80
81
78
85
77
81
77
80
76
83
Traceb
Traceb
Traceb
Traceb
Traceb
Traceb
Traceb
Traceb
Traceb
Traceb
Traceb
6
43.4
42.3
20.5
19.1
41.2
39.8
39.9
19.1
20.5
4.7
41.2
19.4
37.9
4.6
2.2
35.9
1.1
—
—
—
—
—
—
—
—
—
—
—
55.6
53.8
51.6
47.3
50.0
11.8
0.4
4-BrC6H4
4-MeOC6H4
1-Naphthyl
2-Naphthyl
4-PhC6H4
3-ClC6H4
3-BrC6H4
3-MeOC6H4
C6H5
4-MeC6H4
4-ClC6H4
4-BrC6H4
2-Naphthyl
3-BrC6H4
Isoniazid
8
11
7
7
6
Rifampicin
Ciprofloxacin
Ethambutol
Pyrazinamide
0.1
4.7
7.6
50.77
a
Isolated yield after purification by column chromatography.
Noticed in traces in the crude NMR spectra before purification.
b
8.05, d,
6.62, d,
J = 8.7 Hz
H
7.61, dd,
7.86, d, J =9.0 Hz
H
J = 9.0,2.1 Hz
H
J = 8.7 Hz
H
H
2''
H
H124.6
H
7.59, d, J =1.8 Hz
7'''
115.7
8'''
1'''
2'''
131.2
H
129.3 148.3
N
H
N
132.1
Cl
8a'''
O
O
6'''
5'''
4
5
158.8
1''
3'
Cl
131.9
126.2
4a
8a
3
156.0
132.8
Cl
Cl
4''
6
7
4a'''
133.2
3'''
2'
3''
137.6
2
153.7
4'''
H
H
1'
7.79, d,
J = 2.1 Hz
124.4
H
H
N
N
147.0
H
H
131.4
8
7.63, s
119.5
1
4'
135.4
Cl
7.67, dd,
130.6
H
H
H
Cl
J= 9.0, 1.8 Hz
H
128.6
8.17, d,
J = 9.0 Hz
128.7
H
H
7.33, d,
J = 8.4 Hz
7.96, d,
J = 8.4 Hz
Figure 2. Selected HMBCs and chemical shifts of 3n.

1646
N. Paul et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1643–1648
6.53, d,
7.64, d,
J =9.0 Hz
J = 9.0 Hz
H
H
3''
H
H
7.57, d, J = 1.8 Hz
2''
115.2
H
124.6
H
130.2
O
O
O
4
5
O
140.3
3
Cl
4a
8a
1''
Cl
161.0
4''
196.5
CH3
131.9
6
133.4
130.3
CH3
2'
2
7
153.4
135.5
1'
3'
4'
2.44, s
26.3
N
H
N
8
H
H
144.7
131.3
1
135.2
Cl
7.67, dd,
H
Cl
J =9.0, 1.8 Hz
H
H
8.17, d,
J = 9.0 Hz
7.91, d,
H
H
J = 8.7 Hz
7.33, d,
130.6
J =8.7 Hz
128.4
Figure 3. Selected HMBCs and chemical shifts of 4n.
H
O
H
N
O
Ph
H2N
O
-H2O
2
Ar
O
O
Ar
O
Ar
O
Ph
H
O
5
1
O
O
HN
N
Friedlander
annulation
N
-H2O
O
Ph
Ar
Ph
Ar
Ar
H
Ph
3
O
O
H
O
H
O
O
7
6
4
O
O
Scheme 2. Plausible mechanism for the formation of phenoxy linked bisquinolines 3.
study against MTB had MICs ranging from 1.1–55.6
lM and four
O
O
O
O
compounds inhibited MTB with MIC less than 10 M. In both series
l
H
Ar
Ar
3 and 4, all the compounds showed moderate to good activity ex-
cept 3a, 3b, 3e, 3f, 3g, 3k, 3m, 4l, 4m, 4n, 4o and 4p. Four com-
pounds (3j, 3n, 3o and 3q) showed good activity with MICs less
O
OH
than 10
4.7
M are more potent than the standard drug ethambutol37
(MIC: 7.6 M),
M). When compared to ciprofloxacin38 (MIC: 4.7
lM. These four compounds with MICs ranging from 1.1–
Scheme 3. Electron donation from phenoxy oxygen to acetyl carbonyl.
l
l
l
three compounds 3n, 3o and 3q were found to be more potent
against MTB. In both series compounds 3c, 3d, 3h, 3i, 3l and 4q
showed moderate activity with MIC ranging from 11.8 to 20.5.
2-(3-Bromophenyl)-6-chloro-3-[4-(6-chloro-4-phenyl-2-quinolyl)-
phenoxy]-4-phenylquinoline (3q) was found to be the most active
compound in vitro with MIC of 1.1 lM against MTB and was 4.27
times more potent than ciprofloxacin. 2-(4-Bromophenyl)-6-
chloro-3-[4-(6-chloro-4-phenyl-2-quinolyl)phenoxy]-4-phenylquin-
oline (3o) was also found to be more active with MIC of 2.2 lM
their [M+1] peaks at 723.0 (calcd. 722.0 [M+]) and 528.0 (calcd.
527.0 [M+]), respectively.
A possible reaction mechanism for the tandem double Fried-
lander reaction was proposed in Scheme 2. The condensation of
2-aminobenzophenone 2 and ketones 1 promoted by ( )-cam-
phor-10-sulfonic acid (CSA) afforded the imine 5, which tautome-
rises to furnish the enamine 6, whose subsequent cyclization
affords the monoquinoline derivatives 4. This monoquinoline 4
undergoes another Friedlander reaction with 2-aminobenzophe-
none 2 to provide the bisquinolines 3. It is to be noted that this
stepwise reaction pathway proposed is further supported by the
isolation of monoquinolines 4 as minor product. The Friedlander
annulation takes place primarily on the phenoxy end carbonyl
and not on the acetyl end, probably due to the fact that the electron
donation from the phenoxy oxygen makes the acetyl carbonyl less
electrophilic compared to the former (Scheme 3).
The compounds were screened for their in vitro antimycobacte-
rial activity against MTB in Middlebrook 7H11 agar medium
supplemented with OADC by agar dilution method for the determi-
nation of MIC in triplicates.36 The MTB clinical isolate was resistant
to isoniazid, rifampicin, ethambutol and ciprofloxacin. The mini-
mum inhibitory concentration (MIC) of the synthesized com-
pounds along with the standard drugs for comparison is reported
in Table 1. All the twenty three compounds screened in the present
Figure 4. Comparison of cytotoxicity on NIH 3T3 cells after 48 h of incubation with
compounds 3o and 3q using MTT assay.

N. Paul et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1643–1648
1647
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against MTB and was 2.14 and 3.45 times more potent than cipro-
floxacin and ethambutol, respectively.
With respect to the structure-MTB studies, introduction of sub-
stituents, particularly halogens, in the 6 and 6000-positions of bis-
quinolines is found to have enhanced the activity. In general, the
bisquinoline compounds showed better activity than the respec-
tive monoquinoline compounds.
The cytotoxicity of the compounds 3o and 3q were studied
in vitro using NIH 3T3 mouse embryonic fibroblasts cell line
(NIH 3T3) by MTT assay.39 MTT is a yellow colored water soluble
tetrazolium salt. A mitochondrial enzyme in living cells, succi-
nate-dehydrogenase, cleaves the tetrazolium ring, converting the
MTT to an insoluble purple formazan product that was read spec-
trophotometrically 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
given in Figure 4 reveals that the percentage cell viability was
decreased with increasing the concentration of both 3o and 3q.
However, the half maximal inhibitory concentration (IC50) value
determined by GraphPad Prism software was found to be
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333 lM for 3o and 887 lM for 3q. This indicates that the synthe-
sized compounds 3o and 3q are not toxic to the normal fibroblasts
(NIH 3T3).
In conclusion, we have synthesised phenoxy linked bisquino-
lines using ( )-camphor-10-sulfonic acid (CSA) as a metal free
catalyst under reflux condition via the tandem double Friedlander
annulation reaction. The simple experimental procedure, good
yield and utilization of an inexpensive and water soluble catalyst
are the advantages. These mono and bisquinolines displayed good
in vitro antimycobacterial activity against MTB. Both 3o and 3q did
not produce any cytotoxicity on NIH 3T3 cells. This lack of cyto-
toxic potential for compounds 3o and 3q makes them as potential
candidates in the treatment of MTB.
Acknowledgements
28. Tewari, S.; Chauhan, P. M. S.; Bhaduri, A. P.; Fatima, N.; Chatterjee, R. K. Bioorg.
Med. Chem. Lett. 2000, 10, 1409.
29. Strekowski, L.; Say, M.; Zegrocka, O.; Tanious, F. A.; David Wilson, W.; Manzel,
L.; Macfarlane, D. E. Bioorg. Med. Chem. 2003, 11, 1079.
The authors thank DST for funds under IRHPA program towards
high resolution NMR spectrometer and Dr. N. Adhirajan, KMCH
College of Pharmacy, Coimbatore, India for cytotoxicity studies.
Financial support from UGC, New Delhi to one of the authors, NP,
is gratefully acknowledged.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.12.119.
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phenylquinoline (3n): Isolated as colorless solid; mp 250–251 °C; IR (KBr):
3052 (C–H), 1593 (C@N) cmꢁ1 1H NMR (300 MHz, CDCl3) dH: 6.62 (d, 2H,
;
J = 8.7 Hz, Ar-H), 7.33 (d, 2H, J = 8.4 Hz), 7.38–7.40 (m, 4H, Ar-H), 7.45–7.53 (m,
6H, Ar-H), 7.59 (d, 1H, J = 1.8 Hz, Ar-H), 7.61 (dd, 1H, J = 9.0, 2.1 Hz, Ar-H), 7.63
(s, 1H, Ar-H), 7.67 (dd, 1H, J = 9.0, 1.8 Hz, Ar-H), 7.79 (d, 1H, J = 2.1 Hz, Ar-H),
7.86 (d, 2H, J = 8.7 Hz, Ar-H), 7.96 (d, 2H, J = 8.4 Hz, Ar-H), 8.05 (d, 1H,
J = 9.0 Hz, Ar-H), 8.17 (d, 1H, J = 9.0 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC:
115.7, 119.5, 124.4, 124.6, 126.2, 128.4 (2C), 128.5, 128.6, 128.7, 128.8, 129.3
(2C), 129.7, 130.1, 130.4, 130.6, 131.4, 131.9, 132.1, 132.9, 133.2, 135.4 (2C),
135.5, 137.6, 140.5, 143.5, 144.6, 147.0, 148.3, 153.7, 156.0, 158.8. Anal. Calcd
for C42H25Cl3N2O: C, 74.18; H, 3.71; N, 4.12%. Found C, 74.15; H, 3.68; N, 4.17%.
1-(4-[6-Chloro-2-(4-chlorophenyl)-4-phenyl-3-quinolyl]oxyphenyl)-1-
ethanone (4n): Isolated as colorless solid; mp 220–221 °C; IR (KBr): 3068 (C–
H), 1677 (C@O), 1594 (C@N) cmꢁ1 1H NMR (300 MHz, CDCl3) dH: 2.44 (s, 3H,
;
CH3), 6.53 (d, 2H, J = 9.0 Hz, Ar-H), 7.26–7.29 (m, 3H, Ar-H), 7.33 (d, 2H,
J = 8.7 Hz, Ar-H), 7.37–7.39 (m, 2H, Ar-H), 7.57 (d, 1H, J = 1.8 Hz, Ar-H), 7.64 (d,
2H, J = 9.0 Hz, Ar-H), 7.67 (dd, 1H, J = 9.0, 1.8 Hz, Ar-H), 7.91 (d, 2H, J = 8.7 Hz,
Ar-H), 8.17 (d, 1H, J = 9.0 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 26.3, 115.2,
124.6, 128.4, 128.6 (2C), 128.7, 129.6, 130.2, 130.3, 130.6 (2C), 131.3, 131.9,
133.4, 135.2, 135.5, 140.3, 143.2, 144.7, 153.4, 161.0, 196.5. Anal. Calcd for
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C29H19Cl2NO2: C, 71.91; H, 3.95; N, 2.89%. Found C, 71.88; H, 3.90; N, 2.94%.