Synthesis of 3-heteroarylthioquinoline derivatives and their in vitro antituberculosis and cytotoxicity studies

Article abstract of DOI:10.1016/j.ejmech.2011.07.046

A series of 3-heteroarylthioquinoline derivatives has been synthesized by the Friedlander annulation of 2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-1- aryl-1-ethanone/2-(1,3-benzothiazol-2-ylsulfanyl)-1-aryl-1-ethanone/ 1-aryl-2-[(2-phenyl-2H-1,2,3,4-tet

Full text of DOI:10.1016/j.ejmech.2011.07.046

European Journal of Medicinal Chemistry 46 (2011) 4897e4903
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of 3-heteroarylthioquinoline derivatives and their in vitro
antituberculosis and cytotoxicity studies
,
a,
*
Selvam Chitra a, Nidhin Paul b, Shanmugam Muthusubramanian b , Paramasivam Manisankar
,
*
Perumal Yogeeswari c, Dharmarajan Sriram c
a Department of Industrial Chemistry, Alagappa University, Karaikudi 630003, Tamil Nadu, India
b Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India
c Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-heteroarylthioquinoline derivatives has been synthesized by the Friedlander annulation of
2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-1-aryl-1-ethanone/2-(1,3-benzothiazol-2-ylsulfanyl)-1-aryl-
1-ethanone/1-aryl-2-[(2-phenyl-2H-1,2,3,4-tetraazol-5-yl)sulfanyl]-1-ethanone with 2-aminobenzo-
phenone in good yields using YbCl3 as the catalyst. These compounds have been screened for their
in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and among the 21 compounds screened,
2-[2-(4-bromophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thiadiazole (5d) and 2-[2-(4-
chlorophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thiadiazole (5c) were found to be the most
Received 14 May 2011
Received in revised form
25 July 2011
Accepted 26 July 2011
Available online 3 August 2011
Keywords:
Friedlander annulation
Thiadiazole
Benzo[d]thiazole
Tetrazole
active compounds with MIC of 3.2 and 3.5
mouse fibroblasts (NIH 3T3) in vitro were evaluated for 5c and 5d, which displayed no toxic effects
(IC50 > 1000 M) against the mouse fibroblast cell line NIH 3T3.
Ó 2011 Elsevier Masson SAS. All rights reserved.
mM respectively against MTB. The cytotoxic effects against
m
Antimycobacterial activity
Mycobacterium tuberculosis
1. Introduction
effective new drugs [8] and strategies [9] are essential to treat the
TB bacilli.
Tuberculosis (TB) is an infectious disease caused by different
species of mycobacterium. The statistics shows that around 32% of
the world’s population is infected by Mycobacterium tuberculosis,
the main causal agent of TB and today more people die from
tuberculosis than ever before [1,2]. TB continues to be a major cause
of death among HIV-positive individuals [3]. Currently, the six to
nine month multidrug protocol used in the treatment of TB is
highly effective with drug-susceptible TB, but poor patient
compliance promotes development of drug resistance [4]. Although
the existing method of curing is very effective against TB, the length
of treatment, the toxicity and the potential for drugedrug inter-
actions are factors that highlight the need for new anti-tubercular
drugs [5,6]. In addition, Mycobacterium tuberculosis (MTB) is resis-
tant to some of the first and second line drugs [7]. Therefore,
As a privileged fragment, quinoline is a common structural motif
found in many natural products with remarkable pharmacological
properties [10]. Members of this family have wide applications in
medicinal chemistry, being used as antimalarial [11], anti-inflam-
matory [12], anticancer [13], anti-breast cancer [14], antibiotic [15]
and for anti-HIV activities [16]. Ciprofloxacin and moxifloxacin
(Fig. 1) are promising agents for the treatment of TB [17] having
quinoline moiety. Quinoline based mefloquine (Fig. 2) is known for
anti-tubercular activity [18e21] and its analogs have displayed
moderate [22] to submicromolar [23] anti-TB activity. Diary-
lquinoline TMC207 was targeted to the proton pump of Mycobac-
terium tuberculosis ATP synthase and found to have inhibited
mycobacterial growth effectively [24]. As mefloquine and TMC207
(Fig. 2) both target ATP synthase, it is anticipated that synthesis of
new types of molecules incorporating the molecular features of
both mefloquine and TMC207 with quinoline substructure might
produce a new hit against M. tuberculosis. Thus, in continuation to
our exploration for new anti-tubercular agents [25], we planned to
synthesize three series of 3-heteroarylthioquinolines (5e7), having
some structural similarities with mefloquine and TMC207 (Fig. 2).
* Corresponding authors. Tel./fax: þ91 452 2459845.
E-mail addresses: muthumanian2001@yahoo.com (S. Muthusubramanian),
pms11@rediffmail.com (P. Manisankar).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.07.046

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S. Chitra et al. / European Journal of Medicinal Chemistry 46 (2011) 4897e4903
and
2-aryl-4-phenyl-3-[(2-phenyl-2H-1,2,3,4-tetraazol-5-yl)sul-
O
N
O
O
fanyl]quinoline 7aeg respectively (Table 1; Scheme 1). Though
several acid catalysts such as Bronsted acids, Lewis acids and ionic
liquids have been employed for Friedlander reactions [26], some of
these procedures are complicated by harsh reaction conditions, use
of harmful organic solvents, low yields and difficulties in the work-
up procedures. Among the different catalysts tried, ytterbium (III)
chloride (YbCl3) is found to be the best for the generation of 5, 6 and
7. To the best of our knowledge, YbCl3 has not been used as
a catalyst for Friedlander reaction and is now found to be more
effective than other Lewis acids investigated.
F
F
CO2H
OH
N
N
HN
HN
OMe
Moxifloxacin
Ciprofloxacin
Fig. 1. Chemical structures of anti-TB drugs.
The structures of the 3-heteroarylthioquinolines 5, 6 and 7 were
established from 1H, 13C and 2D NMR spectroscopic data as illus-
trated for a representative example, 6e. In the 1H NMR spectrum of
6e, the p-OMe substituted aryl ring H-300 proton showed doublet at
6.84 ppm with J ¼ 9.0 Hz, which shows (i) H, H-COSY correlation
with the doublet at 7.66 ppm (J ¼ 9.0 Hz), [H-200 protons], (ii) C, H-
COSY correlation with the signal at 113.2 ppm assignable to C-300
and (iii) HMBC contours with carbon signals at 132.6, and
159.8 ppm ascribable to C-100 and C-400 respectively (Fig. 3). Further,
H-200 showed C, H-COSY correlation with the signal at 130.8 ppm
and HMBC correlations with carbon signals at 159.8 and 162.2 ppm
confirming the latter signals as C-400 and quinoline ring C-2 carbon
respectively. The quinoline H-7 proton appeared as doublet of
doublet of doublet at 7.79 ppm with J ¼ 8.4, 6.0 and 2.4 Hz, which
2. Results and discussion
2.1. Chemistry
In the present investigation, the Friedlander annulation reac-
tions of aminobenzophenone 1 with different ketones, viz. 2-[(5-
methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-1-aryl-1-ethanone 2, 2-
(1,3-benzothiazol-2-ylsulfanyl)-1-aryl-1-ethanone 3 and 1-aryl-2-
[(2-phenyl-2H-1,2,3,4-tetraazol-5-yl)sulfanyl]-1-ethanone 4 were
carried out in acetonitrile in the presence of YbCl3 as Lewis acid
catalyst at 80 ꢀC for 1 h. The reaction has led to 2-aryl-4-phenyl-3-
quinolyl (5-methyl-1,3,4-thiadiazol-2-yl)sulfides 5aeg, 1,3-
benzothiazol-2-yl [2-aryl-4-phenyl-3-quinolyl]sulphides 6aeg
HO
N
Me
N
H
Me
OH
Br
CF3
N
N
OMe
CF3
Mef loquine
TMC 207
Design Concept
CH3
N
N
N
N
S
N
N
N
S
S
S
S
N
Ar
Ph
N
Ar
N
Ar
5
6
7
O
Ph
NH2
1
O
O
O
N
N
N
S
N
S
S
N
S
Ar
Ar
Ar
N
S
CH3
N
Ph
2
3
4
Fig. 2. Design of quinoline series based on mefloquine and TMC207.

S. Chitra et al. / European Journal of Medicinal Chemistry 46 (2011) 4897e4903
4899
Table 1
Yield and Mycobacterium tuberculosis H37Rv (MTB) activities of quinoline deriva-
tives 5e7.
Entry Compd. Ar
Reaction Yield (%)a mp (ꢀC)
Time (h)
MTB (MIC)
M)
(
m
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
6e
6f
6g
7a
7b
C6H5
1
1
1
1
1
1
1
1
84
82
90
81
86
80
82
85
83
80
83
80
79
81
85
79
81
83
84
78
86
159e160
190e191
192e193
193e194
190e191
150e151
182e183
142e143
144e145
152e153
154e155
30.4
29.4
3.5
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
2-Naphthyl
4-PhC6H4
C6H5
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4 1.5
2-Naphthyl 1.5
4-PhC6H4
C6H5
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
2-Naphthyl
4-PhC6H4
3.2
28.3
13.5
6.4
55.9
54.3
12.9
5.9
Fig. 3. Selected HMBCs of 6e.
9
1.5
1.5
1.5
10
11
12
13
14
15
16
17
18
19
20
21
2.2. Pharmacology
2.2.1. Anti-tubercular activity
162e163 >52.4
165e166
242e243
161e162
143e144
142e143
180e181
148e149
120e121
173e174
50.3
47.2
54.6
53.0
50.8
23.3
51.2
49.2
46.8
0.4
1.5
2
2
2
2
2
2
2
All the newly synthesized compounds were screened for their
in vitro antimycobacterial activity against MTB in Middle brook
7H11 agar medium supplemented with OADC by agar dilution
method similar to that recommended by the National Committee
for Clinical Laboratory Standards for the determination of MIC in
duplicate [28]. The MTB clinical isolate was resistant to isoniazid,
rifampicin, ethambutol, and ciprofloxacin. The MIC is defined as the
minimum concentration of compounds required to inhibit 99% of
bacterial growth. The MIC values of the synthesized compounds
determined at 7.4 pH, along with that of standard drugs are listed in
Table 1.
7c
7d
7e
7f
7g
Isoniazid
Rifampicin
0.1
Ciprofloxacin
Ethambutol
4.7
7.6
a
After purification by column chromatography.
In the first phase of screening against MTB, all the 3-
heteroarylthioquinoline derivatives 5e7 showed good in vitro
showed H, H-COSY correlation with doublet at 8.25 ppm (J ¼ 8.4 Hz,
H-8), C, H-COSY correlation with the signal at 131.1 ppm and HMBC
contours with C-6 at 127.3 ppm and C-8a at 148.2 ppm. The doublet
of H-8 proton also showed C, H-COSY correlation with C-8 at
129.6 ppm and HMB correlations with ipso C-4a at 127.2 ppm and
C-6 at 127.3 ppm. The H-70 proton of benzo[d]thiazole ring appears
as doublet at 7.57 ppm (J ¼ 8.1 Hz) and show: (i) C, H-COSY
correlation with the signal at 120.7 ppm due to C-70 and (ii) HMBC
connections with ipso C-30a at 153.4 ppm. This H-70 proton shows
H, H-COSY correlation with multiplet at 7.16e7.22 ppm, which is
assigned to H-60 proton. The H-60 proton is further showed C, H-
COSY correlation with carbon signal at 124.0 ppm and HMBC
correlations with C-70a at 135.3 ppm. The structure of the quino-
lines 5e7 was further confirmed by a single crystal X-ray crystal-
lographic study of 6f (Fig. 4) [27].
activity against MTB with MIC ranging from 3.2 to 55.9
compounds (5c, 5d, 5g and 6d) inhibited MTB with MIC less than
6.5 M and were more potent than the first line anti-TB drug,
ethambutol (MIC: 7.6 M). When compared to ciprofloxacin (MIC:
4.7 M), two compounds 5c (MIC: 3.5 M) and 5d (MIC: 3.2 M)
mM. Four
m
m
m
m
m
were found to be more potent against MTB. The other two series of
quinolines 6aeg and 7aeg, however, were less potent than rifam-
picin, isoniazid, ciprofloxacin and ethambutol. 2-[2-(4-
Bromophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thia-
diazole (5d) displayed the maximum potency with MIC of 3.2
being 1.47 and 2.38 times more potent than ciprofloxacin and
ethambutol respectively. Another compound, 2-[2-(4-
chlorophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-
mM
O
N
N
S
Ph
Ar
CH3
S
N
S
2
N
S
N
Ar
CH3
O
5
N
S
S
Ph
O
Ar
S
N
YbCl3
Ph
3
S
CH3CN, reflux, 1-2 h
N
Ar
NH2
1
6
O
N
S
N
N
Ar
Ph
N
N
N
S
N
4
Ph
N
N
Ar
Ph
7
Scheme 1. Synthesis of quinoline derivatives 5e7.

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S. Chitra et al. / European Journal of Medicinal Chemistry 46 (2011) 4897e4903
Fig. 4. ORTEP diagram of 6f.
thiadiazole (5c), was also found to be more active with MIC of
3.5 M against MTB and is 1.34 and 2.17 times more potent than
ciprofloxacin and ethambutol respectively.
tetrazolium salt. A mitochondrial enzyme in living cells, succinate-
dehydrogenase, cleaves the tetrazolium ring, converting the MTT to
an insoluble purple formazan product that was read spectropho-
tometrically at 570 nm on the basis of linear absorbance to the
number of living cells in culture. The MTT assay was validated using
various concentrations of DMSO.
The percentage cell viability was decreased with increasing the
concentration of the both 5c and 5d (Fig. 5). However, the half
maximal inhibitory concentration (IC50) value determined by Graph
m
With respect to structure-MTB activity relationship, the data in
Table 1 show that the substituents present in the 3-position of
quinoline ring has a profound effect on the activity of 5e7, the order
of activity, in general, being 2-methyl-1,3,4-thiadiazole > benzo[d]
thiazole > 2-phenyl-2H-tetrazole as revealed by the comparison of
MIC data of compounds 5e7. It is clear that quinolines with sulfur
heterocyclic unit at position 3 are found to be more active than
quinolines having a heterocycle with four nitrogen atoms at this
position. Among the aryl groups in the series of compound 5, the
order of activity is 4-BrC6H4 > 4-ClC6H4 > 4-PhC6H4 > 2-
naphthyl > 4-MeOC6H4 > 4-MeC6H4 > C6H5. In 5 and 6, the pres-
ence of halogens in the aryl ring enhances the antimycobacterial
Pad Prism software was found to be >1000
mM for both 5c (1263 mM)
and 5d (2050 M). This indicates that the synthesized compounds 5c
m
and 5d are not toxic to the normal fibroblasts (NIH 3T3).
3. Conclusions
activity as seen from the MIC values of 5c (MIC: 3.5
3.2 M), 6d (MIC: 5.9 M) (Table 1).
mM), 5d (MIC:
In conclusion, a simple and efficient procedure for the synthesis
of novel 3-heteroarylthioquinoline derivatives in excellent yields
has been developed using Friedlander annulation in the presence of
YbCl3 as a catalyst. These quinolines displayed good in vitro anti-
mycobacterial activity against MTB. Both 5c and 5d did not produce
any cytotoxicity on NIH 3T3 cells and showed the IC50 value of
m
m
2.2.2. Cytotoxicity
The cytotoxicity of the compounds 5c and 5d were studied
in vitro using NIH 3T3 mouse embryonic fibroblasts cell line (NIH
3T3) by MTT assay [29]. MTT is a yellow colored water soluble
>1000 mM. This lack of cytotoxic potential of compounds 5c and 5d
Fig. 5. Comparison of cytotoxicity on NIH 3T3 cells for compounds 5c and 5d.

S. Chitra et al. / European Journal of Medicinal Chemistry 46 (2011) 4897e4903
4901
are of great significance for their possible use in the treatment of
MTB other than cancer.
4.2.4. 2-[2-(4-Bromophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-
methyl-1,3,4-thiadiazole (5d)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 2.59 (s,
3H, CH3), 7.32 (dd, 2H, J ¼ 6.0, 1.5 Hz, AreH), 7.46e7.52 (m, 9H,
AreH), 7.76e7.82 (m, 1H, AreH), 8.19 (d, 1H, J ¼ 8.4 Hz, AreH); 13C
NMR (75 MHz, CDCl3) dC: 15.6, 122.3, 122.9, 127.1, 127.3, 127.4, 128.2,
128.5, 129.1, 129.6, 130.9, 131.0, 131.2, 136.5, 139.2, 147.9, 155.7, 160.7,
165.2, 165.4. Anal. Calcd for C24H16BrN3S2: C, 58.78; H, 3.29; N,
8.57%. Found C, 58.74; H, 3.34; N, 8.61%.
4. Experimental
4.1. General methods
All melting points reported in this work were measured in open
capillaries. The 1H and 13C NMR spectra have been measured at 300
and 75 MHz respectively using Bruker 300 MHz (Avance) instru-
ment in CDCl3 using tetramethylsilane (TMS) as internal standard.
4.2.5. 2-[2-(4-Methoxyphenyl)-4-phenyl-3-quinolyl]sulfanyl-5-
methyl-1,3,4-thiadiazole (5e)
Chemical shifts are reported as
d values (ppm). All one- and two-
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 2.57 (s,
3H, CH3), 3.83, (s, 3H, OCH3), 6.91 (d, 2H, J ¼ 8.4 Hz, AreH),
7.31e7.33 (m, 2H, AreH), 7.45e7.47 (m, 5H, AreH), 7.63 (d, 2H,
J ¼ 8.4 Hz), 7.75e7.80 (m, 1H, AreH), 8.21 (d, 1H, J ¼ 8.4 Hz, AreH);
13C NMR (75 MHz, CDCl3) dC: 15.6, 55.3, 113.3, 122.9, 127.0, 127.1,
127.2, 128.2, 128.4, 129.1,129.5, 130.7, 131.0,132.6,136.7,147.9,155.6,
159.9, 161.4, 165.1, 165.9. Anal. Calcd for C25H19N3OS2: C, 68.00; H,
4.34; N, 9.52%. Found C, 67.94; H, 4.39; N, 9.59%.
dimensional NMR spectra were obtained using standard Bruker
software throughout. Elemental analyses were performed on
a Perkin Elmer 2400 Series II Elemental CHNS analyzer. Crystals
suitable for X-ray crystallographic studies were obtained by crys-
tallization from ethyl acetate. The antimycobial studies were
carried out at Birla Institute of Technology & Science-Pilani,
Hyderabad Campus, while the cytotoxic studies at K M C H College
of Pharmacy, Coimbatore.
4.2.6. 2-Methyl-5-[2-(2-naphthyl)-4-phenyl-3-quinolyl]sulfanyl-
1,3,4-thiadiazole (5f)
4.2. General procedure for quinoline derivatives (5e7)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 2.46 (s,
3H, CH3), 7.36e7.41 (m, 2H, AreH), 7.48e7.58 (m, 6H, AreH),
7.75e7.87 (m, 6H, AreH), 8.03 (s, 1H, AreH), 8.2 (d, 1H, J ¼ 8.4 Hz,
AreH); 13C NMR (75 MHz, CDCl3) dC: 15.4, 123.2, 126.1, 126.5, 126.7,
127.1, 127.2, 127.4, 127.5, 127.6, 128.2, 128.4, 128.5, 128.8, 129.2, 129.7,
131.1, 132.9, 133.0, 136.7, 137.8, 147.9, 155.4, 161.8, 165.4, 165.5. Anal.
Calcd for C28H19N3S2: C, 72.86; H, 4.15; N, 9.10%. Found C, 72.79; H,
4.22; N, 9.16%.
A mixture of equimolar amount of 2-aminobenzophenone 1
(100 mol %, 2.3 mmol) and ketone 2/3/4 (100 mol%, 2.3 mmol) [30]
with YbCl3 (25 mol%, 0.57 mmol) in acetonitrile (5 mL) was refluxed
for 1e2 h. After completion of the reaction (monitored by TLC), the
mixture was poured into ice water (200 mL) and the resulting crude
solid was filtered and dried. The crude product was further purified
through silica gel column (10% ethyl acetate in petroleum ether) to
afford the pure product 5e7. Full characterization data for all the
compounds (5e7) are given below.
4.2.7. 2-(2-(Biphenyl-4-yl)-4-phenylquinolin-3-ylthio)-5-methyl-
1,3,4-thiadiazole (5g)
4.2.1. 2,4-Diphenyl-3-quinolyl (5-methyl-1,3,4-thiadiazol-2-yl)
sulphide (5a)
Isolated as colorlesssolid;1H NMR (300 MHz, CDCl3)dH:2.57(s,3H,
CH3), 7.33e7.38 (m, 2H, AreH), 7.43e7.50 (m, 8H, AreH), 7.60 (d, 2H,
J ¼ 8.1 Hz, AreH), 7.61e7.63 (m, 2H, AreH), 7.72 (d, 2H, J ¼ 8.1 Hz,
AreH), 7.78 (ddd,1H, J ¼ 8.4, 5.1, 3.6 Hz, AreH), 8.24 (d,1H, J ¼ 8.4 Hz,
AreH); 13CNMR(75MHz,CDCl3)dC:15.6,122.8,126.6(2C),127.1,127.2,
127.4, 128.2, 128.5, 128.7, 129.0 (2C), 129.2, 129.7, 131.1, 136.6, 139.2,
140.7,141.2,147.9,155.5,161.6,165.3,165.7. Anal. Calcd for C30H21N3S2:
C, 73.89; H, 4.34; N, 8.62%. Found C, 73.83; H, 4.41; N, 8.67%.
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 2.58 (s,
3H, CH3), 7.35e7.40 (m, 4H, AreH), 7.49e7.53 (m, 6H, AreH), 7.65
(brs, 2H, AreH), 7.82e7.84 (m,1H, AreH), 8.48 (d, 1H J ¼ 7.5 Hz); 13C
NMR (75 MHz, CDCl3) dC: 15.6, 123.0, 127.1, 127.3, 127.4, 127.8, 128.2,
128.5,128.7,128.9,129.1,129.2,131.4,136.3,139.2,146.9,156.1,161.5,
165.3 (2C). Anal. Calcd for C24H17N3S2: C, 70.04; H, 4.16; N, 10.21%.
Found C, 69.99; H, 4.12; N, 10.26%.
4.2.8. 1,3-Benzothiazol-2-yl(2,4-diphenyl-3-quinolyl)sulphide (6a)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 7.21 (dt,
1H, J ¼ 7.4, 0.9 Hz, AreH), 7.30e7.35(m, 6H, AreH), 7.38e7.43 (m, 3H,
AreH), 7.49e7.52 (m, 2H, AreH), 7.58 (d, 1H, J ¼ 7.8 Hz, AreH),
7.62e7.67 (m, 2H, AreH), 7.69 (d,1H, J ¼ 8.1 Hz, AreH), 7.82 (ddd,1H,
J ¼ 8.4, 5.7, 2.4 Hz, AreH), 8.27 (d, 1H, J ¼ 8.4 Hz, AreH); 13C NMR
(75 MHz, CDCl3) dC: 120.6, 121.6, 122.2, 123.9, 125.8, 127.1, 127.2,
127.3, 127.6 (2C), 128.0, 128.3, 128.9, 129.1, 129.6, 131.1, 135.2, 136.4,
140.0, 148.0, 153.2, 156.4, 162.6, 167.4. Anal. Calcd for C28H18N2S2: C,
75.30; H, 4.06; N, 6.27%. Found C, 75.22; H, 4.12; N, 6.32%.
4.2.2. 2-(4-Methylphenyl)-4-phenyl-3-quinolyl(5-methyl-1,3,4-
thiadiazol-2-yl)sulfide (5b)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 2.38 (s,
3H, CH3), 2.58 (s, 3H, CH3), 7.19 (d, 2H, J ¼ 7.8 Hz, AreH), 7.31e7.33
(m, 2H, AreH), 7.46e7.47 (m, 5H, AreH), 7.54 (d, 2H, J ¼ 7.8 Hz,
AreH), 7.75e7.80 (m, 1H, AreH), 8.21 (d, 1H, J ¼ 8.4 Hz, AreH); 13C
NMR (75 MHz, CDCl3) dC: 15.6, 21.3, 122.8, 127.0 (2C), 127.2, 128.1,
128.4, 128.5, 129.0, 129.1, 129.6, 131.0, 136.6, 137.3, 138.3, 147.8,
155.4, 161.9, 165.1, 165.9. Anal. Calcd for C25H19N3S2: C, 70.56; H,
4.50; N, 9.87%. Found C, 70.50; H, 4.55; N, 9.92%.
4.2.9. 1,3-Benzothiazol-2-yl[2-(4-methylphenyl)-4-phenyl-3-
quinolyl]sulphide (6b)
4.2.3. 2-[2-(4-Chlorophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-
methyl-1,3,4-thiadiazole (5c)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 2.31 (s,
3H, CH3), 7.12 (d, 2H, J ¼ 7.8 Hz, AreH), 7.21 (t, 1H, J ¼ 7.8 Hz, AreH),
7.30e7.40 (m, 6H, AreH), 7.48e7.60 (m, 5H, AreH), 7.69 (d, 1H,
J ¼ 7.8 Hz, AreH), 7.81 (ddd, 1H, J ¼ 8.4, 5.1, 2.4 Hz, AreH), 8.26 (d,
1H, J ¼ 8.4 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 21.3, 120.7,
121.7, 122.3, 124.0, 125.9, 127.0, 127.3, 128.1, 128.4, 128.5, 129.0 (2C),
129.2, 129.7, 131.2, 135.4, 136.6, 137.3, 138.3, 148.2, 153.4, 156.7,
162.8, 167.9. Anal. Calcd for C29H20N2S2: C, 75.62; H, 4.38; N, 6.08%.
Found C, 75.56; H, 4.46; N, 6.13%.
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 2.60 (s,
3H, CH3), 7.30e7.33 (m, 2H, AreH), 7.35 (d, 2H, J ¼ 8.4 Hz, AreH),
7.43e7.50 (m, 5H, AreH), 7.59 (d, 2H, J ¼ 8.4 Hz, AreH), 7.80 (ddd,
1H, J ¼ 8.4, 5.1 & 3.0 Hz, AreH), 8.19 (d, 1H, J ¼ 8.4 Hz, AreH); 13C
NMR (75 MHz, CDCl3) dC: 15.6, 122.4, 127.1, 127.3, 127.4, 128.0, 128.2,
128.5,129.1,129.6,130.6,131.2,134.6,136.5,138.7,147.9,155.6,160.7,
165.2, 165.3. Anal. Calcd for C24H16Cl N3S2: C, 64.63; H, 3.62; N,
9.42%. Found C, 64.59; H, 3.67; N, 9.46%.

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S. Chitra et al. / European Journal of Medicinal Chemistry 46 (2011) 4897e4903
4.2.10. 1,3-Benzothiazol-2-yl[2-(4-chlorophenyl)-4-phenyl-3-
quinolyl]sulphide (6c)
128.8, 129.0, 129.2, 129.5, 130.0, 131.3, 132.8, 136.4, 140.0, 147.7,
153.7, 155.8, 161.7. Anal. Calcd for C28H19N5S: C, 73.50; H, 4.19; N,
15.31%. Found C, 73.42; H, 4.24; N, 15.38%.
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 7.21 (t,
1H, J ¼ 7.5 Hz, AreH), 7.25e7.35 (m, 5H, AreH), 7.38e7.47 (m, 3H,
AreH), 7.49e7.63 (m, 5H, AreH), 7.70 (d, 1H, J ¼ 8.1 Hz, AreH),
7.79e7.84 (m, 1H, Ar-H), 8.23 (d, 1H, J ¼ 8.7 Hz, AreH); 13C NMR
(75 MHz, CDCl3) dC: 120.7, 121.8, 122.0, 124.2, 126.0, 127.3, 127.4,
128.0,128.2,128.5,129.0,129.3,129.6,130.6,131.4,134.6,135.2,136.3,
138.5,148.0,153.2,156.7,161.4,167.1. Anal. Calcd for C28H17ClN2S2: C,
69.91; H, 3.56; N, 5.82%. Found C, 69.85; H, 3.61; N, 5.89%.
4.2.16. 2-(4-Methylphenyl)-4-phenyl-3-[(1-phenyl-1H-1,2,3,4-
tetraazol-5-yl)sulfanyl]quinoline (7b)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 2.35 (s,
3H, CH3), 6.95 (dd, 2H, J ¼ 8.1, 1.5, AreH), 7.12 (d, 2H, J ¼ 7.8 Hz,
AreH), 7.31e7.36 (m, 2H, AreH), 7.37e7.46 (m, 10 H, AreH), 7.77
(ddd, 1H, J ¼ 8.4, 5.1, 3.0 Hz, AreH), 8.2 (d, 1H, J ¼ 8.4 Hz, AreH); 13C
NMR (75 MHz, CDCl3) dC: 21.2,120.3,123.9,126.9,127.2,127.3,128.2,
128.5, 128.6, 128.7, 129.0, 129.2, 129.6, 130.0, 131.1, 133.0, 136.6,
137.3, 138.2, 147.9, 153.8, 156.0, 161.9. Anal. Calcd for C29H21N5S: C,
73.86; H, 4.49; N, 14.85%. Found C, 73.79; H, 4.56; N, 14.93%.
4.2.11. 1,3-Benzothiazol-2-yl[2-(4-bromophenyl)-4-phenyl-3-
quinolyl]sulphide (6d)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 7.23 (t,
1H, J ¼ 7.5 Hz, AreH), 7.32e7.34 (m, 2H, AreH), 7.37e7.44 (m, 6H,
AreH), 7.51e7.61 (m, 5H, AreH), 7.71 (d, 1H, J ¼ 8.1 Hz, AreH), 7.82
(ddd,1H, J ¼ 8.4, 5.1, 2.4 Hz, AreH), 8.24 (d,1H, J ¼ 8.4 Hz, AreH); 13C
NMR (75 MHz, CDCl3) dC: 120.8, 121.8 (2C),122.0,123.0,124.2,126.0,
127.4, 127.5, 128.2, 128.6, 129.0, 129.7, 130.9 (2C), 131.4, 135.3, 136.4,
139.0,148.1,153.3,156.8,161.5,167.1. Anal. Calcd for C28H17BrN2S2: C,
66.40; H, 3.26; N, 5.33%. Found C, 66.33; H, 3.32; N, 5.39%.
4.2.17. 2-(4-Chlorophenyl)-4-phenyl-3-[(1-phenyl-1H-1,2,3,4-
tetraazol-5-yl)sulfanyl]quinoline (7c)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 7.00
(dd, 2H, J ¼ 7.2, 1.2 Hz, AreH), 7.26 (d, 2H, J ¼ 8.4 Hz, AreH), 7.32
(dd, 2H, J ¼ 6.3, 3.0 Hz, AreH), 7.38e7.53 (m, 10H, AreH), 7.81 (ddd,
1H, J ¼ 8.4, 6.3, 2.1 Hz, AreH), 8.2 (d, 1H, J ¼ 8.4 Hz, AreH); 13C NMR
(75 MHz, CDCl3) dC: 120.2, 123.7, 123.9, 127.1, 127.6, 128.1, 128.4,
128.7, 129.0, 129.4, 129.7, 130.1, 130.3, 131.5, 132.9, 134.7, 136.5,
138.5, 147.9, 153.6, 155.9, 160.6. Anal. Calcd for C28H18ClN5S: C,
68.35; H, 3.69; N, 14.23%. Found C, 68.26; H, 3.76; N, 14.28%.
4.2.12. 2-[2-(4-Methoxyphenyl)-4-phenyl-3-quinolyl]sulfanyl-1,3-
benzothiazole (6e)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 3.75 (s,
3H, OCH3), 6.84 (d, 2H, J ¼ 9.0 Hz, AreH), 7.16e7.22 (m, 1H, AreH),
7.28e7.41 (m, 6H, AreH), 7.46e7.51 (m, 2H, AreH), 7.57 (d, 1H,
J ¼ 8.1 Hz, AreH), 7.66 (d, 2H, J ¼ 9.0 Hz, AreH), 7.67e7.71 (m, 1H,
AreH), 7.79 (ddd, 1H, J ¼ 8.4, 6.0, 2.4 Hz, AreH), 8.25 (d, 1H,
J ¼ 8.4 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 55.2, 113.2, 120.7,
121.7, 122.3, 124.0, 126.0, 127.0, 127.2, 127.3, 128.1, 128.4, 129.0,
129.6, 130.8, 131.1, 132.6, 135.3, 136.6, 148.2, 153.4, 156.7, 159.7,
162.2, 167.8. Anal. Calcd for C29H20N2OS2: C, 73.08; H, 4.43; N,
5.88%. Found C, 72.99; H, 4.49; N, 5.95%.
4.2.18. 2-(4-Bromophenyl)-4-phenyl-3-[(1-phenyl-1H-1,2,3,4-
tetraazol-5-yl)sulfanyl]quinoline (7d)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 7.00
(dd, 2H, J ¼ 7.7, 2.0 Hz, AreH), 7.34 (d, 2H, J ¼ 7.2 Hz, AreH),
7.39e7.40 (m, 12H, 7.50, AreH), 7.73 (dd, 1H, J ¼ 9.0, 2.4 Hz, AreH),
8.12 (d, 1H, J ¼ 9.0 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 121.5,
123.2, 123.8, 125.7, 128.1, 128.6, 128.9, 129.0, 129.4, 130.2, 130.5,
131.1, 131.3, 132.3, 132.7,133.6, 135.7,138.5, 146.3, 153.3,154.9, 160.8.
Anal. Calcd for C28H18BrN5S: C, 62.69; H, 3.38; N, 13.06%. Found C,
62.63; H, 3.45; N, 13.12%.
4.2.13. 1,3-Benzothiazol-2-yl[2-(5,8-dihydro-2-naphthalenyl)-4-
phenyl-3-quinolyl]sulphide (6f)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 7.15 (dt,
1H, J ¼ 7.2, 0.9 Hz, AreH), 7.26 (dt, 1H, J ¼ 7.5, 1.2 Hz, AreH),
7.34e7.45 (m, 7H, AreH), 7.48e7.55 (m, 3H, AreH), 7.61e7.69 (m,
2H, AreH), 7.75e7.83 (m, 4H, AreH), 8.11 (s, 1H, AreH), 8.29 (d, 1H,
J ¼ 8.4 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 120.6, 121.7, 122.5,
124.1, 125.9 (2C), 126.3, 126.8, 127.2, 127.3, 127.5 (2C), 128.1 (2C),
128.3, 128.5, 128.9, 129.1, 129.7, 131.2, 132.7, 133.0, 135.3, 136.5,
137.6, 148.1, 153.2, 156.7, 162.6, 167.4. Anal. Calcd for C32H20N2S2: C,
77.39; H, 4.06; N, 5.64%. Found C, 77.32; H, 4.13; N, 5.70%.
4.2.19. 2-(4-Methoxyphenyl)-4-phenyl-3-[(1-phenyl-1H-1,2,3,4-
tetraazol-5-yl)sulfanyl]quinoline (7e)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 3.77 (s,
3H, OCH3), 6.81 (d, 2H, J ¼ 9.0 Hz, AreH), 6.96 (dd, 2H, J ¼ 7.8,1.2 Hz,
AreH), 7.27e7.30 (m, 2H, AreH), 7.34e7.43 (m, 8H, AreH), 7.50 (d,
2H, J ¼ 9.0 Hz, AreH), 7.76 (ddd,1H, J ¼ 8.4, 5.1, 3.0 Hz, AreH), 8.2 (d,
1H, J ¼ 8.4 Hz, AreH); 13C NMR (75 MHz, CDCl3) dC: 55.2, 113.3,
120.3, 123.8, 126.9, 127.1, 127.2, 128.2, 128.5, 128.9, 129.2, 129.4,
129.6, 130.3, 131.1, 132.6, 132.9, 136.6, 147.9, 153.7, 155.6, 159.7, 161.4.
Anal. Calcd for C29H21N5OS: C, 71.44; H, 4.34; N, 14.36%. Found C,
71.50; H, 4.40; N, 14.45%.
4.2.14. 2-(2-(Biphenyl-4-yl)-4-phenylquinolin-3-ylthio)benzo[d]
thiazole (6g)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 7.21 (t,
1H, J ¼ 7.5 Hz, AreH), 7.30e7.43 (m, 9H, AreH), 7.50e7.59 (m, 7H,
AreH), 7.69 (d,1H, J ¼ 8.1 Hz, AreH), 7.78 (d, 2H, AreH), 7.79e7.85(m,
4.2.20. 2-(5,8-Dihydro-2-naphthalenyl)-4-phenyl-3-[(1-phenyl-
1H-1,2,3,4-tetraazol-5-yl)sulfanyl]quinoline (7f)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 6.58 (d,
2H, J ¼ 7.8 Hz, AreH), 7.13 (t, 2H, J ¼ 8.1 Hz, AreH), 7.21e7.31 (m, 1H,
AreH), 7.37e7.60 (m, 10H, AreH), 7.70e7.80 (m, 4H, AreH), 7.92 (s,
1H,AreH), 8.32(d,1H,J ¼ 8.4Hz,AreH); 13CNMR(75MHz, CDCl3)dC
:
120.7, 121.8, 122.3, 124.1, 126.0, 126.6, 127.1, 127.2, 127.3, 127.4, 127.5,
128.2, 128.5, 128.6, 129.1, 129.7 (2C), 131.2, 135.4, 136.5, 139.1, 140.7,
141.2, 148.2, 153.3, 156.6, 162.4, 167.6. Anal. Calcd for C34H22N2S2: C,
78.13; H, 4.24; N, 5.36%. Found C, 78.05; H, 4.30; N, 5.43%.
1H,AreH), 8.21 (d,1H, J ¼ 8.4Hz, AreH);13C NMR(75 MHz, CDCl3) dC
:
120.7, 123.7, 126.3, 126.5, 126.6, 127.1, 127.4, 127.5 (2C), 127.6, 128.2,
128.3,128.4,128.6,129.0,129.1, 129.7,129.8,131.3,132.6,132.7,133.0,
136.6, 137.4, 147.9, 153.8, 155.7, 161.8. Anal. Calcd for C32H21N5S: C,
75.72; H, 4.17; N, 13.80%. Found C, 75.65; H, 4.22; N, 13.87%.
4.2.15. 2,4-Diphenyl-3-[(1-phenyl-1H-1,2,3,4-tetrazol-5-yl)
sulfanyl]quinoline (7a)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 6.96 ( d,
2H, J ¼ 7.5 Hz, AreH), 7.33e7.41 (m, 7H, AreH), 7.43e7.50 (m, 6H,
AreH), 7.55 (dd, 2H, J ¼ 7.1, 2.0 Hz, AreH), 7.82 (ddd, 1H, J ¼ 8.4, 5.7,
2.1 Hz, AreH), 8.26 (d, 1H, J ¼ 8.4 Hz, AreH); 13C NMR (75 MHz,
CDCl3) dC: 120.1, 123.9, 127.0, 127.3, 127.4, 127.8, 128.2, 128.4, 128.5,
4.2.21. 2-(Biphenyl-4-yl)-4-phenyl-3-(1-phenyl-1H-tetrazol-5-
ylthio)quinoline (7g)
Isolated as colorless solid; 1H NMR (300 MHz, CDCl3) dH: 6.94 (d,
2H, J ¼ 7.8 Hz, AreH), 7.27e7.30 (m, 2H, AreH), 7.36e7.38 (m, 3H,
AreH), 7.41e7.49 (m, 7H, AreH), 7.53e7.61 (m, 7H, AreH), 7.76e7.82

S. Chitra et al. / European Journal of Medicinal Chemistry 46 (2011) 4897e4903
4903
(m, 1H, AreH), 8.23 (d, J ¼ 8.4 Hz, AreH); 13C NMR (75 MHz, CDCl3)
Appendix. Supplementary data
dC: 120.3, 123.9, 126.6, 127.0 (2C), 127.3, 127.4, 127.5, 128.3, 128.6,
128.8,129.0,129.2,129.3,129.7,130.0,131.3,132.9,136.6,139.1,140.4,
141.2,147.9,153.8,155.7,161.5. Anal. Calcd for C34H23N5S: C, 76.52; H,
4.34; N, 13.12%. Found C, 76.44; H, 4.40; N, 13.19%.
Supplementary data related to this article can be found online at
doi:10.1016/j.ejmech.2011.07.046.
4.3. Anti-tubercular activity
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37 ꢀC, 5% CO2, 95% air and 100% relative humidity for 48 h. The
medium containing without samples were served as control. Trip-
licate was maintained for all concentrations. After 48 h, the cells in
each well were quantified by MTT assay [29]. Briefly, 15 ml of MTT
(5 mg/mL) inphosphatebufferedsaline (PBS) was added toeach well
and incubated at 37 ꢀC for 4 h. The medium with MTT was then
flicked off and the formed formazan crystals were solubilized in
100 ml of DMSO and then measured the absorbance at 570 nm using
micro plate reader. The percentage cell viability was then calculated
with respect to positive control as follows:
% Cell viability ¼ ½AꢂTest=½AꢂControl ꢃ 100
Acknowledgments
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The authors thank DST for funds under IRHPA program toward
high resolution NMR spectrometer and N. Adhirajan, KMCH College of
Pharmacy, Coimbatore, Tamil Nadu, India for cytotoxicity studies.
Financial support from UGC, New Delhi to NP is gratefully
acknowledged.
(b) L. Yimin, Z. Wei, QSAR Comb. Sci. 25 (2006) 728e731;
(c) L. Eberhard, R. Dieter, Z. Chem. 15 (1975) 351e352.