Synthesis and identification of β-aryloxyquinolines and their pyrano[3,2-c]chromene derivatives as a new class of antimicrobial and antituberculosis agents

Article abstract of DOI:10.1016/j.ejmech.2011.06.022

A new class of β-aryloxyquinolines 3a-i and their pyrano[3,2-c] chromene derivatives 6a-r incorporating a validated molecular target has been synthesized via a nucleophilic displacement and a one-pot multicomponent reaction respectively. In vitro antimicr

Full text of DOI:10.1016/j.ejmech.2011.06.022

European Journal of Medicinal Chemistry 46 (2011) 4192e4200
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and identification of b-aryloxyquinolines and their pyrano[3,2-c]
chromene derivatives as a new class of antimicrobial and antituberculosis agents
,
Divyesh C. Mungra a, Manish P. Patel a, Dhanji P. Rajani b, Ranjan G. Patel a
*
a Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, 388120 Gujarat, India
b Microcare Laboratory, Surat 395001, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of b-aryloxyquinolines 3aei and their pyrano[3,2-c]chromene derivatives 6aer incorpo-
Received 18 October 2010
Received in revised form
10 June 2011
Accepted 16 June 2011
Available online 23 June 2011
rating a validated molecular target has been synthesized via a nucleophilic displacement and a one-pot
multicomponent reaction respectively. In vitro antimicrobial activity of the synthesized compounds were
investigated against a representative panel of pathogenic strains specifically Bacillus subtilis, Clostridium
tetani, Streptococcus pneumoniae, Escherichia coli, Salmonella typhi, Vibrio cholera, Aspergillus fumigatus
and Candida albicans. Compounds 3c, 3e, 3g, 6f, 6l and 6q exhibited excellent antibacterial activity while
compound 6p exhibited more potent antifungal activity than that of first line standard drugs. In vitro
antituberculosis activity was evaluated against Mycobacterium tuberculosis H37Rv and compound 6f is
emerged as the promising antimicrobial member with better antitubercular activity. Majority of the
compounds appears to be better antimicrobials but poor antituberculars.
Keywords:
b-Aryloxyquinoline
Pyrano[3,2-c]chromene
Multicomponent reaction
Antimicrobial activity
Antituberculosis activity
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
antimicrobial [13], antituberculosis [14], antimalarial [15,16], anti-
inflammatory [17], anti-cancer [18], antihypertensive [19], tyroki-
An alarming increment in pathogenic resistance to existing
drugs is a serious problem with antimicrobial therapy and neces-
sitates continuing research into new classes of antimicrobials [1].
According to the World Health Organization, one third of human
population is infected by Mycobacterium tuberculosis and approxi-
mately two million people die from tuberculosis annually. The cure
of tuberculosis (isoniazid and rifampicin) [2] is remote from ideal
due to its time-consuming nature. Tuberculosis coupled with HIV
infection constructs a lethal combination. Tuberculosis is currently
to blame for 13% of the number of deaths due to HIV infection [3].
On the core of these reports, the discovery of new therapeutical
targets and the development of newer antimicrobial and antitu-
bercular drugs are urgently looked-for. Consequently, this spot of
research is carrying an immense significance and keeps on
attracting much interest of contemporary medicinal chemistry.
Over the past few years, we have been principally engrossed in
the synthesis of quinoline incorporating structures for antimicro-
bial evaluations [4e12] on the premise that the quinoline moiety is
found in a large variety of naturally occurring compounds and also
chemically useful synthons bearing diverse bioactivities like
nase PDGF-RTK inhibiting agents [20] and anti-HIV [21,22].
It has been well-established that presence of aryl ring appended
by ether linkage at C-2 position of quinoline moiety is highly active
against M. tuberculosis H37Rv and plays a pivotal role in develop-
ment of new antituberculosis drugs [23] and in consequence,
emerged as a validated molecular target. On the other hand, there
are much sound reports expressing that pyrano[3,2-c]chromene is
a class of vital heterocycles with a wide range of biological effects
[24] such as spasmolytic, diuretic, anticoagulant, anti-cancer and
anti-anaphylactic activity [25]. Further fused chromene derivatives
have a relatively broad spectrum with high activity profile against
various bacteria and fungi [26] along with antiproliferative [27],
sexpheromonal [28], mutagenicitical [29], antitumoral [30], anti-
viral [31,32] and central nervous system activities [33]. Despite the
immense pharmacological effects of
b-aryloxyquinolines and pyr-
ano[3,2-c]chromene derivatives, no large systematic study has
been hitherto undertaken either to focus the synthesis of
a heterocycle incorporating both of these biolabile nuclei or to
optimize the fused chromene antimicrobials against MTB.
The molecular manipulation of promising lead compounds is still
an organized and chief approach to widen the vicinity of medicine
research. It involves an initiative to merge the separate pharmaco-
phoricgroupsof analogous activityintoone compound, thus making
structural changes in the biological activity. An attempt has been
* Corresponding author. Tel.: þ91 02692 226856.
E-mail address: patelranjanben@yahoo.com (R.G. Patel).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.06.022

D.C. Mungra et al. / European Journal of Medicinal Chemistry 46 (2011) 4192e4200
4193
through to undertake the synthesis of
b
-aryloxyquinolines and their
material 2-chloro-3-formylquinolines 1aec were prepared accord-
ing to literature procedure [34] by VilsmeiereHaack reaction and
dihydropyrano[3,2-c]chromene derivatives with the assumption
that the assimilation of more than one bioactive moieties into
a single scaffold may produce novel heterocycles with fascinating
antimicrobial activities along with efficacious bioactivity to combat
tuberculosis, a global health emergency.
conveniently converted to
b-aryloxyquinoline-3-carbaldehydes
3aei by nucleophilic displacement of chloro group at C2 in 1aec
withphenols 2aecinrefluxingdimethylformamideusinganhydrous
potassium carbonate as a base. Subsequently, the one-pot three
Intheradianceof theaforementionedfactsandasaprolongationof
our investigations on the synthesis of biologically active heterocyclic
compounds [4e12], we were provoked to synthesize new b-arylox-
yquinolines and their pyrano[3,2-c]chromene derivatives incorpo-
rating avalidated molecular target and evaluate them as antimicrobial
and antitubercular agents. This communication additionallyenable us
to match up between antimicrobialand antimycobacterialactivities of
component cyclocondensation of a series of b-aryloxyquinoline-3-
carbaldehydes 3aei, malononitrile 4 and 4-hydroxycoumarins 5a,b
in ethanol containing a catalytic amount of piperidine afforded the
target compounds 6aer in good to excellent yields (Table 1). The
formation of compounds 6aer may proceed via initial formation of
an intermediate afforded by Knoevenagel condensation of aldehyde
with malononitrilewhich wouldundergointermolecularcyclization,
driven through the nucleophilic attack of 4-hydroxycoumarin in
basic reaction conditions [35].
two structurallyallied candidates specifically b-aryloxyquinolines and
their dihydropyrano[3,2-c]chromene derivatives.
2. Chemistry
3. Pharmacology
The reaction sequences employed for synthesis of title
compounds 3aei and 6aer are depicted in Scheme 1. The starting
The MICs of synthesized compounds were carried out by broth
microdilution method according to National Committee for
Scheme 1. Synthesis of 6-(un)-substituted-2-(4-(un)-substituted-aryloxy)quinoline-3-carbaldehude 3a-i and 2-amino-5-oxo-9-(un)-substituted-4-(6-(un)-substituted-2-2(4-(un)-
substituted aryloxy)quinolin-3-yl)-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile 6a-r. Reagents and reaction conditions. (a) DMF.K2CO3. Reflux, 3.5 h (b) Piperidine, Ethanol,
Reflux, 1.5 h.

4194
D.C. Mungra et al. / European Journal of Medicinal Chemistry 46 (2011) 4192e4200
bearyloxyquinolines 3aei and their dihydropyrano[3,2-c]chromene derivatives 6aer.
Table 1
Physicochemical characteristics of
Compd.
R1
R2
R3
Formula (Mw)
Mp (ꢀC)
Yielda%
Analysis (%) calc./found
C
H
N
3a
3b
3c
3d
3e
3f
H
H
e
C16H11NO2 (249.08)
C17H13NO2 (263.09)
C16H10ClNO2 (283.04)
C17H13NO2 (263.09)
C18H15NO2 (277.11)
C17H12ClNO2 (297.06)
C17H13NO3 (279.09)
C18H15NO3 (293.11)
C17H12ClNO3 (313.05)
C28H17N3O4 (459.12)
C29H19N3O4 (473.14)
C28H16ClN3O4 (493.08)
C29H19N3O4 (473.14)
C30H21N3O4 (487.15)
C29H18ClN3O4 (507.10)
C29H19N3O5 (489.13)
C30H21N3O5 (503.15)
C29H18ClN3O5 (523.09)
C29H19N3O4 (473.14)
C30H21N3O4 (487.15)
C29H18ClN3O4 (507.10)
C30H21N3O4 (487.15)
C31H23N3O4 (501.17)
C30H20ClN3O4 (521.11)
C30H21N3O5 (503.15)
C31H23N3O5 (517.16)
C30H20ClN3O5 (537.11)
126
77
62
74
69
80
67
78
62
65
74
77
80
81
73
82
65
71
79
63
79
68
79
83
80
74
68
78
77.10
77.39
77.55
77.82
67.74
67.52
77.55
77.81
77.96
78.15
68.58
66.83
73.11
73.00
73.71
73.90
65.08
65.34
73.20
73.42
73.56
73.45
68.09
67.99
73.56
73.69
73.91
73.88
68.58
68.69
71.16
71.38
71.56
71.82
66.48
66.22
73.56
73.69
73.91
74.21
68.58
68.89
73.91
74.12
74.24
74.19
69.03
68.85
71.56
71.84
71.94
71.79
66.98
67.23
4.45
4.52
4.98
5.24
3.55
3.76
4.98
5.26
5.45
5.24
4.06
3.96
4.69
4.90
5.15
5.22
3.86
4.02
3.73
3.59
4.04
4.28
3.27
3.02
4.04
4.25
4.34
4.12
3.57
4.77
3.91
3.80
4.20
3.95
3.46
3.68
4.04
4.20
4.34
4.29
3.57
3.68
4.34
4.65
4.62
4.82
3.86
3.69
4.20
4.15
4.48
4.20
3.75
4.02
5.62
5.68
5.32
5.04
4.94
4.68
5.32
5.66
5.05
5.29
4.70
4.86
5.02
5.35
4.78
4.94
4.46
4.78
9.15
8.95
8.87
8.78
8.51
8.84
8.87
8.96
8.62
8.46
8.27
8.53
8.58
8.37
8.35
8.48
8.02
7.84
8.87
8.60
8.62
8.44
8.27
8.11
8.62
3.69
8.38
8.01
8.05
7.83
8.35
8.09
8.12
8.38
7.81
7.65
H
CH3
Cl
e
137ꢁ139
165
H
e
CH3
CH3
CH3
OCH3
OCH3
OCH3
H
H
e
154
CH3
Cl
e
179
e
154
3g
3h
3i
H
e
182ꢁ184
146ꢁ148
180
CH3
Cl
e
e
6a
6b
6c
6d
6e
6f
H
H
234
H
CH3
Cl
H
225ꢁ227
263
H
H
CH3
CH3
CH3
OCH3
OCH3
OCH3
H
H
H
249
CH3
Cl
H
281ꢁ283
264
H
6g
6h
6i
H
H
237
CH3
Cl
H
269ꢁ272
284
H
6j
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
289
6k
6l
H
CH3
Cl
265
H
256ꢁ258
227
6m
6n
6o
6p
6q
6r
CH3
CH3
CH3
OCH3
OCH3
OCH3
H
CH3
Cl
256
269
H
266e268
281
CH3
Cl
239
a
All the yields are on isolated basis.
Clinical Laboratory Standards (NCCLS) [36]. Antibacterial activity
was screened against three Gram positive (Bacillus subtilis MTCC
441, Clostridium tetani MTCC 449, Streptococcus pneumoniae MTCC
1936) and three Gram negative (Escherichia coli MTCC 443,
Salmonella typhi MTCC 98, Vibrio cholerae MTCC 3906) bacteria by
using ampicillin as a standard antibacterial drug. Antifungal
activity was screened against two fungal species (Aspergillus
fumigatus MTCC 3008 and Candida albicans MTCC 227) where
griseofulvin and nystatin used as standard antifungal drugs. The
antimicrobial screening data are shown in Table 2. All MTCC
cultures were collected from Institute of Microbial Technology,
Chandigarh and tested against above mentioned known drugs.
Mueller Hinton broth was used as nutrient medium to grow and
dilute the drug suspension for the test. Inoculum’s size for test
strain was adjusted to 108 CFU (Colony Forming Unit) per milliliter
by comparing the turbidity. DMSO was used as diluents to get
desired concentration of compounds to test upon standard
bacterial strains.
In vitro antituberculosis activity of all the newly synthesized
compounds against M. tuberculosis H37Rv strain was determined by
using LowensteineJensen medium (conventional method) as
described by Rattan [37] and the observed results are presented in
Table 3 in the form of % inhibition, relative to that of standard
antitubercular drug isoniazid. Of the compounds studied, three
compounds those exhibited highest % inhibition, were again
screened to get their MIC values (Table 4).

D.C. Mungra et al. / European Journal of Medicinal Chemistry 46 (2011) 4192e4200
4195
Table 2
Table 4
In vitro antimicrobial activity of
b
earyloxyquinolines 3aei and their dihydropyrano
In vitro antituberculosis activity of title compounds exhibiting higher % inhibition
[3,2-c]chromene derivatives 6aer MICs,
m
g/mL.
Gram negative bacteria Fungi
E.C. S.T. V.C. A.F.
MTCC MTCC MTCC MTCC MTCC MTCC MTCC
against M. tuberculosis H37Rv (MICs, mg/mL).
Compd. Gram positive bacteria
Compd.
% Inhibition
MIC
3a
3f
6f
95
93
98
99
260
310
250
B.S.
C.T.
S.P.
C.A.
MTCC
227
Isoniazid
0.20
441
449
1936
443
98
3906
3008
3a
3b
3c
3d
3e
3f
3g
3h
3i
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
Ampi.
Grise.
Nyst.
1000
500
200
250
250
500
100
250
200
200
200
100
200
100
200
100
200
500
500
250
250
200
1000
500
100
250
250
250
n. t.
n. t.
500
250
500
200
200
500
250
500
200
250
250
200
250
200
250
200
500
500
250
500
500
200
500
250
500
250
500
250
n. t.
n. t.
500
250
62.5
500
200
250
200
500
250
250
250
500
250
200
200
200
200
500
500
250
200
250
1000
500
250
250
500
100
n. t.
n. t.
500
100
100
200
50
500
100
200
200
100
100
100
250
200
250
200
250
200
200
100
100
500
250
500
250
50
200
500
250
500
200
250
100
n. t.
n. t.
500
250
500
250
200
500
200
500
200
250
250
250
200
200
62.5
250
500
500
250
250
500
250
500
200
250
500
500
100
n. t.
n. t.
>1000 >1000
500 500
>1000 250
uted aryloxy)quinolin-3-yl)-4,5-dihydropyrano[3,2-c]chromene-3-
carbonitrile 6aer have been synthesized substantially through
the synthetic route as illustrated in Scheme 1. The structures of all
the newly synthesized compounds were confirmed by FTIR, 1H
NMR, 13C NMR, mass and elemental analysis. The IR spectrum of
compound 3aei exhibited characteristic absorption band in the
range 1230e1240 cmꢁ1 is mainly attributed to the presence of
ether linkage. Absorption band around 1710e1725 cmꢁ1 confirms
the presence of aldehyde functionality as well as absorption band
around 3000e3035 cmꢁ1 is due to aromatic CeH stretching. The 1H
NMR spectra of compound 3aei exhibited the presence of the
500
1000
1000
250
500
500
250
62.5
250
200
200
200
250
100
200
250
100
250
250
200
250
100
100
500
200
500
62.5
250
100
n. t.
n. t.
>1000 1000
1000
1000
500
500
500
1000
1000
1000
500
250
500
250
500
250
500
500
1000
500
aldehyde proton as a singlet around
protons resonate as multiplets at around
NMR spectrum is in well agreement with the structure assigned. In
the 13C NMR spectra, signals around
120.20e161.47 ppm are
attributed to aromatic carbons and the carbonyl carbon was
observed at about 190.49 ppm. The IR spectrum of title
d
10.50 ppm and aromatic
d
>1000 1000
>1000 1000
>1000 >1000
7.11e8.96 ppm. The 13C
500
500
500
500
d
>1000 >1000
500
500
500
500
500
n. t.a
100
100
500
250
100
200
500
n. t.
500
100
d
compounds 6aer revealed the presence of lactone, cyano and
amino groups due to the appearance of absorption bands at around
1730, 2210 and 3450 & 3350 cmꢁ1 respectively. Its 1H NMR spec-
trum indicated the presence of one singlet in the range
d
4.86e4.96 ppm of eCH proton and the disappearance of a singlet
from 10.50 ppm of eCHO clearly confirmed the cyclization of
Knoevenagel intermediate. Moreover, singlet in the range
d
B.S.: Bacillus subtilis, C.T.: Clostridium tetani, S.P.: Streptococcus pneumoniae, E.C.:
Escherichia coli, S.T.: Salmonella typhi, V.C.: Vibrio cholerae, A.F.: Aspergillus fumigatus,
C.A.: Candida albicans, MTCC: Microbial Type Culture Collection, Ampi.: Ampicillin,
Grise.: Griseofulvin, Nyst.: Nystatin.
d
6.80e7.07 ppm and multiplets in the range d 6.84e8.49 ppm
appeared for amine and aromatic protons respectively. In the 13C
a
NMR spectral data of the title compounds 6aer, most characteristic
n. t. not tested.
signal around
chromene ring and the carbonyl carbon was observed at around
160.00 ppm. The signal at around 56.00 ppm is assigned to
carbon attached with carbonitrile while signals around
102.11e159.86 ppm are attributed to all the aromatic carbons of
d 34.00 ppm indicated the formation of pyrano[3,2-c]
4. Results and discussion
d
d
4.1. Analytical results
d
compounds 6aer.
A series of two allied candidates 6-(un)-substituted-2-(4-(un)-
substituted-aryloxy)quinoline-3-carbaldehyde 3aei and 2-amino-
5-oxo-9-(un)-substituted-4-(6-(un)-substituted-2-(4-(un)-substit-
The obtained elemental analysis values are in good agreement
with theoretical data. Mass spectra of all the title compounds gave
expected Mþ peak corresponding with proposed molecular mass.
Physicochemical properties of all the derivatives are shown in
Table 1.
Table 3
In vitro antituberculosis activity (% Inhibition) of
dihydropyrano[3,2-c]chromene derivatives 6aer against M. tuberculosis H37Rv (at
b-aryloxyquinolines 3aei and their
4.2. Biological results
concentration 250
Compd.
m
g/mL).
% Inhibition
Reviewing of the antibacterial activities of b-aryloxyquinolines
and their dihydropyrano[3,2-c]chromene derivatives (Table 2)
indicate that compound 3e (R1 ¼ CH3, R2 ¼ CH3) and 6l (R1 ¼ H,
Compd.
% Inhibition
3a
3b
3c
3d
3e
3f
3g
3h
3i
6a
6b
6c
6d
6e
95
74
64
62
84
93
42
23
54
21
10
32
52
74
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
98
11
24
32
91
45
23
10
24
38
45
61
27
99
R2 ¼ Cl, R3 ¼ CH3) showed highest activity i.e. 50
mg/mL against E.
coli and S. typhi respectively. Interestingly, compound 3c (R1 ¼ H,
R2 ¼ Cl) showed MIC 200
m
g/mL and 500 g/mL against B. subtilis
m
and C. tetani respectively and upon cyclocondensation with malo-
nonitrile and 4-hydroxycoumarin resulted compound 6c (R1 ¼ H,
R2 ¼ Cl, R3 ¼ H) which have been found to possess increased
potency i.e. 100 mg/mL against B. subtilis and 200 mg/mL against C.
tetani. In case of inhibiting Gram negative bacteria E. coli,
compound 3g (R1 ¼ OCH3, R2 ¼ H) and 6q (R1 ¼ OCH3, R2 ¼ CH3,
R3 ¼ CH3) displayed better activity i.e. 62.5
mg/mL while compound
6f (R1 ¼ CH3, R2 ¼ Cl, R3 ¼ H) displayed better activity against Gram
Isoniazid

4196
D.C. Mungra et al. / European Journal of Medicinal Chemistry 46 (2011) 4192e4200
negative bacteria V. cholerae. The majority of compounds are found
to possess higher potency as compared to standard bactericidal
ampicillin against Gram positive bacteria B. subtilis.
chromatography (TLC, on aluminium plates coated with silica gel
60 F254, 0.25 mm thickness, Merck) carried on fluorescent coated
plates and detection of the components was made by exposure to
iodine vapors or UV light. Melting points were determined in open
capillaries and the declared values are not corrected. Infrared
spectra were recorded on Shimadzu FTIR 8401 spectrophotometer
using potassium bromide pellets in the range 4000e400 cmꢁ1 and
frequencies of only characteristic peaks are expressed in cmꢁ1. 1H &
13C Nuclear Magnetic Resonance spectra were recorded in DMSO-d6
on a Bruker Avance 400F (MHz) spectrometer (Bruker Scientific
Corporation Ltd., Switzerland) using residual solvent signal as an
internal standard at 400 MHz and 100 MHz respectively. Chemical
shifts are reported in parts per million (ppm). Mass spectra were
scanned on a Shimadzu LCMS 2010 spectrometer (Shimadzu,
Tokyo, Japan) at Oxygen Healthcare Research Pvt. Ltd., Ahmedabad.
Elemental analyses were performed by PerkineElmer 2400 series-
II elemental analyzer (PerkineElmer, USA) at Sophisticated
Instrumentation Centre for Applied Research & Training (SICART),
Vallabh Vidyanagar and all compounds are within ꢂ0.4% of the
theoretical compositions. Yields are not optimized. Ampicillin,
griseofulvin, nystatin and isoniazid were commercial.
Antifungal study revealed that all the synthesized
b-arylox-
yquinolines and their dihydropyrano[3,2-c]chromene derivatives
have poor activity against Aspergillus fumigatus. In comparison with
standard fungicidal griseofulvin, among
b-aryloxyquinolines,
compound 3c (R1 ¼ H, R2 ¼ Cl), 3d (R1 ¼ CH3, R2 ¼ H), 3h
(R1 ¼ OCH3, R2 ¼ CH3) and among dihydropyrano[3,2-c]chromenes,
compound 6a (R1 ¼ H, R2 ¼ H, R3 ¼ H), 6c (R1 ¼ H, R2 ¼ Cl, R3 ¼ H),
6o (R1 ¼ CH3, R2 ¼ Cl, R3 ¼ CH3), 6p (R1 ¼ OCH3, R2 ¼ H, R3 ¼ CH3)
and 6q (R1 ¼ OCH3, R2 ¼ CH3, R3 ¼ CH3) displayed better activity
against C. albicans.
The encouraging results from the antimicrobial studies
prompted us to go for the preliminary screening of the title
compounds for their in vitro antituberculosis activity against
M. tuberculosis H37Rv. Of the compounds screened for antituber-
culosis activity, compound 3a (R1 ¼ H, R2 ¼ H) and compound 6f
(R1 ¼ CH3, R2 ¼ Cl, R3 ¼ H) found to possess better activity against
M. tuberculosis H37Rv. Antitubercular potency of compound 3f
(R1 ¼ CH3, R2 ¼ Cl) i.e. 93% was found to get intensified to 98%, upon
cyclocondensation with malononitrile and unsubstituted 4-
hydroxycoumarin which results compound 6f (R1 ¼ CH3, R2 ¼ Cl,
R3 ¼ H). MIC values of three compounds those exhibited highest %
6.1.1. General procedure for the synthesis of 6-(un)-substituted-2-
(4-(un)-substituted-aryloxy)quinoline-3-carbaldehyde 3aei
A 100 mL round bottomed flask, fitted with a reflux condenser,
was charged with a mixture of 2-chloro-3-formylquinoline 1aec
(5 mmol), appropriate phenol 2aec (5 mmol), anhydrous potas-
sium carbonate (10 mmol) in dimethylformamide (5 mL). The
mixture was heated under reflux for 3.5 h and the progress of the
reaction was monitored by TLC. After the completion of reaction
(as evidenced by TLC), the reaction mixture was cooled to room
temperature and then poured into chilled water (50 mL) with
continuous stirring followed by neutralization with 1.5 N HCl until
pH 7 resulted. The solid mass separated was collected by filtra-
tion, washed well with water, dried and crystallized from ethyl
acetate.
inhibition, are found to be 260
R2 ¼ H), 310 g/mL for 3f (R1 ¼ CH3, R2 ¼ Cl) and 250
(R1 ¼ CH3, R2 ¼ Cl, R3 ¼ H).
m
g/mL for compound 3a (R1 ¼ H,
m
m
g/mL for 6f
Compound 6f (R1 ¼ CH3, R2 ¼ Cl, R3 ¼ H) has been emerged as
the promising antimicrobial member along with better antituber-
cular activity (Table 2,3 and 4) of this series of compounds. Unfor-
tunately, majority of compounds showed poor inhibition of
M. tuberculosis growth.
5. Conclusion
In this paper, we report the synthesis, antimicrobial and anti-
tuberculosis activity of two structurally correlated heterocyclic
candidates i.e.
b
-aryloxyquinolines 3aei and their pyrano[3,2-c]
6.1.1.1. 2-Phenoxyquinoline-3-carbaldehyde (3a). IR (KBr, nmax, cmꢁ1):
3030 (ArCeH), 1685 (C]O stretching), 1235 cmꢁ1 (CeOeC ether
chromene derivatives 6aer. The engaged synthetic strategy effi-
ciently involves the multicomponent reaction (MCR) approach and
allows the construction of relatively complicated nitrogen and
oxygen carrying heterocyclic system as well as the introduction of
stretching). 1H NMR (400 MHz, DMSO-d6):
d
7.29e8.93 (m, 10H,
AreH), 10.51 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6)
d: 120.61,
122.43, 125.36, 125.66, 126.28, 127.35, 130.09, 130.56, 133.52, 141.79,
various substituted
b-aryloxyquinolines, the validated molecular
148.06, 153.49, 160.54 (13C, AreC),189.33 (CHO); MS (m/z): 249 (Mþ).
target at 4- position of pyrano[3,2-c]chromene. Reviewing and
comparing the activity data (Table 2,3 and 4), it is worthy to
mention that the biological activity of the target compounds
depends not only on the bicyclic heteroaromatic pharmacophore
appended through ether linked aryl ring but also on the nature of
the peripheral substituents and may also upon their spatial rela-
tionship and positional changes. Of the compounds studied, we
identified the most effective antimicrobial member possessing
better antituberculosis activity proved to be having methyl
substituted quinoline, ether linked 4-chloro substituted phenyl ring
and unsubstituted pyrano[3,2-c]chromene ring. These studies
provide insight to defining the ample scope and boundaries of both
allied candidates for further detailed preclinical investigations.
6.1.1.2. 2-(4-Methylphenoxy)quinoline-3-carbaldehyde (3b). IR (KBr,
nmax, cmꢁ1): 3020 (ArCeH), 1710 (C]O stretching), 1230 cmꢁ1
(CeOeC ether stretching). 1H NMR (400 MHz, DMSO-d6):
d
2.50 (s,
3H, CH3), 7.26e8.90 (m, 9H, AreH), 10.57 (s, 1H, CHO). 13C NMR
(100 MHz, DMSO-d6) : 21.31 (CH3), 120.23, 122.47, 124.82, 125.72,
d
126.32, 127.30, 130.40, 130.86, 132.41, 140.65, 148.45, 153.96, 160.12
(13C, AreC), 190.87 (CHO); MS (m/z): 263 (Mþ).
6.1.1.3. 2-(4-Chlorophenoxy)quinoline-3-carbaldehyde (3c). IR (KBr,
nmax, cmꢁ1): 3025 (ArCeH), 1720 (C]O stretching), 1230 cmꢁ1
(CeOeC ether stretching). 1H NMR (400 MHz, DMSO-d6):
d
7.22e8.96 (m, 9H, AreH), 10.59 (s, 1H, CHO). 13C NMR (100 MHz,
DMSO-d6) d: 120.21, 122.52, 124.21, 125.70, 126.41, 127.34, 130.92,
6. Experimental
130.99, 132.56, 140.41, 148.82, 154.25, 160.00 (13C, AreC), 189.42
(CHO); MS (m/z): 283 (Mþ), 285 (Mþ2).
6.1. Chemistry
6.1.1.4. 6-Methyl-2-phenoxyquinoline-3-carbaldehyde (3d). IR (KBr,
nmax, cmꢁ1): 3015 (ArCeH), 1715 (C]O stretching), 1240 cmꢁ1
All reactions were performed with commercially available
reagents and they were used without further purification. Organic
solvents were purified by standard methods [38] and stored over
molecular sieves. All reactions were monitored by thin-layer
(CeOeC ether stretching). 1H NMR (400 MHz, DMSO-d6):
d
2.53 (s,
3H, CH3), 7.19e8.94 (m, 9H, AreH), 10.50 (s, 1H, CHO). 13C NMR
(100 MHz, DMSO-d6) : 21.48 (CH3), 120.20, 122.63, 124.08, 125.26,
d

D.C. Mungra et al. / European Journal of Medicinal Chemistry 46 (2011) 4192e4200
4197
126.32, 127.76, 130.44, 130.88, 132.00, 140.61, 147.06, 153.81, 160.16
(ArCeH), 2210 (C^N stretching), 1730 (C]O lactone stretching),
1235 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
(13C, AreC), 191.09 (CHO); MS (m/z): 263 (Mþ).
d6):
d
4.92 (s, 1H, chromene H4), 6.91 (s, 2H, NH2), 7.03e8.43 (m,
: 34.01 (chromene C4),
6.1.1.5. 6-Methyl-2-(4-methylphenoxy)quinoline-3-carbaldehyde (3e).
IR (KBr, nmax, cmꢁ1): 3030 (ArCeH), 1710 (C]O stretching), 1225 cmꢁ1
14H, AreH). 13C NMR (100 MHz, DMSO-d6)
d
56.15 (CeCN), 102.67, 113.10, 118.12, 120.40, 121.91, 122.00, 125.88,
125.96, 126.70, 127.00,127.76,128.28, 130.55, 133.36, 134.56, 136.94,
139.52, 145.70, 151.94, 152.12, 154.60, 158.59, 159.37 (23C, AreC),
160.39 (C]O); MS (m/z): 459 (Mþ).
(CeOeC ether stretching). 1H NMR (400 MHz, DMSO-d6):
d
2.39 (s,
3H, CH3), 2.57 (s, 3H, CH3), 7.11e8.90 (m, 8H, AreH),10.48 (s,1H, CHO).
13C NMR (100 MHz, DMSO-d6)
: 20.09 (CH3), 21.42 (CH3), 120.26,
d
122.47, 124.98, 125.66, 126.00, 127.18, 130.04, 130.76, 132.07, 140.43,
146.14, 153.42, 161.47 (13C, AreC), 190.49 (CHO); MS (m/z): 277 (Mþ).
6.1.2.2. 2-Amino-5-oxo-4-(2-(4-methylphenoxy)quinolin-3-yl)-4,5-
dihydropyrano [3,2-c]chromene-3-carbonitrile (6b). IR (KBr, nmax
,
6.1.1.6. 2-(4-Chlorophenoxy)-6-methylquinoline-3-carbaldehyde (3f).
cmꢁ1): 3440 & 3355 (asym. & sym. stretching of eNH2), 3025
(ArCeH), 2215 (C^N stretching), 1725 (C]O lactone stretching),
1230 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
IR (KBr, nmax
1230 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-d6):
2.50 (s, 3H, CH3), 7.11e8.91 (m, 8H, AreH), 10.55 (s, 1H, CHO). 13
NMR (100 MHz, DMSO-d6) : 21.55 (CH3), 121.06, 122.35, 124.48,
,
cmꢁ1): 3000 (ArCeH), 1695 (C]O stretching),
d
C
d6):
d
2.29 (s, 3H, CH3), 4.98 (s, 1H, chromene H4), 6.94 (s, 2H, NH2),
: 20.83
d
6.96e8.37 (m, 13H, AreH). 13C NMR (100 MHz, DMSO-d6)
d
125.86, 126.37, 127.00, 131.42, 131.89, 132.88, 140.60, 147.35, 153.36,
(CH3), 33.84 (chromene C4), 56.19 (CeCN), 102.78, 113.45, 117.08,
119.76, 121.44, 122.86, 125.12, 125.48, 126.25, 127.00, 127.11, 128.16,
130.25, 133.39, 134.04, 136.45, 139.43, 145.27, 151.74, 152.72, 154.82,
159.34, 159.86 (23C, AreC), 160.22 (C]O); MS (m/z): 473 (Mþ).
161.39 (13C, AreC), 190.26 (CHO); MS (m/z): 297 (Mþ), 299 (Mþ2).
6.1.1.7. 6-Methoxy-2-phenoxyquinoline-3-carbaldehyde
(KBr, nmax, cmꢁ1): 3010 (ArCeH), 1715 (C]O stretching), 1235 cmꢁ1
(CeOeC ether stretching). 1H NMR (400 MHz, DMSO-d6):
3.97 (s,
3H, OCH3), 7.14e8.96 (m, 9H, AreH), 10.58 (s, 1H, CHO). 13C NMR
(100 MHz, DMSO-d6) : 56.31 (OCH3),120.63,122.00,124.16,125.65,
(3g). IR
d
6.1.2.3. 2-Amino-5-oxo-4-(2-(4-chlorophenoxy)quinolin-3-yl)-4,5-
dihydropyrano [3,2-c]chromene-3-carbonitrile (6c). IR (KBr, nmax
,
d
cmꢁ1): 3435 & 3365 (asym. & sym. stretching of eNH2), 3020
(ArCeH), 2225 (C^N stretching), 1710 (C]O lactone stretching),
1225 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
126.82, 127.70, 130.34, 130.49, 132.07, 140.92, 147.22, 153.36, 161.22
(13C, AreC), 190.84 (CHO); MS (m/z): 279 (Mþ).
d6):
d
4.90 (s, 1H, chromene H4), 6.83 (s, 2H, NH2), 6.99e8.35 (m,
: 34.66 (chromene C4),
6.1.1.8. 6-Methoxy-2-(4-methylphenoxy)quinoline-3-carbaldehyde
(3h). IR (KBr, nmax, cmꢁ1): 3035 (ArCeH), 1710 (C]O stretching),
1230 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
13H, AreH). 13C NMR (100 MHz, DMSO-d6)
d
56.26 (CeCN), 103.12, 112.50, 117.52, 118.78, 121.52, 122.84, 125.77,
125.98, 126.76, 127.11, 127.54, 128.38, 129.21, 133.30, 134.14, 136.64,
139.25, 145.44, 150.72, 153.71, 154.00, 158.01, 159.12 (23C, AreC),
160.92 (C]O); MS (m/z): 493 (Mþ), 495 (Mþ2).
d6):
d
2.39 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 7.14e8.92 (m, 8H, AreH),
: 20.09 (CH3),
10.42 (s, 1H, CHO). 13C NMR (100 MHz, DMSO-d6)
d
54.92 (OCH3), 120.20, 122.33, 124.90, 125.67, 126.52, 128.09, 130.16,
130.96, 132.35, 140.77, 146.10, 153.57, 160.09 (13C, AreC), 191.08
(CHO); MS (m/z): 293 (Mþ).
6.1.2.4. 2-Amino-5-oxo-4-(6-methyl-2-phenoxyquinolin-3-yl)-4,5-di-
hydropyrano [3,2-c]chromene-3-carbonitrile (6d). IR (KBr, nmax
,
cmꢁ1): 3430 & 3365 (asym. & sym. stretching of eNH2), 3020
(ArCeH), 2230 (C^N stretching), 1735 (C]O lactone stretching),
1225 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-d6):
6.1.1.9. 2-(4-Chlorophenoxy)-6-methoxyquinoline-3-carbaldehyde
(3i). IR (KBr, nmax, cmꢁ1): 3015 (ArCeH), 1725 (C]O stretching),
1235 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
d
2.38 (s, 3H, CH3), 4.86 (s, 1H, chromene H4), 6.90 (s, 2H, NH2),
d6):
d
3.76 (s, 3H, OCH3), 7.16e8.94 (m, 8H, AreH), 10.51 (s, 1H,
: 56.14 (OCH3), 121.74, 122.59,
6.91e8.39 (m, 13H, AreH). 13C NMR (100 MHz, DMSO-d6)
d: 21.74
CHO). 13C NMR (100 MHz, DMSO-d6)
d
(CH3), 34.53 (chromene C4), 56.20 (CeCN), 102.40, 112.00, 116.88,
119.55, 121.40, 122.87, 125.23, 125.85, 126.03, 127.74, 127.99, 128.56,
129.20, 133.39, 134.65, 136.12, 138.47, 144.20, 151.65, 152.36, 154.80,
158.35, 159.12 (23C, AreC), 161.27 (C]O); MS (m/z): 473 (Mþ).
124.36, 125.92, 126.37, 127.07, 131.47, 131.99, 132.45, 140.95, 146.36,
153.95, 160.56 (13C, AreC), 191.20 (CHO); MS (m/z): 313 (Mþ), 315
(Mþ2).
6.1.2. General procedure for the synthesis of 2-amino-5-oxo-9-
(un)-substituted-4-(6-(un)-substituted-2-(4-(un)-substituted
aryloxy)quinolin-3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-
carbonitrile 6a-r
6.1.2.5. 2-Amino-5-oxo-4-(6-methyl-2-(4-methylphenoxy)quinolin-
3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6e). IR
(KBr, nmax, cmꢁ1): 3400 & 3370 (asym. & sym. stretching of eNH2),
3010 (ArCeH), 2220 (C^N stretching), 1730 (C]O lactone
stretching), 1225 cmꢁ1 (CeOeC ether stretching). 1H NMR
A 100 mL round bottomed flask, fitted with a reflux condenser,
was charged with a mixture of
b
-aryloxyquinoline-3-carbaldehyde
(400 MHz, DMSO-d6):
1H, chromene H4), 6.84 (s, 2H, NH2), 6.92e8.41 (m, 12H, AreH). 13
NMR (100 MHz, DMSO-d6) : 20.91 (CH3), 21.33 (CH3), 34.04
(chromene C4), 56.59 (CeCN), 102.16, 112.14, 117.64, 119.70, 120.40,
122.46, 125.65, 125.94, 126.25, 127.07, 127.17, 128.96, 131.20, 133.55,
134.65, 136.18, 139.73, 145.27, 151.43, 152.00, 154.98, 159.08, 159.80
(23C, AreC), 161.52 (C]O); MS (m/z): 487 (Mþ).
d 2.28 (s, 3H, CH3), 2.40 (s, 3H, CH3), 4.90 (s,
3aei (5 mmol), malononitrile 4 (5 mmol), 4-hydroxycoumarin 5a,b
(5 mmol), and a catalytic amount of piperidine (1 mmol) in ethanol
(15 mL). The mixture was heated under reflux for 1.5 h and the
progress of the reaction was monitored by TLC. After the comple-
tion of reaction (as evidenced by TLC), the reaction mixture was
cooled to room temperature and stirred magnetically for further
20 min, the solid mass separated was collected by filtration, washed
well with ethanol (15 mL) and purified by leaching in equal volume
ratio of chloroform and methanol (20 mL) to obtain pure solid
sample.
C
d
6.1.2.6. 2-Amino-5-oxo-4-(2-(4-chlorophenoxy)-6-methylquinolin-3-
yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6f). IR (KBr,
nmax, cmꢁ1): 3405 & 3360 (asym. & sym. stretching of eNH2), 3020
(ArCeH), 2220 (C^N stretching), 1715 (C]O lactone stretching),
1225 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
6.1.2.1. 2-Amino-5-oxo-4-(2-phenoxyquinolin-3-yl)-4,5-
dihydropyrano [3,2-c]chromene-3-carbonitrile (6a). IR (KBr, nmax
,
d6):
d
2.20 (s, 3H, CH3), 4.92 (s, 1H, chromene H4), 6.90 (s, 2H, NH2),
: 20.92
cmꢁ1): 3450 & 3350 (asym. & sym. stretching of eNH2), 3030
6.97e8.46 (m, 12H, AreH). 13C NMR (100 MHz, DMSO-d6)
d

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D.C. Mungra et al. / European Journal of Medicinal Chemistry 46 (2011) 4192e4200
(CH3), 34.04 (chromene C4), 56.59 (CeCN), 102.18, 112.20, 117.64,
119.32, 120.41, 122.40, 125.91, 125.94, 126.00, 127.04, 127.23, 128.90,
131.12, 134.50, 134.66, 137.69, 139.70, 145.20, 150.52, 152.01, 155.08,
159.18, 159.74 (23C, AreC), 161.50 (C]O); MS (m/z): 507 (Mþ), 509
(Mþ2).
(chromene C4), 56.26 (CeCN), 102.60, 113.25, 116.85, 119.56, 121.40,
122.39, 126.19, 126.23, 126.96, 127.02, 130.24, 132.16, 133.90, 134.25,
134.44, 134.70, 138.80, 143.63, 150.92, 151.80, 154.06, 159.12, 159.44
(23C, AreC), 161.03 (C]O); MS (m/z): 487 (Mþ).
6.1.2.12. 2-Amino-5-oxo-9-methyl-4-(2-(4-chlorophenoxy)quinolin-
3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6l). IR
(KBr, nmax, cmꢁ1): 3425 & 3365 (asym. & sym. stretching of eNH2),
3005 (ArCeH), 2220 (C^N stretching), 1730 (C]O lactone
stretching), 1230 cmꢁ1 (CeOeC ether stretching). 1H NMR
6.1.2.7. 2-Amino-5-oxo-4-(6-methoxy-2-phenoxyquinolin-3-yl)-4,5-
dihydropyrano [3,2-c]chromene-3-carbonitrile (6g). IR (KBr, nmax
,
cmꢁ1): 3430 & 3365 (asym. & sym. stretching of eNH2), 3010
(ArCeH), 2235 (C^N stretching), 1735 (C]O lactone stretching),
1235 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
(400 MHz, DMSO-d6):
6.90 (s, 2H, NH2), 6.93e8.21 (m, 12H, AreH). 13C NMR (100 MHz,
DMSO-d6) : 20.80 (CH3), 34.16 (chromene C4), 56.41 (CeCN),
d 2.33 (s, 3H, CH3), 4.90 (s, 1H, chromene H4),
d6):
d 3.84 (s, 3H, OCH3), 4.86 (s, 1H, chromene H4), 6.86 (s, 2H,
NH2), 6.98e8.42 (m, 13H, AreH). 13C NMR (100 MHz, DMSO-d6)
d:
d
34.53 (chromene C4), 56.20 (CeCN), 56.70 (OCH3), 102.17, 112.74,
116.00, 119.36, 121.47, 122.93, 125.23, 125.48, 126.00, 127.65, 127.76,
128.50, 129.21, 133.30, 134.01, 136.66, 138.40, 145.04, 151.25, 152.25,
154.98, 158.30, 159.17 (23C, AreC), 161.21 (C]O); MS (m/z): 489
(Mþ).
103.04, 113.14, 116.09, 119.84, 121.16, 122.30, 126.25, 126.46, 126.90,
127.11, 130.20, 132.52, 133.90, 134.17, 134.44, 134.73, 138.86, 143.98,
150.54, 151.80, 154.74, 159.30, 159.56 (23C, AreC), 160.71 (C]O);
MS (m/z): 507 (Mþ), 509 (Mþ2).
6.1.2.13. 2-Amino-5-oxo-9-methyl-4-(6-methyl-2-phenoxyquinolin-
3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6m). IR
(KBr, nmax, cmꢁ1): 3400 & 3375 (asym. & sym. stretching of eNH2),
3010 (ArCeH), 2220 (C^N stretching), 1745 (C]O lactone
stretching), 1230 cmꢁ1 (CeOeC ether stretching). 1H NMR
6.1.2.8. 2-Amino-5-oxo-4-(6-methoxy-2-(4-methylphenoxy)quinolin-
3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6h). IR (KBr,
nmax, cmꢁ1): 3405 & 3355 (asym. & sym. stretching of eNH2), 3010
(ArCeH), 2230 (C^N stretching), 1735 (C]O lactone stretching),
1240 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
(400 MHz, DMSO-d6):
1H, chromene H4), 6.90 (s, 2H, NH2), 6.93e8.27 (m, 12H, AreH). 13
NMR (100 MHz, DMSO-d6) : 20.81 (CH3), 20.93 (CH3), 34.13
d 2.25 (s, 3H, CH3), 2.28 (s, 3H, CH3), 4.93 (s,
d6):
6.80 (s, 2H, NH2), 6.92e8.49 (m, 12H, AreH). 13C NMR (100 MHz,
DMSO-d6) : 20.86 (CH3), 34.04 (chromene C4), 56.53 (OCH3), 56.59
d
2.24 (s, 3H, CH3), 2.80 (s, 3H, OCH3), 4.94 (s,1H, chromene H4),
C
d
d
(chromene C4), 56.26 (CeCN), 102.43, 113.11, 116.45, 119.72, 121.05,
122.30, 126.12, 126.87, 126.96, 127.14, 130.65, 132.22, 133.90, 134.44,
134.48, 134.86, 138.36, 143.63, 150.87, 151.12, 154.74, 159.30, 159.46
(23C, AreC), 160.12 (C]O); MS (m/z): 487 (Mþ).
(CeCN), 102.25, 112.10, 117.90, 119.77, 120.65, 123.00, 125.08, 125.64,
126.20, 127.17, 127.28, 128.65, 131.20, 133.16, 134.65, 136.89, 139.70,
145.21, 151.36, 152.07, 154.65, 159.16, 159.74 (23C, AreC), 161.44 (C]
O); MS (m/z): 503 (Mþ).
6.1.2.14. 2-Amino-5-oxo-9-methyl-4-(6-methyl-2-(4-methylphenoxy)
quinolin-3-yl)-4,5 dihydropyrano [3,2-c]chromene-3-carbonitrile
(6n). IR (KBr, nmax, cmꢁ1): 3405 & 3360 (asym. & sym. stretching
of eNH2), 3010 (ArCeH), 2200 (C^N stretching),1730 (C]O lactone
stretching), 1235 cmꢁ1 (CeOeC ether stretching). 1H NMR
6.1.2.9. 2-Amino-5-oxo-4-(2-(4-chlorophenoxy)-6-methoxyquinolin-
3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6i). IR
(KBr, nmax, cmꢁ1): 3400 & 3350 (asym. & sym. stretching of eNH2),
3025 (ArCeH), 2200 (C^N stretching), 1730 (C]O lactone
stretching), 1230 cmꢁ1 (CeOeC ether stretching). 1H NMR
(400 MHz, DMSO-d6):
3H, CH3), 4.92 (s,1H, chromene H4), 6.91 (s, 2H, NH2), 6.94e8.24 (m,
11H, AreH). 13C NMR (100 MHz, DMSO-d6)
: 20.82 (CH3), 20.96
d 2.28 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.42 (s,
(400 MHz, DMSO-d6):
H4), 7.07 (s, 2H, NH2), 7.10e8.30 (m, 12H, AreH). 13C NMR
(100 MHz, DMSO-d6) : 33.41 (chromene C4), 55.88 (CeCN), 56.33
d 3.84 (s, 3H, OCH3), 4.97 (s, 1H, chromene
d
d
(CH3), 21.34 (CH3), 34.01 (chromene C4), 56.15 (CeCN), 102.67,
113.10, 116.85, 119.80, 121.45, 122.38, 126.19, 126.77, 126.96, 127.06,
130.24, 132.20, 133.93, 134.18, 134.44, 134.77, 138.86, 143.63, 150.90,
151.86, 154.74, 159.37, 159.40 (23C, AreC), 160.33 (C]O); MS (m/z):
501 (Mþ).
(OCH3), 102.83, 106.71, 113.40, 117.06, 119.78, 122.31, 122.83, 123.14,
125.13, 127.43, 127.61, 128.45, 128.71, 129.80, 133.40, 138.67, 140.58,
152.70, 153.23, 154.80, 156.99, 157.84, 159.21 (23C, AreC), 160.21
(C]O); MS (m/z): 523 (Mþ), 525 (Mþ2).
6.1.2.10. 2-Amino-5-oxo-9-methyl-4-(2-phenoxyquinolin-3-yl)-4,5-
6.1.2.15. 2-Amino-5-oxo-9-methyl-4-(2-(4-chlorophenoxy)-6-methy-
dihydropyrano [3,2-c]chromene-3-carbonitrile (6j). IR (KBr, nmax
,
quinolin-3-yl)-4,5-dihydropyrano
[3,2-c]chromene-3-carbonitrile
cmꢁ1): 3415 & 3370 (asym. & sym. stretching of eNH2), 3010
(ArCeH), 2225 (C^N stretching), 1730 (C]O lactone stretching),
1235 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
(6o). IR (KBr, nmax, cmꢁ1): 3410 & 3385 (asym. & sym. stretching
of eNH2), 3015 (ArCeH), 2225 (C^N stretching),1735 (C]O lactone
stretching), 1235 cmꢁ1 (CeOeC ether stretching). 1H NMR
d6):
d
2.29 (s, 3H, CH3), 4.94 (s, 1H, chromene H4), 6.93 (s, 2H, NH2),
: 20.84
(400 MHz, DMSO-d6):
1H, chromene H4), 6.91 (s, 2H, NH2), 6.94e8.22 (m, 11H, AreH). 13
NMR (100 MHz, DMSO-d6) : 20.82 (CH3), 20.91 (CH3), 34.16
(chromene C4), 56.20 (CeCN), 102.47, 113.11, 116.40, 119.77, 121.94,
122.35, 126.12, 126.74, 126.90, 127.22, 130.60, 132.21, 133.96, 134.45,
134.49, 134.96, 138.30, 143.52, 149.56, 151.14, 154.04, 159.37, 159.78
(23C, AreC), 161.05 (C]O); MS (m/z): 521 (Mþ), 523 (Mþ2).
d 2.25 (s, 3H, CH3), 2.31 (s, 3H, CH3), 4.98 (s,
6.96e8.29 (m, 13H, AreH). 13C NMR (100 MHz, DMSO-d6)
d
C
(CH3), 34.09 (chromene C4), 56.22 (CeCN), 102.11, 113.36, 116.80,
119.84, 121.63, 122.30, 126.10, 126.57, 126.96, 127.36, 130.20, 132.27,
133.93, 134.20, 134.47, 134.81, 138.80, 142.12, 150.74, 151.06, 154.04,
159.30, 159.48 (23C, AreC), 160.19 (C]O); MS (m/z): 473 (Mþ).
d
6.1.2.11. 2-Amino-5-oxo-9-methyl-4-(2-(4-methylphenoxy)quinolin-
3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6k). IR
(KBr, nmax, cmꢁ1): 3400 & 3355 (asym. & sym. stretching of eNH2),
3010 (ArCeH), 2225 (C^N stretching), 1720 (C]O lactone
stretching), 1225 cmꢁ1 (CeOeC ether stretching). 1H NMR
(400 MHz, DMSO-d6):
1H, chromene H4), 6.88 (s, 2H, NH2), 6.93e8.25 (m, 12H, AreH). 13
NMR (100 MHz, DMSO-d6) : 20.86 (CH3), 20.95 (CH3), 34.11
6.1.2.16. 2-Amino-5-oxo-9-methyl-4-(6-methoxy-2-phenoxyquinolin-
3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6p). IR (KBr,
nmax, cmꢁ1): 3405 & 3350 (asym. & sym. stretching of eNH2), 3010
(ArCeH), 2235 (C^N stretching), 1715 (C]O lactone stretching),
1235 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-d6):
d 2.29 (s, 3H, CH3), 2.48 (s, 3H, CH3), 4.97 (s,
C
d
2.25 (s, 3H, CH3), 2.84 (s, 3H, OCH3), 4.91 (s,1H, chromene H4), 6.87
d
(s, 2H, NH2), 6.90e8.41 (m, 12H, AreH). 13C NMR (100 MHz, DMSO-

D.C. Mungra et al. / European Journal of Medicinal Chemistry 46 (2011) 4192e4200
4199
d6)
d: 20.39 (CH3), 34.95 (chromene C4), 56.48 (OCH3), 56.68 (CeCN),
6.2.2. In vitro evaluation of antituberculosis activity
103.83, 112.25, 117.65, 119.89, 120.60, 123.36, 125.00, 125.64, 126.37,
127.08, 127.65, 128.60, 131.24, 133.54, 134.67, 136.80, 139.73, 145.21,
151.30, 152.77, 154.49, 159.45, 159.82 (23C, AreC), 160.36 (C]O); MS
(m/z): 503 (Mþ).
An antituberculosis activity of the title compounds against M.
tuberculosis H37Rv was performed by LowensteineJensen method
[37] with minor modification where 250
compound was added to LowensteineJensen medium and then
media was sterilized by inspissation method. culture of
mg/mL dilution of each test
A
6.1.2.17. 2-Amino-5-oxo-9-methyl-4-(6-methoxy-2-(4-methylphenoxy)
quinolin-3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile (6q).
IR (KBr, nmax, cmꢁ1): 3400 & 3350 (asym. & sym. stretching of eNH2),
3000 (ArCeH), 2230 (C^N stretching), 1740 (C]O lactone stretch-
ing), 1230 cmꢁ1 (CeOeC ether stretching). 1H NMR (400 MHz, DMSO-
M. tuberculosis H37Rv growing on LowensteineJensen medium was
harvested in 0.85% saline in bijou bottle. Each test compound was
diluted to 250 mg/mL concentration using DMSO as diluents. These
tubes were then incubated at 37 ꢀC for 24 h followed by streaking of
M. tuberculosis H37Rv (5 ꢃ 104 bacilli per tube). The growth of
bacilli was seen after 28 days of incubation. The tubes having the
compounds were compared with control tubes where medium
alone was incubated with M. tuberculosis H37Rv. The antitubercu-
d6):
chromene H4), 6.84 (s, 2H, NH2), 6.90e8.43 (m, 11H, AreH). 13C NMR
(100 MHz, DMSO-d6) : 20.84 (CH3), 20.93 (CH3), 34.04 (chromene
d 2.27 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.82 (s, 3H, OCH3), 4.97 (s, 1H,
d
C4), 56.51 (OCH3), 56.57 (CeCN), 102.27, 112.90, 117.84, 119.52, 120.64,
123.48, 125.16, 125.53, 126.32, 127.87, 127.98, 128.60, 131.54, 133.16,
134.04, 136.80, 139.57, 145.20, 151.30, 152.56, 154.75, 159.65, 159.86
(23C, AreC), 160.36 (C]O); MS (m/z): 517 (Mþ).
losis activity of b-aryloxyquinolines 3aei and their pyrano[3,2-c]
chromene derivatives 6aer is expressed as % inhibition (Table 3),
relative to that of standard drug isoniazid. The concentration at
which no development of colonies occurred or < 20 colonies was
taken as MIC of test compound. MIC values of three compounds
with highest % inhibition i.e. 3a, 3f and 6f are shown in Table 4. The
standard strain M. tuberculosis H37Rv was tested with standard
drug isoniazid for comparison purpose.
6.1.2.18. 2-Amino-5-oxo-9-methyl-4-(2-(4-chlorophenoxy)-6-metho-
xyquinolin-3-yl)-4,5-dihydropyrano [3,2-c]chromene-3-carbonitrile
(6r). IR (KBr, nmax, cmꢁ1): 3415 & 3365 (asym. & sym. stretching
of eNH2), 3000 (ArCeH), 2215 (C^N stretching),1725 (C]O lactone
stretching), 1225 cmꢁ1 (CeOeC ether stretching). 1H NMR
Acknowledgment
(400 MHz, DMSO-d6):
1H, chromene H4), 6.84 (s, 2H, NH2), 6.90e8.47 (m, 11H, AreH). 13
NMR (100 MHz, DMSO-d6) : 20.80 (CH3), 34.01 (chromene C4),
d 2.26 (s, 3H, CH3), 2.85 (s, 3H, OCH3), 4.90 (s,
C
The authors express their sincere thanks to Department of
Chemistry, Sardar Patel University for providing research facilities,
Vaibhav Analytical Laboratory, Ahmedabad for IR spectral analysis,
Sophisticated Instrumentation Centre for Applied Research &
Training (SICART), Vallabh Vidyanagar for elemental analysis as
well as Oxygen Healthcare Research Pvt. Ltd., Ahmedabad for
providing mass spectroscopy facilities.
d
56.53 (OCH3), 56.61 (CeCN), 102.21, 112.78, 117.33, 119.77, 120.60,
123.00, 125.74, 125.64, 126.42, 127.14, 127.36, 128.61, 131.27, 133.35,
134.41, 136.92, 139.71, 145.75, 151.36, 152.37, 154.67, 159.27, 159.78
(23C, AreC), 160.62 (C]O); MS (m/z): 537 (Mþ), 539 (Mþ2).
6.2. Biological assay
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