New quinolin-4-yl-1,2,3-triazoles carrying amides, sulphonamides and amidopiperazines as potential antitubercular agents

Article abstract of DOI:10.1016/j.ejmech.2011.03.039

Three new series of quinoline-4-yl-1,2,3-triazoles carrying amides, sulphonamides and amidopiperazines were synthesized through multi-step reactions. The required intermediate, [1-(6-methoxy-2-methylquinolin-4-yl)-1H-1, 2,3-triazol-4-yl]methanol (2) was p

Full text of DOI:10.1016/j.ejmech.2011.03.039

European Journal of Medicinal Chemistry 46 (2011) 2503e2512
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
New quinolin-4-yl-1,2,3-triazoles carrying amides, sulphonamides and
amidopiperazines as potential antitubercular agents
,
,
c
a
d
K.D. Thomas a b, Airody Vasudeva Adhikari b , Imran H. Chowdhury , E. Sumesh , Nishith K. Pal
*
a Anthem Biosciences Pvt. Ltd, No. 49, Bommasandra Industrial Area, Bommasandra, Bangalore 560099, Karnataka, India
b Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Srinivasnagar, Mangalore 575025, Karnataka, India
c Department of Biochemistry, Dr. B.C. Roy Post Graduate Institute of Basic Medical Education and Research (IPGME&R), 244B, A.J.C. Bose Road, Kolkata 700020, India
d Department of Microbiology, Dr. B.C. Roy Post Graduate Institute of Basic Medical Education and Research (IPGME&R), 244AB, A.J.C. Bose Road, Kolkata 700020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Three new series of quinoline-4-yl-1,2,3-triazoles carrying amides, sulphonamides and amidopiperazines
were synthesized through multi-step reactions. The required intermediate, [1-(6-methoxy-2-methyl-
quinolin-4-yl)-1H-1,2,3-triazol-4-yl]methanol (2) was prepared by treating 4-azido-6-methoxy-2-
methylquinoline (1) with propargyl alcohol. Three different series of compounds were synthesized from
this intermediate. All the newly synthesized compounds were characterized by spectral and elemental
analyses. The structure of 2 was confirmed by X-ray crystallographic study. Further, the title compounds
were evaluated for their in vitro anti-bacterial activity against five different bacterial strains and anti-
mycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis (ATCC
19420) and Mycobacterium fortuitum (ATCC 19542). Title compounds, 6a, 6d, 6i, 6j, 7e, 10a and 10i were
found to be active against Mycobacterium tuberculosis H37Rv strain and could be lead molecules of
interest.
Received 16 February 2011
Received in revised form
8 March 2011
Accepted 16 March 2011
Available online 13 April 2011
Keywords:
Quinoline
1,2,3-triazole
Antimycobacterial
Amidopiperazine
Propargyl alcohol
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
shown to possess antimalarial [2e4], antibiotic [5,6], anticancer [7],
anti-inflammatory [8], antihypertensive [9], tyrokinase PDGF-RTK
Tuberculosis (TB) is a lung infection caused mainly by Myco-
bacterium tuberculosis (Mtb). It is considered to be one of the most
contagious and deadly diseases and is a major threat for public
health. In combination with the HIV-1 infection tuberculosis is
today amongst the biggest threat to the mankind. A large propor-
tion of these new cases and deaths occur mostly in developing
countries and the number of HIV-positive patients coinfected with
Mtb is constantly rising [1]. As a result, the TB situation may
become even worse with the spread of HIV-1 worldwide, emer-
gence of multi-drug (isoniazid and rifampin) resistant (MDR-TB)
and the extensively drug resistant (XDR-TB) strains.
It has been established that heterocyclic compounds play an
important role in designing new class of structural entities for
medicinal applications. Among pharmacologically important
heterocyclic compounds, quinoline and its derivatives are signifi-
cant because of their wide spectrum of biological activities and
their presence in naturally occurring compounds. They have been
inhibition [10] and anti-HIV [11,12] properties because of which
a large number of currently available drugs contain quinoline
nucleus as an important pharmacophore. Consequently, the quin-
oline skeleton is being chosen for the design of new bioactive
molecules by a large number of researchers.
Over the past two decades, 1,2,3-triazole and its derivatives have
attracted continued interest in the medicinal field owing to their
varied biological activities such as anti-bacterial [13], antifungal
[14], anti-allergic [15e17], anti-HIV [18], anticonvulsant [19], anti-
inflammatory [20,21] and
b -lactamase inhibition propeties [22].It
is quite obvious that the favorable properties of 1,2,3-triazole ring
like moderate dipole character, hydrogen bonding capability,
rigidity and stability under in vivo conditions are responsible for
their enhanced biological activities [23].
It is evident from the literature that quinoline-based
compounds are known to exhibit excellent anti-TB properties
[24e28]. Besides, some azole derivatives have also been shown to
possess strong inhibitory activities in vitro and in vivo against
M. tuberculosis strains [29]. Azoles may be regarded as a new class
of effective antitubercular agents, which are reported to inhibit
bacteria by blocking the biosynthesis of certain bacterial lipids and/
or by additional mechanisms [30]. Among the azole derivatives,
* Corresponding author. Tel.: þ91 (0) 824 2474000x3203; fax: þ91 (0) 824
2474033.
E-mail addresses: avadhikari123@yahoo.co.in, avchem@nitk.ac.in (A.V. Adhikari).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.03.039

2504
K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
triazoles are also known to exhibit antimycobacterial properties
[31]. An extensive literature survey reveals that till date enough
efforts have not been made to combine quinoline and 1,2,3-tri-
azoles moieties in a single molecular scaffold and to study its
antitubercular activity. It has been established that more efficacious
antimicrobial compounds can be designed by joining two or more
been envisioned that these structural modifications could lead to
a process of finding a molecule of interest for further exploration.
2. Results and discussion
2.1. Chemistry
biologically active heterocyclic systems together in
molecular framework [32].
a single
The general synthesis of title compounds 6aej, 7aeg and 10aek
is outlined in Scheme 1. The procedure for the synthesis of 4-azido-
6-methoxy-2-methylquinoline (1) has been reported in our earlier
work [33]. As mentioned in Scheme 1, the intermediate 2 was
obtained by heating a mixture of 4-azido-6-methoxy-2-methyl-
quinoline (1) and propargyl alcohol in dry THF/toluene (1:1) at
120 ꢀC for 6 h. The intermediate 2 was then conveniently converted
to its mesyl derivative 3, which was further used as a key inter-
mediate to obtain three different series of title compounds. The
azide derivative 4 was obtained from the compound 3, by treating it
with sodium azide in DMF at 25 ꢀC. It was further reduced with
hydrogen under pressure using Pd/C as a catalyst to get 1-[1-(6-
ethoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methan-
amine (5) in good yield.
The title compounds, 6aej were synthesized by reacting the
amine scaffold 5 with alkyl and substituted aryl acid chlorides,
while the compounds 7aeg were obtained by treating the
compound 5 with substituted aryl sulfonyl chlorides at 0 ꢀC in
dichloromethane using pyridine as a base. In another reaction
sequence the mesyl derivative 3 was treated with tert-butyl
piperazine-1-carboxylate in acetonitrile to obtain an intermediate
8, which was later converted to the intermediate 9 by treating it
with trifluoroacetic acid in dichloromethane at 0 ꢀC. The target
The limitations of the existing anti-TB drugs are many which
include their drug resistance, the serious side effects, lack of effi-
cacy and the treatment of resistant strains requires a prolongation
of the therapy that employs more toxic drugs, increases the
financial burden and thus making TB a vicious cycle. These factors
necessitate the search for new antimycobacterial agents which are
synthetically feasible, lacking side effects, and have physicochem-
ical properties allowing oral administration. Therefore, it is inevi-
table to discover and develop new drugs for treatment of dreadful
tuberculosis that has spread worldwide now.
Against this background, and as a part of our continued research
for new antitubercular agents, we have designed new bi-heterocy-
clic systems containing 1,2,3-triazole ring at position-4 of quinoline
ring linked with interesting pharmocophores like amides, sulpho-
namides and amidopiperazine, hoping that new molecules would
exhibit enhanced biological activity. In this communication, we
herein report the synthesis of 1-[quinolin-4-yl)-1H-1,2,3-triazol-4-
yl]methylamides (6aej), 1-[1-(quinolin-4-yl)-1H-1,2,3-triazol-4-yl]
methyl sulphonamides (7aeg), 4-[4-(piperazin-1-ylmethyl)-1H-
1,2,3-triazol-1-yl]quinoline amides (10aek) and evaluation of their
in vitro anti-bacterial activity and antituberculosis activity. Further,
single crystal X-ray study of compound 2 has been reported. It has
OH
N
N
N
N3
MeO
MeO
i
N
N
2
1
ii
OMs
N3
N
NHBOC
N
N
N
N
N
N
N
N
N
MeO
MeO
iii
vii
MeO
N
N
iv
N
3
4
8
viii
O
1
NH2
R
N
N
NH.TFA
NH
N
N
N
N
N
N
N
N
MeO
v
MeO
O
N
5
N
N
9
vi
2
NHSO2R
ix
6a-j
3
N
R
N
N
N
N
N
O
N
MeO
N
MeO
N
7a-g
N
10a-k
Scheme 1. 1-[1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methanamine derivatives (i) Propargyl alcohol, THF/Toluene (1:1), 120 ꢀC, 6 h (ii) MsCl, DCM, 25 ꢀC, 2 h
(iii) Sodium azide, DMF, 25e26 ꢀC, 2 h (iv) Pd/C, MeOH, 2 h (v) R1COCl, dichloromethane, pyridine, 0e25 ꢀC, 1 h (vi) R2SO2Cl, pyridine, DCM, 0e25 ꢀC, 1 h (vii) Piperazine-1-
carboxylic acid tert-butyl ester, CH3CN, 80 ꢀC, 1 h (viii) TFA, dichloromethane, 0 ꢀC and then 26e30 ꢀC, 4 h (ix) dichloromethane, triethylamine, R3COCl, 0 ꢀC, 1 h.

K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
2505
compounds 10aek were synthesized by reacting 6-methoxy-2-
methyl-4-[4-(piperazin-1-ylmethyl)-1H-1,2,3-triazol-1-yl] quinoli-
ne.TFA salt (9) with alkyl and substituted aryl acid chlorides in
presence of triethylamine in dichloromethane medium at 0 ꢀC. The
crude product was purified on a Biotage parallel column purifier
using ethyl acetate/pet ether (4:1) to methanol (2e4%) in
dichloromethane as eluant. The newly synthesized compounds
were characterized by 1H NMR, 13C NMR, IR, LCMS and elemental
analyses.
chain. Finally, the cyclization was established by its mass spectrum,
wherein the compound 2 showed molecular ion peak at m/z 271
(Mþ1), confirming its molecular formula C14H14N4O2. This was
further evidenced by a single crystal X-ray crystallographic analysis
of the intermediate 2.
Conversion of hydroxyl derivative 2 to mesylate compound 3
was confirmed by its 1H NMR spectral study. In its 1H NMR spec-
trum, methyl protons of mesylate group resonated at
d 3.32 ppm
(OSO2Me). Further, the formation of amine scaffold 5 from inter-
mediate 4 was evidenced by its spectral data. Its FTIR spectrum
showed a broad peak at 3425 cmꢁ1 due to NH stretching. In its 1H
Formation of the intermediate 2 from azide intermediate 1 was
confirmed by spectral studies. In its FTIR spectrum, a broad band
was observed at 3595 cmꢁ1 indicating the presence of OH group.-
NMR spectrum, the appearance of a broad peak at
d 4.35 ppm
Further, its 1H NMR spectrum showed a singlet at
d
8.66 ppm for an
aromatic proton of the triazole ring. Also, a doublet was observed at
4.69 ppm accounting for the two methylene protons of 1,2,3-tri-
azole-4yl methanol. The cyclization was further confirmed by its
13C NMR spectrum, which showed two peaks at
116.98 and
indicates the presence of amine which disappeared on D2O
exchange. Finally its structure was confirmed by its mass spectrum,
where it showed a molecular ion peak at m/z 270.13 (Mþ1) which
corresponds to its molecular formula C14H15N5O.
d
d
The formation of title compound 6a was confirmed by spectral
150.27 ppm for the carbons belonging to triazole ring and side
analysis. The 1H NMR spectrum of compound 6a showed a singlet
Table 1
Characterization and anti-bacterial screening data of compounds 6aej, 7aeg and 10aek
O
1
3
R
2
R
NHSO2R
NH
N
N
N
N
N
O
N
N
N
N
N
N
MeO
MeO
MeO
N
N
N
10a-k
6a-j
7a-g
Cpda
R1/R2/R3
Mol. For. M.Wt.
(%)b
clogPc
MIC(mg/mL)
S.ad
S.pe
P.af
K.pg
E.ch
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
7a
7b
7c
7d
7e
7f
7g
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
CIP
Acetyl
Cyclopropyl
Cyclobutyl
C16H17N5O2311.33
C18H19N5O2337.37
C19H21N5O2351.40
C21H18FN5O2391.39
C21H18FN5O2391.39
C21H18ClN5O2407.85
C23H23N5O2401.46
90
87
80
90
50
76
69
92
87
78
87
79
67
85
96
78
86
91
87
80
90
50
76
69
92
87
78
65
e
1.70
2.42
2.84
3.76
3.76
4.16
4.50
4.09
3.47
4.52
3.60
4.36
4.56
3.93
3.31
4.34
3.44
1.69
2.42
2.83
3.75
3.75
4.15
4.50
4.08
3.46
3.59
4.71
e
0.4
0.4
1.6
0.8
0.8
1.6
3.12
1.6
0.8
0.4
0.4
0.8
1.6
3.12
6.25
6.25
12.5
0.4
0.8
1.6
0.8
0.8
3.12
6.25
6.25
0.8
0.8
6.25
1.0
0.2
0.4
0.8
0.2
0.2
1.6
0.8
0.2
0.1
0.2
1.6
0.2
0.1
0.4
1.6
0.2
4-Fluoro benzoyl
2-Fluoro benzoyl
2-Chloro benzoyl
4-Ethyl benzoyl
4-Methyl benzoyl
4-Methoxy benzoyl
4-Trifluoro methylbenzoyl
4-Fluoro benzene
2-Trifluoro methylbenzene
3,4-Dichloro benzene
4-Methyl benzene
4-Methoxy benzene
4-Ethyl benzene
Benzene
Acetyl
Cyclopropyl
Cyclobutyl
4-Fluoro benzoyl
2-Fluoro benzoyl
2-Chloro benzoyl
4-Ethyl benzoyl
4-Methyl benzoyl
4-Methoxy benzoyl
Benzoyl
0.2
0.4
0.2
0.4
3.12
3.12
0.8
0.4
0.2
6.25
6.25
6.25
0.4
0.4
0.8
3.12
3.12
3.12
0.1
0.2
3.12
0.4
3.12
6.25
1.6
6.25
6.25
0.1
0.2
3.12
0.8
3.12
3.12
3.12
0.1
0.4
3.12
0.2
12.5
6.25
3.12
6.25
6.25
0.1
0.4
1.6
0.8
1.6
6.25
3.12
6.25
0.4
0.4
3.12
0.05
C22H21N5O2387.43
C22H21N5O3403.43
C22H18F3N5O2441.40
C20H18FN5O3S 427.45
C21H18F3N5O3S 477.45
C20H17Cl2N5O3S 478.35
C21H21N5O3S 423.48
C21H21N5O4S 439.48
0.4
0.4
0.4
3.12
6.25
1.6
6.25
6.25
0.2
0.4
1.6
0.4
0.4
3.12
6.25
6.25
1.6
0.8
0.8
12.5
6.25
1.6
12.5
6.25
0.2
0.4
0.8
1.6
3.12
3.12
6.25
12.5
3.12
0.4
C22H23N5O3S 437.51
C20H19N5O3S 409.46
C20H24N6O2380.44
C22H26N6O2406.21
C23H28N6O2420.50
C25H25FN6O2460.50
C25H25FN6O2460.50
1.6
C25H25ClN6O2476.95
3.12
3.12
12.5
1.6
0.4
0.8
C27H30N6O2470.56
C26H28N6O2387.43
C26H28N6O3403.43
C25H26N6O2442.51
C25H24Cl2N6O2511.40
e
3,4-Dichloro benzoyl
Ciprofloxacin
0.8
0.4
0.4
0.05
a
Compound.
Isolated yield.
CHEMDRAW 8.
Staphylococcus aureus (ATCC-25923).
Streptococcus Pyogenes.
Pseudomonas aeruginosa (ATCC-27853).
Klebsiella pneumoniae.
Escherichia coli (ATCC-25922).
b
c
d
e
f
g
h

2506
K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
for three methyl protons of the acetyl group at
the NH proton of the amide group resonated at
d
2.05 ppm whereas,
6.42 ppm.
which corresponds to the carbonyl carbon of the amide. This was
also evidenced by its FTIR spectrum where a strong band was seen
at 1645 cmꢁ1 that corresponds to the carbonyl group. Further, its
structure was confirmed by its mass spectrum, which showed
a base peak at 457.23 (Mþ1) matching with its molecular formula
C26H28N6O2. The spectral data of the title compounds, 10aek are
listed in experimental section. The characterization data and the
anti-bacterial screening data of the title compounds are summa-
rized in Table 1.
d
Furthermore, in its 13C NMR spectrum the carbonyl carbon reso-
nated at 174.81 ppm which confirms the presence of an amidic
carbon. Its structure was further evidenced by its mass spectrum,
where it showed a mass peak of 312.3 (Mþ1) which is matching to
its molecular formula C16H17N5O2. The spectral data of all other
intermediates and title compounds, 6aej and 7aeg are given in
experimental section.
Similarly, the formation of title compound 10h was confirmed
by its spectral data. In its 1H NMR spectrum, three protons of the
CH3 group of 4-methylbenzoyl moiety were found to resonate at
2.2. Biological activity
d
2.43 ppm. The four protons of piperazine ring appeared at
d 2.58,
All the title compounds were screened for their in vitro anti-
bacterial and antitubercular properties following standard
methods.
while other four protons resonated at 3.38e3.41 and
d
3.65e3.68 ppm respectively. Its structure was further confirmed by
its 13C NMR spectrum, wherein it showed a peak at
d 169.73 ppm
2.2.1. Antibacterial study
Antibacterial activity of title compounds were investigated
against five different bacterial strains, Staphylococcus aureus,
Streptococcus pyogenes, Pseudomonas aeruginosa, Klebsiella pneu-
moniae and Escherichia coli using ciprofloxacin as reference, by
serial dilution method. Table 1 summarizes the anti-bacterial
Table 2
Preliminary and second level in vitro antimycobacterial screening data of the title
compounds, 6a-j, 7a-g and 10a-k.
O
O
O
1
3
S
R
2
R
screening results (MIC mg/mL) of tested compounds in comparison
R
N
NH
NH
N
N
N
N
with that of the standard.
O
N
N
N
N
N
N
2.2.2. Antitubercular study
MeO
MeO
MeO
Based on the promising results from the anti-bacterial
screening, title compounds were further tested for their both
preliminary and second level in vitro antimycobacterial activity
against Mycobacterium tuberculosis H37Rv, Mycobacterium smeg-
matis (ATCC 19420) and Mycobacterium fortuitum (ATCC 19542)
using isoniazid (INH) and rifampicin (RIF) as standards. The results
of preliminary and second level antimycobacterial screening of the
tested compounds are tabulated in Table 2.
N
N
N
6a-j
7a-g
10a-k
Cpda
Preliminary in vitro screening
results; MIC( g/mL)
Second level screening
results; MIC( g/mL)
m
m
MTBb
MSc
MFd
%
MTB
MS
MF
e
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
7a
7b
7c
7d
7e
7f
1
1
10
1
1
10
100
100
1
1
1
10
10
95
90
85
90
90
80
80
e
0.625
1.25
10
0.625
1.25
10
10
e
10
e
100
100
10
100
100
100
100
10
100
100
100
100
100
100
100
10
e
e
10
e
e
Table 3
e
Crystal data and measurement details for compound 2.
e
e
Crystal data
e
e
e
e
e
e
Empirical formula
Formula weight
Crystal system
Crystal dimension
Space group
C14H14N4O2
270.29
Triclinic
95
95
85
90
e
0.625
0.625
1.25
1.25
e
5
10
e
10
5
10
10
100
10
100
100
100
100
10
100
100
10
e
0.18 mm ꢂ 0.18 mm ꢂ 0.16 mm
1
e
10
e
P1
100
10
1
100
100
1
10
10
1
100
100
10
100
100
100
100
100
10
100
100
100
100
10
e
a(Å)
8.0203(5)
85
90
e
10
0.625
e
e
e
8.0203(5)
8.0203(5)
10
e
10
e
b(Å)
9.6239(6)
7g
e
e
e
e
c(Å)
10.3396(7)
661.21(7)
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
INHf
RIFg
95
90
90
90
90
e
0.625
5
10
1.25
1.25
10
10
e
e
Volume (Å3)
100
100
1
e
Angle
Z
a
,
b
,
g
101.995(4), 110.072(3), 109.012(3)
2
1.358
284
0.095
0.09
296(2)
0.71073
MoKa
e
e
1.25
5
10
e
Crystal density, g/cm3
F000
1
10
100
100
100
1
10
10
0.7
0.5
100
100
100
10
100
100
50
e
e
m
(mmꢁ1
)
e
e
e
e
Absorption coefficient
Temperature (T)
Radiation wavelength
Radiation type
Radiation source
Radiation monochromator
hmin
e
e
e
e
90
85
85
95
95
0.625
10
5
0.7
0.5
5
e
10
e
100
100
12.5
1.5
e
e
Fine-focus sealed tube
50
1.5
12.5
1.5
Graphite
ꢁ11
1.5
hmax
11
a
Compound.
Mycobacterium tuberculosis H37Rv.
Mycobacterium smegmatis (ATCC 19420).
Mycobacterium fortuitum (ATCC 19542).
Percentage of inhibition against M. tuberculosis H37Rv.
Isoniazid.
kmin
kmax
ꢁ13
b
c
d
e
f
13
lmin
lmax
ꢁ14
14
Reflns (Fo)
Structure refinement
3917
SHELXL-97
g
Rifampicin, ‘-’ Not detected.

K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
2507
2.3. X-ray crystallographic study of compound 2
second level screening with concentration ranging from 0.3125 to
g/mL. In the second level testing, the compounds 6a, 6d and 6i
showed promising activity against M. tuberculosis H37Rv at
0.625 g/mL. In addition the title compounds 6a, 6d and 6iej are
active against M. smegmatis at 5 and 10 g/mL and also 6a and 6iej
are the active compounds against M. fortuitum between 5 and
10 g/mL and showed significant activity than the reference
compound isoniazid (MIC ¼ 0.7 g/mL against Mycobacterium
tuberculosis H37Rv, 50 g/mL against Mycobacterium smegmatis and
12.5 g/mL against Mycobacterium fortuitum). Among the sulfon-
amide derivatives (7aeg), 7e displayed promising activity at
5
m
The X-ray crystallographic analysis of the intermediate 2 was
carried out on
a
colorless plate crystal, with approximate
m
dimensions 0.18 mm ꢂ 0.18 mm ꢂ 0.16 mm, grown from the slow
evaporation of a dilute ethanol solution at room temperature.
The crystal structure solution was worked out by full matrix
least-squares method using SHELXL97. All the atoms were
located in different Fourier maps and refined isotropically, using
a riding model and all the projections were generated using
ORTEP. The details of the crystal data and refinement are shown
in Table 3. Also the single crystal image for compound 2 is given
in Fig. 1.
m
m
m
m
m
0.625
at 10
m
g/mL against Mycobacterium tuberculosis H37Rv and active
mg/mL against M. smegmatis and M. fortuitum.
Among the amidopiperazines (10aek), the compounds 10a and
10i showed substantial activity at 0.625 g/mL against Mycobacte-
2.4. Biological results
m
rium tuberculosis H37Rv. Further the compounds 10a, 10dee and
10i were more potent than isoniazid against M. smegmatis.
Furthermore, the compound 10d showed significant activity at
The anti-bacterial screening data of compounds 6aej, 7aeg and
13aek displayed promising activities against all the tested bacterial
strains at MIC 0.1e12.5
results, it has been observed that 6a, 6dee, 6iej, 7b and 10aeb are
the active compounds against all the three Gram positive bacterial
m
g/mL concentrations. From the screening
1.25
1.5
10i showed activity at 10
m
g/mL in comparison to rifampicin (RIF) whose MIC value is
g/mL against M. smegmatis. Similarly the compounds 10d and
g/mL against M. fortuitum.
m
m
strains, viz. S. aureus, S. pyogenes, P. aeruginosa at 0.2e0.8
concentrations whereas the compounds 6b, 7a and 10dee are
active against S. aureus and S. pyogenes at 0.4e0.8 g/mL concen-
trations. Similarly, the compounds 6a, 6i and 10a displayed
substantial activity at 0.1 g/mL concentrations against
K. pneumoniae and E. coli strains whereas 6b, 6dee, 6j and 10b is
active at 0.2 g/mL against K. pneumoniae. On similar lines, the
compounds 6b, 6dee, 6j, 7b, 10b and 10iej exhibited promising
activity against E. coli at 0.2e0.4 g/mL concentrations.
The active compounds, 6a, 6d, 6e, 6iej, 7b and 10aeb which
showed promising activity against all the Gram positive bacterial
strains comprised of important pharmacophoric groups like acetyl,
fluoro, methoxy, trifluoromethyl, cyclopropyl groups in their
structures are responsible for substantial activity.
m
g/mL
The promising antitubercular activity of 6a, 6d, 6iej and 7e is
mainly due to the presence of amide derivatives carrying simple
pharmacophoric groups like acetyl, fluoro, methoxy and tri-
fluoromethyl. Similarly the significant activity of 10a, 10dee and
10i can be attributed to the amidopiperazines carrying pharmaco-
phoric groups like acetyl, fluoro, methoxy groups in the title
molecules. It is well known from the literature that the presence of
these groups imparts a variety of properties including steric, elec-
tronic properties, enhanced binding interactions, metabolic
stability, changes in physical properties and selective reactivities
[34,35].
m
m
m
m
3. Conclusion
The newly synthesized title compounds were further screened
against three different TB strains. Initially the compounds were
In our present research work we have accomplished the
synthesis of twenty eight new derivatives of quinoline-4-yl-1,2,3-
triazoles carrying amides, sulphonamide and piperazine moieties.
The new chemical entities were characterized by spectral and
elemental analyses. The title compounds were tested for their in
vitro anti-bacterial properties against five different bacterial strains,
viz., ATCC-25922 Escherichia coli, ATCC-25923 Staphylococcus
aureus, ATCC-27853 Pseudomonas aeruginosa, clinical isolate of
Klebsiella pneumoniae and S. Pyogenes and also antimycobacterial
activity against three different strains, viz. M. tuberculosis H37Rv,
M. smegmatis and M. fortuitum. Among the tested compounds, 6a,
6d, 6i, 6j, 7e, 10a and 10i showed significant antitubercular activity
when compared to isoniazid. The substantial activity of these
compounds may be attributed to the important pharmacophoric
groups present in the molecule, viz., acetyl, methoxy, tri-
fluoromethyl and fluoro group. Further, 6a, 6i, 6j, 7e and 10i were
active against all the three mycobacterial strains and were more
potent than the isoniazid. In summary these compounds from our
present research work could be lead molecules of interest.
tested at 1, 10 and 100
mg/mL concentrations. The compounds,
6aef, 6iej, 7aeb, 7dee, 10aee and 10iek are active at 1 and 10
mg/
mL concentrations. These compounds were further taken for
4. Experimental
4.1. General
Melting points were determined using Buchi B-540 by open
capillary and are uncorrected. The IR spectra (in KBr pellets) were
recorded on
a Shimadzu FTIR 157 spectrophotometer. Final
compound purifications were carried out using Quad biotage Flash
purifier (A Dyax Corp. Company). All 1H and 13C NMR spectra were
recorded on a Bruker AM-300 (300.12 MHz), Bruker BioSpin Corp.,
Fig. 1. ORTEP diagram showing the X-ray crystal structure of compound 2.

2508
K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
Germany, using TMS (tetra methyl silane) as an internal standard.
All chemical shifts ( ) are reported in parts per million (ppm)
7.09 (d, 1H, J ¼ 3Hz, ArH), 7.37 (s, 1H, ArH), 7.45 (dd, 1H, J ¼ 9.3Hz,
ArH), 8.03 (s, 1H, ArH), 8.05 (d, 1H, J ¼ 9.3Hz, ArH); LC/MS (ESI-MS)
m/z 296.12 (Mþ1). Anal. Calcd for C14H14N4O2; C, 62.21; H, 5.22; N,
20.73; Found; C, 62.27; H, 5.31; N, 20.68.
d
downfield from tetramethylsilane. The mass spectra were recorded
either on Single quadrapole mass or XCT Ion trap spectrometer
operating at 70 eV. The mass spectra of a few were recorded on
a 410 Prostar binary PDA detector (Varian Inc, USA). Elemental
analysis was performed on Flash EA 1112 Thermo Electron Corpo-
ration CHNSO analyzer. The homogeneity of the compounds was
monitored by thin layer chromatography (TLC) on silica gel 40 F254
(Merck, Darmstadt, Germany) coated on aluminum plates, visual-
ized by UV light and KMnO4 solution. Starting materials were
purchased from Aldrich Chemical Company or Spectrochem
Chemical Company and used without further purification. All
solvents were of analytical grade and freshly distilled prior to use.
4.5. Procedure for the preparation of 1-[1-(6-methoxy-2-
methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methanamine (5)
To a solution of 4-[4-(azidomethyl)-1H-1,2,3-triazol-1-yl]-6-
methoxy-2-methylquinoline (4) (3 g, 10.0 mmol) in methanol
(40 mL) was added Pd/C (0.3 g). The reaction mass carried out
under H2 pressure. The catalyst was filtered and the filtrate was
concentrated under reduced pressure to get a pale yellow color
viscous liquid (Yield-86%). IR (KBr,cmꢁ1
)
nmax: 3425 (NH), 1498
2.80 (s, 3H,
(CH),1210 (CO),1140 (CeN); 1H NMR (CDCl3-300 MHz)
d
4.2. Procedureforthepreparationof[1-(6-methoxy-2-methylquinolin-
CH3), 3.85 (s, 3H, OCH3), 4.20 (t, 2H, J ¼ 5.3Hz, CH2), 4.35 (br, 2H,
NH2) 7.09 (d, 1H, J ¼ 3.0 Hz, ArH), 7.37 (s, 1H, ArH), 7.45 (dd, 1H,
J ¼ 9.3Hz, ArH), 8.03 (s, 1H, ArH), 8.06 (d, 1H, J ¼ 9.3Hz, ArH); LC/MS
(ESI-MS) m/z 270.13 (Mþ1). Anal. Calcd for C14H14N4O2; C, 62.44; H,
5.61; N, 26.01; Found; C, 62.52; H, 5.72; N, 26.06.
4-yl)-1H-1,2,3-triazol-4-yl]methanol (2)
A mixture of 4-azido-6-methoxy-2-methylquinoline (1) (10 g,
0.046 mol), propargyl alcohol (12.89 g, 0.23 mol) in dry THF/
toluene (10 vol, 1:1) was heated to 120 ꢀC and the reaction was
maintained for 6 h. The reaction mass was concentrated under
reduced pressure and purified by flash chromatography over silica
gel (230e400 mesh) using 3e6% methanol in dichloromethane as
4.6. General procedure for the preparation of 1-[1-(6-methoxy-2-
methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methylamide series
(6aej)
eluant to obtain
195.8e196.1 ꢀC; IR (KBr,cmꢁ1
(CO),1140 (CeN); 1H NMR (CDCl3-300 MHz)
a
yellow color solid (7.57 g, 60%). m.p.
nmax: 3595 (OH), 1498 (CH), 1210
2.70 (s, 3H, CH3), 3.81
)
d
Pyridine (0.146 g, 1.85 mmol) was added to a solution of 1-[1-(6-
methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl] methan-
amine (5) (0.2 g, 0.74 mmol) in dichloromethane (4 mL) followed by
corresponding acid chlorides (0.74 mmol) at 0 ꢀC. The reaction
completion was monitored by TLC and the reaction was completed.
The reaction mass was concentrated under reduced pressure. The
crude product was purified on a Biotage parallel column purifier
using solvent ethyl acetate: petroleum ether (4:1) to methanol
(2e3%) in dichloromethane as eluant.
(s, 3H, CH3), 4.69 (d, 2H, J ¼ 5.4Hz, CH2), 5.40 (m, 1H, OH), 7.20 (d,
1H, J ¼ 2.7Hz, ArH), 7.51 (dd, 1H, J ¼ 9.3Hz, ArH), 7.65 (s, 1H, ArH),
8.01 (d, 1H, J ¼ 9.3Hz, ArH), 8.66 (s, 1H, ArH); 13C
d ppm (CDCl3-
75 MHz) ¼ 23.48, 53.60, 56.60,106.96, 112.18,116.98, 121.30,129.75,
133.19, 144.93, 150.27, 155.90, 162.73; LC/MS (ESI-MS) m/z 271.11
(Mþ1). Anal. Calcd for C14H14N4O2; C, 62.21; H, 5.22; N, 20.73;
Found; C, 62.27; H, 5.31; N, 20.68.
4.3. Procedureforthepreparationof[1-(6-methoxy-2-methylquinolin-
4-yl)-1H-1,2,3-triazol-4-yl]methyl methanesulfonate (3)
The characterization data including spectral data for the final
compounds, 6aej are given below.
To a cooled solution of [1-(6-methoxy-2-methylquinolin-4-yl)-
1H-1,2,3-triazol-4-yl] methanol (2) (6 g, 22.0 mmol) in dichloro-
methane (60 mL), triethylamine (5.61 g, 55 mmol) was added
methane sulfonyl chloride (3.02 g, 26.4 mmol) drop wise. The
reaction mass was stirred at 25 ꢀC for 1 h. The reaction completion
was monitored by TLC. When the reaction was complete, the mass
was diluted with methylene chloride, washed with water, brine
solution, dried over anhydrous sodium sulfatesulfate and concen-
trated under reduced pressure to afford an off white color solid
4.6.1. N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-
4-yl)methyl) acetamide (6a)
Appearance: white solid; m.p.155.7e156 ꢀC; IR (KBr,cmꢁ1
)
nmax
3480 (NH), 1630 (C]O), 1210 (CeO), 1140 (CeN); 1H NMR (CDCl3-
300 MHz) 2.05 (s, 3H, CH3), 2.79 (s, 3H, CH3), 3.86 (s, 3H, OCH3),
:
d
4.66 (d, 2H, J ¼ 5.7Hz, CH2), 6.42 (br, 1H, NH), 7.16 (d, 1H, J ¼ 2.7Hz,
ArH), 7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 8.02 (s, 1H,
ArH), 8.06 (d, 1H, J ¼ 9.3Hz, ArH); 13C NMR (CDCl3-75 MHz)
d 22.80,
(7.11 g, 92%). 1H NMR (CDCl3-300 MHz)
d 2.71 (s, 3H, CH3), 3.32 (s,
23.48, 30.63, 56.60, 107.18, 112.10, 117.02, 119.75, 121.30, 129.75,
135.82, 141.10, 145.20, 156.12, 162.73, 174.81; MS: (ESI, m/z, %): 312
(Mþ1, 45), 284 (7), 225 (18), 173 (10), 95 (33), 70 (67), 56 (100);
Anal. Calcd for C16H17N5O2; C, 61.72; H, 5.50; N, 22.49; Found; C,
61.79; H, 5.61; N, 22.44.
3H, OSO2Me), 3.80 (s, 3H, OCH3), 5.53 (s, 2H, CH2), 7.10 (d, 1H,
J ¼ 2.7Hz, ArH), 7.52 (dd, 1H, J ¼ 9.3Hz, ArH), 7.71(s, 1H, ArH), 8.01
(d, 1H, J ¼ 9.3Hz, ArH), 9.01 (s, 1H, ArH); LC/MS (ESI-MS) m/z 349.09
(Mþ1).
4.4. Procedure for the preparation of 4-[4-(azidomethyl)-1H-1,2,3-
triazol-1-yl]-6- methoxy-2-methylquinoline (4)
4.6.2. N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-
4-yl)methyl)cyclopro panecarboxamide (6b)
Appearance: off white solid; m.p. 168.4e169.1 ꢀC; 1H NMR
A mixture of [1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-
triazol-4-yl] methyl methanesulfonate (3) (4 g, 11.0 mmol), sodium
azide (1.49 g, 22.0 mmol) in dry DMF (50 mL) was stirred at 25 ꢀC
for 2 h. The reaction completion was monitored by TLC. After the
completion of the reaction, it was quenched with ice cold water.
The off white color solid obtained was filtered, washed with water
and vacuum dried (2.98 g, 88%). m.p. 218e219.2 (decomp); IR
(CDCl3-300 MHz) d 0.98 (m, 2H, CH2), 1.01 (m, 2H, CH2), 1.45 (m, 1H,
CH), 2.77 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.66 (d, 2H, J ¼ 5.7Hz, CH2),
6.71(br, 1H, NH), 7.16 (d, 1H, J ¼ 2.7Hz, ArH), 7.35 (s, 1H, ArH), 7.44
(dd, 1H, J ¼ 9.3Hz, ArH), 8.03 (s, 1H, ArH), 8.06 (d, 1H, J ¼ 9.3Hz,
ArH); 13C NMR (CDCl3-75 MHz)
d 7.17, 20.61, 23.48, 31.64, 56.60,
107.18, 112.10, 117.02, 121.30, 121.34, 129.75, 134.53, 141.10, 144.37,
156.12, 162.73, 178.61; LC/MS (ESI-MS) m/z 338.16 (Mþ1). Anal.
Calcd for C18H19N5O2; C, 64.08; H, 5.68; N, 20.76; Found; C, 64.17; H,
5.73; N, 20.73.
(KBr,cmꢁ1
300 MHz)
)
d
nmax: 2925 (CH),1210 (CO),1140 (CeN); 1H NMR (CDCl3-
2.80 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 4.69 (s, 3H, CH2),

K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
2509
4.6.3. N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-
4-yl)methyl)cyclo butanecarboxamide (6c)
7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H,
ArH); 13C NMR (CDCl3-75 MHz)
20.90, 23.48, 27.90, 31.55, 56.60,
107.18, 112.10, 117.02, 118.39, 121.30, 125.27, 126.72, 129.75, 135.85,
136.95,141.10,149.42, 149.74,156.12,162.73,168.28; LC/MS(ESI-MS)
m/z 388.17 (Mþ1).
d
Appearance: Pale yellow solid; m.p. 183.6e184 ꢀC; 1H NMR
(CDCl3-300 MHz)
d 1.01e1.2 (m, 2H, CH2), 1.36e1.48 (m, 4H, CH2),
1.98 (m, 1H, CH), 2.77 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.66 (d, 2H,
J ¼ 5.7Hz, CH2), 7.01 (br, 1H, NH), 7.16 (d, 1H, J ¼ 2.7Hz, ArH), 7.35 (s,
1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 8.03 (s,1H, ArH), 8.06 (d, 1H,
4.6.9. 4-Methoxy-N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-
1,2,3-triazol-4-yl)methyl) benzamide (6i)
J ¼ 9.3Hz, ArH); 13C NMR (CDCl3-75 MHz)
d 17.60, 23.48, 25.11,
31.64, 38.48, 56.60, 107.18, 112.10, 117.02, 121.30, 121.34, 129.75,
134.53, 141.10, 144.37, 156.12, 162.73, 177.88; LC/MS(ESI-MS) m/z
352.17(Mþ1).
Appearance: white solid; m.p. 216e216.9 ꢀC; 1H NMR (CDCl3-
300 MHz) d 2.78 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
4.86 (d, 2H, J ¼ 5.7Hz, CH2), 7.08 (d, 2H, J ¼ 8.0Hz, ArH), 7.16 (d, 1H,
J ¼ 2.7Hz, ArH), 7.23 (d, 2H, J ¼ 8.0Hz, ArH), 7.35 (s, 1H, ArH), 7.44
(dd, 1H, J ¼ 9.3Hz, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H,
ArH); LC/MS (ESI-MS) m/z 404.17 (Mþ1).
4.6.4. -Fluoro-N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-
triazol-4-yl)methyl) benzamide (6d)
Appearance: white solid; m.p. 201.4e202 ꢀC; 1H NMR(CDCl3-
4.6.10. N-[1-(6-Methoxy-2-methyl-quinolin-4-yl)-1H- [1,2,3]
triazol-4-ylmethyl]-4- trifluoromethyl-benzamide (6j)
300 MHz)
d 2.79 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.86 (d, 2H,
J ¼ 5.7Hz, CH2), 7.11e7.16 (m, 2H, ArH), 7.17 (d, 1H, J ¼ 2.7Hz, ArH),
7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.70e7.72 (m, 2H,
ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H, ArH); 13C NMR
Appearance: yellow color gummy solid; 1H NMR (CDCl3-
300 MHz)
d
2.78 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.86 (d, 2H, J ¼ 5.7Hz,
CH2), 7.16 (d, 1H, J ¼ 2.7Hz, ArH), 7.35 (s, 1H, ArH), 7.44 (dd, 1H,
J ¼ 9.3Hz, ArH), 7.80 (m, 2H, ArH) 8.03 (d,1H, J ¼ 9.3Hz, ArH), 8.05 (m,
2H, -ArH), 8.16 (s, 1H, ArH); LC/MS (ESI-MS) m/z 442.14 (Mþ1).
(CDCl3-75 MHz) d 23.48, 31.55, 56.60, 107.18, 112.10, 113.90, 114.60,
117.02, 118.39, 121.30, 126.93, 127.10, 129.75, 133.13, 136.95, 141.10,
149.74, 156.12, 159.97, 162.73, 166.47, 168.28; MS: (ESI, m/z, %): 392
(Mþ1, 38), 364 (9), 225 (19), 167 (13), 149 (80), 84 (30), 70 (57),
56 (94).
4.7. General procedure for the preparation of 1-[1-(6-Methoxy-2-
methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl] methyl sulphonamide
series (7aeg)
4.6.5. 2-Fluoro-N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-
1,2,3-triazol-4-yl)methyl) benzamide (6e)
Appearance: off white solid; m.p. 210e210.8 ꢀC; 1H NMR (CDCl3-
To a cooled solution of 1-[1-(6-Methoxy-2-methylquinolin-4-
yl)-1H-1,2,3-triazol-4-yl] methanamine (5) (0.2 g, 0.74 mmol) in
dichloromethane (4 mL) was added pyridine (0.146 g, 1.85 mmol)
followed by corresponding sulfonyl chlorides (0.74 mmol) at 0 ꢀC.
The reaction completion was monitored by TLC. After the reaction
was complete, the solvent was evaporated under reduced pressure.
The crude product was purified on a Biotage parallel column
purifier using ethyl acetate: petroleum ether (4:1) to methanol
(2e4%) in dichloromethane as eluant. The characterization and
spectral data for the title compounds 7a-g are given below.
300 MHz)
d 2.77 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.92 (d, 2H,
J ¼ 5.7Hz, CH2), 7.17 (d, 1H, J ¼ 2.7Hz, ArH) 7.26e7.32 (m, 2H, ArH),
7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.47e7.55 (m, 2H,
ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.09e8.12 (m, 1H, NH), 8.17 (s, 1H,
ArH); LC/MS (ESI-MS) m/z 392.15(Mþ1).
4.6.6. 2-Chloro-N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-
1,2,3-triazol-4-yl)methyl) benzamide (6f)
Appearance: white color solid; m.p. 148.7e149.1 ꢀC; 1H NMR
(CDCl3-300 MHz) d 2.78 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.66 (d, 2H,
J ¼ 5.7Hz, CH2), 7.12 (m, 1H, ArH), 7.16 (d, 1H, J ¼ 2.7Hz, ArH), 7.32
(m, 1H, Ar), 7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.55 (m,
2H, ArH), 8.0 (br, 1H, NH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H,
4.7.1. 4-Fluoro-N-[1-(6-methoxy-2-methyl-quinolin-4-yl)-1H-
[1,2,3]triazol-4-methyl]- benzenesulfonamide (7a)
Appearance: pale yellow solid; m.p. 232.9e233.4 ꢀC; 1H (CDCl3-
ArH); 13C NMR (CDCl3-75 MHz)
d 23.48, 31.55, 56.60, 107.18, 112.10,
300 MHz)
d 2.79 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.86 (d, 2H,
117.02, 118.39, 121.30, 125.40, 126.10, 128.60, 129.75, 132.23, 133.27,
134.40, 136.95, 141.10, 149.74, 156.12, 162.73, 166.73; LC/MS (ESI-
MS) m/z 408.3 (Mþ1).
J ¼ 5.7Hz, CH2), 7.17 (d, 1H, J ¼ 2.7Hz, ArH), 7.26e7.30 (m, 2H, ArH),
7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.65e7.72 (m, 2H,
ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H, ArH); 13C NMR (CDCl3-
75 MHz)
d 23.48, 49.11, 56.60, 107.18, 112.10, 115.20, 115.91, 117.02,
4.6.7. 4-Ethyl-N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-
triazol-4-yl)methyl) benzamide (6g)
119.53, 121.30, 128.17, 128.34, 129.75, 133.70, 139.61, 140.73, 141.10,
156.12, 162.73, 168.91; LC/MS (ESI-MS) m/z 428.11 (Mþ1).
Appearance: pale yellow solid; m.p. 208.7e209.3 ꢀC; 1H NMR
(CDCl3-300 MHz)
d
1.2 (t, 3H, J ¼ 7.2Hz, CH3), 2.2 (q, 2H, J ¼ 7.2Hz,
4.7.2. N-[1-(6-methoxy-2-methyl-quinolin-4-yl)-1H- [1,2,3]triazol-
4-ylmethyl]-2-trifluoro methyl-benzenesulfonamide (7b)
CH2), 2.78 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.86 (d, 2H, J ¼ 5.7Hz, CH2),
7.15 (d, 2H, J ¼ 8.0Hz, ArH), 7.16 (d, 1H, J ¼ 2.7Hz, ArH), 7.23 (d, 2H,
J ¼ 8.0Hz, ArH), 7.35 (s,1H, ArH), 7.44 (dd,1H, J ¼ 9.3Hz, ArH), 8.03 (d,
1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H, ArH); 13C NMR (CDCl3-75 MHz)
Appearance: white solid; m.p. 213.8 ꢀC; 1H NMR (CDCl3-
300 MHz)
d 2.78 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.86 (d, 2H,
J ¼ 5.7Hz, CH2), 7.08e7.15 (m, 2H, ArH), 7.16 (d, 1H, J ¼ 2.7Hz, ArH),
7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.54e7.62 (m, 4H,
ArH),8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H, ArH); LC/MS (ESI-MS)
m/z 478.11 (Mþ1).
d
14.60, 23.48, 27.90, 31.55, 56.60, 107.18, 112.10, 117.02, 118.39,
121.30, 127.49, 127.67, 129.75, 135.85, 136.95, 141.10, 149.42,149.74,
156.12, 162.73, 168.28; LC/MS (ESI-MS) m/z 402.19 (Mþ1).
4.6.8. N-((1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-
4-yl)methyl)-4- methylbenzamide (6h)
4.7.3. 3,4-Dichloro-N-[1-(6-methoxy-2-methyl-quinolin-4-yl)-1H-
[1e3]triazol-4-ylmeth yl]-benzenesulfonamide (7c)
Appearance: off white solid; m.p. 200e200.9 ꢀC; 1H NMR
Appearance: white solid; m.p. 217.3e217.8 ꢀC; 1H NMR (CDCl3-
(CDCl3-300 MHz)
d 2.33 (s, 1H, CH3), 2.78 (s, 3H, CH3), 3.86 (s, 3H,
300 MHz)
d 2.78 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.66 (d, 2H,
OCH3), 4.86 (d, 2H, J ¼ 5.7Hz, CH2), 7.15 (d, 2H, J ¼ 8.0Hz, ArH), 7.16
J ¼ 5.7Hz, CH2), 7.16 (d, 1H, J ¼ 2.7Hz, ArH), 7.35 (s, 1H, ArH), 7.44
(d, 1H, J ¼ 2.7Hz, ArH), 7.23 (d, 2H, J ¼ 8.0Hz, ArH), 7.35 (s, 1H, ArH),
(dd, 1H, J ¼ 9.3Hz, ArH), 7.83e7.93 (m, 2H, ArH), 8.02 (s, 1H, ArH),

2510
K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H, ArH), 8.61 (t, 1H, J ¼ 5.7Hz,
NH); LCMS (ESI-MS) m/z 478.05 (Mþ1).
purified on a column chromatography using ethyl acetate/pet
ether (4:1) as eluant to get a white solid (yield-94%). m.p.
140.2e141 ꢀC; 1H NMR (CDCl3 -300 MHz)
d 1.45 (s, 9H, CH3), 2.33
4.7.4. N-[1-(6-methoxy-2-methyl-quinolin-4-yl)-1H- [1,2,3]triazol-
4-ylmethyl]-4-methyl-benzenesulfonamide (7d)
(s, 3H, CH3), 2.53 (m, 4H, NCH2), 2.58 (m, 4H, NCH2), 3.86 (s, 3H,
OCH3), 3.88 (s, 2H, CH2), 7.20 (d, 1H, J ¼ 3.0Hz, ArH), 7.35 (s, 1H,
ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.96 (s, 1H, ArH), 8.05 (s, 1H,
J ¼ 9.3Hz, ArH).
Appearance: pale yellow solid; m.p. 198.2e199.3 ꢀC; 1H NMR
(CDCl3-300 MHz)
d 2.33 (s, 1H, CH3), 2.78 (s, 3H, CH3), 3.86 (s, 3H,
OCH3), 4.86 (d, 2H, J ¼ 5.7Hz, CH2), 7.15 (d, 2H, J ¼ 8.0Hz, ArH), 7.16
(d,1H, J ¼ 2.7Hz, ArH), 7.35 (s,1H, ArH), 7.44 (dd,1H, J ¼ 9.3Hz, ArH),
7.56 (d, 2H, J ¼ 8.0Hz, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H,
4.9. Procedure for the preparation of 6-methoxy-2-methyl-4-[4-
(piperazin-1-ylmethyl)-1H-1,2,3-triazol-1-yl]quinoline (9)
ArH), 8.35 (t, 1H, J ¼ 5.7Hz, NH); 13C NMR (CDCl3-75 MHz)
d
21.60,
23.48, 49.11, 56.60, 107.18, 112.10, 117.02, 119.53, 121.30, 126.21,
128.08, 129.75, 133.70, 139.61, 141.10, 141.58, 145.38, 156.12, 162.73;
LCMS (ESI-MS) m/z424.14 (Mþ1).
To a solution of tert-butyl 4e((1-(6-methoxy-2-methylquinolin-
4-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazine-1-carboxylate
(8)
(7 g, 0.0159 mol) in DCM (70 mL) was added trifluoroacetic acid
(15 mL) at 0 ꢀC. The reaction mixture was stirred at 26e30 ꢀC for
4 h. The reaction mixture was concentrated under reduced pressure
to get 9 as a pale yellow gummy solid (7.2 g, 100%). 1H NMR(CDCl3-
4.7.5. 4-Methoxy-N-[1-(6-methoxy-2-methyl-quinolin-4-yl)-1H-
[1,2,3]triazol-4-ylmethyl]- benzenesulfonamide (7e)
Appearance: white solid; m.p. 256e256.7 ꢀC; 1H NMR (CDCl3-
300 MHz)
d
2.78 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
300 MHz) d 2.33 (s, 3H, CH3), 2.46 (m, 4H, NCH2), 2.51 (m, 4H,
4.86 (d, 2H, J ¼ 5.7Hz, CH2), 7.08 (d, 2H, J ¼ 8.0Hz, ArH), 7.16 (d, 1H,
J ¼ 2.7Hz, ArH), 7.30 (d, 2H, J ¼ 8.0Hz, ArH), 7.35 (s, 1H, ArH), 7.44
(dd, 1H, J ¼ 9.3Hz, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H,
NCH2), 3.86 (s, 3H, OMe), 3.88 (s, 2H, CH2), 7.20 (d,1H, J ¼ 3Hz, ArH),
7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.96 (s, 1H, ArH), 8.05
(d, 1H, J ¼ 9.3Hz ArH).
ArH), 8.28 (t, 1H, J ¼ 5.7Hz, NH); 13C NMR (CDCl3-75 MHz)
d 23.48,
49.11, 55.50, 56.60, 107.18, 112.10, 114.38, 117.02, 119.53, 121.30,
124.40, 129.75, 133.70, 138.21, 139.61, 141.10, 156.12, 162.73, 162.89;
LCMS(ESI-MS) m/z 440.13 (Mþ1).
4.10. General procedure for the preparation of 6-methoxy-2-methyl-4-
[4-(piperazin-1-ylmethyl)-1H-1,2,3-triazol-1-yl]quinoline amide series
(10aek)
4.7.6. 4-Ethyl-N-[1-(6-methoxy-2-methyl-quinolin-4-yl)-1H-
[1,2,3]triazol-4-ylmethyl]-ben zenesulfonamide (7f)
Triethylamine (0.139 g, 1.375 mmol) was added to a solution of
6-methoxy-2-methyl-4-[4-(piperazin-1-ylmethyl)-1H-1,2,3-tri-
azol-1-yl]quinoline.TFA salt (9) (0.25 g, 0.55 mmol) in dry
dichloromethane (6 mL) followed by the addition of different
substituted acid chlorides (0.55 mmol) at 0 ꢀC. The reaction mixture
was stirred at the same temperature for another 30 min. The
reaction completion was monitored by TLC. After the completion of
the reaction, the mass was concentrated under reduced pressure.
The crude product was purified on a Biotage parallel column
purifier using ethyl acetate: pet ether (4:1) to MeOH (3e5%) in
dichloromethane. The characterization data for the title
compounds 10aek are given below.
Appearance: off white solid; m.p. 211e211.2 ꢀC; 1H NMR (CDCl3-
300 MHz)
d
1.2 (t, 3H, J ¼ 7.2Hz, CH3), 2.2 (q, 2H, J ¼ 7.2Hz, CH2), 2.78
(s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.86 (d, 2H, J ¼ 5.7Hz, CH2), 7.15 (d,
2H, J ¼ 8.0Hz, ArH), 7.16 (d, 1H, J ¼ 2.7Hz, ArH), 7.32 (d, 2H,
J ¼ 8.0Hz, ArH), 7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 8.03
(d, 1H, J ¼ 9.3Hz, ArH), 8.16 (s, 1H, ArH), 8.38 (t, 1H, J ¼ 5.7Hz, NH);
13C NMR (CDCl3-75 MHz)
d 15.68, 23.48, 28.48, 49.11, 56.60, 107.18,
112.10, 117.02, 119.53, 121.30, 125.32, 129.75, 131.48, 133.70, 139.61,
141.10, 145.65, 147.07, 156.12, 162.73; LCMS (ESI-MS) m/z 438.15
(Mþ1).
4.7.7. N-[1-(6-methoxy-2-methyl-quinolin-4-yl)-1H- [1e3]triazol-
4-ylmethyl]-benzene sulfonamide (7g)
4.10.1. 1-{4-[1-(6-Methoxy-quinolin-4-yl)-1H- [1,2,3]triazol-4-
ylmethyl]-piperazin-1-yl}- ethanone (10a)
Appearance: yellow gummy solid; 1H NMR (CDCl3-300 MHz)
Appearance: viscous liquid; IR (KBr,cmꢁ1
)
nmax: 2925 (CH), 1645
(C]O), 1498 (CH), 1210 (CeO), 1140 (CeN); 1H NMR (CDCl3-
300 MHz)
d
2.79 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.20 (d, 2H, J ¼ 5.7Hz, CH2),
7.16 (d, 1H, J ¼ 2.7Hz, ArH), 7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3 Hz,
ArH), 7.61e7.68 (m, 3H, ArH), 7.88e7.91 (m, 2H, ArH), 8.03 ( d, 1H,
J ¼ 9.3Hz, ArH), 8.16 (s,1H, ArH), 8.35 (t,1H, J ¼ 5.7Hz, NH); 13C NMR
d
2.10 (s, 3H, CH3), 2.58 (t, 2H, J ¼ 4.8Hz, NCH2), 4.64 (t,
2H, J ¼ 4.8Hz, NCH2), 2.79 (s, 3H, CH3), 3.52 (t, 2H, J ¼ 4.8Hz, NCH2),
3.67 (t, 2H, J ¼ 4.8Hz, NCH2), 3.86 (s, 3H, OCH3), 3.88 (s, 2H, CH2),
7.18 (d, 1H, J ¼ 2.7Hz, ArH), 7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz,
ArH), 7.95 (s, 1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH); 13C NMR (CDCl3-
(CDCl3-75 MHz)
d 23.48, 49.11, 56.60, 107.18, 112.10, 117.02, 119.53,
121.30, 124.93, 127.95, 129.75, 133.17, 133.70, 139.61, 141.10, 144.12,
156.12, 162.73; LCMS (ESI-MS) m/z ¼ 410.12 (Mþ1).
75 MHz)
d 21.09, 23.48, 44.67, 46.61, 48.98, 56.01, 56.60, 107.18,
112.10, 117.02, 118.34, 121.30, 129.75, 134.27, 141.07, 141.10, 156.12,
4.8. Procedure for the preparation of tert-butyl 4e((1-(6-methoxy-
2-methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)piperazine-1-
carboxylate (8)
162.73, 169.73; LC/MS (ESI-MS) m/z 381.2 (Mþ1).
4.10.2. Cyclopropyl-{4-[1-(6-methoxy-quinolin-4-yl)-1H- [1,2,3]
triazol-4-ylmethyl]-piperazin-1- yl}-methanone (10b)
A
mixture of [1-(6-methoxy-2-methylquinolin-4-yl)-1H-
Appearance: pale yellow solid; m.p. 120.1e120.3 ꢀC; 1H NMR
1,2,3-triazol-4-yl]methyl methane sulfonate (3) (8 g, 0.022 mol),
tert-butyl piperazine-1-carboxylate (0.025 mol), potassium
carbonate (6.33 g, 0.045 mol) in acetonitrile (100 mL) was heated
to 80 ꢀC for 1 h. The completion of reaction was monitored by
TLC. After the reaction was complete, the mass was concen-
trated, diluted with ethyl acetate, washed with water, brine
solution, dried over anhydrous sodium sulphate and finally
concentrated under reduced pressure. The crude product was
(CDCl3-300 MHz) d 0.98 (m, 2H, CH2), 1.01 (m, 2H, CH2), 1.45 (m, 1H,
CH), 2.20 (s, 3H, CH3), 2.56e2.66 (m, 4H, NCH2), 2.79 (s, 3H, CH3),
3.50e3.68 (m, 4H, NCH2), 3.85 (s, 3H, OCH3), 3.88 (s, 2H, CH2), 7.18
(d,1H, J ¼ 2.7Hz, ArH), 7.35 (s,1H, ArH), 7.44 (dd,1H, J ¼ 9.3Hz, ArH),
7.95 (s, 1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH); 13C NMR (CDCl3-
75 MHz) d 7.40, 21.43, 23.48, 44.67, 46.61, 48.98, 56.01, 56.60, 107.18,
112.10, 117.02, 118.34, 121.30, 129.75, 134.27, 141.07, 141.10, 156.12,
162.73, 169.73; LC/MS (ESI-MS) m/z 406.22 (Mþ1).

K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
2511
4.10.3. Cyclobutyl-{4-[1-(6-methoxy-quinolin-4-yl)-1H- [1,2,3]
4.10.9. (4-Methoxy-phenyl)-{4-[1-(6-methoxy-quinolin-4-yl)-1H-
triazol-4-ylmethyl]-piperazin-1- yl}-methanone (10c)
[1,2,3]triazol-4-ylmethyl]- piperazin-1-yl}-methanone (10i)
Appearance: yellow solid; m.p. 127.8e128 ꢀC; 1H NMR (CDCl3-
Appearance: yellow solid; m.p. 113.4 ꢀC; 1H NMR (CDCl3-
300 MHz)
d
2.13e2.20 (m, 6H, CH2), 2.57 (m, 4H, NCH2), 2.79 (s, 3H,
300 MHz) d 2.58 (m, 4H, NCH2), 2.79 (s, 3H, CH3), 3.38e3.41 (m, 2H,
CH3), 3.21e3.27 (m, 1H, CH), 3.38e3.41 (m, 2H, NCH2), 3.65e3.68
(m, 2H, NCH2), 3.85 (s, 3H, OCH3), 3.86 (s, 2H, CH2), 7.18 (d, 1H,
J ¼ 2.7Hz, ArH), 7.35 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.95
(s, 1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH); 13C NMR (CDCl3-75 MHz):
NCH2), 3.65e3.68 (m, 2H, NCH2), 3.72 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 3.94 (s, 2H, CH2), 7.08 (d, 2H, J ¼ 8.0Hz, ArH), 7.18 (d, 1H,
J ¼ 2.7Hz, ArH), 7.23 (d, 2H, J ¼ 8.0Hz, ArH), 7.37 (s, 1H, ArH), 7.44
(dd, 1H, J ¼ 9.3Hz, ArH), 7.95 (s, 1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz,
d
17.60, 23.48, 25.62, 40.98, 44.67, 46.61, 48.98, 56.01, 56.60, 107.18,
ArH); 13C NMR (CDCl3-75 MHz)
d 24.86, 52.94, 55.29, 55.60, 107.18,
112.10, 117.02, 118.34, 121.30, 129.75, 134.27, 141.07, 141.10, 156.12,
112.10, 113.93, 117.02, 118.34, 121.30, 127.90, 128.41, 129.75, 134.27,
141.07, 141.10, 156.12, 160.54, 162.73, 169.73; LC/MS (ESI-MS) m/z
473.22 (Mþ1).
162.73, 169.73; LC/MS (ESI-MS) m/z 421.23 (Mþ).
4.10.4. (4-Fluoro-phenyl)-{4-[1-(6-methoxy-quinolin-4-yl)-1H-
[1,2,3]triazol-4-ylmethyl]- piperazin-1-yl}-methanone (10d)
Appearance: off white solid; m.p. 135.3e136 ꢀC; 1H NMR (CDCl3-
4.10.10. {4-[1-(6-Methoxy-2-methyl-quinolin-4-yl)-1H- [1e3]
triazol-4-ylmethyl]-piperazin-1- yl}-phenyl-methanone(10j)
Appearance: pale yellow solid; m.p. 99.8e100.2 ꢀC; 1H NMR
300 MHz) d2.57 (m, 4H, NCH2), 2.79 (s, 3H, CH3), 3.38e3.41 (m, 2H,
NCH2), 3.65e3.68 (m, 2H, NCH2), 3.85 (s, 3H, OCH3), 3.86 (s, 2H,
CH2), 7.18 (d, 1H, J ¼ 2.7Hz, ArH), 7.26e7.30 (m, 2H, ArH), 7.35 (s, 1H,
ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.65e7.72 (m, 2H, ArH), 7.95 (s,
1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH); LC/MS (ESI-MS) m/z 461.20
(Mþ1).
(CDCl3-300 MHz) d 2.58 (m, 4H, NCH2), 2.79 (s, 3H, CH3), 3.38e3.41
(m, 2H, NCH2), 3.65e3.68 (m, 2H, NCH2), 3.85 (s, 3H, OCH3), 3.94 (s,
2H, CH2), 7.10 (m, 3H, ArH), 7.18 (d, 1H, J ¼ 2.7Hz, ArH), 7.21e7.26
(m, 2H, ArH), 7.37 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.95 (s,
1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH); 13C NMR (CDCl3-75 MHz)
d
24.86, 52.94, 55.60, 107.18, 112.10, 117.02, 118.34, 128.17, 21.30,
4.10.5. (2-Fluoro-phenyl)-{4-[1-(6-methoxy-quinolin-4-yl)-1H-
[1,2,3]triazol-4-ylmethyl]- piperazin-1-yl}-methanone (10e)
Appearance: white solid; m.p. 111.2 ꢀC; 1H NMR (CDCl3-
126.49, 129.75, 130.03, 132.44, 134.27, 141.07, 141.10, 156.12, 162.73,
169.73; LC/MS (ESI-MS) m/z 443.21 (Mþ1).
300 MHz)
d
2.62e2.74 (m, 4H, NCH2), 2.77 (s, 3H, CH3), 3.40 (m, 2H,
4.10.11. (3,4-Dichloro-phenyl)-{4-[1-(6-methoxy-quinolin-4-yl)-
1H- [1,2,3]triazol-4- ylmethyl]-piperazin-1-yl}-methanone (10k)
Appearance: tan color solid; m.p. 180.8e181 ꢀC; 1H NMR (CDCl3-
NCH2), 3.83 (s, 3H, OCH3), 3.87 (m, 2H, NCH2), 3.90 (s, 2H, CH2),
7.05e7.22 (m, 3H, ArH), 7.33 (s, 1H, ArH), 7.36e7.38 (m, 2H, ArH),
7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.95 (s, 1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz,
ArH); LC/MS (ESI-MS) m/z 461.20 (Mþ1).
300 MHz)
d 2.55e2.74 (m, 4H, NCH2), 2.79 (s, 3H, CH3), 3.24e3.38
(m, 4H, NCH2), 3.85 (s, 3H, OCH3), 3.89 (s, 2H, CH2), 7.18e7.31(m,
4H, ArH), 7.37 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.95 (s, 1H,
4.10.6. (2-Chloro-phenyl)-{4-[1-(6-methoxy-quinolin-4-yl)-1H-
[1,2,3]triazol-4-ylmethyl]- piperazin-1-yl}-methanone (10f)
Appearance: tan colored solid; m.p. 123.3e124 ꢀC; 1H NMR
ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH); 13C NMR (CDCl3-75 MHz)
d 21.3,
24.86, 52.94, 55.60, 107.18, 112.10, 117.02, 118.34, 121.30, 126.72,
127.63, 129.75, 131.89, 133.98, 134.27, 134.89, 136.56, 141.07, 141.10,
156.12, 162.73, 169.73; LC/MS (ESI-MS) m/z 511.14 (Mþ1).
(CDCl3-300 MHz)
d 2.55e2.74 (m, 4H, NCH2), 2.79 (s, 3H, CH3),
3.24e3.38 (m, 4H, NCH2), 3.85 (s, 3H, OCH3), 3.89 (s, 2H, CH2),
7.18e7.31(m, 5H, ArH), 7.37 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz,
ArH), 7.95 (s, 1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH); LC/MS (ESI-MS)
m/z 477.18 (Mþ1).
4.11. Antibacterial study
The newly synthesized title compounds were evaluated for their
in vitro anti-bacterial activity against ATCC-25922 Escherichia coli,
ATCC-25923 Staphylococcus aureus, ATCC-27853 Pseudomonas aer-
uginosa, clinical isolate of Klebsiella pneumoniae and Streptococcus
Pyogenes bacterial strains by serial plate dilution method. The
compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and
was diluted further (A two-fold serial dilutions) using Muller Hin-
ton broth. Serial dilutions of the drug in Muller-Hinton broth were
taken in tubes and their pH was adjusted to 7.2e7.4 using phos-
phate buffer. A standardized suspension of the test bacterium (as
per the CLSI guidelines) was inoculated and incubated for 18e24 h
at 37 ꢀC [36]. The minimum inhibitory concentration (MIC) was
noted by seeing the lowest concentration of the drug at which there
was no visible growth. Activity of each compound was compared
with ciprofloxacin as standard [37,38]. Minimum inhibitory
4.10.7. (4-Ethyl-phenyl)-{4-[1-(6-methoxy-quinolin-4-yl)-1H-
[1,2,3]triazol-4-ylmethyl]- piperazin-1-yl}-methanone (10g)
Appearance: off white solid; m.p.124e124.6 ꢀC; 1H NMR (CDCl3-
300 MHz)
d
1.2 (t, 3H, J ¼ 7.2Hz, CH3), 2.2 (q, 2H, J ¼ 7.2Hz, CH2), 2.58
(m, 4H, NCH2), 2.79 (s, 3H, CH3), 3.38e3.41 (m, 2H, NCH2),
3.65e3.68 (m, 2H, NCH2), 3.85 (s, 3H, OCH3), 3.94 (s, 2H, CH2), 7.08
(d, 2H, J ¼ 8.0Hz, ArH), 7.18 (d, 1H, J ¼ 2.7Hz, ArH), 7.23 (d, 2H,
J ¼ 8.0Hz, ArH), 7.37 (s, 1H, ArH), 7.44 (dd, 1H, J ¼ 9.3Hz, ArH), 7.95
(s, 1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz, ArH); 13C NMR (CDCl3-75 MHz)
d
14.60, 24.86, 27.90, 52.94, 55.60, 107.18, 112.10, 117.02, 118.34,
121.30, 125.75, 127.93, 129.75, 131.82, 134.27, 141.07, 141.10, 149.42,
156.12, 162.73, 169.73; LC/MS (ESI-MS) m/z 471.25 (Mþ1).
4.10.8. {4-[1-(6-Methoxy-quinolin-4-yl)-1H- [1,2,3]triazol-4-
ylmethyl]-piperazin-1-yl}-p-tolyl- methanone (10h)
concentrations (mg/mL) were determined for 6aej, 7aeg and
10aek and the corresponding results are summarized in Table 1.
Appearance: yellow solid; m.p. 119.6 ꢀC; 1H NMR (CDCl3-
300 MHz)
d
2.43 (s, 3H, CH3), 2.58 (m, 4H, NCH2), 2.79 (s, 3H, CH3),
4.12. Antituberculosis study
3.38e3.41 (m, 2H, NCH2), 3.65e3.68 (m, 2H, NCH2), 3.85 (s, 3H,
OCH3), 3.94 (s, 2H, CH2), 7.15 (d, 2H, J ¼ 8.0Hz, ArH), 7.18 (d, 1H,
J ¼ 2.7Hz, ArH), 7.23 (d, 2H, J ¼ 8.0Hz, ArH), 7.37 (s, 1H, ArH), 7.44
(dd, 1H, J ¼ 9.3Hz, ArH), 7.95 (s, 1H, ArH), 8.03 (d, 1H, J ¼ 9.3Hz,
The compounds were screened for their in vitro anti-
mycobacterial activity against M. tuberculosis H37Rv ATCC 27294,
and non-tubercular mycobacterial (NTM) species like M. smegmatis
(MC2) ATCC 19420, and M. fortuitum ATCC 19542 by Resazurin
Assay method [39] and their MIC values were determined. The
standard drugs, viz. isoniazid (INH) and rifampicin (RIF) were used
for comparison.
ArH); 13C NMR (CDCl3-75 MHz)
d 21.3, 24.86, 52.94, 55.60, 107.18,
112.10, 117.02, 118.34, 121.30, 126.32, 128.83, 129.52, 129.75, 134.27,
140.06, 141.07, 141.10, 156.12, 162.73, 169.73; LC/MS (ESI-MS) m/z
457.23 (Mþ1).

2512
K.D. Thomas et al. / European Journal of Medicinal Chemistry 46 (2011) 2503e2512
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Acknowledgement
Authors are thankful to Dr. Ganesh Sambhasivam, CEO, Anthem
biosciences, Bangalore, India, for allocation of resources for this
work. They are also grateful to the Head, Chemistry Department,
NITK, India for providing necessary laboratory facilities for the
research work and valuable support.
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