Synthesis and biological evaluation of new [1,3,4]thiadiazepino[7,6-b] quinolin-2-amines as potent anti-microbial agents

Article abstract of DOI:10.1007/s00044-012-0389-z

Four series of 56 new thiadiazepinoquinoline amines were synthesized and characterized by spectroscopic techniques (NMR, IR, and MS) and elemental analysis. All the compounds were screened for in vitro anti-microbial activity. Highest inhibitory activity (MIC of 0.03 mg/ml) was exerted by 2e against Bacillus subtilis and Streptococcus pyogenes, 2f against Escherichia coli and Streptococcus pyogenes, and 4k against only Bacillus subtilis. Only compounds 1g and 2g revealed potent anti-fungal activity (MIC 0.03 mg/ml) compared to the standard against Alternaria alternata. Most of the compounds exhibited better anti-bacterial activity than anti-fungal activity against the microorganisms employed in this study. These studies suggest that the thiadiazepinoquinoline scaffold may serve as a new promising template for further elaboration as anti-bacterial and anti-fungal drugs. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-012-0389-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0389-z
ORIGINAL RESEARCH
Synthesis and biological evaluation of new
[1,3,4]thiadiazepino[7,6-b]quinolin-2-amines as potent
anti-microbial agents
•
Hasnain Muhammad Raza Nada-E-Ali Rizvi
•
•
Hamid Latif Siddiqui Arshad Javaid
•
Mazhar Iqbal
Received: 7 July 2012 / Accepted: 4 December 2012
Ó Springer Science+Business Media New York 2012
Abstract Four series of 56 new thiadiazepinoquinoline
amines were synthesized and characterized by spectro-
scopic techniques (NMR, IR, and MS) and elemental
analysis. All the compounds were screened for in vitro anti-
microbial activity. Highest inhibitory activity (MIC of
0.03 mg/ml) was exerted by 2e against Bacillus subtilis and
Streptococcus pyogenes, 2f against Escherichia coli and
Streptococcus pyogenes, and 4k against only Bacillus
subtilis. Only compounds 1g and 2g revealed potent anti-
fungal activity (MIC 0.03 mg/ml) compared to the standard
against Alternaria alternata. Most of the compounds
exhibited better anti-bacterial activity than anti-fungal
activity against the microorganisms employed in this study.
These studies suggest that the thiadiazepinoquinoline
scaffold may serve as a new promising template for further
elaboration as anti-bacterial and anti-fungal drugs.
Introduction
Heterocyclic compounds are well known for their wide
range of biological applications. Six- and seven-membered
heterocycles occupy a unique position due to dominant
pharmacological applications (Forest et al., 1992; Natalya
et al., 2002). Quinolines and their derivatives, which rep-
resent a major class of heterocycles (Meth-Cohn and
Narine, 1978), are widely found in natural products
(Michael, 2003; Michael, 2004) and drugs (Alhaider et al.,
1985; Campbell et al., 1988; Du, 2003) and exhibit sig-
nificant role in medicinal chemistry. Several quinoline
derivatives have been reported to possess bactericidal
(Awad et al., 1991), anti-malarial (Ginsburg et al., 1999),
anti-allergenic (Althuis et al., 1980) and anti-inflammatory
(Dillard et al., 1973) properties. Some of the famous anti-
malarial drugs, containing quinoline ring system, available
in the market are plasmoquine (Manske and Kulka, 1953),
primaquine, and chloroquine (Singh et al., 1978). Simi-
larly, some quinoline derivatives are found to have anti-
cancer and anti-tumor activities (Loaiza et al., 2004).
Among the quinolines, 2-chloro-3-formylquinolines find an
important place in synthetic organic chemistry, as these are
key intermediates for further b-annelation of a wide variety
of ring systems and for the inter-conversions of many
functional groups (Meth-Cohn, 1993). Certain thiadiaze-
pine analogs have displayed neuroprotection against neu-
rodegenerative diseases such as Alzheimer’s disease
(Gonzalez-Munoz et al., 2010). Thiadiazepines show anti-
microbial (Demirbas et al., 2005; Dandia et al., 2006;
Reddy and Reddy, 2010), anti-viral (Farghalya et al.,
2006), anthelmintic (Kritsanida et al., 2002), and anti-HIV
activities (Artico et al., 1996).
Keywords 2-Chloro-3-formylquinoline Á
[1,3,4]Thiadiazepino[7,6-b]quinolin-2-amines Á
Thiosemicarbazides Á Anti-microbials
H. M. Raza (&) Á Nada-E-AliRizvi Á H. L. Siddiqui
Institute of Chemistry, University of the Punjab,
Lahore 54590, Pakistan
e-mail: hmraza786@yahoo.com
A. Javaid
Institute of Agricultural Sciences, University of the
Punjab, Lahore, Pakistan
M. Iqbal
National Institute of Biotechnology and Genetic
Engineering, Faislabad 38000, Pakistan
In continuation of our on-going research on various
biologically active quinoline derivatives (Rizvi et al.,
123

Med Chem Res
O
O
N
N
HN
N
HO
Cl
N
H
S-9-Methoxymappic ine
(Anti cancer and Anti HIV)
Chloroquine
(Antimalarial)
N
N
S
NH2
S
Ph
N
N
N
N
Cl
O
N
Ph
O
N
Ph
1,4,5-Dibenzo[b,f]thiadiazepine analogue
(exhibits neuroprotection against
neurodegenerative diseases)
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepines
(Potent antiviral agent)
Fig. 1 Structures of some quinoline- and thiadiazepine-based drugs
2010, 2012) and due to versatile anti-microbial activities
of thiadiazepines, we herein report synthesis of four
series of new (2Z,4Z)-9-chloro-10-methyl/8-methyl/10-
methyl/8-methoxy-N-aryl/alkyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amines (1a–n, 2a–n, 3a–n, and 4a–n) with the
perception that the synergism of quinoline and thiadiaze-
pino nuclei would likely to possess significant biological
activities (Fig. 1; Table 1).
them with diverse thiosemicarbazides, following reported
procedure (Raghavendra et al., 2006; Scheme 1).
All the condensation reactions were also attempted under
microwaves and found more effective than in thermal
conditions due to greater yield and lesser reaction time
(Table 2). Thiadiazepine ring closure was proved to be
more effective relative to reported procedure in terms of
substitution pattern of tricyclic thiadiazepino quinoline
skeleton, reaction kinetics, and yields (Table 2). The
acceleration of ring closure may be attributed to greater
stabilization of cyclized product through resonance (Fig. 2).
Structure of the synthesized compounds (1a–n, 2a–n,
3a–n, and 4a-n) was confirmed on the basis of elemental
analysis and spectral data (IR, 1HNMR, and MS). IR
spectra of all the compounds showed absorption bands
in the regions 1,600–1,660 cm-1 corresponding to C=N
stretching bands because of ring closure. Absorption bands
at 3,401–3,492 cm-1 and 1,384 cm-1 were also observed
due to NH and C–S, respectively.
Results and discussion
Chemistry
(2Z,4Z)-9-Chloro-10-methyl/8-methyl/10-methyl/8-methoxy-
N-aryl/alkyl-[1,3,4]thiadiazepino[7,6-b]quinolin-2-amines
(1a–n, 2a–n, 3a–n, and 4a–n) were synthesized from
commercially available four anilines following a three-step
synthetic route. The latter were initially N-acetylated, using
AcOH with H3PO4 or AcOH with Zn-dust under conven-
tional as well as microwave conditions to get acetanilides in
excellent yields (Redasani et al., 2010; Kwon et al., 1997;
Brahmachari et al., 2010). 2-Chloro-3-formylquinoline,
backbone, in turn was constructed by Meth-Cohn cycliza-
tion of acetanilides using conventional and microwave
procedures (Meth-Cohn et al., 1981; Paul et al., 2000;
Ajaypal and Chourasia, 2011). Finally, cyclocondensation
of 2-chloro-3-formylquinolines was achieved by treating
1
In H NMR spectra of all the compounds, NH proton
was observed at d 8.48–9.87 ppm, while H-5 appeared at d
8.50–9.19 each as singlet. The possible explanation for H-5
being more shielded in compound 2j compared to 2a is the
steric hindrance between the two methyl groups at C2/C6 in
ring D and ‘‘S’’ atom in ring C which are in close prox-
imity, pushes the former ring out of the plane (Figs. 2, 3).
In continuation of our endeavors, we have synthesized four
series of 56 new compounds and evaluated their anti-bacterial
123

Med Chem Res
Table 1 Alkyl or aryl moiety in [1,3,4]thiadiazepino[7,6-b]quinolin-
2-amines (1a–n), (2a–n), (3a–n), and (4a–n)
Table 1 continued
Compounds
R1
R2
R3
R4
Compounds
R1
R2
R3
R4
4g
4h
4i
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4-Chlorophenyl
o-Tolyl
1a
1b
1c
1d
1e
1f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
H
Phenyl
H
2-Fluorophenyl
3-Fluorophenyl
4-Fluorophenyl
2-Chlorophenyl
3-Chlorophenyl
4-Chlorophenyl
o-Tolyl
p-Tolyl
H
4j
2,6-Dimethylphenyl
2,4-Dimethylphenyl
4-Ethylphenyl
Benzyl
H
4k
4l
H
H
4m
4n
1g
1h
1i
H
2-Morpholinoethyl
H
H
p-Tolyl
1j
H
2,6-Dimethylphenyl
2,4-Dimethylphenyl
4-Ethylphenyl
Benzyl
activity against three Gram-positive bacteria (Bacillus subtilis,
Staphylococcus aureus, and Streptococcus pyogenes) and
three Gram-negative bacteria (Escherichia coli, Klebsiella
aerogenes, and Salmonella typhimurium) by determining their
minimum inhibitory concentrations (MICs) using the agar
dilution technique (Hanel and Raether, 1988) and chloram-
phenicol as reference drug. Chloramphenicol is considered a
prototypical broad spectrum antibiotic and frequently found as
a drug of choice in the third world and is effective against a
wide variety of Gram-positive bacteria (including most strains
of MRSA), Gram-negative bacteria, and anaerobes (Shakila
et al., 2007). Due to resistance and safety concerns, it is no
longer a first-line agent for any infection in developed nations,
although it is sometimes used topically for eye infections.
Nevertheless, the global problem of advancing bacterial
resistance to newer drugs has led to renewed interest in its use
(Falagas et al., 2008).
1k
1l
H
H
1m
1n
2a
2b
2c
2d
2e
2f
H
H
2-Morpholinoethyl
Phenyl
H
H
2-Fluorophenyl
3-Fluorophenyl
4-Fluorophenyl
2-Chlorophenyl
3-Chlorophenyl
4-Chlorophenyl
o-Tolyl
H
H
H
H
2g
2h
2i
H
H
H
p-Tolyl
2j
H
2,6-Dimethylphenyl
2,4-Dimethylphenyl
4-Ethylphenyl
Benzyl
2k
2l
H
H
MICs of the active compounds against the suscepti-
ble pathogenic organisms are presented in Table 3. The
anti-microbial spectrum of thiadiazepino[7,6-b]quinolin-2-
amines against all strains demonstrated that all the com-
pounds were the most active ones. Most of the compounds
presented an MIC in the range of 0.03–0.50 mg/ml against
all strains. An insight to the activities of different compounds
obtained reveals that 11 compounds (2c, 2e, 2f–g, 4b–c,
4g–h, 4j–k, 4m) are more active against B. subtilis (Gram-
positive bacterium, MIC 0.03–0.06 mg/ml). Likewise,
compounds (4a, 4f, and 4k) exhibited more activity against
E. coli (Gram-negative bacterium, MIC 0.06 mg/ml). By
screening a large number of compounds, we were able to
establish some general trends with respect to the structure–
activity relationship, but it was not possible to draw clear and
detailed relationships for any of the bioactivities. Higher
activity of all the compounds generally against all the strains
may be attributed to the presence of NH group flanked by
rings C and D. Moreover, it seems that incorporation of either
OMe/Cl in ring A or F/Cl in ring D regardless of their ori-
entation enhances the anti-microbial activity.
2m
2n
3a
3b
3c
3d
3e
3f
H
H
2-Morpholinoethyl
Phenyl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
2-Fluorophenyl
3-Fluorophenyl
4-Fluorophenyl
2-Chlorophenyl
3-Chlorophenyl
4-Chlorophenyl
o-Tolyl
H
H
H
H
3g
3h
3i
H
H
H
p-Tolyl
3j
H
2,6-Dimethylphenyl
2,4-Dimethylphenyl
4-Ethylphenyl
Benzyl
3k
3l
H
H
3m
3n
4a
4b
4c
4d
4e
4f
H
H
2-Morpholinoethyl
Phenyl
H
H
2-Fluorophenyl
3-Fluorophenyl
4-Fluorophenyl
2-Chlorophenyl
3-Chlorophenyl
H
H
H
Antifungal activity of the synthesized compounds was
also elucidated against five strains of fungi, Trichoderma
H
123

Med Chem Res
Scheme 1 Reaction protocol
for the conversion of anilines to
(2Z, 4Z)-9-chloro-10-methyl/8-
methyl/10-methyl/8-methoxy-
N-aryl/alkyl-
[1,3,4]thiadiazepino[7,6-
b]quinolin-2-amines. (i) AcOH,
H3PO4, reflux/microwaves or
AcOH, Zn dust, reflux/
microwaves, (ii) POCl3, DMF,
reflux/microwaves, and (iii)
thiosemicarbazides, p-TsOH,
DMF/EtOH, reflux/microwaves
General procedure for the synthesis of (2Z,4Z)-9-chloro-10-
methyl/8-methyl/10-methyl/8-methoxy-N-aryl/alkyl-[1,3,4]
thiadiazepino[7,6-b]quinolin-2-amines (1a–n, 2a–n, 3a–n,
and 4a–n)
reesei, Aspergillus flavus, Alternaria alternata, Aspergillus
niger, and Drechslera australiensis by determining the
MICs through microdilution technique (Espinel-Ingroff,
2001). Activity of each compound was compared with
mancozeb as standard and the results are shown in Table 4.
Twenty-one compounds (1h, 1j–k, 1n, 2b, 2g, 3h, 3j–k,
3n, and 4a–k) exhibited excellent activity (MIC
0.06–0.25 mg/ml) against T. reesei. Similarly, 13 com-
pounds (1g, 2b, 2d, 2f–g, 2k, 4a, 4d–e, 4g–h, and 4j–k)
also showed promising activity (0.030–0.25 mg/ml) against
A. alternata.
First, four precursors, 7-chloro-8-methyl/6-methyl/8-methyl/
6-methoxy-substituted 2-chloro-3-formyl quinolines, were
synthesized according to the literature method (Meth-Cohn
et al., 1981; Paul et al., 2000; Ajaypal and Chourasia, 2011).
Cyclocondensation was achieved following reported proce-
dure (Raghavendra et al., 2006). A mixture of substituted
quinoline (0.5 mmol), thiosemicarbazide (0.5 mmol), cata-
lytic amount of p-toluenesulfonic acid (p-TsOH), and
absolute EtOH (20 ml) was refluxed till completion of the
reaction (for yields, reaction conditions, and reaction times,
see Table 1). After completion of reaction (as indicated by
TLC), the contents were poured over crushed ice, stirred
well and filtered. Precipitates obtained were recrystallised
from aqueous DMF to get pure compounds (1a–n, 2a–n,
3a–n, and 4a–n).
Experimental
General
All the chemicals were purchased from E. Merck, Alpha
Aesar or Fluka and used without purification. However, sol-
vents were purified through distillation. 1H NMR spectra were
recorded on a Bruker/XWIN NMR (300 and 400 MHz).
Chemical shifts are reported in ppm referenced to the residual
solvent signal. FT-IR spectra were recorded on a Thermo
Nicolet IR 200 spectrometer. Mass spectra were recorded on
LTQXL (Thermo Fisher Scientific) instrument using CI
mode. Melting points were recorded on a Gallenkamp melting
point apparatus and are uncorrected. Microwave-assisted
reactions were carried out in a household MW oven (Oriente-
NN-781JF) equipped with inverter technology (generating
fixed frequency throughout the required time) for realistic
control of the microwaves operating at multiples of 100 up to
1,000 W generating 2,450-MHz frequency. The apparatus
was modified for laboratory applications, equipped with
magnetic stirrer and an external reflux condenser. Elemental
analysis was carried out using a Perkin Elmer 2400-CHN
Analyzer.
Using microwaves A mixture of substituted quinoline
(0.5 mmol) and thiosemicarbazide (0.5 mmol), catalytic
amount of p-toluenesulfonic acid (p-TsOH) and anhydrous
dimethylformamide (DMF) (15 ml) were added and con-
tents were irradiated under microwave oven for 50–120 s at
an interval of 20–30 s at 210 W (for yields, reaction con-
ditions, and reaction times, see Table 1). After completion
of the reaction (as indicated by TLC), the contents were
poured over crushed ice, stirred well and filtered. Precipi-
tates obtained were recrystallised from aqueous DMF to get
the pure product (1a–n, 2a–n, 3a–n, and 4a–n).
(2Z,4Z)-8-Methyl-N-phenyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (1a) Yellow solid; m.p. 106 °C. IR
(KBr) cm-1: 3,466 (N–H), 1,660 (C=N), 1,549, 1,586
123

Med Chem Res
Table 2 Physical and analytical data (CHN analysis) of [1,3,4]thiadiazepino[7,6-b]quinolin-2-amines (1a–n), (2a–n), (3a–n), and (4a–n)
Compounds
Reaction conditions
Conventional
Mol. formula
Analysis %
Microwave (210 W)
Calculated (found)
Time (min)
Yield (%)
Time (s)
Yield (%)
C
H
N
1a
1b
1c
1d
1e
1f
90
75
70
40
55
50
45
40
35
55
50
45
50
35
75
80
60
30
45
40
40
35
40
60
45
35
50
40
60
40
50
40
35
60
60
60
45
30
45
80
40
50
45
30
80
50
78
80
79
81
76
82
85
78
83
72
77
81
84
78
76
79
81
83
72
79
80
80
81
80
82
84
81
79
72
80
76
78
76
78
78
74
78
76
81
75
78
74
80
80
76
81
60
60
60
50
50
60
60
90
120
60
50
60
50
50
60
60
60
90
60
60
50
60
120
60
60
60
60
60
70
90
90
90
90
60
60
120
120
90
50
60
50
70
100
90
90
90
93
94
93
93
82
88
94
82
88
83
94
93
88
89
88
94
94
94
83
88
94
83
84
94
89
94
85
84
91
90
91
90
87
88
88
87
88
92
89
88
88
87
93
86
89
82
C18H14N4S
67.90 (67.88)
64.27 (67.29)
64.27 (67.29)
64.27 (67.29)
61.27 (67.30)
61.27 (67.30)
61.27 (67.30)
68.65 (68.67)
68.65 (68.67)
69.34 (69.32)
69.34 (69.32)
69.34 (69.37)
68.65 (68.67)
60.82 (60.84)
64.65 (64.64)
61.35 (61.37)
61.35 (61.38)
61.35 (61.36)
58.61 (58.63)
58.61 (58.60)
58.61 (58.63)
65.50 (65.53)
65.50 (65.53)
66.28 (66.31)
66.28 (66.31)
66.28 (66.30)
65.50 (65.52)
58.20 (58.17)
67.90 (67.87)
64.27 (67.29)
64.27 (67.29)
64.27 (67.28)
61.27 (67.30)
61.27 (67.30)
61.27 (67.28)
68.65 (68.67)
68.65 (68.67)
69.34 (69.32)
69.34 (69.32)
69.34 (69.37)
68.65 (68.67)
60.82 (60.84)
61.27 (61.30)
58.30 (58.32)
58.30 (58.31)
58.30 (58.32)
4.43 (4.45)
3.90 (3.88)
3.90 (3.88)
3.90 (3.88)
3.71 (3.69)
3.71 (3.69)
3.71 (3.69)
4.85 (4.84)
4.85 (4.84)
5.24 (5.25)
5.24 (5.25)
5.24 (5.22)
4.85 (4.84)
5.95 (5.93)
4.22 (4.24)
3.72 (3.70)
3.72 (3.70)
3.72 (3.71)
3.55 (3.56)
3.55 (3.56)
3.55 (3.55)
4.63 (4.65)
4.63 (4.65)
5.01 (5.00)
5.01 (5.00)
5.01 (5.02)
4.63 (4.66)
5.70 (5.72)
4.43 (4.45)
3.90 (3.89)
3.90 (3.88)
3.90 (3.88)
3.71 (3.70)
3.71 (3.69)
3.71 (3.69)
4.85 (4.84)
4.85 (4.84)
5.24 (5.25)
5.24 (5.25)
5.24 (5.22)
4.85 (4.84)
5.95 (5.93)
3.71 (3.70)
3.26 (3.27)
3.26 (3.27)
3.26 (3.28)
17.60 (17.61)
16.66 (16.59)
16.66 (16.59)
16.66 (16.59)
15.88 (15.88)
15.88 (15.80)
15.88 (15.80)
16.85 (16.84)
16.85 (16.84)
16.17 (16.17)
16.17 (16.18)
16.17 (16.18)
16.85 (16.84)
19.70 (19.70)
16.75 (16.75)
15.90 (15.91)
15.90 (15.90)
15.90 (15.91)
15.19 (15.18)
15.19 (15.18)
15.19 (15.19)
16.08 (16.09)
16.08 (16.09)
15.46 (15.48)
15.46 (15.48)
15.46 (15.48)
16.08 (16.07)
18.85 (18.84)
17.60 (17.61)
16.66 (16.59)
16.66 (16.59)
16.66 (16.59)
15.88 (15.88)
15.88 (15.60)
15.88 (15.88)
16.85 (16.84)
16.85 (16.85)
16.17 (16.17)
16.17 (16.18)
16.17 (16.18)
16.85 (16.84)
19.70 (19.70)
15.88 (15.90)
15.11 (15.10)
15.11 (15.10)
15.11 (15.11)
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
18H13FN4S
18H13FN4S
18H13FN4S
18H13ClN4S
18H13ClN4S
18H13ClN4S
19H16N4S
1g
1h
1i
19H16N4S
1j
20H18N4S
1k
1l
20H18N4S
20H18N4S
1m
1n
2a
2b
2c
2d
2e
2f
19H16N4S
18H21N5OS
18H14N4OS
18H13FN4OS
18H13FN4OS
18H13FN4OS
18H13ClN4OS
18H13ClN4OS
18H13ClN4OS
19H16N4OS
19H16N4OS
20H18N4OS
20H18N4OS
20H18N4OS
19H16N4OS
18H21N5O2S
18H14N4S
2g
2h
2i
2j
2k
2l
2m
2n
3a
3b
3c
3d
3e
3f
18H13FN4S
18H13FN4S
18H13FN4S
18H13ClN4S
18H13ClN4S
18H13ClN4S
19H16N4S
3g
3h
3i
19H16N4S
3j
20H18N4S
3k
3l
20H18N4S
20H18N4S
3m
3n
4a
4b
4c
4d
19H16N4S
18H21N5OS
18H13ClN4S
18H12ClFN4S
18H12ClFN4S
18H12ClFN4S
123

Med Chem Res
Table 2 continued
Compounds
Reaction conditions
Mol. formula
Analysis %
Conventional
Time (min)
Microwave (210 W)
Calculated (found)
Yield (%)
Time (s)
Yield (%)
C
H
N
4e
4f
35
40
45
45
30
30
35
70
60
45
78
76
75
81
78
84
78
80
76
82
60
60
60
90
90
90
90
90
50
70
84
85
88
89
89
91
91
86
89
89
C18H12Cl2N4S
55.82 (55.81)
55.82 (55.84)
55.82 (55.84)
62.20 (62.22)
62.20 (62.23)
63.07 (67.06)
63.07 (67.05)
63.07 (67.05)
62.20 (62.23)
55.45 (55.46)
3.12 (3.13)
3.12 (3.12)
3.12 (3.13)
4.12 (4.11)
4.12 (4.13)
4.50 (4.51)
4.50 (4.50)
4.50 (4.51)
4.12 (4.10)
5.17 (5.17)
14.47 (14.49)
14.47 (14.47)
14.47 (14.47)
15.27 (15.28)
15.27 (15.29)
14.71 (14.70)
14.71 (14.71)
14.71 (14.71)
15.27 (15.28)
17.96 (17.97)
C
C
C
C
C
C
C
C
C
18H12Cl2N4S
18H12Cl2N4S
19H15ClN4S
19H15ClN4S
20H17ClN4S
20H17ClN4S
20H17ClN4S
19H15ClN4S
18H20ClN5OS
4g
4h
4i
4j
4k
4l
4m
4n
Isolated yields based on (2Z,4Z)-9-chloro-10-methyl/8-methyl/10-methyl/8-methoxy-N-aryl/alkyl-[1,3,4]thiadiazepino[7,6-b]quinolin-2-amines
(C=C), 1,384 (C–S).1H NMR(CDCl3) d: 2.52 (3H, s, CH3),
7.57–7.94 (7H, m, ArH), 8.36 (1H, s, ArH), 8.58 (1H, s,
ArH), 9.20 (1H, s, H–C=N), 9.87 (1H, s, NH). MS m/z: 319
[M?H]?.
102 °C. IR (KBr) cm-1: 3,490 (N–H), 1,638 (C=N), 1,384
(C–S). 1H NMR(CDCl3) d: 2.52 (3H, s, CH3), 7.09 (1H, d,
J = 11.6 Hz, ArH), 7.58–7.63 (4H, m, ArH), 7.90 (1H, d,
J = 11.6 Hz, ArH), 8.35 (1H, s, ArH), 8.57 (1H, s, ArH),
9.10 (1H, s, H–C=N), 9.81 (1H, s, NH). MS m/z: 337
[M?H]?.
(2Z,4Z)-N-(2-Fluorophenyl)-8-methyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (1b) Yellow solid; m.p. 160 °C.
IR (KBr) cm-1: 3,480 (N–H), 1,637 (C=N), 1,384 (C–S).1H
NMR(CDCl3) d: 2.54 (3H, s, CH3), 7.87–7.94 (4H, m,
ArH), 8.47–8.55 (2H, m, ArH), 8.94 (1H, s, ArH), 9.18 (1H,
s, ArH), 9.41 (1H, s, H–C=N), 9.79 (1H, s, NH). MS m/z:
337 [M?H]?.
(2Z,4Z)-N-(2-Chlorophenyl)-8-methyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (1e) Brownish yellow solid;
m.p. 104 °C. IR (KBr) cm-1: 3,400 (N–H), 1,617 (C=N),
1,547 (C=C), 1,384 (C–S). 1H NMR(CDCl3) d: 2.53 (3H, s,
CH3), 7.24 (1H, s, ArH), 7.34 (1H, t, J = 9.6 Hz, ArH),
7.45 (1H, d, J = 10.4 Hz, ArH), 7.59 (1H, s, ArH), 7.90
(1H, d, J = 12.0 Hz, ArH), 8.36 (1H, s, ArH), 8.63 (1H, s,
ArH), 8.70 (1H, d, J = 10.0 Hz, ArH), 9.18 (1H, s, H–
C=N), 9.67 (1H, s, NH). MS m/z: 353 [M?H]?, 355
[M?H?2]?.
(2Z,4Z)-N-(3-Fluorophenyl)-8-methyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (1c) Yellow solid; m.p. 98 °C.
IR (KBr) cm-1: 3,490 (N–H), 1,638 (C=N), 1,384 (C–S).
1H NMR(CDCl3) d: 2.52 (3H, s, CH3), 6.95 (1H, t,
J = 10.0 Hz, ArH), 7.24 (1H, s, ArH), 7.58–7.69 (3H, m,
ArH), 7.90 (1H, d, J = 11.2 Hz, ArH), 8.35 (1H, s, ArH),
8.58 (1H, s, ArH), 9.22 (1H, s, H–C=N), 9.73 (1H, s, NH).
MS m/z: 337 [M?H]?.
(2Z,4Z)-N-(3-Chlorophenyl)-8-methyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (1f) Yellow solid; m.p. 102 °C.
IR (KBr) cm-1: 3,466 (N–H), 1,660 (C=N), 1,549, 1,585
(C=C), 1,384 (C–S). 1H NMR(CDCl3) d: 2.53 (3H, s, CH3),
7.24 (1H, s, ArH), 7.66 (3H, m, ArH), 7.75 (1H, s, ArH),
7.90 (1H, d, J = 11.2 Hz, ArH), 8.35 (1H, s, ArH), 8.58
(2Z,4Z)-N-(4-Fluorophenyl)-8-methyl-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (1d) Yellow solid; m.p.
Fig. 2 Phenyl ring showing planarity with the orbitals of nitrogen
and thiadiazepine ring
Fig. 3 Resonance effect operates through p framework to shield H5
anti-bacterial activities
123

Med Chem Res
Table 3 Anti-bacterial activities of compounds 1a–n, 2a–n, 3a–n, and 4a–n tested by microdilution method (MIC mg/ml)
Entry
Compounds
Susceptible microorganism
Gram-positive bacteria
Gram-negative bacteria
B. subtilis
S. aureus
S. pyogenes
E. coli
K. aerogenes
S. typhimurium
1
1a
1b
1c
1d
1e
1f
1.0
1.0
1.0
0.5
0.5
1.0
[1.0
1.0
0.5
0.5
1.0
2
0.06
3
[1.0
0.25
1.0
[1.0
0.25
1.0
[1.0
0.5
[1.0
0.5
[1.0
[1.0
0.25
1.0
4
0.125
0.06
0.25
1.0
5
0.5
0.5
6
1.0
1.0
[1.0
[1.0
0.5
1.0
1.0
7
1g
1h
1i
1.0
1.0
[1.0
1.0
[1.0
1.0
8
0.5
0.5
0.5
9
1.0
[1.0
1.0
1.0
1.0
0.06
1.0
0.06
1.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
1j
1.0
1.0
1.0
1k
1l
0.5
0.5
0.5
0.5
0.5
0.5
1.0
[1.0
1.0
[1.0
1.0
[1.0
1.0
[1.0
1.0
[1.0
1.0
1m
1n
2a
2b
2c
2d
2e
2f
1.0
[1.0
0.5
1.0
[1.0
0.06
0.5
0.5
1.0
1.0
0.5
0.5
0.125
0.06
[1.0
1.0
1.0
0.5
1.0
[1.0
0.5
0.06
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.06
0.125
0.25
0.5
0.25
0.06
0.5
0.03
0.06
0.06
1.0
1.0
0.03
0.03
0.5
0.5
0.5
0.03
0.25
0.5
2g
2h
2i
0.5
1.0
1.0
1.0
1.0
0.125
0.5
0.25
1.0
0.5
0.5
0.5
0.5
2j
1.0
0.5
0.5
0.5
0.5
2k
2l
1.0
1.0
1.0
0.5
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2m
2n
3a
3b
3c
3d
3e
3f
1.0
1.0
1.0
1.0
0.125
1.0
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
1.0
0.5
0.5
0.25
0.5
1.0
0.5
0.5
1.0
1.0
0.5
0.25
[1.0
1.0
0.25
[1.0
1.0
0.25
[1.0
1.0
0.5
0.5
[1.0
1.0
[1.0
[1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.06
0.5
0.5
1.0
3g
3h
3i
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3j
1.0
1.0
1.0
1.0
1.0
3k
3l
1.0
1.0
1.0
1.0
1.0
0.25
[1.0
1.0
0.5
0.5
0.5
1.0
3m
3n
4a
4b
4c
4d
[1.0
1.0
[1.0
1.0
[1.0
1.0
[1.0
1.0
0.125
0.06
0.06
0.125
[1.0
0.5
0.06
0.06
1.0
0.06
0.5
[1.0
0.5
1.0
0.5
1.0
1.0
0.06
0.5
1.0
123

Med Chem Res
Table 3 continued
Entry
Compounds
Susceptible microorganism
Gram-positive bacteria
Gram-negative bacteria
B. subtilis
S. aureus
S. pyogenes
E. coli
K. aerogenes
S. typhimurium
47
48
49
50
51
52
53
54
55
56
4e
0.5
0.5
0.5
1.0
0.5
0.5
0.5
0.5
1.0
1.0
0.25
1.0
0.5
0.5
0.5
1.0
0.5
0.25
0.5
0.5
0.5
1.0
0.5
0.25
1.0
0.5
4f
0.125
0.06
0.06
0.125
0.06
0.03
0.125
0.06
0.25
1.0
0.125
0.5
0.06
0.5
1.0
4g
1.0
4h
0.25
0.25
0.06
0.06
0.5
0.25
0.25
0.125
0.06
1.0
0.5
4i
0.5
4j
1.0
4k
0.5
4l
1.0
4m
1.0
1.0
0.06
0.125
1.0
4n
0.25
1.0
0.5
Chloramphenicol
1.0
(1H, s, ArH), 9.18 (1H, s, H–C=N), 9.67 (1H, s, NH). MS
m/z: 353 [M?H]?, 355 [M?H?2]?.
CH3 9 2), 2.35 (3H, s, CH3), 7.12 (1H, d, J = 8.0 Hz,
ArH), 7.14 (2H, d, J = 7.6 Hz, ArH), 7.45 (1H, dd,
J = 2.8, 7.8 Hz, ArH), 7.93 (1H, d, J = 9.1 Hz, ArH),
8.35 (1H, s, ArH), 8.55 (1H, s, ArH), 8.65 (1H, s, H–C=N),
9.70 (1H, s, NH). MS m/z: 347 [M?H]?.
(2Z,4Z)-N-(4-Chlorophenyl)-8-methyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (1g) Yellow solid; m.p. 98 °C.
IR (KBr) cm-1: 3,491 (N–H), 1,637 (C=N), 1,549 (C=C),
1,384 (C–S). 1H NMR(CDCl3) d: 2.51 (3H, s, CH3),
7.24–7.36 (4H, m, ArH), 7.58 (1H, d, J = 11.2 Hz, ArH),
7.88 (1H, d, J = 11.6 Hz, ArH), 8.38 (1H, s, ArH), 8.56
(1H, s, ArH), 9.15 (1H, s, H–C=N), 10.06 (1H, s, NH). MS
m/z: 353 [M?H]?, 355 [M?H?2]?.
(2Z,4Z)-8-Methyl-N-(2,4-dimethylphenyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (1k) Yellow solid; m.p.
184 °C.IR (KBr) cm-1: 3,467 (N–H), 1,636 (C=N), 1,384
(C–S).1H NMR (CDCl3) d: 2.45 (3H, s, CH3), 3.84 (6H, s,
CH3 9 2), 7.01 (1H, d, J = 8.4 Hz, ArH), 7.24 (1H, s,
ArH), 7.53 (1H, d, J = 8.4 Hz, ArH), 7.57 (1H, s, ArH),
7.81 (1H, s, ArH), 8.36 (1H, s, ArH), 8.58 (1H, s, ArH), 8.89
(1H, s, H–C=N), 9.11 (1H, s, NH). MS m/z: 347 [M?H]?.
(2Z,4Z)-8-Methyl-N-o-tolyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (1h) Yellow solid; m.p. 196 °C. IR
(KBr) cm-1: 3,492 (N–H), 1,616 (C=N), 1,384 (C–S).1H
NMR(CDCl3) d: 2.44 (3H, s, CH3), 3.38 (3H, s, CH3), 7.24
(2H, s, ArH), 7.51 (1H, s, ArH), 7.53 (1H, s, ArH), 7.78
(1H, s, ArH), 7.87 (1H, s, ArH), 8.36 (1H, s, ArH), 8.57
(1H, s, ArH), 8.96 (1H, s, H–C=N), 9.09 (1H, s, NH). MS
m/z: 333 [M?H]?.
(2Z,4Z)-N-(4-Ethylphenyl)-8-methyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (1l) Yellow solid; m.p.
100 °C.IR (KBr) cm-1: 3,400 (N–H), 1,621 (C=N), 1,548,
1
1,529 (C=C), 1,384 (C–S). H NMR (CDCl3) d: 1.24 (3H,
t, J = 7.5 Hz, CH3), 2.66 (2H, q, J = 7.8 Hz, CH2), 2.52
(3H, s, CH3), 7.53–7.63 (4H, m, ArH), 7.23 (1H, s, ArH),
7.89 (1H, d, J = 11.6 Hz, ArH), 8.34 (1H, s, ArH), 8.57
(1H, s, ArH), 9.18 (1H, s, H–C=N), 9.83(1H, s, NH). MS
m/z: 347 [M?H]?.
(2Z,4Z)-8-Methyl-N-p-tolyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (1i) Brown solid; m.p. 90 °C. IR
(KBr) cm-1: 3,433 (N–H), 1,636 (C=N), 1,384 (C–S).1H
NMR(CDCl3) d: 2.36 (3H, s, CH3), 2.52 (3H, s, CH3), 7.24
(2H, s, ArH), 7.51 (2H, d, J = 8.4 Hz, ArH), 7.91 (2H, d,
J = 8.8 Hz, ArH), 8.58 (1H, s, ArH), 8.94 (1H, s, ArH),
9.11 (1H, s, ArH), 9.18 (1H, s, H–C=N), 9.78 (1H, s, NH).
MS m/z: 333 [M?H]?.
(2Z,4Z)-N-benzyl-8-methyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (1m) Yellow solid; m.p. 192 °C.IR
(KBr) cm-1: 3,410 (N–H), 1,637 (C=N), 1,546 (C=C),
1,384 (C–S).1H NMR (CDCl3) d: 2.44 (3H, s, CH3), 4.93
(2H, d, J = 4 Hz, CH2), 7.24–7.35 (3H, m, ArH), 7.54
(1H, s, ArH), 7.51 (1H, d, J = 8.8 Hz, ArH), 7.79 (1H, d,
J = 8.8 Hz, ArH), 7.81 (1H, s, ArH), 8.10 (1H, s, ArH),
8.18 (1H, s, ArH), 8.29 (1H, s, H–C=N), 8.48 (1H, s, NH).
MS m/z: 333 [M?H]?.
(2Z,4Z)-8-Methyl-N-(2,6-dimethylphenyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (1j) Yellow solid; m.p.
170 °C. IR (KBr) cm-1: 3,440 (N–H), 1,622 (C=N), 1,413
(C=C), 1,384 (C–S). 1H NMR(CDCl3) d: 2.32 (6H, s,
123

Med Chem Res
Table 4 Anti-fungal activities of compounds 1a–n, 2a–n, 3a–n, and
4a–n tested by microdilution method (MIC mg/ml)
Table 4 continued
Entry Compounds Susceptible microorganism
Entry Compounds Susceptible microorganism
T.
reesei flavus alternata niger australiensis
A.
A.
A.
D.
T.
reesei flavus alternata niger australiensis
A.
A.
A.
D.
47
48
49
50
51
52
53
54
55
56
4e
4f
0.06
0.25
0.125
0.06
0.25
0.25
0.25
1.0
0.5
0.5
0.06
0.5
0.5
0.5
0.5
0.5
1.0
0.5
0.5
0.25
1.0
0.5
0.5
1.0
0.5
0.5
1
1a
1b
1c
1d
1e
1f
0.5
0.5
[1.0
1.0
1.0
1.0
0.5
1.0
1.0
0.5
0.03
1.0 [1.0
[1.0 [1.0
1.0 [1.0
1.0 [1.0
2
1.0
4g
4h
4i
1.0
0.25
0.25
0.5
3
1.0
1.0
4
1.0
[1.0
0.5
1.0
5
1.0
[1.0
1.0
1.0
1.0
0.5
4j
0.5
0.125
0.25
1.0
6
0.5
1.0
4k
4l
0.5
7
1g
1h
1i
0.5
1.0
0.5
[1.0
0.5
1.0 [1.0
8
0.125
0.5
0.125 1.0
0.25 1.0
4m
4n
0.5
0.5
0.5
1.0
0.5
1.0
9
1.0
1.0
0.5
1.0
[1.0
0.5
0.5
0.5
0.5
[1.0
0.5
0.5
0.5
0.5
1.0
0.5
1.0
0.5
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
0.5
0.5
1.0
0.5
0.5
0.125
0.5
0.06
0.5
0.06
0.03
1.0
0.5
1.0
0.25
0.5
1.0
1.0
1.0
1.0
0.5
0.5
1.0
0.5
1.0
1.0
1.0
0.5
1.0
0.5
0.5
0.5
1.0
1.0
0.5
0.5
0.5
1.0
[1.0
1.0
1.0
0.5
1.0
1.0
1.0
1.0
0.5
1.0
1.0
0.5
0.5
0.5
0.5
1.0
0.5
0.5
0.5
1.0
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
1j
0.25
0.125
0.5
Mancozeb 0.25
0.25 0.25
0.25 0.25
1k
1l
1m
1n
2a
2b
2c
2d
2e
2f
0.5
(2Z,4Z)-8-Methyl-N-(2-morpholinoethyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (1n) Yellow solid; m.p.
210 °C.IR (KBr) cm-1: 3,468 (N–H), 1,660 (C=N), 1,549,
1,585 (C=C), 1,384 (C–S).1H NMR (CDCl3) d: 2.48 (3H, s,
CH3), 2.52 (4H, s, CH2 9 2), 2.64–2.72 (2H, m, CH2)
3.73–3.78 (6H, m, CH2 9 3), 7.24 (1H, s, ArH), 7.55 (2H,
d, J = 7.2 Hz, ArH), 7.83 (1H, d, J = 8.8 Hz, ArH), 8.26
(1H, s, H–C=N), 8.58 (1H, s, NH). MS m/z: 356 [M?H]?.
0.25
1.0
0.25
1.0
0.5
0.5
0.5
2g
2h
2i
0.25
0.5
(2Z,4Z)-8-Methoxy-N-phenyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (2a) Yellow solid; m.p. 174 °C. IR
(KBr) cm-1: 3,464 (N–H), 1,636 (C=N), 1,384 (C–S).1H
NMR(CDCl3) d: 3.92 (3H, s, OCH3), 7.12 (1H, d,
J = 2.8 Hz, ArH), 7.39–7.45 (3H, m, ArH), 7.66 (2H, d,
J = 8.0 Hz, ArH), 7.89 (1H, d, J = 9.2 Hz, ArH), 8.33
(1H, s, ArH), 8.56 (1H, s, ArH), 9.19 (1H, s, H–C=N), 9.73
(1H, s, NH). MS m/z: 335 [M?H]?.
1.0
2j
0.5
2k
2l
0.5
0.5
2m
2n
3a
3b
3c
3d
3e
3f
0.5
1.0
0.5
1.0 [1.0
[1.0
1.0
1.0
1.0
1.0
0.5
1.0
0.5
0.5
1.0
1.0
0.5
0.5
1.0
0.5
1.0
1.0
1.0
0.5
0.5
1.0
1.0
[1.0
0.5
1.0
0.5
1.0
1.0
1.0
0.5
0.5
0.5
1.0
0.5
1.0
0.5
(2Z,4Z)-N-(2-Fluorophenyl)-8-methoxy-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (2b) Yellow solid; m.p.
190 °C. IR (KBr) cm-1: 3,495 (N–H), 1,640 (C=N), 1,384
(C–S).1H NMR(CDCl3) d: 3.93 (3H, s, OCH3), 7.1 (1H, d,
J = 2.4 Hz, ArH), 7.19–7.21 (2H, m, ArH), 7.41 (1H, dd,
J = 2.8 Hz, ArH), 7.90 (1H, d, J = 9.2 Hz, ArH), 8.32
(1H, s, ArH), 8.46–8.50 (1H, m, ArH), 8.59 (1H, s, ArH),
9.37 (1H, s, H–C=N), 9.53 (1H, s, NH). MS m/z: 353
[M?H]?.
0.5
1.0
1.0
3g
3h
3i
1.0
0.25 0.5
0.125 1.0
0.125
0.5
0.5
0.5
0.5
1.0
1.0
1.0
0.5
0.5
0.5
1.0
3j
0.25
0.25
0.5
3k
3l
3m
3n
4a
4b
4c
4d
1.0
(2Z,4Z)-N-(3-Fluorophenyl)-8-methoxy-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (2c) Yellow solid; m.p.
156 °C. IR (KBr) cm-1: 3,476 (N–H), 1,617 (C=N), 1,548,
1,531 (C=C) 1,384 (C–S). 1H NMR(CDCl3) d: 3.92 (3H, s,
OCH3), 6.95 (1H, d, J = 9.6 Hz, ArH), 7.24 (1H, s, ArH),
7.58–7.69 (3H, m, ArH), 7.90 (1H, d, J = 11.2 Hz, ArH),
0.25
0.25
0.25
0.25
0.25
0.25 0.5
0.5
0.5
1.0
0.5
0.25
0.5
1.0
0.25
123

Med Chem Res
8.32 (1H, s, ArH), 8.55 (1H, s, ArH), 9.20 (1H, s, H–C=N),
9.74 (1H, s, NH). MS m/z: 353 [M?H]?.
(KBr) cm-1: 3,437 (N–H), 1,624 (C=N), 1,529, 1,495
(C=C), 1,384 (C–S). 1H NMR(CDCl3) d: 2.36 (3H, s, CH3),
3.92 (3H, s, OCH3), 7.24 (1H, s, ArH), 7.50 (2H, d,
J = 8.0 Hz, ArH), 7.89 (2H, d, J = 9.2 Hz, ArH), 8.31
(1H, s, ArH), 8.57 (1H, s, ArH), 8.94 (1H, s, ArH), 9.10
(1H, s, H–C=N),9.63 (1H, s, NH). MS m/z: 349 [M?H]?.
(2Z,4Z)-N-(4-Fuorophenyl)-8-methoxy-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (2d) Yellow solid; m.p.
160 °C. IR (KBr) cm-1: 3,490 (N–H), 1,617 (C=N), 1,549
(C=C), 1,384 (C–S). 1H NMR(CDCl3) d: 3.92 (3H, s,
OCH3), 7.08–7.13 (4H, m, ArH), 7.57–7.61 (2H, m, ArH),
8.30 (1H, s, ArH), 8.57 (1H, s, ArH), 9.18 (1H, s, H–C=N),
9.48 (1H, s, NH). MS m/z: 353 [M?H]?.
(2Z,4Z)-8-Methoxy-N-(2,6-dimethylphenyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (2j) Yellow solid; m.p.
218 °C. IR (KBr) cm-1: 3,406 (N–H), 1,635 (C=N), 1,495
(C=C), 1,384 (C–S). 1H NMR(CDCl3) d: 2.34 (6H, s,
CH3 9 2), 3.90 (3H, s, OCH3), 7.10 (1H, d, J = 2.4 Hz,
ArH), 7.14 (2H, d, J = 7.6 Hz, ArH), 7.39–7.42 (1H, dd,
J = 2.4, 2.8 Hz, ArH), 7.90 (1H, d, J = 9.2 Hz, ArH),
8.34 (1H, s, ArH), 8.56 (1H, s, ArH), 8.69 (1H, s, H–C=N),
9.73 (1H, s, NH). MS m/z: 363 [M?H]?.
(2Z,4Z)-N-(2-Chlorophenyl)-8-methoxy-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (2e) Brownish solid; m.p.
86 °C. IR (KBr) cm-1: 3,405 (N–H), 1,660 (C=N), 1,549,
1,585 (C=C), 1,384 (C–S). 1H NMR(CDCl3) d: 3.93 (3H, s,
OCH3), 7.0 (1H, d, J = 2.8 Hz, ArH), 7.24 (1H, s, ArH),
7.42 (1H, d, J = 2.4 Hz, ArH), 8.0 (1H, s, ArH), 8.34
(1H, s, ArH), 8.61 (1H, s, ArH), 8.94 (1H, s, ArH), 9.16
(1H, s, ArH), 9.59 (1H, s, H–C=N), 9.77 (1H, s, NH). MS
m/z: 369 [M?H]?, 371 [M?H?2]?.
(2Z,4Z)-8-Methoxy-N-(2,4-dimethylphenyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (2k) Yellow solid; m.p.
208 °C. IR (KBr) cm-1: 3,467 (N–H), 1,618 (C=N), 1,528,
1,495 (C=C), 1,384 (C–S).1H NMR(CDCl3) d: 2.32 (3H, s,
CH3), 2.33 (3H, s, CH3), 3.90 (3H, s, OCH3), 7.08 (2H, m,
ArH), 7.24 (1H, s, ArH), 7.40 (1H, d, J = 8.4 Hz,
J = 2.8 Hz, ArH), 7.89 (1H, d, J = 9.2 Hz, ArH), 8.33
(1H, s, ArH), 8.55 (1H, s, ArH), 8.87 (1H, s, H–C=N), 9.72
(1H, s, NH). MS m/z: 363 [M?H]?.
(2Z,4Z)-N-(3-Chlorophenyl)-8-methoxy-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (2f) Yellow solid; m.p. 82 °C.
IR (KBr) cm-1: 3,410 (N–H), 1,641 (C=N), 1,384 (C–S).
1H NMR(CDCl3) d: 3.93 (3H, s, OCH3), 7.14 (1H, d,
J = 2.8 Hz, ArH), 7.23 (1H, d, J = 8.8 Hz, ArH), 7.41
(1H, dd, J = 2.8 Hz, ArH), 7.64 (1H, d, J = 8.0 Hz, ArH),
7.73 (1H, s, ArH), 7.90 (1H, d, J = 9.6 Hz, ArH), 8.34
(1H, s, ArH), 8.56 (1H, s, ArH), 9.16 (1H, s, H–C=N), 9.66
(1H, s, NH). MS m/z: 369 [M?H]?, 371 [M?H?2]?.
(2Z,4Z)-N-(4-Ethylphenyl)-8-methoxy-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (2l) Yellow solid; m.p. 90 °C.
IR (KBr) cm-1: 3,466 (N–H), 1,622 (C=N), 1,547, 1,528
(C=C), 1,384 (C–S).1H NMR(CDCl3) d: 1.24 (3H, t,
J = 7.6 Hz, CH3), 2.66 (2H, q, J = 7.6 Hz, CH2), 3.92
(3H, s, OCH3), 7.11 (1H, d, J = 2.4 Hz, ArH), 7.24 (1H, s,
ArH), 7.41 (1H, dd, J = 2.8 Hz, ArH), 7.54 (2H, d,
J = 8.4 Hz, ArH), 7.90 (1H, d, J = 9.2 Hz, ArH), 8.28
(1H, s, ArH), 8.57 (1H, s, ArH), 9.11 (1H, s, H–C=N), 9.40
(1H, s, NH). MS m/z: 363 [M?H]?.
(2Z,4Z)-N-(4-Chlorophenyl)-8-methoxy-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (2g) Yellow solid; m.p.
102 °C. IR (KBr) cm-1: 3,420 (N–H), 1,619 (C=N), 1,547,
1,529 (C=C), 1,384 (C–S).1H NMR(CDCl3) d: 3.92 (3H, s,
OCH3), 7.36 (2H, d, J = 8.8 Hz ArH), 7.62 (2H, d,
J = 8.8 Hz, ArH), 7.89 (2H, d, J = 9.2 Hz, ArH), 8.33
(1H, s, ArH), 8.56 (1H, s, ArH), 9.16 (1H, s, H–C=N), 9.67
(1H, s, NH). MS m/z: 369 [M?H]?, 371 [M?H?2]?.
(2Z,4Z)-N-benzyl-8-methoxy-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (2m) Yellow solid; m.p. 206 °C. IR
(KBr) cm-1: 3,460 (N–H), 1,623 (C=N), 1,548, 1,529
(C=C), 1,384 (C–S).1H NMR(CDCl3) d: 3.89 (3H, s,
OCH3), 5.01 (2H, d, J = 6.0 Hz, CH2), 7.00 (1H, d,
J = 2.8 Hz, ArH), 7.30–7.45 (5H, m, ArH), 7.75 (1H, s,
ArH), 7.87 (1H, d, J = 9.2 Hz, ArH,), 8.25 (1H, s, ArH),
8.47 (1H, s, H–C=N), 9.46 (1H, s, NH). MS m/z: 349
[M?H]?.
(2Z,4Z)-8-Methoxy-N-o-tolyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (2h) Yellow solid; m.p. 198 °C. IR
(KBr) cm-1: 3,404 (N–H), 1,619 (C=N), 1,547, 1,528
(C=C), 1,384 (C–S). 1H NMR(CDCl3) d: 2.37 (3H, s, CH3),
3.90 (3H, s, OCH3), 7.09 (1H, d, J = 2.8 Hz, ArH), 7.28
(1H, s, ArH), 7.40 (1H, dd, J = 2.8 Hz, ArH), 7.60 (1H, d,
J = 7.6 Hz, ArH), 7.90 (1H, d, J = 9.6 Hz, ArH), 8.33
(1H, s, ArH), 8.55 (1H, s, ArH), 8.90 (1H, s, ArH), 8.98
(1H, s, H–C=N), 9.68 (1H, s, NH). MS m/z: 349 [M?H]?.
(2Z,4Z)-8-Methoxy-N-(2-morpholinoethyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (2n) Yellow solid; m.p.
200 °C. IR (KBr) cm-1: 3,480 (N–H), 1,620 (C=N), 1,539,
1,496 (C=C), 1,384 (C–S).1H NMR(CDCl3) d: 2.57 (4H, t,
J = 4.4 Hz, J = 4.0 Hz, CH2 9 2), 2.69 (2H, t, J = 6.4 Hz,
(2Z,4Z)-8-methoxy-N-p-tolyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (2i) Yellow solid; m.p. 90 °C. IR
123

Med Chem Res
(2Z,4Z)-N-(3-Chlorophenyl)-10-methyl-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (3f) Yellow solid; m.p.
120 °C. IR (KBr) cm-1: 3,456 (N–H), 1,618 (C=N), 1,384
(C–S). 1H NMR (CDCl3) d: 2.75 (3H, s, ArCH3), 7.33 (1H,
t, J = 8.0 Hz, ArH), 7.46–7.51 (2H, m, ArH), 7.62 (2H, d,
J = 7.2 Hz, ArH), 7.75 (1H, s, ArH), 8.35 (1H, s, ArH),
8.63 (1H, s, ArH), 9.17 (1H, s, H–C=N), 9.53 (1H, s, NH).
MS m/z: 353 [M?H]?, 355 [M?H?2]?.
J = 6.0 Hz, CH2), 3.78–3.83 (6H, m, CH2 9 3), 3.91 (3H,
s, OCH3), 7.00 (1H, d, J = 2.8 Hz, ArH), 7.40 (1H, dd,
J = 2.8 Hz, ArH), 7.89 (1H, d, J = 9.2 Hz, ArH), 8.21
(1H, s, ArH), 8.59 (1H, s, H–C=N), 9.38 (1H, s, NH). MS
m/z: 372 [M?H]?.
(2Z,4Z)-10-Methyl-N-phenyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (3a) Yellow solid; m.p. 210 °C. IR
1
(KBr) cm-1: 3,432 (N–H), 1,660 (C=N), 1,384 (C–S). H
(2Z,4Z)-N-(4-Chlorophenyl)-10-methyl-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (3g) Yellow solid; m.p.
108 °C. IR (KBr) cm-1: 3,484 (N–H), 1,616 (C=N), 1,384
(C–S). 1H NMR (CDCl3) d: 2.75 (3H, s, ArCH3), 7.37 (2H,
d, J = 8.4 Hz, ArH), 7.46–7.51 (2H, m, ArH), 7.62 (1H, s,
ArH), 7.72 (1H, d, J = 8.0 Hz, ArH), 8.36 (1H, s, ArH),
8.63 (1H, s, ArH), 9.14 (1H, s, H–C=N), 9.63 (1H, s, NH).
MS m/z: 353 [M?H]?, 355 [M?H?2]?.
NMR (CDCl3) d: 2.75 (3H, s, ArCH3), 7.61 (2H, d,
J = 8.4 Hz, ArH), 7.67 (2H, d, J = 8.0 Hz, ArH), 7.72
(1H, d, J = 8.0 Hz, ArH), 7.78 (1H, d, J = 8.0 Hz, ArH),
8.32 (1H, s, ArH), 8.64 (1H, s, ArH), 8.99 (1H, s, ArH),
9.19 (1H, s, H–C=N), 9.42 (1H, s, NH). MS m/z: 319
[M?H]?.
(2Z,4Z)-N-(2-Fluorophenyl)-10-methyl-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (3b) Yellow solid; m.p.
200 °C. IR (KBr) cm-1: 3,439 (N–H), 1,627 (C=N), 1,384
(C–S). 1H NMR (CDCl3) d: 2.75 (3H, s, ArCH3), 7.17–7.21
(2H, m, ArH), 7.46–7.51 (2H, m, ArH), 7.61 (1H, d,
J = 7.2 Hz, ArH), 7.73 (1H, d, J = 8.4 Hz, ArH), 8.35
(1H, s, ArH), 8.66 (1H, s, ArH), 9.40 (1H, s, H–C=N), 9.56
(1H, s, NH). MS m/z: 337 [M?H]?.
(2Z,4Z)-10-Methyl-N-o-tolyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (3h) Yellow solid; m.p. 214 °C. IR
1
(KBr) cm-1: 3,424 (N–H), 1,617 (C=N), 1,384 (C–S). H
NMR (CDCl3) d: 2.75 (3H, s, ArCH3), 2.37 (3H, s,
ArCH3), 7.45–7.48 (2H, m, ArH), 7.60–7.70 (4H, m, ArH),
8.34 (1H, s, ArH), 8.61 (1H, s, ArH), 8.99 (1H, s, H–C=N),
9.55 (1H, s, NH). MS m/z: 333 [M?H]?.
(2Z,4Z)-N-(3-Fluorophenyl)-10-methyl-[1,3,4]thiadiazepi-
no[7,6-b] quinolin-2-amine (3c) Yellow solid; m.p.
138 °C. IR (KBr) cm-1: 3,490 (N–H), 1,616 (C=N), 1,384
(C–S). 1H NMR (CDCl3) d: 2.75 (3H, s, ArCH3), 6.93–6.97
(1H, m, ArH), 7.41 (1H, d, J = 8.4 Hz, ArH), 7.46–7.51
(2H, m, ArH), 7.62–7.64 (1H, d, ArH), 7.73 (1H, d,
J = 8.0 Hz, ArH), 8.35 (1H, s, ArH), 8.63 (1H, s, ArH),
9.21 (1H, s, H–C=N), 9.59 (1H, s, NH). MS m/z: 337
[M?H]?.
(2Z,4Z)-10-Methyl-N-p-tolyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (3i) Dark yellow solid; m.p. 200 °C.
IR (KBr) cm-1: 3,420 (N–H), 1,637 (C=N), 1,384 (C–S).
1H NMR (CDCl3) d: 2.75 (3H, s, ArCH3), 2.36 (3H, s,
ArCH3), 7.45–7.52 (4H, m, ArH), 7.61 (1H, d, J = 7.2 Hz,
ArH), 7.72 (1H, d, J = 8.0 Hz, ArH), 8.31 (1H, s, ArH),
8.64 (1H, s, ArH), 9.10 (1H, s, H–C=N), 9.39 (1H, s, NH).
MS m/z: 333 [M?H]?.
(2Z,4Z)-10-Methyl-N-(2,6-dimethylphenyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (3j) Light yellow solid; m.p.
216 °C. IR (KBr) cm-1: 3,480 (N–H), 1,637 (C=N), 1,384
(C–S). 1H NMR (CDCl3) d: 2.76 (3H, s, ArCH3), 2.33 (6H,
s, ArCH3), 7.14 (2H, d, J = 7.2 Hz, ArH), 7.47 (1H, d,
J = 8.0 Hz, ArH), 7.61 (1H, d, J = 6.8 Hz, ArH), 7.70
(1H, d, J = 8.0 Hz, ArH), 8.32 (1H, s, ArH), 8.62 (1H, s,
ArH), 8.68 (1H, s, H–C=N), 9.43 (1H, s, NH). MS m/z: 347
[M?H]?.
(2Z,4Z)-N-(4-Fluorophenyl)-10-methyl-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (3d) Yield: 90 %. Dark
yellow solid; m.p. 88 °C. IR (KBr) cm-1: 3,441 (N–H),
1
1,637 (C=N), 1,384 (C–S). H NMR (CDCl3) d: 2.75 (3H,
s, ArCH3), 7.10 (1H, s, ArH), 7.48 (1H, d, J = 8.0 Hz,
ArH), 7.57–7.64 (3H, m, ArH), 7.71 (1H, d, J = 8.0 Hz,
ArH), 8.35 (1H, s, ArH), 8.64 (1H, s, ArH), 9.09 (1H, s,
H–C=N), 9.55 (1H, s, NH). MS m/z: 337 [M?H]?.
(2Z,4Z)-N-(2-Chlorophenyl)-10-methyl-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (3e) Dark yellow solid; m.p.
100 °C. IR (KBr) cm-1: 3,478 (N–H), 1,635 (C=N), 1,384
(C–S). 1H NMR (CDCl3) d: 2.75 (3H, s, ArCH3), 7.32–7.36
(1H, m, ArH), 7.61 (2H, d, J = 8.8 Hz, ArH), 7.69 (1H, d,
J = 8.0 Hz, ArH), 7.78 (1H, d, J = 8.0 Hz, ArH), 8.36
(1H, s, ArH), 8.69 (2H, s, ArH), 9.52 (1H, s, H–C=N), 9.83
(1H, s, NH). MS m/z: 353 [M?H]?, 355 [M?H?2]?.
(2Z,4Z)-10-Methyl-N-(2,4-dimethylphenyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (3k) Light yellow solid; m.p.
210 °C. IR (KBr) cm-1: 3,414 (N–H), 1,624 (C=N), C–S
1
(1,383). H NMR: (CDCl3) d: 2.76 (3H, s, ArCH3), 2.31
(6H, s, ArCH3), 7.09 (1H, s, ArH), 7.43–7.51 (2H, m,
ArH), 7.69 (1H, d, J = 8.4 Hz, ArH), 7.78 (1H, d,
J = 8.0 Hz, ArH), 8.32 (1H, s, ArH), 8.62 (1H, s, ArH),
123

Med Chem Res
8.89 (1H, s, H–C=N), 9.49 (1H, s, NH). MS m/z: 347
[M?H]?.
(3H, s, ArCH3), 7.32–7.41 (2H, m, ArH), 7.56 (1H, d,
J = 8.8 Hz, ArH), 7.67 (2H, d, J = 8.0 Hz, ArH), 8.33
(1H, s, ArH), 8.60 (1H, s, ArH), 9.19 (1H, s, H–C=N), 9.60
(1H, s, NH). MS m/z: 371 [M?H]?, 373 [M?H?2]?.
(2Z,4Z)-N-(4-Ethylphenyl)-10-methyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine
(3l) Yellow
solid;
m.p.
194 °C.IR (KBr) cm-1: 3,440 (N–H), 1,637 (C=N), 1,384
(2Z,4Z)-9-Chloro-N-(4-fluorophenyl)-10-methyl-[1,3,4]
thiadiazepino[7,6-b]quinolin-2-amine (4d) Yel-
low solid; m.p. 190 °C. IR (KBr) cm-1: 3,415 (N–H),
1
(C–S). H NMR (CDCl3) d: 1.24 (3H, t, J = 8.0 Hz, CH3),
2.66 (2H, q, J = 7.6 Hz, CH2), 2.75 (3H, s, ArCH3), 7.25 (1H,
s, ArH),7.48 (1H, d, J = 8.0 Hz, ArH), 7.54 (2H, d,
J = 8.0 Hz, ArH), 7.61 (1H, d, J = 7.2 Hz, ArH), 7.72 (1H,
d, J = 8.0 Hz, ArH), 8.30 (1H, s, ArH), 8.63 (1H, s, ArH),
9.12 (1H, s, H–C=N), 9.33 (1H, s, NH). MS m/z:347 [M?H]?.
1
1,638 (C=N), 1,384 (C–S). H NMR (CDCl3) d: 2.80 (3H,
s, ArCH3), 7.10 (2H, t, J = 8.8 Hz, ArH), 7.54–7.58 (2H,
m, ArH), 7.65 (1H, d, J = 8.8 Hz, ArH), 8.34 (1H, s, ArH),
8.60 (1H, s, ArH), 9.07 (1H, s, H–C=N), 9.77 (1H, s, NH).
MS m/z: 371 [M?H]?, 373 [M?H?2]?.
(2Z,4Z)-N-Benzyl-10-methyl-[1,3,4]thiadiazepino[7,6-b]
quinolin-2-amine (3m) Yellow solid; m.p. 188 °C.IR
(2Z,4Z)-9-Chloro-N-(2-chlorophenyl)-10-methyl-[1,3,4]
thiadiazepino[7,6-b]quinolin-2-amine (4e) Dark yel-
low solid; m.p. 120 °C. IR (KBr) cm-1: 3,419 (N–H),
1
(KBr) cm-1: 3,410 (N–H), 1,637 (C=N), 1,384 (C–S). H
NMR(CDCl3) d: 2.73 (3H, s, ArCH3), 5.00 (2H, d, J = 5.6,
CH2), 7.30 (1H, d, J = 7.2 Hz, ArH), 7.33–745 (4H, m,
ArH), 7.58 (1H, d, J = 6.8 Hz, ArH), 7.66 (1H, d,
J = 8.4 Hz, ArH), 7.75 (1H, s, ArH), 8.26 (1H, s, ArH),
8.53 (1H, s, H–C=N), 9.42 (1H, s, NH). MS m/z: 333
[M?H]?.
1
1,629 (C=N), 1,384 (C–S). H NMR (CDCl3) d: 2.80 (3H,
s, ArCH3), 7.32–8.00 (5H, m, ArH), 8.36 (1H, s, ArH), 8.76
(1H, s, ArH), 9.73 (1H, s, H–C=N), 9.80 (1H, s, NH). MS
m/z: 387 [M?H]?, 389 [M?H?2]?, 391 [M?H?4]?.
(2Z,4Z)-9-Chloro-N-(3-chlorophenyl)-10-methyl-[1,3,4]
thiadiazepino[7,6-b]quinolin-2-amine (4f) Yellowish
brown solid; m.p. 170 °C. IR (KBr) cm-1: 3,480 (N–H),
(2Z,4Z)-10-Methyl-N-(2-morpholinoethyl)-[1,3,4]thiadiaze-
pino[7,6-b]quinolin-2-amine (3n) Light yellow solid;
m.p. 202 °C. IR (KBr) cm-1: 3,420 (N–H), 1,637 (C=N),
1
1,610 (C=N), 1,384 (C–S). H NMR (CDCl3) d: 2.80 (3H,
1
1,384 (C–S). H NMR (CDCl3) d: 2.75 (3H, s, ArCH3),
s, ArCH3), 7.41–7.73 (4H, m, ArH), 8.00 (1H, s, ArH),8.37
(1H, s, ArH), 8.60 (1H, s, ArH), 8.96 (1H, s, H–C=N), 9.80
(1H, s, NH). MS m/z: 386.9 [M?H]?, 389 [M?H?2]?,
391 [M?H?4]?.
2.57 (4H, s,CH2), 2.69 (2H, t, J = 5.6 CH2), 3.80 (6H, m,
CH2), 7.60–7.65 (2H, m, ArH), 8.21 (2H, s, ArH), 8.62
(1H, s, H–C=N), 9.13 (1H, s, NH). MS m/z: 356 [M?H]?.
(2Z,4Z)-9-Chloro-10-methyl-N-phenyl-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (4a) Light yellow solid; m.p.
220 °C. IR (KBr) cm-1: 3,442 (N–H), 1,630 (C=N), 1,384
(2Z,4Z)-9-Chloro-N-(4-chlorophenyl)-10-methyl-[1,3,4]
thiadiazepino[7,6-b]quinolin-2-amine
(4g) Yellow
solid; m.p. 116 °C. IR (KBr) cm-1: 3,437 (N–H), 1,617
1
1
(C–S). H NMR: (CDCl3) d: 2.81 (3H, s, ArCH3), 7.25
(C=N), 1,384 (C–S). H NMR: (CDCl3) d: 2.86 (3H, s,
(1H, d, J = 7.6 Hz, ArH), 7.40 (2H, d, J = 8.0 Hz, ArH),
7.66 (3H, d, J = 8.0, ArH), 8.32 (1H, s, ArH), 8.61 (1H, s,
ArH), 9.16 (1H, s, H–C=N), 9.58 (1H, s, NH). MS m/z: 353
[M?H]?, 355 [M?H?2]?.
ArCH3), 7.37 (2H, d, J = 8.8 Hz, ArH), 7.56 (1H,
d,J = 8.8 Hz, ArH), 7.62 (2H, d, J = 8.8 Hz, ArH), 8.33
(1H, s, ArH), 8.60 (1H, s, ArH), 9.11 (1H, s, H–C=N), 9.61
(1H, s, NH). MS m/z: 387 ([M?H]?, 12), 389 [M?H?2]?,
391 [M?H?4]?.
(2Z,4Z)-9-Chloro-N-(2-fluorophenyl)-10-methyl-[1,3,4]
thiadiazepino[7,6-b]quinolin-2-amine (4b) Dark
yellow solid; m.p. 150 °C. FT-IR (KBr) cm-1: 3,463
(2Z,4Z)-9-Chloro-10-methyl-N-o-tolyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (4h) Yellow solid; m.p. 190 °C.
IR (KBr) cm-1: 3,425 (N–H), 1,611 (C=N), 1,384 (C–S).
1H NMR: (CDCl3) d: 2.80 (3H, s, ArCH3), 2.36 (3H, s,
ArCH3), 7.27 (2H, d, J = 8.0 Hz, ArH), 7.54 (1H, d,
J = 8.8 Hz, ArH), 7.62 (2H, d, J = 8.8 Hz, ArH), 8.35
(1H, s, ArH), 8.58 (1H, s, ArH), 8.96 (1H, s, H–C=N), 9.79
(1H, s, NH). MS m/z: 367 [M?H]?, 369 [M?H?2]?.
1
(N–H), 1,601 (C=N), 1,384 (C–S). H NMR (CDCl3) d:
2.80 (3H, s, ArCH3), 7.54 (1H, s, ArH), 7.55 (1H, s, ArH),
7.63–7.70 (3H, m, ArH), 8.35 (1H, s, ArH), 8.62 (1H, s,
ArH), 9.37 (1H, s, H–C=N), 9.78 (1H, s, NH). MS m/z: 371
[M?H]?, 373 [M?H?2]?.
(2Z,4Z)-9-Chloro-N-(3-fluorophenyl)-10-methyl-[1,3,4]
thiadiazepino[7,6-b]quinolin-2-amine (4c) Dark yel-
low solid; m.p. 198 °C. IR (KBr) cm-1: 3,430 (N–H),
1,604 (C=N), C–S (1,383). 1H NMR: (CDCl3) d: 2.81
(2Z,4Z)-9-Chloro-10-methyl-N-p-tolyl-[1,3,4]thiadiazepi-
no[7,6-b]quinolin-2-amine (4i) Yellow solid; m.p.
178 °C. IR (KBr) cm-1: 3,490 (N–H), 1,640 (C=N), 1,384
123

Med Chem Res
1
In vitro anti-bacterial activity assay
(C–S). H NMR: (CDCl3) d: 2.80 (3H, s, ArCH3), 2.35
(3H, s, ArCH3), 7.20 (1H, d, J = 8.4 Hz, ArH), 7.49 (2H,
d, J = 7.6 Hz, ArH), 7.54 (1H, d, J = 8.8 Hz, ArH), 7.65
(1H, d, J = 8.8 Hz, ArH), 8.32 (1H, s, ArH), 8.60 (1H, s,
ArH), 9.09 (1H, s, H–C=N), 9.73 (1H, s, NH). MS m/z: 367
[M?H]?, 369 [M?H?2]?.
The anti-bacterial assay of all the synthesized compounds
was carried outbymicrodilution method (Hanel and Raether,
1988; Voet and Voet, 2004) against the human pathogenic
bacteria. The bacterial suspensions were adjusted with sterile
saline to a concentration of 1.0 9 105 colony forming unit
(CFU)/ml. The inocula were prepared daily and stored at
?4 °C until use. Dilutions of the inocula were cultured on
solid medium to verify the absence of contamination and to
check the validity of the inoculum. The MICs were deter-
mined using 5-ml test tubes. Compounds under investigation
were dissolved in broth LB medium (100 ml) with bacterial
inoculum (1.0 9 104 cfu per tube) to achieve the desired
concentrations (1 mg/ml). All the test tubes were incubated
for 24 h at 48 °C. The lowest concentrations without visible
growth (at the binocular microscope) were defined as con-
centrations that completely inhibited bacterial growth
(MICs). Chloramphenicol was used as a positive control,
whereas DMSO was used as negative control (1 mg/ml).
(2Z,4Z)-N-(2,6-Dimethylbenzyl)-9-chloro-10-methyl-[1,3,4]thia-
diazepino[7,6-b]quinolin-2-amine (4j) Light Yellow solid.
m.p. 198 °C. IR (KBr) cm-1: 3,490 (N–H), 1,636 (C=N),
1
C–S (1,383). H NMR (CDCl3) d: 2.81 (3H, s, ArCH3),
2.32 (6H, s, ArCH3), 7.14 (2H, d, J = 7.6 Hz, ArH), 7.54
(1H, d, J = 8.8 Hz, ArH), 7.62 (1H, d, J = 8.8 Hz, ArH),
8.33 (1H, s, ArH), 8.59 (1H, s, ArH), 8.68 (1H, s,
H–C=N), 9.71 (1H, s, NH). MS m/z: 381 [M?H]?, 383
[M?H?2]?.
(2Z,4Z)-N-(2,4-Dimethybenzyl)-9-chloro-10-methyl[1,3,4]thia-
diazepino[7,6-b]quinolin-2-amine (4k) Light Yellow solid;
m.p. 180 °C. IR (KBr) cm-1: 3,488 (N–H), 1,611 (C=N),
1
C–S (1,383). H NMR (CDCl3) d: 2.81 (3H, s, ArCH3),
2.31 (6H, s, ArCH3), 7.42 (1H, d, J = 7.2 Hz, ArH), 7.54
(2H, d, J = 8.8 Hz, ArH), 7.64 (1H, s, ArH), 8.31 (1H, s,
ArH), 8.59 (1H, s, ArH), 8.86 (1H, s, H–C=N), 9.57 (1H, s,
NH). MS m/z: 381 [M?H]?, 383 [M?H?2]?.
In vitro anti-fungal assay
Anti-fungal screening of the newly synthesized com-
pounds was carried out by microdilution technique (Hanel
and Raether, 1988) against T. reesei, A. flavus, A. alter-
nata, A. niger, and D. australiensis. The micromycetes
were maintained on malt agar and the cultures were
stored at 4 °C and sub-cultured once a month (Booth,
1971). The inocula were stored at 4 °C for further use.
Dilutions of the inocula were cultured on solid malt agar
to verify the absence of contamination and to check the
validity of the inoculum. MIC determinations were per-
formed by a serial dilution technique using 5-ml test
tubes. The compounds investigated were dissolved in
DMSO (1 mg/ml) and added in broth malt medium with
inoculum. The tubes were incubated for 72 h at 28 °C.
The lowest concentrations without visible growth (at the
binocular microscope) were defined as MICs. DMSO was
used as a negative control, while commercially available
fungicide, mancozeb, was used as positive control
(1–3,000 lg/ml).
(2Z,4Z)-9-Chloro-N-(4-ethylphenyl)-10-methyl-[1,3,4]thia-
diazepino[7,6-b]quinolin-2-amine (4l) Yellow solid; m.p.
110 °C. IR (KBr) cm-1: 3,438 (N–H), 1,635 (C=N), 1,384
(C–S). 1H NMR (CDCl3) d: 1.24 (3H, t, J = 7.5 Hz, CH3),
2.66 (2H, q, J = 7.5 Hz, CH2), 2.83 (3H, s, ArCH3),
7.22–7.24 (2H, m, ArH), 7.52–7.56 (2H, m, ArH), 7.65
(1H, d, J = 8.8 Hz, ArH), 8.30 (1H, s, ArH), 8.67 (1H, s,
ArH), 9.10 (1H, s, H–C=N), 9.54 (1H, s, NH). MS m/z: 381
[M?H]?, 383 [M?H?2]?.
(2Z,4Z)-9-Chloro-N-benzyl-10-methyl-[1,3,4]thiadiazepino
[7,6-b]quinolin-2-amine (4m) Light Yellow solid; m.p.
190 °C. IR (KBr) cm-1: 3,453 (N–H), 1,612 (C=N), C–S
1
(1,383). H NMR (CDCl3) d: 2.79 (3H, s, ArCH3), 4.99
(2H, d, J = 6 Hz, CH2), 7.30–7.42 (4H, m, ArH), 7.52
(1H, d, J = 8.8 Hz, ArH), 7.60 (1H, d, J = 8.8 Hz, ArH),
7.72 (1H, s, ArH), 8.23 (1H, s, ArH), 8.50 (1H, s, H–C=N),
9.33 (1H, s, NH). MS m/z: 367 [M?H]?, 369 [M?H?2]?.
Conclusion
(2Z,4Z)-9-Chloro-10-methyl-N-(2-morpholinoethyl)-[1,3,4]
thiadiazepino[7,6-b]quinoline-2-amine (4n) Light Yellow
solid; m.p. 240 °C. IR (KBr) cm-1: 3,485 (N–H), 1,662
(C=N), 1,384 (C–S). 1H NMR (CDCl3) d: 2.61 (3H, s,
ArCH3), 2.80 (4H, s,CH2), 2.68 (2H, t, J = 5.5 Hz, CH2),
3.80 (6H, m, CH2), 7.53–7.59 (2H, m, ArH), 8.18 (1H, s,
ArH), 8.65 (1H, s, H–C=N), 9.17 (1H, s, NH). MS m/z: 390
[M?H]?, 392 [M?H?2]?.
Keeping in view, well-established anti-bacterial and anti-
fungal properties of thiadiazepines, two rings viz. quinoline
and thiadiazepine were fused and four series of new (2Z,4Z)-
9-chloro-10-methyl/8-methyl/10-methyl/8-methoxy-N-aryl/
alkyl-[1,3,4]thiadiazepino[7,6-b]quinolin-2-amines (1a–n,
2a–n, 3a–n, and 4a–n) were synthesized by conven-
tional procedure as well as under the influence
123

Med Chem Res
Du W (2003) Towards new anticancer drugs: a decade of advances in
synthesis of camptothecins and related alkaloids. Tetrahedron
59:8649–8687
Espinel-Ingroff A (2001) Comparison of the E-test with the NCCLS
M38-P method for antifungal susceptibility testing of common
and emerging pathogenic filamentous fungi. J Clin Microbiol
39:1360–1367
Falagas ME, Grammatikos AP, Michalopoulos A (2008) Potential of
old-generation antibiotics to address current need for new
antibiotics. Expert Rev Anti Infect Ther 6:593–600
Farghalya AR, Clercq ED, El-Kashefa H (2006) Synthesis and
antiviral activity of novel[1,2,4]triazolo[3,4-b][1,3,4]thiadiaz-
oles,[1,2,4]triazolo[3,4-b][1,3,4] thiadiazines and [1,2,4]triazolo
[3,4-b][1,3,4]thiadiazepines. ARKIVOC 10:137–151
Forest MC, Lahouratate P, Martin M, Nadler G, Quiniou MJ,
Zimmermann RG (1992) A novel class of cardiotonic agents:
synthesis and biological evaluation of 5-substituted 3,6-dihy-
drothiadiazin-2-ones with cyclic AMP phosphodiesterase inhib-
iting and myofibrillar calcium sensitizing properties. J Med
Chem 35:163–172
of microwaves. All the compounds were assayed in
vitro for the evaluation of their anti-microbial activity.
Most of the compounds exhibited better anti-bacterial than
anti-fungal activity against the microorganisms employed
in this study. Furthermore, it revealed that the compounds
obtained by the synergism could be useful as a template for
further development through modification or derivatization
to design more potent biologically active compounds.
Facilitation of the syntheses with microwaves was found
quite useful to obtain higher yields and purity compared to
conventional refluxing and duration of reaction was
reduced considerably to 1–2 min.
Acknowledgments Authors are grateful to HEJ research Institute of
Chemistry, University of Karachi, Pakistan, for the spectral analysis.
Ginsburg H, Ward SA, Bray PG (1999) An integrated model of
chloroquine action. Parasitol Today 15:357–360
´
Gonzalez-Munoz GC, Arce MP, Lopez B, Perez C, Villarroya M,
References
Lopez MG, Garcia AG, Conde S, Rodriguez-Franco MI (2010)
Old phenothiazine and dibenzothiadiazepine derivatives for
tomorrow’s neuroprotective therapies against neurodegenerative
diseases. Eur J Med Chem 45:6152–6158
Ajaypal P, Chourasia OP (2011) A microwave synthesis and
characterization of some quinoline derivatives and tested their
antimicrobial activity. Int J Pharma Res Dev 2:53–57
Alhaider AA, Abdelkader MA, Lien EJ (1985) Design, synthesis,
and pharmacological activities of 2-substituted 4-phenyl quino-
lines as potential antidepressant drugs. J Med Chem 28:1394–
1398
Althuis TH, Khadin SB, Czuba LJ, Moore PF, Hess HJ (1980)
Structure–activity relationships in a series of novel 3,4-dihydro-
4-oxopyrimido[4,5-b]quinoline-2-carboxylic acid antiallergy
agents. J Med Chem 23:262–269
Hanel H, Raether W (1988) A more sophisticated method of
determining the fungicidal effect of water-insoluble preparations
with a cell harvester, using miconazole as an example. Mycoses
31:148–154
Kritsanida M, Mouroutsou A, Marakos P, Pouli N, Papakonstantinou-
Garoufalias S, Pannecouque C, Witvrouw M, De Clercq E
(2002) Synthesis and antiviral activity evaluation of some new
6-substituted 3-(1-adamantyl)-1,2,4-triazolo[3,4-b][1,3,4]thi-
adiazoles. Il Farmaco 57:253–257
Kwon PS, Kim JK, Kwon TW, Kim YH, Chung SK (1997)
Microwave irradiated acetylation and nitration of aromatic
compounds. Bull Korean Chem Soc 18:1118–1119
Artico M, Silvestri R, Pagnozzi E, Stefancich G, Massa S, Loi AG,
Putzolu M, Corrias S, Spiga MG, Colla PL (1996) 5H-
pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): a novel class
of non-nucleoside reverse transcriptase inhibitors. Bioorg Med
Chem 4:837–850
Awad IMA, Abdel-Rehman AE, Bakhite EA (1991) Synthesis and
application of some new S-(substituted) thio- and thienoquino-
line derivatives as antimicrobial agents. Collect Czech Chem
Commun 56:1749–1760
Booth C (1971) Fungal culture media. In: Norris JR, Ribbons DW
(eds) Methods in microbiology, vol 4. Academic Press, London,
pp 49–94
Brahmachari G, Laskar S, Sarkar S (2010) A green approach to
chemoselective N-acetylation of amines using catalytic amount
of zinc acetate in acetic acid under microwave irradiation. Indian
J Chem 49B:1274–1281
Campbell SF, Hardstone JD, Palmer MJ (1988) 2,4-Diamino-6,7-
dimethoxyquinoline derivatives as alpha1-adrenoceptor antago-
nists and antihypertensive agents. J Med Chem 31:1031–1035
Dandia A, Singh R, Khaturia S (2006) Microwave enhanced solid
support synthesis of fluorine containing benzopyrano-triazolo-
thiadiazepines as potent as antifungal agents. Bioorg Med Chem
14:1303–1308
Demirbas N, Demirbas A, Karaoglu SA, Celikb E (2005) Synthesis
and antimicrobial activities of some new [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazoles and [1,2,4]triazolo[3,4-b] [1,3,4]thiadia-
zines. ARKIVOC 1:75–91
´
Loaiza PR, Quintero A, Rodrıguez-Sotres R, Solano JD, Rocha AL
(2004) Synthesis and evaluation of 9-anilinothiazolo[5,4-b]quino-
line derivatives as potential antitumorals. Eur J Med Chem 39:5–10
Manske RHF, Kulka M (1953) The skraup synthesis of quinolines.
Org React 7:59–98
Meth-Cohn O (1993) The synthesis of pyridines, quinolines and other
related systems by the Vilsmeier and reverse Vilsmeier method.
Heterocycles 35:539–557
Meth-Cohn O, Narine B (1978) A versatile new synthesis of
quinolines, thiopyrimidines and related fused pyridines. Tetra-
hedron Lett 23:2045–2048
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:1520–1530
Michael JP (2003) Quinoline, quinazoline and acridone alkaloids. Nat
Prod Rep 20:476–493
Michael JP (2004) Quinoline, quinazoline and acridone alkaloids. Nat
Prod Rep 21:650–668
Natalya N, Volkova EV, Tarasov LVM, Suzanne T, Wim D, Vasiliy
AB (2002) Reaction of 5-halo-1,2,3-thiadiazoles with arylenedi-
amines as a new approach to tricyclic 1,3,6-thiadiazepines.
J Chem Soc Perkin Trans I:1574–1580
Paul S, Gupta M, Gupta R (2000) Vilsmeier reagent for formylation in
solvent-free conditions using microwaves. Synlett 8:1115–1118
Raghavendra M, Bhojya Naik HS, Sherigara BS (2006) One pot
synthesis of some new 2-hydrazino-[1,3,4]thiadiazepino[7,6-b]
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
123

Med Chem Res
quinolines under microwave irradiation conditions. ARKIVOC
15:153–159
Redasani VK, Kumawat VS, Kabra RP, Kansagara P, Surana SJ
(2010) Applications of green chemistry in organic synthesis. Int
J ChemTech Res 2:1856–1859
Reddy VM, Reddy KR (2010) Synthesis and antibacterial activity of
some novel 6-(1H-benz[d]imidazol-2-yl)-8-(5-nitro-2-furyl)-3-
(4-pyridyl)-7,8-dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiaze-
pines. Chem Pharm Bull 58:1081–1084
Rizvi SUF, Siddiqui HL, Parvez M, Ahmad M, Siddiqui WA,
Yasinzai MM (2010) Antimicrobial and antileishmanial studies
of novel (2E)-3-(2-chloro-6-methyl/methoxyquinolin-3-yl)-1-
(aryl)prop-2-en-1-ones. Chem Pharm Bull 58:301–330
Rizvi SUF, Siddiqui HL, Ahmad MN, Ahmad M, Bukhari MH (2012)
Novel quinolyl-thienyl chalcones and their 2-pyrazoline deriv-
atives with diverse substitution pattern as antileishmanial agents
against Leishmania major. Med Chem Res 21:1322–1333
Shakila RJ, Saravanakumar R, Vyla SAP, Jeyasekaran G (2007) An
improved microbial assay for the detection of chloramphenicol
residues in shrimp tissues. Innovat Food Sci Emerg Technol
8:515–518
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
Voet D, Voet JD (2004) Biochemistry, 3rd edn. Wiley, New York,
pp 1341–1342
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