Antioxidant and antimicrobial studies of novel N′-(substituted-2- chloroquinolin-3-yl)methylidene-4-hydroxy-2H-1,2-benzothiazine-3- carbohydrazides 1,1-dioxides

Article abstract of DOI:10.1007/s00044-011-9755-5

N′-(2-Chloroquinolin-3-yl)methylidene-4-hydroxy-2H-1, 2-benzothiazine-3-carbohydrazides 1,1-dioxide (4a-4j) were prepared starting fromcorrespondingmethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate (1a and 1b) by condensation with hydrazine hydrate, followed by treatment with substituted 2-chloro-3-formyl quinolines (3a-3e) under ultrasonic irradiation. On the other hand, substituted 2-chloro-3-formyl quinolines were prepared in a facile way from respective acetanilides under microwave irradiation in very short duration of time (1.5-3.0 min) obtaining excellent yields. The compounds (4a-4j) were tested for their superoxide scavenging and antimicrobial activities. Almost all the compounds showedmoderate superoxide scavenging activity and compounds 4a, 4d, 4g, and 4j were found active against gram-positive bacterial strains. In addition, 4a, 4e, and4i were active against fungi (Aspergillus flavus, Aspergillus niger, Fusarium oxysporum).

Full text of DOI:10.1007/s00044-011-9755-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2340–2348
DOI 10.1007/s00044-011-9755-5
ORIGINAL RESEARCH
Antioxidant and antimicrobial studies of novel N0-(substituted-2-
chloroquinolin-3-yl)methylidene-4-hydroxy-2H-1,2-benzothiazine-
3-carbohydrazides 1,1-dioxides
•
Matloob Ahmad Syed Umar Farooq Rizvi
•
•
Hamid Latif Siddiqui Saeed Ahmad
•
•
Masood Parvez Ruqia Suliman
Received: 14 February 2011 / Accepted: 19 July 2011 / Published online: 3 August 2011
Ó Springer Science+Business Media, LLC 2011
Abstract N0-(2-Chloroquinolin-3-yl)methylidene-4-hydroxy-
2H-1,2-benzothiazine-3-carbohydrazides1,1-dioxide(4a–4j)
werepreparedstartingfromcorrespondingmethyl4-hydroxy-
2H-1,2-benzothiazine-3-carboxylate (1a and 1b) by conden-
sation with hydrazine hydrate, followed by treatment with
substituted 2-chloro-3-formyl quinolines (3a–3e) under
ultrasonic irradiation. On the other hand, substituted 2-chloro-
3-formyl quinolines were prepared in a facile way from
respective acetanilides under microwave irradiation in very
short duration of time (1.5–3.0 min) obtaining excellent
yields. The compounds (4a–4j) were tested for their super-
oxide scavenging and antimicrobial activities. Almost all the
compounds showed moderate superoxide scavenging activity
and compounds 4a, 4d, 4g, and 4j were found active against
gram-positivebacterial strains. Inaddition, 4a, 4e, and 4i were
active against fungi (Aspergillus flavus, Aspergillus niger,
Fusarium oxysporum).
Keywords Benzothiazine dioxides ꢀ Formyl quinolines ꢀ
Hydrazides ꢀ Antioxidant studies ꢀ Antimicrobial studies
Introduction
1,2-Benzothiazine 1,1-dioxide nucleus has got considerable
attention after the discovery of 4-hydroxy-2-methyl-2H-1,2-
benzothiazine-3-carboxamides 1,1-dioxides (oxicams) as
potent anti-inflammatory and analgesic agents (Lomabardi-
no and Wiseman, 1972; Zinnes et al., 1973). Since then a
variety of benzothiazine dioxides have been prepared and
they have shown a diverse range of biological activities like,
anti-allergy (Ikeda et al., 1992), antimicrobial (Zia-ur-rehman
et al., 2006), central nervous system depressants (Shavel and
Zinnes, 1967), anti-thrombotic agents (Constantine, 1967),
antimalarial (Barazarte et al., 2009) etc. While continuing
our research on 1,2-benzothiazine derivatives, we have
explored N0-Arylmethylidene-2-(3,4-dimethyl-5,5-dioxido-
pyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetohydrazides
as potent antioxidants (Ahmad et al., 2010).
M. Ahmad ꢀ S. U. F. Rizvi ꢀ H. L. Siddiqui (&)
Institute of Chemistry, University of the Punjab,
Lahore 54590, Pakistan
e-mail: drhamidlatif@yahoo.com
On the other hand, quinolines represent a potentially
biologically active class of heterocyclic compounds. They
have been studied as bactericidal (Ibrahim et al., 1991),
fungicidal (Jiang and Isaacson, 1987), antimalarial (Gins-
burg et al., 1999), anti-inflammatory (Dillard et al., 1973),
etc. Some of the famous antimalarial drugs that contain
quinoline ring system are already available in the market
like plasmaquine (Manske and Kulka, 1953), primaquine,
and chloroquine (Singh et al., 1978).
M. Ahmad
Applied Chemistry Research Centre, PCSIR Laboratories
Complex, Ferozpur Road, Lahore 54600, Pakistan
S. Ahmad
Department of Chemistry, Gomal University,
Dera Ismail Khan, Pakistan
M. Parvez
Department of Chemistry, University of Calgary,
2500 University Drive, N. W. Calgary, Calgary,
AB T2N 1N4, Canada
Despite of wide spread derivatives of 1,2-benzothiazines
and quinolines, no attempts were previously made for the
synergism of these two heterocyclic ring systems. Keeping
in view the antimicrobial and antioxidant activities of
R. Suliman
Department of Mycology and Plant Pathology,
University of the Punjab, Lahore, Pakistan
123

Med Chem Res (2012) 21:2340–2348
2341
H
N
R'
R'
CHO
Cl
R'
NH2
CH3COOH
o-H3PO4
DMF/POCl3
Microwave irradiation
O
N
(3a-3e)
R'
CHO
Cl
R'
OH
O
R
OH
O
R
OH
O
N
(3a-3e)
NH2
N
N
O
N2H4.H2O
EtOH, Reflux
N
H
N
H
N
N
N
Cl
S
EtOH, Reflux
S
S
R
O
O
O
O
O
O
(4a-4j)
1a; R=H
1b; R=Me
(2a-2b)
Scheme 1 Lay out for the synthesis of substituted 2-chloro-3-formylquinolines and N0-[(substituted 2-chloroquinolin-3-yl)methylidene]-4-
hydroxy-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide (4a–4j)
molecules with enhanced activities. In continuation of
our research study, we synergized both nuclei in a series of
novel N0-(2-chloroquinolin-3-yl)methylidene-4-hydroxy-2H-
1,2-benzothiazine-3-carbohydrazides 1,1-dioxides (Scheme 1).
The compounds were found to possess potent antioxidant
and antimicrobial properties.
Chemistry
Methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate1,1-
dioxide (1a or 1b) prepared according to the literature
method (Manjarrez et al., 1996) were condensed with
hydrazine hydrate under ultrasonic conditions to produce the
respective carbohydrazides (2a or 2b). We have previously
shown that treating 3-acetyl-4-hydroxy-2-methyl-2H-1,2-
Fig. 1 ORTEP II diagram of compound 2b with the numbering
benzothiazine 1,1-dioxide with hydrazine hydrate results in
scheme. Displacement ellipsoids are drawn at the 50% probability
the formation of pyrazolo[4,3-c][1,2]benzothiazine 5,5-
dioxide ring system (Ahmad et al., 2010). However, in this
case, such type of ring system was not formed as is confirmed
with the help of XRD of 2b (Fig. 1). This may be attributed to
the absence of 1,3-diketo system that is more prone toward
cyclization (Scheme 2).
level; H atoms are represented by circles of arbitrary radii
benzothiazine (Zia-ur-Rehman et al., 2006; Ahmad et al.,
2010) and quinoline derivatives (Ibrahim et al., 1991;
Sankaran et al., 2010), it was perceived that synergism of
these two bioactive heterocycles may result in new
Scheme 2 Formation of
hydrazide functionality (2)
rather than cyclized product (20)
OH
O
N
S
NH
R
OH
O
N2H4.H2O
X
R' '
O
N2H4.H2O
N
N
N
S
S
R
O
(1')
O
O
O
(2')
O
O
(1)
N2H4.H2O
R = H or Me
R' '= Me or OH
OH
O
R
NH2
N
H
N
S
O
O
(2)
123

2342
Med Chem Res (2012) 21:2340–2348
Table 1 Reaction parameters
of compounds N0-[(substituted
2-chloroquinolin-3-
S. no. Product
R
R1
Reaction
time (min)
Yield %a Analysis %
Calculated (found)
yl)methylidene]-4-hydroxy-2H-
1,2-benzothiazine-3-
C
H
N
carbohydrazide 1,1-dioxide
(4a–4j)
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
H
H
H
H
H
6-Methyl
7-Methyl
8-Methyl
4
71
84
87
80
81
82
82
83
89
79
54.24 (54.25) 3.41 (3.40) 12.65 (12.66)
54.24 (54.25) 3.41 (3.41) 12.65 (12.63)
54.24 (54.23) 3.41 (3.40) 12.65 (12.66)
52.35 (52.33) 3.29 (3.30) 12.21 (12.21)
52.35 (52.36) 3.29 (3.28) 12.21 (12.20)
55.20 (55.22) 3.75 (3.74) 12.26 (12.26)
55.20 (55.19) 3.75 (3.77) 12.26 (12.27)
55.20 (55.21) 3.75 (3.75) 12.26 (12.27)
53.34 (53.35) 3.62 (3.63) 11.85 (11.83)
53.34 (53.35) 3.62 (3.62) 11.85 (11.84)
4
4.5
6-Methoxy 4.5
7-Methoxy 5.0
CH3 6-Methyl
CH3 7-Methyl
CH3 8-Methyl
CH3 6-Methoxy
CH3 7-Methoxy
4
4g
4h
4i
4
a
Isolated yields based on
4.5
5
4-hydroxy-2H-1,2-
benzothiazine-3-
carbohydrazides 1,1-dioxide
(2a–2b)
4j
5
Second, we devised an efficient procedure for the syn-
thesis of quinoline derivatives (Scheme 1). The method
involves the synthesis of substituted 2-chloro-3-formyl-
quinolines by cyclizing substituted acetanilides with Vils-
meier Haack reagent (POCl3/DMF) under microwave
heating, without employing any catalyst. The reaction
resulted in excellent yields (73–82%) and extra ordinary
short reaction times (90–180 s). Organic reactions under
microwave irradiation are being extensively studied due to
their operational simplicity, increased yields and much
shorter reaction time (Caddick, 1995; Galema, 1997;
Varma, 1999). In this study, we employed a domestic
microwave oven. The mixture was irradiated at 350 W for
a specific time. Subsequently, work-up and purification
provided corresponding chloroquinolinecarbaldehyde.
Earlier, these quinoline derivatives (3a–e) have been
reported to be synthesized by Vilsmeier Haack cyclization
of acetanilides under thermal conditions in long reaction
times (4–16 h) and at elevated temperatures (Meth-Cohn
et al., 1981). Various efforts have already been made for
the improvement of the procedure by using catalysts and
ultrasonic mediated procedures (Ali et al., 2001, 2002).
The main advantage of our procedure is that it takes
maximum of 3 min to complete the reaction. The yields are
also better than those of the conventional thermal methods.
Also, it involves very simple workup procedure. This
proves the superiority of microwave-assisted reaction over
the classical method (thermal conditions) as well as over
recently reported methods (Meth-Cohn et al., 1981; Ali
et al., 2001, 2002) in terms of rate and yields.
using methanol and chloroform in 1:10 as eluent and silica
gel as stationary phase. IR spectra of compounds 4a–4j
showed C=N peaks in the range of 1609–1620 cm-1 and
all the peaks due to NH2 and formyl group disappeared in
the final compounds. All the spectroscopic data was in
good agreement to the proposed structures.
X-ray studies
The structure contains independent molecules of 2b
(Fig. 2); selected molecular dimensions have been listed in
Table 3. The heterocyclic thiazine ring adopts a half-chair
conformation, with atoms S1 and N1 displaced by 0.467(4)
˚
and -0.351(4) A, respectively, from the plane formed by
atoms C1/C6/C7/C8; the puckering parameters (Cremer
˚
and Pople, 1975) are: Q = 0.5451(15) A, h = 65.45(17)°
and u = 25.66(19)°. Similar conformations of the corre-
sponding rings have been reported in some closely related
compounds (Siddiqui et al., 2008). The structure is stabi-
lized by extensive hydrogen bonds of the types N–HꢀꢀꢀO,
O–HꢀꢀꢀN, O–HꢀꢀꢀO, and C–HꢀꢀꢀO (Table 4).
Antioxidant studies
Reactive oxygen species (ROS) and free radicals invivo is
involved in a wide range of human diseases (Gutteridge,
1993). ROS, including superoxide anion, hydrogen perox-
ide, and hydroxyl radical are byproducts of a variety of
pathways of aerobic metabolism (Foroumadi et al., 2007).
These are unstable and react readily with a wide range of
biological substrates, such as lipids, DNA, and protein
molecules, consequently resulting in the cell damage
(Braughler et al., 1986).
Finally, the quinolines (3a–3e) were condensed with the
carbohydrazides (2a or 2b) to get novel N0-(2-chloroquin-
olin-3-yl)methylidene-4-hydroxy-2H-1,2-benzothiazine-3-
carbohydrazides 1,1-dioxides (4a–4j). It is worth men-
tioning that ultrasonic irradiation resulted in relatively pure
compounds in shorter times (Table 1). Column chroma-
tography was performed to further purify the compounds
The compounds were subjected to superoxide scaveng-
ing activity and interesting results were observed (Table 5).
123

Med Chem Res (2012) 21:2340–2348
2343
Table 2 Crystal data and structure refinement for 2bꢀ2(CH3OH)
Empirical formula
Formula weight
Temperature
C10H11N3O4Sꢀ2(CH3OH)
333.36
Theta range for data collection
Index ranges
3.3°–25.0°
-8 B h B 8,
-9 B k B 9,
-17 B l B 17
4736
173(2) K
˚
0.71073 A
Wavelength
Crystal system
Space group
Triclinic
P-1
Reflections collected
Independent reflections
Completeness to theta = 24.99°
Absorption correction
2498 [R(int) = 0.026]
98.6%
Unit cell dimensions
˚
a = 6.9671(2) A
a = 94.628(2)°
b = 95.082(2)°
c = 114.842(2)°
Multi-scan
˚
b = 7.7486(4) A
Max. and min. transmission
Refinement method
0.9745 and 0.9522
Full-matrix least-squares on F2
˚
c = 14.8722(7) A
3
˚
Volume
719.52(5) A
Data/restraints/parameters
Goodness-of-fit on F2
2498/0/219
Z
2
1.033
Density (calculated)
Absorption coefficient
F(000)
1.539 mg/m3
0.260 mm-1
352
Final R indices [I [ 2sigma(I)]
R indices (all data)
R1 = 0.0506, wR2 = 0.1410
R1 = 0.0536, wR2 = 0.1451
-3
˚
0.507 and -0.681 e A
Largest diff. peak and hole
Crystal size
0.19 9 0.14 9 0.10 mm3
CH3
CH3
˚
Table 4 Hydrogen bonds for 2bꢀ2(CH3OH) (A and °)
D-HꢀꢀꢀA
CH3
OH
S
O
d(D-H) d(HꢀꢀꢀA) d(DꢀꢀꢀA) \(DHA)
N
HN
NH
CH3
N
N(2)–H(2N)ꢀꢀꢀO(3)
N(2)–H(2N)ꢀꢀꢀO(60)#1
N(3)–H(32N)ꢀꢀꢀO(4)
N(3)–H(31N)ꢀꢀꢀO(4)#2
N(3)–H(32N)ꢀꢀꢀO(5)#2
O(3)–H(3O)ꢀꢀꢀN(2)
O(3)–H(3O)ꢀꢀꢀO(6)#3
O(5)–H(5A)ꢀꢀꢀO(3)#4
O(6)–H(6)ꢀꢀꢀN(3)#1
O(60)–H(60)ꢀꢀꢀO(4)#5
C(2)–H(2)ꢀꢀꢀO(2)#6
0.88
0.88
1.98
2.62
2.675(3) 134.5
3.24(2) 127.5
2.724(3) 105(2)
3.233(3) 165(3)
3.414(3) 162(3)
2.675(3) 123.3
2.79(2) 119.7
2.762(2) 166.8
2.94(2) 152.6
2.87(2) 145.8
3.382(3) 156.7
3.551(3) 169.2
2.862(3) 105.4
N
0.86(3) 2.37(3)
0.86(3) 2.39(3)
0.86(3) 2.59(3)
Cl
N
O
O
(Chloroquine)
(Piroxicam)
Fig. 2 Structural formulas of anti-inflammatory drug (Piroxicam)
and antimalarial drug (Chloroquine)
0.84
0.84
0.84
0.84
0.84
0.95
2.12
2.28
1.94
2.17
2.14
2.49
2.58
2.44
˚
Table 3 Selected (a) bond lengths (A), (b) bond angles (°), (c) and
torsion angles (°) for 2bꢀ2(CH3OH)
(a)
S(1)–O(2)
1.435(2)
1.437(2)
1.639(2)
1.755(2)
1.296(3)
O(4)–C(9)
N(1)–C(8)
N(1)–C(10)
N(2)–C(9)
N(2)–N(3)
1.253(3)
1.449(3)
1.481(3)
1.342(3)
1.419(3)
C(11)–H(11B)ꢀꢀꢀO(1)#4 0.98
C(10)–H(10B)ꢀꢀꢀO(2) 0.98
S(1)–O(1)
S(1)–N(1)
S(1)–C(1)
Symmetry transformations used to generate equivalent atoms
O(3)–C(7)
(b)
#1 - x ? 2, -y ? 1, -z ? 1, #2 -x ? 1, -y ? 1, -z ? 1, #3 x,
y ? 1, z, #4 x - 1, y, z #5 -x ? 1, -y, -z ? 1, #6 -x ? 1, -y, -z
O(2)–S(1)–O(1)
O(2)–S(1)–N(1)
O(1)–S(1)–N(1)
O(2)–S(1)–C(1)
O(1)–S(1)–C(1)
(c)
118.31(11) N(1)–S(1)–C(1)
108.66(11) C(8)–N(1)–C(10)
107.27(10) C(8)–N(1)–S(1)
109.86(11) C(10)–N(1)–S(1)
109.48(11) C(9)–N(2)–N(3)
101.98(11)
115.83(18)
113.25(15)
116.52(16)
121.7(2)
system (4d, 4e, 4i, and 4j) were more potent in activity
than those bearing methyl substitution. The same phe-
nomenon is observed in the literature that electron donating
substituents enhance the antioxidant activity (Eiserich and
´
Shibamoto, 1994; Simic et al., 2007). Methoxy substituted
C(1)–S(1)–N(1)–C(8) -54.9(2)
C(1)–C(6)–C(7)–C(8) -20.6(3)
compounds can be arranged in decreasing order of activity:
4e [ 4d [ 4i [ 4j. This may be attributed to greater
electron donating ability of methoxy group. Moreover, 4d
and 4e bearing NH on benzothiazine moiety were more
active than 4i and 4j, having N-methyl benzothiazine
nucleus. Overall order of antioxidant activity is 7-OMe [
6-OMe [ 8-Me [ 6-Me [ 7-Me.
N(1)–S(1)–C(1)–C(6)
S(1)–C(1)–C(6)–C(7)
36.2(2)
C(6)–C(7)–C(8)–N(1)
S(1)–N(1)–C(8)–C(7)
-0.4(3)
-1.6(3)
41.7(3)
Almost all the synthesized compounds were found to
exhibit significant activity. However, it was observed that
compounds bearing methoxy substituents on quinoline ring
123

2344
Med Chem Res (2012) 21:2340–2348
OMe
N
OMe
OH
O
OH O
N
N
N
N
N
H
H
NH
Cl
NH
Cl
S
S
O
O
O
O
(4e)
(4d)
compounds were found to exhibit weak antimicrobial
activity. The results showed that gram-positive bacteria are
selectively inhibited by 4a, 4d, 4g, and 4j having 6-methyl,
6-methoxy, 7-methyl, and 7-methoxy substitutions on
quinoline ring, respectively. This may probably be due to
the electron donating nature of substituents on quinoline
ring. However, no activity was observed against gram-
negative bacteria (Escherichia coli, Enterobacter cloacae,
Salmonella gallinarum). 4a, 4e, and 4i having 6-methyl,
7-methoxy, and 6-methoxy substituents on quinoline ring
system were found active against fungi (Aspergillus flavus,
Aspergillus niger, Fusarium oxysporum).
Table 5 Superoxide anion radical scavenging activity
S. no.
Compound
% RSA
1
4a
51.8
49.1
52.5
69.7
72.1
51.2
51.9
61.3
67.2
65.1
91.3
2
4b
3
4c
4
4d
5
4e
6
4f
7
4g
8
4h
9
4i
10
11
4j
n-Propyl gallate
Experimental
Compounds 4d and 4e were found to be the most potent
antioxidants among the series.
Materials
All the chemicals were purchased from E. Merck, BDH or
Fluka and used without purification. However, solvents
1
were purified through distillation. H-NMR spectra were
Antimicrobial studies
recorded on a Bruker DPX-400 instrument at 400 MHz.
Chemical shifts are reported in ppm referenced to the
residual solvent signal. FT-IR spectra were recorded on a
The compounds (4a–4j) were also subjected to antimicro-
bial (antibacterial/antifungal) activity and variable results
were recorded (Table 6). Most of the synthesized
Table 6 Antimicrobial activity
Compound
(100 lg/ml)
Gram-negative bacteria
Gram-positive bacteria
Fungi
of compounds against bacteria
and fungi, expressed as minimal
inhibitory concentration (MIC)
(lg/ml)
E. coli
E. cl
S. gal
B. f
B. s
B. th
A. f
A. n
F. oxy
[100
4a
[1000
[1000
[1000
[1000
[1000
[1000
[1000
[1000
[1000
[1000
2
[1000 [1000
[100
[100
[100
[100
[1000
[1000
[500
[200
[1000
[1000
[1000
[100
[1000
2
[100
4b
[1000 [1000 [1000 [1000 [1000
[1000 [1000 [1000 [1000 [1000
[1000 [1000
[1000 [1000
4c
4d
[1000 [1000
[100
[100
[100
[100
[100
[500
[200
[500
[200
4e
[1000 [1000 [1000
4f
[1000 [1000 [1000 [1000 [1000
[1000 [1000 [100 [100 [100
[1000 [1000 [1000 [1000 [1000
[1000 [1000
[1000 [1000
[1000 [1000
E. c Escherichia coli,
E. cl Enterobactercloacae,
S. g Salmonella gallinarum,
B. s Bacillus subtilis;
B. th Bacillus thuringiensis,
B. f Bacillus fortis,
A. f Aspergillus flavus,
A. n Aspergillus niger,
F.oxy Fusarium oxysporum
4g
4h
4i
[1000 [1000
[1000 [1000
[200
[100
3
[200
[100
6
[200
[100
2
[100
[100
4j
[1000 [1000
Amoxicillin
Streptomycin
2
1
2
1
2
1
2
1
0.7
1
3
0.9
0.7
123

Med Chem Res (2012) 21:2340–2348
2345
2-Chloro-6-methoxy-3-formylquinoline (3d)
Thermo Nicolet IR 200 spectrometer. Mass spectra were
recorded on Agilent 5973N instrument using EI mode.
Melting points were recorded on a Gallenkamp melting
point apparatus and are uncorrected. Ultrasonic mediated
reactions were carried out in Clifton Ultrasonic Bath
(2 9 T2A, 300W, DU-4) made by Nickel Electro Ltd.
Brown powder; yield: 77%; mp 144–145°C; IR (KBr,
cm-1) : 1676 (CO), 1575 (C=N); 1H NMR (CDCl3): d 3.91
(s, 3H, Ar-OMe), 7.15 (d, 1H, J = 2.85 Hz, Ar–H), 7.47
(dd, 1H, J1 = 9.0 Hz and J2 = 2.9 Hz, Ar–H), 7.90 (d, 1H,
J = 9.0 Hz, Ar–H), 8.57 (s, 1H, Ar–H), 10.50 (s,1H,
CHO); elemental analysis calculated for C11H8ClNO2: C,
59.61; H, 3.64; N, 6.32. Found: C, 59.63; H, 3.62; N, 6.28.
MS m/z: 221.1 (M?).
General procedure for the preparation of 2-chloro-3-
formylquinolines
Vilsmeier reagent was prepared by adding POCl3 (64.4 ml,
0.70 mol) dropwise in DMF (19.2 ml, 0.25 mol) at 0°C
with constant stirring. To this solution was added the
acetanilide (0.10 mol) and the mixture was stirred (15 min)
at room temperature. Then this mixture was subjected to
microwave irradiation at 350 W for the time period as
mentioned in Table 1. After the completion of the reaction
(TLC monitoring), the mixture was poured in ice cold
water (500 ml) and stirred vigorously (30 min) at 0–10°C.
The 2-chloro-3-quinolinecarbaldehyde was precipitated
out, which was filtered off, washed with water (200 ml),
dried, and recrystallized from ethyl acetate.
2-Chloro-7-methoxy-3-formylquinoline (3e)
Yellow ochre; Yield: 82%; mp 196–197°C; IR (KBr,
cm-1) : 1690 (CO), 1585 (C=N); 1H NMR (CDCl3): d 3.92
(s, 1H, Ar-OMe), 7.21 (dd, 1H, J = 9.03 Hz, Ar–H), 7.33
(s, 1H, Ar–H), 7.97 (d, 1H, J = 9 Hz, Ar–H), 8.69 (s, 1H,
Ar–H), 10.85 (s, 1H, CHO); elemental analysis calculated
for C11H8ClNO2: C, 59.61; H, 3.64; N, 6.32. Found: C,
59.60; H, 3.63; N, 6.28. MS m/z: 221.1 (M?).
General synthesis of 4-hydroxy-2H-1,2-benzothiazine-
3-carbohydrazides 1,1-dioxide (2a–2b)
2-Chloro-6-methyl-3-formylquinoline (3a)
Respective ester i–e methyl 4-hydroxy-2H-1,2-benzothia-
zine-3-carboxylate 1,1-dioxide (1a) or methyl 4-hydroxy-
2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide
(1b) (100 mmol) was mixed hydrazine hydrate (500 mmol).
The mixture was irradiated under ultrasonics for 10–12 min.
After completion of reaction, the mixture was poured on ice
cold water and the pH of resultant solution was maintained at
5.0–5.5 by dil. HCl. The product obtained was washed with
excess water and recrystallized from EtOH. Yield: 76% (2a),
78% (2b).
Dull yellow powder; Yield: 73%; mp 124.5–125°C; IR
1
(KBr, cm-1): 1690 (CO), 1580 (C=N); H NMR (CDCl3):
d 2.52 (s, 3H, Ar-CH3), 7.69 (d, 1H, J = 9.0 Hz, Ar–H),
7.76 (s, 1H, Ar–H), 7.87 (d, 1H, J = 9.1 Hz, Ar–H), 8.57
(s, 1H, Ar–H), 10.42 (s,1H, CHO); elemental analysis
calculated for C11H8ClNO: C, 64.25; H, 3.92; N, 6.81.
Found: C, 64.22; H, 3.94; N, 6.80. MS m/z: 205.1 (M?).
2-Chloro-7-methyl-3-formylquinoline (3b)
4-Hydroxy-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (2a)
Yellow ochre material; Yield: 80%; mp 144–146°C; IR
1
(KBr, cm-1): 1690 (CO), 1581 (C=N); H NMR (CDCl3):
d 2.61 (s, 3H, Ar-CH3), 7.48 (d, 1H. J = 9.0 Hz, Ar–H),
7.79 (s, 1H, Ar–H), 7.95 (d, 1H, J = 9.08 Hz, Ar–H), 8.63
(s, 1H, Ar–H), 10.45 (s,1H, CHO); elemental analysis
calculated for C11H8ClNO: C, 64.25; H, 3.92; N, 6.81.
Found: C, 64.23; H, 3.92; N, 6.81. MS m/z: 205.0 (M?).
Orange yellow powder; mp 251–253°C. IR (KBr) cm-1
:
3365; 2982; 1331; 1171. 1H-NMR (DMSO-d6) (300 MHz)
d 4.50 (2H, s, NH2), 7.72–7.81 (3H, m, Ar–H), 7.93–7.96
(1H, m, Ar–H), 9.88 (1H, br-s, NH), 13.93 (1H, br-s, O–H).
Elemental analysis calculated for C9H9N3O4S: C, 42.35; H,
3.55; N, 16.46. Found: C, 42.34; H, 3.55; N, 16.45. MS
m/z: 255.4 (M?).
2-Chloro-8-methyl-3-formylquinoline (3c)
Light yellow; yield: 75%; mp 138–138.5°C; IR (KBr,
cm-1) : 1685 (CO), 1585 (C=N); 1H NMR (CDCl3): d 2.69
(s, 3H, Ar-OMe), 7.48 (t, 1H, J = 8.1 Hz, Ar–H), 7.65 (d,
1H, J = 8.2 Hz and J = 2 Hz, Ar–H), 7.82 (dd, 1H,
J = 8.1 Hz and J = 2 Hz, Ar–H), 8.66 (s, 1H, Ar–H),
10.52 (s,1H, CHO); elemental analysis calculated for
C11H8ClNO: C, 64.25; H, 3.92; N, 6.81. Found: C, 64.27;
H, 3.91; N, 6.81. MS m/z: 205.1 (M?).
4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-
carbohydrazide 1,1-dioxide (2b)
Brownish red; mp 222°C. IR (KBr) cm-1: 3467; 3364;
2982; 1331; 1171. 1H-NMR (DMSO-d6) (400 MHz) d 2.73
(3H, s, CH3), 4.69 (2H,br-s, NH2), 7.81-7.86 (3H, m,
Ar–H), 7.95-7.97 (1H, d, J = 7.6 Hz, Ar–H), 10.04 (1H,
123

2346
Med Chem Res (2012) 21:2340–2348
N0-(2-Chloro-6-methoxyquinolin-3-yl)methylidene-4-
hydroxy-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4d)
br-s, NH), 14.23 (1H, br-s, O–H). Elemental analysis cal-
culated for C10H11N3O4S: C, 44.60; H, 4.12; N, 15.60.
Found: C, 44.62; H, 4.10; N, 15.62. MS m/z: 269.0 (M?).
General procedure for the synthesis of N0-[(substituted-
2-chloroquinolin-3-yl)methylidene]-4-hydroxy-2H-1,2-
benzothiazine-3-carbohydrazide 1,1-dioxide (4a–4j)
Light green powder; mp 283°C (decomposed). IR (KBr)
cm-1: 3442; 3293;3009; 1620; 1378; 1168. 1H-NMR
(DMSO-d6) (400 MHz) d 3.96 (3H, s, O–CH3), 7.31–7.35
(1H, dd, J1 = 2.4 Hz, J2 = 9.0 Hz, Ar–H), 7.37 (1H, d,
J = 2.4 Hz, Ar–H), 7.81–7.91 (3H, m, Ar–H), 8.03–8.05
(1H, dd, J1 = 2.0 Hz, J2 = 10.4 Hz, Ar–H), 8.13 (1H, d,
J = 12.0 Hz), 8.88 (1H, s), 9.14 (1H, s), 9.63 (1H, s, N–H),
12.25 (1H, s, NH), 13.93 (1H, br-s, O–H). MS m/z: 458.88
(M?).
A mixture of 4-hydroxy-2H-1,2-benzothiazine-3-carbohy-
drazides 1,1-dioxide (2a or 2b), substituted 2-chloro-3-
formyl quinoline (3a–3e) and 3–5 drops of glacial acetic
acid in ethanol was irradiated under ultrasonics for
4.0–5.0 min at 50°C. The precipitates formed were filtered
and washed with excess ethanol and dried.
N0-(2-Chloro-7-methoxyquinolin-3-yl)methylidene-4-
hydroxy-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4e)
N0-(2-Chloro-6-methylquinolin-3-yl)methylidene-4-
hydroxy-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4a)
Bright yellow powder; mp 281°C (decomposed). IR (KBr)
cm-1: 3440; 3291;3018; 1619; 1379; 1170. 1H-NMR
(DMSO-d6) (400 MHz) d 3.91 (3H, s, O–CH3), 7.32–7.36
(1H, dd, J1 = 2.4 Hz, J2 = 8.7 Hz, Ar–H), 7.39 (1H, d,
J = 2.4 Hz, Ar–H), 7.79–7.87 (3H, m, Ar–H), 8.03–8.05
(1H, dd, J1 = 2.0 Hz, J2 = 10.4 Hz, Ar–H), 8.17 (1H, d,
J = 12.0 Hz), 8.88 (1H, s), 9.16 (1H, s), 9.59 (1H, s, N–H),
12.31 (1H, s, NH), 13.87 (1H, br-s, O–H). MS m/z: 458.88
(M?).
Off white powder; mp 283°C (decomposed). IR (KBr)
cm-1: 3547; 3379; 3266; 1613; 1312; 1174. 1H-NMR
(DMSO-d6) (400 MHz) d 2.53 (3H, s, CH3), 7.69–7.72
(1H, dd, J1 = 1.8 Hz, J2 = 8.7 Hz, Ar–H), 7.86–7.92 (4H,
m, Ar–H), 7.98 (1H, s, Ar–H), 8.03–8.06 (1H, dd,
J1 = 1.8 Hz, J2 = 8.7 Hz, Ar–H), 8.83 (1H, s), 9.15 (1H,
s), 9.65 (1H, s), 12.30 (1H, s, NH), 13.88 (1H, br-s, O–H).
MS m/z: 442.0(M?).
N0-(2-Chloro-6-methylquinolin-3-yl)methylidene-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4f)
N0-(2-Chloro-7-methylquinolin-3-yl)methylidene-4-
hydroxy-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4b)
Off white powder; mp 291°C (decomposed). IR (KBr)
Bright yellow powder; mp 281°C (decomposed). IR (KBr)
cm-1: 3540; 3382; 3260; 1618; 1330; 1174. 1H-NMR
(DMSO-d6) (300 MHz) d 3.16 (3H, s, CH3), 7.53–7.56
(1H, dd, J1 = 1.5 Hz, J2 = 8.4 Hz, Ar–H), 7.83–7.91 (4H,
m, Ar–H), 8.03–8.06 (1H, dd, J1 = 1.5 Hz, J2 = 6.9 Hz,
Ar–H), 8.13 (1H, d, J = 8.4 Hz), 8.91 (1H, s), 9.16 (1H, s),
9.62 (1H, s, N–H), 12.29 (1H, s, NH), 13.89 (1H, br-s, O–
H). MS m/z: 442.0 (M?).
1
cm-1: 3276; 3015; 1612; 1344; 1180. H-NMR (DMSO-
d6) (400 MHz) d 2.53 (3H, s, C–CH3), 2.87 (3H, s, N–
CH3), 7.71 (1H, d, J = 8.4 Hz, Ar–H), 7.87–7.93 (4H, m,
Ar–H), 8.00 (1H, s), 8.04 (1H, d, J = 8.0 Hz), 8.85 (1H, s),
9.15 (1H, s), 12.33 (1H, s, NH), 14.07 (1H,br s, O–H). MS
m/z: 456.9 (M?).
N0-(2-Chloro-7-methylquinolin-3-yl)methylidene-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4g)
N0-(2-Chloro-8-methylquinolin-3-yl)methylidene-4-
hydroxy-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4c)
Off white powder; mp 293°C (decomposed). IR (KBr)
1
cm-1: 3281; 2983; 1612; 1342; 1177. H-NMR (DMSO-
Brownish yellow powder; mp 282°C (decomposed). IR
1
(KBr) cm-1: 3539; 3389; 3273; 1609; 1313; 1172. H-
d6) (400 MHz) d 2.54 (3H, s, C–CH3), 2.87 (3H, s, N–
CH3), 7.53 (1H, d, J = 8.4 Hz, Ar–H), 7.77 (1H, s),
7.89–7.94 (3H, m, Ar–H), 8.04–8.06 (1H, d, J = 8.0 Hz,
Ar–H), 8.12–8.14 (1H, d, J = 8.4 Hz), 8.91 (1H, s), 9.14
(1H, s), 12.31 (1H, s, NH), 14.09 (1H, s, O–H). MS m/z:
456.9 (M?).
NMR (DMSO-d6) (300 MHz) d 2.68 (3H, s, CH3), 7.59
(1H, t, J = 7.2 Hz, Ar–H), 7.72 (1H, d, J = 7.2 Hz,
Ar–H), 7.85–7.92 (3H, m, Ar–H), 8.03–8.08 (2H, m,
Ar–H), 8.93 (1H, s), 9.18 (1H, s), 9.66 (1H, s, N–H), 12.31
(1H, s, NH), 13.87 (1H, br-s, O–H). MS m/z: 441.9 (M?).
123

Med Chem Res (2012) 21:2340–2348
2347
N0-(2-Chloro-8-methylquinolin-3-yl)methylidene-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4h)
of sample. Percent radical scavenging activity was deter-
mined in comparison with control using the formula given
below and are presented in Table 5.
% RSA ¼ 100
Pale orange powder; mp 295°C (decomposed). IR (KBr)
ꢁ fðOD test compound=OD controlÞ ꢂ 100g:
1
cm-1: 3245; 3050; 1611; 1334; 1156. H-NMR (DMSO-
d6) (400 MHz) d 2.68 (3H, s, C–CH3), 2.88 (3H, s,
N–CH3), 7.59 (1H, t, J = 8.0 Hz, Ar–H), 7.73 (1H, d,
J = 6.8 Hz, ArH), 7.88–7.93 (3H, m, Ar–H), 8.06 (2H, t,
J = 7.6 Hz, Ar–H), 8.94 (1H, s), 9.17 (1H, s), 12.34 (1H, s,
NH), 14.07 (1H, s, O–H). MS m/z: 456.9 (M?).
Antimicrobial studies
The susceptibility tests were performed using the agar
dilution assay—a modified version of the National Com-
mittee for Clinical Laboratory Standards (NCCLS), Villa-
nova, Pa (1993). The test components (extracts, fractions,
and compounds) were dissolved in dimethyl sulfoxide
(DMSO) and added to twofold serial Mueller–Hinton agar
medium (Oxoid) for the bacteria and Sabouraud dextrose
agar medium (BBl) for the fungi to achieve a final volume
of 1 ml and concentrations ranging from 10 to 1000 lg/ml.
Drugs (amoxicillin and streptomycin) (Microgen) as well
as growth and blank (media and solvent 2%) controls were
added to each test. The microbial inoculum sizes were
1.5 9 106 cells/ml for bacteria (National Committee for
Clinical Laboratory Standards, 1993) and 106 cells/ml for
fungus (Espinel-Ingroff and Pfaller, 1995). The minimal
inhibitory concentration (MIC) values were taken as the
lowest concentration of extracts, fractions, or compounds
that inhibited the growth of the organism after 24 h of
incubation at 37°C for bacteria and 3–5 days at 25°C for
fungus.
N0-(2-Chloro-6-methoxyquinolin-3-yl)methylidene-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4i)
Lemon yellow powder; mp 293°C (decomposed). IR (KBr)
1
cm-1: 3282; 3041; 1611; 1335; 1162. H-NMR (DMSO-
d6) (400 MHz) d 2.88 (3H, s, N–CH3), 3.89 (3H, s,
O–CH3), 7.31 (1H, d, J = 8.8 Hz, Ar–H), 7.39 (1H, s),
7.89–7.93 (3H, m, Ar–H), 8.04–8.06 (1H, d, J = 8.0 Hz,
Ar–H), 8.14–8.17 (1H, d, J = 9.2 Hz, ArH), 8.90 (1H, s),
9.15 (1H, s), 12.31 (1H, s, NH), 14.10 (1H, s, O–H). MS
m/z: 472.7 (M?).
N0-(2-Chloro-7-methoxyquinolin-3-yl)methylidene-4-
hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide
1,1-dioxide (4j)
Light yellow powder; mp 289°C (decomposed). IR (KBr)
1
cm-1: 3280; 3039; 1615; 1339; 1161. H-NMR (DMSO-
X-ray studies
d6) (400 MHz) d 2.87 (3H, s, N–CH3), 3.94 (3H, s,
O–CH3), 7.33 (1H, d, J = 8.8 Hz, Ar–H), 7.39 (1H, s),
7.89–7.93 (3H, m, Ar–H), 8.03–8.05 (1H, d, J = 8.0 Hz,
Ar–H), 8.14–8.17 (1H, d, J = 9.2 Hz, ArH), 8.89 (1H, s),
9.14 (1H, s), 12.27 (1H, s, NH), 14.12 (1H, s, O–H). MS
m/z: 472.7 (M?).
A colorless block crystal of C10H11N3O4Sꢀ2(CH3OH) was
coated with Paratone 8277 oil (Exxon) and mounted on a
glass fiber. All measurements were made on a Bruker
APEX2 CCD installed on a Nonius Kappa Goniometer
diffractometer with graphite monochromated Mo-Ka radi-
ation. Details of crystal data and structure refinement have
been provided in Table 2. The data were collected (Otwi-
nowski and Minor, 1997) using x and u scans. The data
were corrected for Lorentz and polarization effects and for
absorption using multi-scan method (Hooft, 1998).
Antioxidant studies
Compounds were assessed by the method used by literature
method (Gaulejac et al., 1999). The reaction mixture
comprises 40 ll of 280 lM b-nicotinamide adenine dinu-
cleotide reduced form (NADH), 40 ll of 80 lM nitro blue
tetrazolium (NBT), 20 ll of 8 lM phenazine methosul-
phate (PMS), 10 ll of 1 mM sample, and 90 ll of 0.1 M
phosphate buffer (pH 7.4). The reagents were prepared in
buffer and sample in DMSO. The reaction was performed
in 96-well microtitre plate at room temperature and
absorbance was measured at 560 nm. The formation of
superoxide was monitored by measuring the formation of
water soluble blue formazan dye. A lower absorbance
of reaction mixture indicates a higher scavenging activity
The structure was solved by the direct methods (Alto-
mare et al. 1993) and expanded using Fourier techniques
(Beurskens et al., 1994). The asymmetric unit contains two
molecules of methanol of salvation one of which was
disordered. The non-hydrogen atoms were refined aniso-
tropically. The H atoms were included at geometrically
idealized positions and were not refined; H atoms bonded
to N3 were allowed to refine. The final cycle of full-matrix
least-squares refinement using SHELXL97 (Sheldrick,
2008) converged with unweighted and weighted agree-
ment factors, R = 0.0506 and wR = 0.1410 (all data),
123

2348
Med Chem Res (2012) 21:2340–2348
Gaulejac NSC, Glories Y, Vivas N (1999) Free radical scavenging
effect of anthocyanins in red wines. Food Res Int 32:327–333
Ginsburg H, Ward SA, Bray PG (1999) An integrated model of
chloroquine action. Parasitol Today 15:357–360
respectively, and Goodness-of-fit, S = 1.033. The weight-
ing scheme was based on counting statistics and the final
difference Fourier map was essentially featureless. The
figures are plotted with the aid of ORTEP-3 for Windows
(Farrugia, 1997).
Gutteridge JMC (1993) Free radicals in disease processes:
a
compilation of cause and consequence. Free Radic Res Commun
19:141–158
Hooft R (1998) COLLECT. Nonius BV, Delft
Ibrahim A, Rahman A, Abdu E, Etity BA (1991) Synthesis and
application of some new S-(substituted)thio- and thienoquinoline
derivatives as antimicrobial agents. Collect Czech Chem Com-
mun 56:1749–1760
Ikeda T, Kakegawa H, Miyataka H, Matsumoto H, Satoht T (1992)
Anti-allergic and anti-inflammatory actions of 20-(tetrazole-5-yl)-
4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxanilide 1,1-
dioxide. Biorg Med Chem Lett 2:709–714
Acknowledgments The authors (MA, SUFR and HLS) are grateful
to Higher Education Commission, Pakistan for financial assistance.
We are also thankful to International Centre for Chemical and Bio-
logical Sciences, HEJ Research Institute of Chemistry, University of
Karachi, Karachi and Institute of Chemistry, University of the Punjab
for research facilities, spectral measurements and antioxidant studies.
References
Jiang JB, Isaacson D (1987) Polyfluorinated substituted tricyclic
quinoline mono and dioxo antifungal agents and process for their
preparation, US Patent 4,656,274, Apr 7, 1987
Lomabardino JG, Wiseman ED (1972) Sudoxicam and related N-
heterocyclic carboxamides of 4-hydroxy-2H-1,2-benzothiazine
1,1-dioxide. Potent nonsteroidal anti-inflammatory agents. J Med
Chem 15:848–849
Ahmad M, Siddiqui HL, Zia-ur-Rehman M, Parvez M (2010) Anti-
oxidant and anti-bacterial activities of novel N0-arylmethylidene-
2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2
(4H)-yl) acetohydrazides. Eur J Med Chem 45:698–704
Ali MM, Tasneem T, Rajanna KC, Saiprakash PK (2001) An efficient
and facile synthesis of 2-chloro-3-formyl quinolines from
acetanilides in micellar media by Vilsmeier–Haack cyclisation.
Synlett 2:251–253
Ali MM, Sana S, Tasneem T, Rajanna KC, Saiprakash PK (2002)
Ultrasonically accelerated Vilsmeier Haack cyclisation and
formylation reactions. Synth Commun 32:1351–1356
Altomare A, Cascarano M, Giacovazzo C, Guagliardi A (1993)
Completion and refinement of crystal structures with SIR92.
J Appl Cryst 26:343–350
Barazarte A, Lobo G, Gamboa N, Rodrigues JR, Capparelli MV,
Alvarez-Larena A, Lopez SE, Charris JE (2009) Synthesis and
antimalarial activity of pyrazolo and pyrimido benzothiazine
dioxide derivatives. Eur J Med Chem 44:1303–1310
Beurskens PT, Admiraal G, Beurskens G, Bosman WP, de Gelder R,
Israel R, Smits JMM (1994) The DIRDIF-94 program system,
technical report of the crystallography laboratory, University of
Nijmegen, The Netherlands
´
´
Manjarrez N, Perez HI, Solıs A, Luna H (1996) A facile one-pot
synthesis of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-
benzothiazine 1,1-dioxide, a key intermediate in the synthesis of
oxicam anti-inflammatory agents. Synth Commun 26:1405–1410
Manske RHF, Kulka M (1953) The Skraup synthesis of quinolines.
Org React 7:59
Meth-Cohn O, Narine B, Tarnowski B (1981) A versatile new
synthesis of quinolines and related fused pyridines, part 5, The
synthesis of 2-chloroquinoline-3-carbaldehydes. J Chem Soc
Perkin Trans I 5:1520–1530
National Committee for Clinical Laboratory Standards (NCCLS)
(1993) Methods for dilution antimicrobial susceptibility test
for bacteria that grow aerobically, 3rd ed. Approved standard
M7-A3. NCCLS, Villanova
Otwinowski Z, Minor W (1997) Processing of X-ray diffraction data
collected in oscillation mode. Methods Enzymol 276:307–326
Sankaran M, Kumarasamy C, Chokkalingam U, Mohan PS (2010)
Synthesis, antioxidant and toxicological study of novel pyrimido
quinoline derivatives from 4-hydroxy-3-acyl quinolin-2-one.
Bioorg Med Chem Lett 20:7147–7151
Braughler JM, Duncan LA, Chase RL (1986) The involvement of iron
in lipid peroxidation. Importance of ferric to ferrous ratios in
initiation. J Biol Chem 261:10282–10289
Shavel Jr J, Zinnes H (1967) Pyrazolo [4, 3-c][1, 2] benzothiazine 5,5-
dioxides and process for their production. US Patent 3,346,572,
Oct 10, 1967
Sheldrick GM (2008) A short history of SHELX. Acta Cryst
A64:112–122
Siddiqui WA, Ahmad S, Siddiqui HL, Tariq MI, Parvez M (2008) N-(X-
Chlorophenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-car-
boxamide 1,1-dioxide (with X = 2 and 4). Acta Cryst C64:04–06
Caddick S (1995) Microwave assisted organic reactions. Tetrahedron
51:10403–10432
Constantine JW (1967) Aggregation and adhesion of rat platelets.
Nature 214:1084–1086
Cremer D, Pople JA (1975) General definition of ring puckering
coordinates. J Am Chem Soc 97:1354–1358
Dillard RD, Pavey DE, Benslay DN (1973) Synthesis and antiin-
flammatory activity of some 2,2-dimethyl-1,2-dihydroquino-
lines. J Med Chem 16:251–253
Eiserich JP, Shibamoto T (1994) Antioxidative activity of volatile
heterocyclic compounds. J Agric Food Chem 42:1060–1063
Espinel-Ingroff A, Pfaller MA (1995) Antifungal agents and suscep-
tibility testing. In: Murray PR, Baron EJ, Pfaller MA, Tenover
FC, Yolken RH (eds) Manual of clinical microbiology, 6th edn.
ASM Press, Washington
Farrugia LJ (1997) ORTEP-3 for Windows—a version of ORTEP-III
with a Graphical User Interface (GUI). J Appl Cryst 30:565
Foroumadi A, Samzadeh-Kermani A, Emami S, Dehghan G, Sorkhi M,
Arabsorkhi F, Heidari MR, Abdollahi M, Shafiee A (2007)
Synthesis and antioxidant properties of substituted 3-benzylidene-
7-alkoxychroman-4-ones. Bioorg Med Chem Lett 17:6764–6769
Galema SA (1997) Microwave chemistry. Chem Soc Rev 26:233–238
ˇ
´
´
´
Simic A, Manojlovic D, Segan D, Todorovic M (2007) Electrochem-
ical behavior and antioxidant and prooxidant activity of natural
phenolics. Molecules 12:2327–2340
Singh SP, Parmar SS, Stenberg VI (1978) Carbon-13 nuclear
magnetic resonance spectra of potent antimalarials: primaquine
and chloroquine. J Heterocycl Chem 15:9–11
Varma RS (1999) Solvent-free synthesis of heterocyclic compounds
using microwaves. J Heterocycl Chem 36:1565–1571
Zia-ur-rehman M, Choudary JA, Ahmad S, Siddiqui HL (2006)
Synthesis of potential biologically active 1,2-benzothiazin-3-yl-
quinazolin-4(3H)-ones. Chem Pharm Bull 54:1175–1178
Zinnes H, Lindo N, Sircar AJC, Schwartz ML, Shavel J Jr (1973) 1,2-
Benzothiazines. 6. 3-Carbamoyl-4-hydroxy-2H-1,2-benzothiazine
1,1-dioxides as antiinflammatory agents. J Med Chem 16:44–48
123