An efficient one-pot cyclization of quinoline thiosemicarbazones to quinolines derivatized with 1,3,4-thiadiazole as anticancer and anti-tubercular agents

Article abstract of DOI:10.1007/s00044-010-9522-z

A series of 6,7,8-substituted thiosemicarbazones (2a-j) of 2-chloro-3-formyl-quinoline derivatives were cyclized to the title compounds (3a-j) using acetic anhydride. The structures of the final compounds (3a-j) were confirmed by elemental and spectral (IR, ¹H NMR and MS) analysis. Some of the title compounds have shown promising anticancer and antitubercular activities. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9522-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:185–191
DOI 10.1007/s00044-010-9522-z
ORIGINAL RESEARCH
An efficient one-pot cyclization of quinoline thiosemicarbazones
to quinolines derivatized with 1,3,4-thiadiazole as anticancer
and anti-tubercular agents
Sheetal B. Marganakop
•
•
Ravindra R. Kamble
Tasneem Taj Mahadevappa Y. Kariduraganvar
•
Received: 24 July 2010 / Accepted: 18 November 2010 / Published online: 8 December 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of 6,7,8-substituted thiosemicarbazones
2a–j) of 2-chloro-3-formyl-quinoline derivatives were
(Fig. 1). 2-Chloroquinoline constitutes one of the most
(
active classes of compounds possessing diversified bio-
logical activities (Hirao et al., 1976; Pokalwar et al., 2006;
Kategaonkar et al., 2010).
cyclized to the title compounds (3a–j) using acetic
anhydride. The structures of the final compounds (3a–j) were
1
confirmed by elemental and spectral (IR, H NMR and MS)
Literature survey reveals that 1,3,4-thiadiazole deriva-
tives have been incorporated into a large number of com-
pounds with potential medicinal values such as
antibacterial, antifungal, antitubercular and antitumor
activities (Solak and Rollas, 2006; Padmavathi et al., 2010;
Lamani et al., 2009; Meng et al., 2009). Many drugs
containing 1,3,4-thiadiazole as lead nucleus such as acet-
azolamide, methazolamide, sulfamethizole, are presently
available in the market (Fig. 1).
analysis. Some of the title compounds have shown promising
anticancer and antitubercular activities.
Keywords Quinoline Á 1,3,4-Thiadiazole Á Cyclization Á
Anticancer activity Á Antitubercular activity Á SAR Á
c log P
Introduction
Tuberculosis is the single largest infectious disease
having a high mortality rate and due to this every year
0.10–0.30% of population is being infected in the devel-
oping as well as in the developed countries. It is commonly
known that Mycobacterium tuberculosis has developed
resistance to the majority of the existing drugs. Ring
substituted quinolines have been reported as new structural
class of anti-TB agents which can act by their mechanism
and these are different from those of currently used drugs
against a panel of drug sensitive and drug resistant strains
(Vangapandu et al., 2004). Cancer is another major cause
of the death in the world. It is a devastating disease caused
due to the uncontrolled growth of the cells which are
characterized by their out of limit growth. In view of the
above mentioned facts and as a part of SAR studies we
have made an attempt to achieve novel molecules with
better anticancer and anti-TB properties. And hence in this
report 1,3,4-thiadiazole as a substituent is incorporated
on 2-chloroquinoline nucleus viz., N-[4-acetyl-5-(6,7,8-
substituted-2-chloroquinolin-3-yl)-4,5-dihydro-1,3,4-thia-
diazol-2-yl]-acetamides (3a–j) and further screened them
for anticancer activity against cervical cancer cell (Hela)
The design as well as identification of new molecules for
the treatment of diseases such as the cancer and tubercu-
losis is an important undertaking in medicinal chemistry
research. The quinoline derivatives have been known to
possess wide spectrum of pharmacological properties
(
Nayar and Jain, 2008; Lilienkampf et al., 2009;
Mital et al., 2006; Leclerc et al., 1986). They are the
backbone in numerous commercial products such as
perfumes, dyes including pharmaceuticals. Quinoline
derivatives viz., ofloxacin, norfloxacin, ciprofloxacin,
chloroquine, etc., have been used as efficient drugs till date
S. B. Marganakop Á R. R. Kamble (&) Á T. Taj Á
M. Y. Kariduraganvar
PG Department of Studies in Chemistry,
Karnatak University, Dharwad 580003, India
e-mail: kamchem9@gmail.com
123

1
86
Med Chem Res (2012) 21:185–191
O
N
O
O
N
O
F
O-
F
N
N
HN
HN
CH3
Ciprofloxacin
Norfloxacin
O
O
O
H C
3
O
N
H
S
N
H N
S
2
S
N
S
S
N
N
O
S
NH2
CH3
HN
N
O
N
N
H C
3
O
O
H N
2
Sulfamethizole
Acetazolamide
Methazolamide
Fig. 1 Structurally related bio-active compounds
and antitubercular activity assay against Mycobacterium
tuberculosis H Rv.
Results and discussion
3
7
The structures of the final compounds (3a–j) were con-
1
firmed by their elemental analysis, IR, H NMR and mass
Chemistry
spectral data.
The IR spectra of the title compounds (3a–j) have
shown mainly a sharp strong absorption band around
The thiosemicarbazones (2a–j) were prepared by the con-
densation of 6,7,8-substituted-2-chloro-3-formyl-quinolines
-
1
1655–1685 cm which corresponds to amide carbonyl
group. Another medium absorption band was observed at
(
1a–j) with thiosemicarbazide in ethanol. The intermediate
thiosemicarbazones (2a–j) were further converted to N-
4-acetyl-5-(6,7,8-substituted-2-chloroquinolin-3-yl)-4,5-
-
around 1602–1642 cm due to C=N stretching.
1
1
The H NMR spectral analysis of the title compounds
[
dihydro-1,3,4-thiadiazol-2-yl]-acetamides (3a–j) by the
action of acetic anhydride on the compounds (2a–j)
(3a–j) has shown a characteristic singlet in the range d
6.2–7.3 ppm responsible for C –H of the 1,3,4-thiadiazole
5
(
Scheme 1). The proposed mechanism for the conversion of
thiosemicarbazones (2a–j) to the quinolines derivatized with
,3,4-thiadiazoles (3a–j) is given in (Scheme 2).
ring. The aldehydic proton (–CH=N) in the corresponding
thiosemicarbazones (2a–j) appeared around d 8.05–
8.35 ppm. This shift in the signal to d 6.2–7.3 ppm in the
1
Scheme 1 Overview of
synthetic pathway of
N-[4-acetyl-5-(6,7,8-
O
H
R2
R2
CNNHCSNH2
H
2
NH NHCSNH2
substituted-2-chloroquinolin-
3
-yl)-4,5-dihydro-1,3,4-
thiadiazol-2-yl]-acetamides
3a–j)
R3
N
Cl
EtOH,H O,1-2 hr
2
R3
N
Cl
R1
(
R1
2
a-j
1a-j
(
CH CO) O
3
2
8
0-90 OC,1hr
H COC
3
N
N
NHCOCH3
R2
S
R3
N
Cl
R1
3a-j
1
23

Med Chem Res (2012) 21:185–191
187
Scheme 2 Proposed
mechanism for the
transformation of
thiosemicarbazones 2 (a–j)
to 1,3,4-thiadiazole
derivatives 3 (a–j)
O
H
O
.
N
.
CH3
H3COC
NHCOCH 3
O
H
N
N
H3C
NH2
:
N
R2
R3
S
R2
S
H
H
-AcO
N
Cl
N
Cl
R3
R1
R1
2
a-j
O
-
O
CH3
H
H3COC
N
N
NHCOCH 3
R2
R3
S
3 a-j
-
AcOH
N
Cl
R1
title compounds (3a–j) confirmed the cyclization of thio-
semicarbazone to 1,3,4-thiadiazole. The protons of the
substituent groups and the aromatic protons appeared in
their respective regions.
administration and all the synthesized compounds have
molecular weight within acceptable range (200–500). The
synthesized compounds did not show any of the toxic
properties like, mutagenicity, tumorigenicity, irritant nat-
ure, reproductive effect. On the basis of these properties,
we can ascertain that these may exhibit better drug likeli-
ness property and drug score.
A lead molecule to consider it as a drug candidate,
parameters set by Lipinski’s rule of five is analyzed. The
c log P is an important physiochemical property indicating
the lipophilicity which determines the ability of molecule
to cross the various biological membranes. The calcula-
tions of c log P values of compounds were done at self
Anticancer activity was carried out against cervical
cancer cell lines (Hela). The activity of the compounds 3b
(methyl at C of quinoline), 3c (methoxy at C of quino-
6
6
consistent field theory level using PM (Hamiltonian Inc.)
3
line) and 3h (two methoxy groups at C and C of quino-
7 8
in MOPAC 6.0 PACKAGE (Stewart, 1989, 1990) and are
tabulated in Table 1. According to Lipinski’s rule of five
the c log P value below 5 is feasible for a compound to be
future drug (Lipinski et al., 1997). The synthesized com-
pounds showed a marginal lipophilicity within the range of
line) are encouraging. These compounds have shown very
good anticancer activity and the cell lyses occurred only at
10 lg/ml. However, the compounds 3a (with no sub-
stituent), 3f (methoxy group at C8 of quinoline) and
3g (methoxy group at C of quinoline) have also exhib-
7
1
.91–3.25, indicating that these compounds have better
ited anticancer activity and the cell lyses was found at
15 lg/ml. Where as the compounds 3d, 3e, 3i and 3j have
shown poor activity (Table 2; Fig. 2).
penetrating power into the cell membrane. The molecular
weight property of the compound is related to its in vivo
Table 1 Physical data and yields of N-[4-acetyl-5-(6,7,8-substituted-2-chloroquinolin-3-yl)-4,5-dihydro-1,3,4-thiadiazol-2-yl]-acetamides
3a–j)
(
Compound
R
1
R
2
R
3
Formula
Mol. wt.
c log P
Drug likeliness
Drug score
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
H
H
H
C
15
C
16
C
16
C
16
C
16
C
16
C
16
C
17
C
15
C
15
H
H
H
H
H
H
H
H
H
H
13ClN
15ClN
15ClN
15ClN
15ClN
15ClN
15ClN
17ClN
4
4
4
4
4
4
4
4
O
O
O
O
O
O
O
O
2
2
3
2
2
3
3
4
S
S
S
S
S
S
S
S
348.80
362.83
378.83
362.83
362.83
378.83
378.83
408.86
383.25
427.70
2.91
3.22
2.02
3.22
3.22
2.80
2.02
1.91
2.74
2.74
4.49
3.48
3.10
4.70
3.48
4.74
3.10
3.52
3.25
3.02
0.76
0.70
0.81
0.71
0.70
0.74
0.80
0.80
0.74
0.74
H
CH
3
H
H
OCH
H
3
H
CH
H
3
H
H
CH
H
3
OCH
H
3
H
g
h
i
H
OCH
OCH
Cl
3
3
H
OCH
H
3
H
2
12Cl N
4
O
2
S
j
H
Br
H
12BrClN
4
O
2
S
123

1
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Med Chem Res (2012) 21:185–191
Table 2 Anticancer activity of the compounds (3a–j) against human
cervical cancer cell lines (HELA)
Table 3 Antitubercular activities of the synthesized compounds
(3a–j)
a
Entry no.
Concentration (lg/ml)
Entry no.
Concentration (lg/ml)
5
10
25
3
3
3
3
3
3
3
3
3
3
a
a
b
c
d
e
f
15.0
10.0
10.0
25.0
20.0
15.0
15.0
10.0
20.0
20.0
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
R
R
R
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
S
g
h
i
g
h
i
R
R
R
R
j
Minimum concentration at which cell mortality (lyses) occur
3j
Standard: streptomycin (inhibition at 10 lg/ml)
R resistant, S sensitive
Antitubercular activity was carried out against Myco-
bacterium tuberculosis H Rv. The assay reveals that the
3
7
compounds 3d and 3f (with methyl and methoxy groups at
the C of quinoline nucleus, respectively) have shown the
8
1
inhibition (MIC) at 5 lg/ml. The remaining compounds 3a,
Nicolet 5700 using KBr pellets. The H NMR spectra were
recorded on a Varian (300 MHz) FT-NMR spectrometer in
3
b, 3c, 3e, 3g, 3h, 3i and 3j have shown the activity at
1
0 lg/ml. Encouraging activity may be attributed to the
presence of electron donating groups viz., OCH and CH
DMSO-d with TMS as an internal standard. Mass spectra
6
3
3
were recorded on a GCMS-SC\AD\17-004 Mass spec-
trometer. Elemental analyses were performed on Heraus
CHN analyzer. All the reagents and solvents were of ana-
lytical grade, and used as supplied unless otherwise stated.
TLC was performed on silica gel coated plates for moni-
toring the reactions. 2-Chloro-3-formyl-quinoline deriva-
tives (1a–j) and the corresponding thiosemicarbazones
at C of quinoline nucleus (Table 3). It is interesting to
8
note that the compounds which have shown anticancer
activity have not exhibited the antitubercular activity and
vice versa, suggesting that the compounds exhibited
selectivity either as anticancer or as antitubercular agents.
(
2a–j) were prepared as per the reported method (Otto
Experimental
and Bramha, 1978, 1981). Anticancer and antitubercular
activity assay were carried out according to the literature
method (Doyle and Griffiths, 2000) at the Department of
Molecular Biology and Immunology, N.G.H. Institute of
Melting points were measured with open capillary in a
melting point apparatus. FT-IR spectra were recorded on
Fig. 2 Photographs showing
the cervical cancer cell lysis at
different concentrations by the
title compounds 3a, 3b, 3c, 3d,
3
f and the control
1
23

Med Chem Res (2012) 21:185–191
189
Dental Sciences and Research Centre, Belgaum, Karna-
taka, India.
C, 50.79; H, 4.00; N, 14.79. Found: C, 50.84; H, 4.08; N,
14.81.
General procedure for the preparation of N-(4-acetyl-
5
N-(4-Acetyl-5-(2-chloro-8-methylquinolin-3-yl)-4,5-
dihydro-1,3,4-thiadiazol-2-yl)-acetamide (3d)
-(6,7,8-substituted-2-chloroquinolin-3-yl)-4,5-
dihydro-1,3,4-thiadiazol-2-yl)-acetamides (3a–j)
Yellow crystals. Yield; 65.2% mp (°C); 200–203. IR (m
max
-
1
1
A mixture of the compounds (2a–j) (0.005 mol) and acetic
anhydride (4 ml) was heated at 80–90°C for 1 h. The
reaction mixture was cooled to room temperature and then
poured into the ice-cold water. The precipitate thus
obtained was filtered off, washed with water, dried and
crystallized from alcohol to get pale yellow to brown
needles of the compounds (3a–j).
in cm ); 3430, 2922, 1655, 1612. H NMR (300 MHz, d
ppm, DMSO-d ); 2.18 (s, 3H, CH of NHCOCH ), 2.20 (s,
6
3
3
3H, CH of N –COCH ), 2.34 (s, 3H, CH of Ar–CH ),
3
4
3
3
3
7.20 (s, 1H, C –H), 8.22 (m, 3H, Ar–H, quin C –H, C –H,
5
5
6
C –H), 8.92 (s, 1H, Ar–H, quin C –H), 11.69 (s, 1H,
7
4
NHCO). LC–MS (70 eV, m/z); 363.0 (M ? 1, 32.3), 197.2
(21.2), 161.8 (100). CHN Analysis; Calculated for
C H ClN O S: C, 52.98; H, 4.17; N,15.44. Found: C,
1
6
15
4 2
N-(4-Acetyl-5-(2-chloroquinolin-3-yl)-4,5-dihydro-
,3,4-thiadiazol-2-yl)-acetamide (3a)
53.08; H, 4.23; N, 15.50.
1
N-(4-Acetyl-5-(2-chloro-7-methylquinolin-3-yl)-4,5-
dihydro-1,3,4-thiadiazol-2-yl)-acetamide (3e)
Pale yellow crystals. Yield; 65% mp (°C); 210–213. IR
mmax in cm ); 3421, 2926, 1659, 1615. H NMR (300
-
1
1
(
MHz, d ppm, DMSO-d ); 2.14 (s, 3H, CH of NHCOCH ),
Yellow crystals. Yield; 72.3% mp (°C); 195–197. IR (m
6
3
3
max
-
1
1
2
8
8
.21 (s, 3H, CH of N –COCH ), 6.59 (s, 1H, C –H),
3
in cm ); 3400, 2899, 1668, 1618. H NMR (300 MHz, d
ppm, DMSO-d ); 2.08 (s, 3H, CH of NHCOCH ), 2.11 (s,
4
3
5
.30–8.16 (m, 4H, Ar–H, quin C –H, C –H, C –H, C –H),
5
6
7
8
6
3
3
.78 (s, 1H, quin C –H), 11.72 (s, 1H, NHCO). LCMS
4
3H, CH of N –COCH ), 2.29 (s, 3H, CH of Ar–CH ),
3 4 3 3 3
(
70 eV, m/z); 352.2 (M ? 1, 18.3), 188 (8.2), 153 (100).
CHN Analysis; Calculated for C H ClN O S: C, 51.65;
6.88 (s, 1H, C –H), 8.80 (s, 1H, ArH, quin C –H),
5 4
8.02–8.25 (m, 3H, Ar–H quin C –H, C –H, C –H), 11.54
5
1
5
13
4
2
6
8
H, 3.76; N, 16.06. Found: C, 51.60; H, 3.70; N, 15.99.
(s, 1H, NHCO). LC–MS (70 eV, m/z); 362.2 (M ? 1,
5.3), 198.2 (20.2), 161.0 (100). CHN Analysis; Calculated
for C H ClN O S: C, 52.82; H, 4.15; N, 15.32. Found: C,
2
N-(4-Acetyl-5-(2-chloro-6-methylquinolin-3-yl)-4,5-
dihydro-1,3,4-thiadiazol-2-yl)-acetamide (3b)
1
6
15
4 2
52.88; H, 4.12; N, 15.38.
Yellow crystals. Yield; 75% mp (°C); 168–170. IR (m
in
N-(4-Acetyl-5-(2-chloro-8-methoxyquinolin-3-yl)-
4,5-dihydro-1,3,4-thiadiazol-2-yl)-acetamide (3f)
max
-
1
1
cm ); 3430, 2922, 1655, 1612. H NMR (300 MHz, d
ppm, DMSO-d ); 2.16 (s, 3H, CH of NHCOCH ), 2.18 (s,
6
3
3
3
7
8
H, CH of N –COCH ), 2.34 (s, 3H, CH of Ar–CH ),
3
Yellow crystals. Yield; 75.8% mp (°C); 205–207. IR (m
3
4
3
3
max
-
1
1
.00 (s, 1H, C –H), 8.97 (s, 1H, ArH, quin C –H)
5
in cm ); 3389, 2984, 1669, 1617. H NMR (300 MHz, d
ppm, DMSO-d ); 2.13 (s, 3H, CH of NHCOCH ), 2.18 (s,
4
.06–8.16 (m, 3H, Ar–H, quin C –H, C –H, C –H), 11.86
5
7
8
6
3
3
(
s, 1H, NHCO). LC–MS (70 eV, m/z); 363.2 (M ? 1,
0.3), 197.6 (22.2), 162.5 (100). CHN Analysis; Calculated
for C H ClN O S: C, 52.96; H, 4.17; N, 15.44. Found: C,
3H, CH of N –COCH ), 3.55 (s, 3H, OCH of OCH ),
3 4 3 3 3
3
6.86 (s, 1H, C –H), 8.25–8.40 (m, 3H, Ar–H, quin C –H,
5 5
C –H, C –H), 8.78 (s, 1H, Ar–H, quin C –H), 11.89 (s, 1H,
4
1
6
15
4
2
6
7
5
3.06; H, 4.08; N, 15.52.
NHCO). LC–MS (70 eV, m/z); 380.2 (M ? 1, 33.0), 215.8
20.3), 153.5 (100). CHN Analysis; Calculated for
C H ClN O S: C, 50.72; H, 3.3.78; N, 14.62. Found: C,
(
N-(4-Acetyl-5-(2-chloro-6-methoxyquinolin-3-yl)-4,5-
dihydro-1,3,4-thiadiazol-2-yl)-acetamide (3c)
1
6
15
4 3
50.80; H, 3.85; N, 14.69.
Yellow crystals. Yield; 72% mp (°C); 200–205. IR (m
in
N-(4-Acetyl-5-(2-chloro-7-methoxyquinolin-3-yl)-4,5-
dihydro-1,3,4-thiadiazol-2-yl)-acetamide (3g)
max
-
1
1
cm ); 3434, 2974, 1660, 1620. H NMR (300 MHz, d
ppm, DMSO-d ); 2.13 (s, 3H, CH of NHCOCH ), 2.16 (s,
6
3
3
3
H, CH of N –COCH ), 3.45 (s, 3H, of OCH ), 6.91 (s,
3
Yellow crystals. Yield; 64.3% mp (°C); 203–205. IR (m
4
3
3
max
-
1
1
1
H, C –H), 8.22–8.32 (m, 3H, Ar–H, quin C –H, C –H,
5
in cm ); 3299, 2872, 1672, 1616. H NMR (300 MHz, d
ppm, DMSO-d ); 2.11 (s, 3H, CH of NHCOCH ), 2.14 (s,
5
7
C –H), 8.82 (s, 1H, quin C –H), 11.80 (s, 1H, NHCO).
8
4
6
3
3
LC–MS (70 eV, m/z); 380.0 (M ? 1, 31.0), 216 (20), 153
100). CHN Analysis: Calculated for C H ClN O S:
3H, CH of N –COCH ), 3.68 (s, 3H, OCH ), 6.98 (s, 1H,
3 4 3 3
(
C –H), 8.32–8.42 (m, 3H, Ar–H, quin C –H, C –H, C –H),
5
1
6
15
4
3
5
6
8
123

1
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Med Chem Res (2012) 21:185–191
8
.82 (s, 1H, Ar–H, quin C –H) 11.40 (s, 1H, NHCO). LC–
4
Anticancer activity
MS (70 eV, m/z); 380.2 (M ? 1, 28.0), 215.2 (18.3), 153.8
(
100). CHN Analysis; Calculated for C H ClN O S: C,
1
Anticancer activity assay was carried out against cervical
cancer cell lines (Hela) and involves the following steps.
The cell lines were detached by tapping and centrifuged for
6
15
4 3
5
1
0.84; H, 3.82; N, 14.85 Found: C, 50.91; H, 3.88; N,
4.87.
6
min at 300 rpm. Eagle’s medium was prepared by adding
N-(4-Acetyl-5-(2-chloro-6,7-dimethoxyquinolin-3-yl)-4,5-
dihydro-1,3,4-thiadiazol-2-yl)-acetamide (3h)
Eagle’s powder (500 mg) and sodium bicarbonate
(93.74 mg) to 50 ml of distilled warm water. To this, a
mixture of antibiotic solution (streptopenicillin, 1 ml), FBS
(2.5 ml), gentamycin (25 ll) and fluconazole (50 ll) was
added. The prepared media of 200 ll was added into the
wells of micro titre culture plate in laminar air flow cabinet.
Supernatant solution from the centrifuged cell line was
discarded and required quantity of the cell line was trans-
ferred into the well containing the media. The test solutions
of different concentrations (10, 15, 20, 25 lg/ml) were
transferred to well. One well was left without the test
solution (control). The cell lines were observed under
inverted microscope after 24, 36, 48, 72 h for cell line lyses.
The results were recorded and photographs were taken out.
Pale brown crystals. Yield; 68.8% mp (°C); 220–222. IR
-
1
1
(
mmax in cm ); 3339, 2962, 1682, 1614. H NMR
(
300 MHz, d ppm, DMSO-d ); 2.13 (s, 3H, CH3 of
6
NHCOCH ), 2.18 (s, 3H, CH of N –COCH ), 3.59 (s, 6H,
3
3
3
4
OCH of Ar–OCH ), 6.78 (s, 1H, C –H), 8.62 (s, 1H, ArH,
3
3
5
quin C –H), 7.94 (s, 1H, ArH, quin C –H), 7.99 (s, 1H,
4
5
ArH, quin C –H), 11.32 (s, 1H, NHCO). LC–MS (70 eV,
8
m/z); 409.6 (M ? 1, 31.0), 250.2 (18.3), 208.8 (100). CHN
Analysis; Calculated for C H ClN O S: C, 49.94; H,
1
7
17
4 4
4
.19; N, 13.70. Found: C, 50.11; H, 4.22; N, 13.66.
N-(4-Acetyl-5-(2,6-dichloroquinolin-3-yl)-4,5-dihydro-
,3,4-thiadiazol-2-yl)-acetamide (3i)
1
Antitubercular assay
Pale brown crystals. Yield; 63.7% mp (°C); 205–207. IR
mmax in cm ); 3359, 2951, 1687, 1619. H NMR
-
1
1
(
The antitubercular activity of the test compounds was
(
300 MHz, d ppm, DMSO-d ); 2.08 (s, 3H, CH3 of
evaluated against standard strain of Mycobacterium tuber-
culosis H Rv. Antibiotic standards used were streptomycin
6
NHCOCH ), 2.15 (s, 3H, CH of N –COCH ), 6.50 (s, 1H,
3
3
4
3
37
C –H), 8.78 (s, 1H, ArH, quin C –H), 8.65 (s, 1H, ArH,
5
and pyrazinamide. The procedure followed for antituber-
cular activity involves the use of Middlebrook 7H-9 broth
and standard strain of M. tuberculosis H Rv. The basal
4
quin C –H), 8.12–8.26 (m, 2H, ArH, quin C –H, C –H),
5
7
8
1
1.46 (s, 1H, NHCO). LC–MS (70 eV, m/z); 384.3
M ? 1, 27.0), 220.2 (20.3), 185.8 (100). CHN Analysis;
Calculated for C H Cl N O S: C, 47.10; H, 3.16; N,
3
7
(
medium was prepared according to manufacturer’s instruc-
tions (Hi-Media) and sterilized by autoclaving. Then 4.5 ml
of broth was poured into each one of the sterile bottles. To
this, 0.5 ml of ADC supplement was added. The supplement
consists of catalase, dextrose and BSA fraction v. A stock
solution was prepared (10 mg/ml). From this, an appropriate
amount of solution was transferred to media bottles to
achieve final concentrations of 5, 10 and 25 lg/ml. Finally
1
5
12
2 4 2
1
4.62. Found: C, 47.18; H, 3.22; N, 14.59.
N-(4-Acetyl-5-(6-bromo-2-chloroquinolin-3-yl)-4,5-
dihydro-1,3,4-thiadiazol-2-yl)-acetamide (3j)
Dark yellow crystals. Yield; 60.8% mp (°C); 222–223. IR
-
1
1
(
mmax in cm ); 3400, 2998, 1689, 1617. H NMR
10 ll suspension of M. tuberculosis H Rv strain (1 lakh
37
(
300 MHz, d ppm, DMSO-d ); 2.05 (s, 3H, CH3 of
organisms/ml adjusted by McFarmland’s turbidity standard)
was transferred to each of the tubes and incubated at 37°C.
Along with this, one growth control without compound and
drug controls were also set up. The bottles were inspected for
growth twice a week for a period of 3 weeks. The appear-
ance of turbidity indicated the growth and infers the resis-
tance to the compound. The growth was confirmed by
making a smear from each bottle and performing a ZN stain.
6
NHCOCH ), 2.20 (s, 3H, CH of N –COCH ), 6.78 (s, 1H,
3
3
4
3
C –H), 8.69 (s, 1H, ArH, quin C –H), 8.58 (s, 1H, Ar–H,
5
4
quin C –H), 8.22–8.34 (m, 2H, ArH, quin C –H, C –H),
7
5
6
1
1.46 (s, 1H, NHCO). LC–MS (70 eV, m/z); 427.7
M ? 1, 27.0), 310.6 (20.3), 230.7 (100). CHN Analysis;
Calculated for C H BrClN O S: C, 42.12; H, 2.83; N,
(
1
5
12
4 2
1
3.10. Found: C, 42.18; H, 2.89; N, 13.15.
Pharmacological evaluation
Conclusions
The title compounds were subjected to pharmacological
evaluation viz., anticancer and anti-tubercular activities.
We have successfully derivatized a potent quinoline moiety
with 1,3,4-thiadiazole. The newly synthesized compounds
1
23

Med Chem Res (2012) 21:185–191
191
(
3a–j) have exhibited pharmacological properties viz.,
nonreplicating Mycobacterium tuberculosis.
2:2109–2118
Lipinski A, Franco L, Dominy BW, Feeney PJ (1997) Experimental
and computational approaches to estimate solubility and perme-
ability in drug discovery and development settings. Adv Drug
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new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing
c-butenolide moiety and preliminary evaluation of in vitro
anticancer activity. Eur J Med Chem 44:3340–3344
J
Med Chem
5
anticancer and antitubercular activities. As all these com-
pounds have shown better drug likeliness, drug score and
suitable c log P values, there is a scope for the in vivo and
quantitative evaluation for their activities and also for their
bioavailability by silico study. SAR study confirmed that
3c, 3d and 3f are potent lead compounds for drug discovery
with negligible toxicity.
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cobacterial activities of certain trifluoromethyl-aminoquinoline
derivatives. ARKIVOC x:220–227
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pyrimidine and related fused pyridines. Tetrahedron Lett 23:
Acknowledgments The authors are thankful to the USIC, Karnatak
1
University, Dharwad for carrying out the spectral (IR, H NMR, MS)
and elemental analyses.
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