Schiff's base derivatives bearing 2-thiophenoxyquinoline nucleus as new antibacterial agents

Article abstract of DOI:10.1007/s00044-013-0655-8

A series of new Schiff's base derivatives 4a-x bearing 2- thiophenoxyquinoline nucleus have been designed and synthesized by reaction of 2-thiophenoxyquinoline-3-carbaldehydes 2a-d with various benzohydrazides 3a-f in the presence of Ni(NO₃)

Full text of DOI:10.1007/s00044-013-0655-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0655-8
ORIGINAL RESEARCH
Schiff’s base derivatives bearing 2-thiophenoxyquinoline nucleus
as new antibacterial agents
•
Jigar A. Makawana Chetan B. Sangani
•
•
Shashikant B. Teraiya Hai-Liang Zhu
Received: 17 March 2013 / Accepted: 28 May 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of new Schiff’s base derivatives
4a–x bearing 2-thiophenoxyquinoline nucleus have been
designed and synthesized by reaction of 2-thiophenox-
yquinoline-3-carbaldehydes 2a–d with various benzohyd-
razides 3a–f in the presence of Ni(NO3)2ꢀ6H2O as a
catalyst. In vitro antibacterial screening was carried out
against two Gram-positive bacteria (Bacillus subtilis
ATCC 6633 and Staphylococcus aureus ATCC 6538) and
two Gram-negative bacteria (Escherichia coli ATCC
35218 and Pseudomonas aeruginosa ATCC 13525). Of the
compounds studied, compound 4e showed chief activity
(MIC = 3.13 lg/mL) against S. aureus, and compounds
4p, 4k, and 4w were found to possess effective antibacte-
rial activity against employed strains compared with stan-
dards used. The structures of Schiff’s base derivatives were
established by using various spectroscopic methods. A
crystal structure of compound 4k has been determined by
X-ray diffraction analysis.
more effective agents. Consequently, searching for new
antimicrobial agents with specific activity, possibly acting
through mechanism, which are distinct from those of well-
known classes is of prime interest. The molecular manipula-
tion of promising lead compounds is still an organized and
ruler approach to widen the vicinity of antimicrobial medicine
research. It involves an initiative to merge the separate phar-
macophoric groups of analogous activity into one compound,
thus making structural changes in the biological activity.
Schiff’s bases constitute an important class of biologi-
cally active drug molecules, which have attracted attention
of medicinal chemists because of their wide range of phar-
macological properties. These compounds are being syn-
thesized as drugs by many researchers to combat diseases
with minimal toxicity and maximal effects. These predic-
tions have provided therapeutic pathway to develop new
effective biologically active Schiff’s base derivatives. A
number of Schiff’s base derivatives have been reported to
exert notably antibacterial (Joshi et al., 2008), antitubercular
(Hearn et al., 2009), antitumor (Zhong et al., 2007), antile-
ishmanial (Rando et al., 2008), DNA-binding activities, etc.
On the other hand, quinoline derivatives are also known for
their well-known biological properties including antibacte-
rial (Kalluraya et al., 2008), antimycobacterial (Mital et al.,
2006), antimalarial (Dave et al., 2009; Charris et al., 2005),
analgesic (Bhovi et al., 2010), anticonvulsant (Xie et al.,
2005), antioxidant, hemolytic, and cytotoxic activities
(Roopan and Khan, 2009). Encouraged by their potential
clinical applications and in continuation of our previous
investigations on biopotent heterocycles (Song et al., 2009;
Li et al., 2011; Xiao et al., 2011; Makawana et al., 2011a, b,
2012a, b, c), our efforts are focused to design and synthesize
biologically potent hydrazone derivatives by reaction
between 2-thiophenoxyquinoline-3-carbaldehyde and ben-
zohydrazide derivatives.
Keywords Schiff’s base ꢀ Quinoline ꢀ
Antibacterial activity ꢀ X-ray diffraction
Introduction
The frequency of infectious diseases in humans has increased
dramatically because of multidrug resistance. The increasing
clinical significance of drug-resistant bacterial and fungal
pathogens has impelled additional urgency to research for
J. A. Makawana (&) ꢀ C. B. Sangani ꢀ S. B. Teraiya ꢀ
H.-L. Zhu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing
University, Nanjing 210093, People’s Republic of China
e-mail: jigarsynthesis@yahoo.in
123

Med Chem Res
Results and discussion
incompletion of reaction, long reaction time, loss of
yield, and purification problems. Therefore, we applied
Ni(NO3)2ꢀ6H2O as a catalyst for this reaction to avoid such
drawbacks as well as to developeasy and efficient method for
the synthesis of new Schiff’s base derivatives 4a–x.
Chemistry
Schiff’s base derivatives 4a–x have been synthesized by
reaction between 2-thiophenoxyquinoline-3-carbaldehyde
2a–d and various benzohydrazides 3a–f in the presence of
nickel(II) nitrate as a catalyst in methanol at room temper-
ature, obtaining good yield (86–97 %) (Scheme 1). The
reaction was also attempted using AcOH (Sirisoma et al.,
2009; Li et al., 2009), and conc. H2SO4 (Jorge et al., 2009);
however, some shortcomings were observed, such as
The key intermediate, 2-thiophenoxyquinoline-3-car-
baldehyde 2a–d has been synthesized by refluxing
2-chloroquinoline-3-carbaldehyde 1a–b and various thi-
ophenols for 2–3 h in DMF in the presence of K2CO3 as a
catalyst. The required 2-chloroquinoline-3-carbaldehyde
1a–b was prepared by Vilsmeier–Haack reaction according
to the literature procedure (Meth-Cohn and Bramha, 1978).
Scheme 1 Synthetic pathway for the compounds 4a–x
123

Med Chem Res
The structures of all the new synthesized compounds were
established by 1H NMR, 13C NMR, FT-IR, elemental
analysis, and molecular weights of some selected com-
pounds confirmed by mass spectrometry. Mass spectros-
copy of compounds showed molecular ion peak (M?1)
corresponding to the exact mass.
Table 1 Crystal data for compound 4k
Crystal parameters
Compound 4k
Moiety formula
C25H22N4OS
426.53
MW (g/mol)
Moiety ? ethanol trapped
Crystal size (mm)
Crystal system
C27H28N4O2S (472.60)
0.2 9 0.2 9 0.1
Orthorhombic
Crystal structure determination
3
˚
V (A )
5,067
Crystal structure determination of compound 4k has been
carried out on a Nonius CAD4 diffractometer equipped
Z
9.0
˚
a (A)
9.394
˚
with graphite monochromated Mo Ka (k = 0.71073 A)
˚
b (A)
21.544
˚
c (A)
radiation (Fig. 1). The structure was resolved by direct
methods and refined on F2 by full matrix least-squares
methods using SHELX-97 (Sheldrick, 1997). All non-
hydrogen atoms of compound 4k were refined with
anisotropic thermal parameters. All hydrogen atoms were
placed in geometrically idealized positions and constrained
to ride on their parent atoms. The crystal data, data col-
lection, and refinement parameters for the compound 4k
are listed in Table 1.
25.040
a (°)
b (°)
c (°)
F (000)
h limits (°)
hkl limits
90
90
90
2,000
2.37 B h B 25.32
-23 B h B 26, -11 B k B 10,
-30 B l B 30
Data/restraints/parameters
Absorption coefficient (mm-1
4,827/0/315
0.776
Among these compounds, a crystal structure for com-
pound 4k has been determined by X-ray diffraction anal-
ysis. Crystal was obtained by slow evaporation of diluted
solution of 4k in ethanol. The crystal unit of compound is
composed of itself and ethanol molecule, but compound 4k
is not linked with ethanol. Figure 1 gives perspective views
of 4k with the atomic labeling system.
)
Reflection collected
4,827
Independent reflections
2,189
R1
0.0563
0.2165
0.991
wR2
GOF
Fig. 1 Crystal structure of
compound 4k
123

Med Chem Res
Antimicrobial activity
Table 2 Antibacterial activity of compounds 4a–x
Minimum inhibitory concentration (MIC) expressed in lg/mL
In vitro antibacterial activity assay
Compounds
Gram-positive bacteria
Gram-negative bacteria
The antibacterial activity of the synthesized compounds was
tested against Bacillus subtilis, Escherichia coli, Pseudo-
monas aeruginosa, and S. aureus using MH medium (Mu-
eller–Hinton medium: casein hydrolysate 17.5 g, soluble
starch 1.5 g, beef extract 1,000 mL). The minimum inhibi-
tory concentrations (MICs) of the test compounds were
determined by a colorimetric method using the dye (3-(4,
5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide)
(MTT) (Meletiadis et al., 2000). A stock solution of the
synthesized compound (100 lg/mL) in DMSO was prepared
and graded quantities of the test compounds were incorpo-
rated in specified quantity of sterilized liquid MH medium. A
specified quantity of the medium containing the compound
was poured into microtitration plates. Suspension of the
microorganism was prepared to contain approximately
105 cfu/mL and applied to microtitration plates with serially
diluted compounds in DMSO to be tested and incubated at
37 °C for 24 h. After the MICs were visually determined on
each of the microtitration plates, 50 lL of PBS (phosphate
buffered saline 0.01 mol/L, pH 7.4, Na2HPO4ꢀ12H2O 2.9 g,
KH2PO4 0.2 g, NaCl 8.0 g, KCl 0.2 g, distilled water
1,000 mL) containing 2 mg of MTT/mL was added to each
well. Incubation was continued at room temperature for
4–5 h. The content of each well was removed, and 100 lL of
isopropanol containing 5 % 1 mol/L HCl was added to
extract the dye. After 12 h of incubation at room tempera-
ture, the optical density was measured with a microplate
reader at 550 nm. The observed MICs are presented in
Table 2.
B. subtilis
ATCC
6633
S. aureus
ATCC
6538
E. coli P. aeruginosa
ATCC
35218
ATCC
13525
4a
4b
4c
4d
4e
4f
50
100
[100
[100
[100
3.13
25
100
50
100
[100
100
50
6.25
100
25
50
100
12.5
25
25
6.25
25
50
4g
4h
4i
100
100
100
12.5
3.13
100
6.25
100
[100
100
50
100
50
100
[100
100
100
3.13
100
100
100
25
25
25
12.5
50
12.5
100
100
[100
[100
100
3.13
100
100
[100
[100
25
4j
4k
4l
12.5
100
100
25
4m
4n
4o
4p
4q
4r
4s
25
6.25
100
100
50
50
100
100
100
100
50
50
50
4t
100
3.13
100
25
50
4u
4v
4w
4x
50
100
100
6.25
100
3.13
6.25
12.5
50
50
50
25
50
[100
3.13
3.13
Kanamycin B 1.56
Penicillin G 1.56
1.56
6.25
Upon examination of antibacterial activity data, it has
been observed that a majority of the compounds were
found to be active against employed strains.
the 2nd position and –OH at the 4th position of ben-
zohydrazide ring were found to be more effective in the
series compared with other compounds.
Against Gram-positive bacteria S. aureus, compound 4e
(MIC = 3.13 lg/mL) showed excellent activity, and com-
pound 4p (MIC = 6.25 lg/mL) showed comparable activ-
ity relative to penicillin G (MIC = 6.25 lg/mL). Compound
4k (MIC = 6.25 lg/mL) has shown activity against Gram-
negative bacteria E. coli equal to those of both standards used
(MIC = 6.25 lg/mL). Against Gram-negative bacteria
P. aeruginosa, compound 4e (MIC = 6.25 lg/mL) and 4w
(MIC = 6.25 lg/mL) showed activities equal to that of
penicillin G (MIC = 6.25 lg/mL). The rest of the com-
pounds showed effective antibacterial activities against
respective employed strains.
Experimental
Materials and measurements
All chemicals and reagents used in the current study were
of analytic grade. Melting points (uncorrected) were
determined on an XT4 MP apparatus (Taike Corp., Beijing,
China). All the 1H NMR and 13C NMR spectra were
recorded on a Bruker DPX300 model Spectrometer in
DMSO-d6, and chemical shifts were reported in ppm (d).
FTIR spectra (KBr) were run on a Nexus 870 FT-IR
spectrophotometer. ESI–MS spectra were recorded on a
Moreover, reviewing and comparing the activity data, it
is worthy to mention that the antimicrobial activity of the
target compounds depends not only on the heteroaromatic
pharmacophore, but also on the nature of the substituents
and their spatial relationship. Compounds having –NH2 at
123

Med Chem Res
Mariner System 5304 Mass spectrometer. Elemental anal-
yses were performed on a CHN-O-Rapid instrument. TLC
was performed on the glass-supported silica gel sheets
(Silica Gel 60 GF254) and visualized in UV light
(254 nm).
–CH=N ? Ar–H), 12.13 (s, broad peak, 2H, OH ? NH).
13C NMR (DMSO-d6) d ppm: d 21.34 (C-16; CH3), 122.07,
123.29, 127.09, 127.78, 128.07, 129.29, 129.90, 130.06,
132.67, 133.89, 134.00, 134.69, 136.87, 138.00, 139.18,
142.07, 143.79, 144.59 (–CH=N–), 155.80, 157.30 (Ar–C),
163.59 (C=O).
General synthetic procedure for the compounds 4a–x
(E)-4-hydroxy-N0-((2-(p-tolylthio)quinolin-3-yl)methylene)
benzohydrazide (4d) Yield 90 %, m.p. 232–234 °C, anal.
calcd. for C24H19N3O2S (413.49 g/mol): C 69.71, H 4.63, N
10.16 %. Found: C 69.55, H 4.81, N 10.24 %. IR (KBr, m,
cm-1): 3190 (NH str.), 3020 (ArC–H str.), 1695 (C=O str.),
1590 (CH=N str.), 792 (C–S–C str.). 1H NMR (DMSO-d6) d
ppm: 2.38 (s, 3H, CH3), 6.97–9.10 (m, 14H, –CH=N ? Ar–
H), 12.08 (s, broad peak, 2H, OH ? NH). 13C NMR (DMSO-
d6)dppm:20.89(C-16;CH3),125.15,126.18,127.88,128.03,
128.93, 129.44, 130.19, 130.47, 132.00, 133.10, 134.00,
135.09, 136.57, 138.32, 142.52, 144.90 (–CH=N–), 155.30,
157.30 (Ar–C), 163.63 (C=O). MS: 414 (M?1).
2-Thiophenoxyquinoline-3-carbaldehyde 2a–d (1.0 mol),
benzohydrazide 3a–f (1.25 mol), and Ni(NO3)2ꢀ6H2O
(10 mol%) were mixed together in methanol (7 mL) and
stirred at room temperature for 1–2 h. After the completion
of reaction (checked by TLC), the solid separated was fil-
tered, washed well with methanol (5 mL) and water
(10 mL), and finally dried and recrystallized from ethanol to
get the pure solid sample 4a–x. Physical, analytic, and
spectroscopic characterization data of the compounds
4a–x are presented hereafter.
(E)-4-methyl-N0-((2-(p-tolylthio)quinoline-3-yl)methylene)
benzohydrazide (4a) Yield 92 %, m.p. 248–250 °C, anal.
calcd. for C25H21N3OS (411.52 g/mol): C 72.97, H 5.14, N
10.21 %. Found: C 72.81, H 5.01, N 10.33 %. IR (KBr, m,
cm-1): 3180 (NH str.), 3020 (ArC–H str.), 1695 (C=O str.),
(E)-2-amino-N0-((2-(p-tolylthio)quinolin-3-yl)methylene)
benzohydrazide (4e) Yield 88 %, m.p. 284–286 °C, anal.
calcd. for C24H20N4OS (412.51 g/mol): C 69.88, H 4.89, N
13.58 %. Found: C 69.72, H 4.78, N 13.61 %. IR (KBr, m,
cm-1): 3195 (NH str.), 3020 (ArC–H str.), 1695 (C=O str.),
1
1590 (CH=N str.), 790 (C–S–C str.). H NMR (DMSO-d6)
1
1580 (CH=N str.), 796 (C–S–C str.). H NMR (DMSO-d6)
d ppm: 2.35 (s, 3H, CH3), 2.37 (s, 3H, CH3), 7.23–9.01 (m,
14H, –CH=N ? Ar–H), 12.20 (s, 1H, NH). 13C NMR
(DMSO-d6) d ppm: 20.67 (C-16; CH3), 21.12 (C-25; CH3),
126.09, 127.04, 127.98, 128.89, 129.10, 129.56, 130.36,
131.15, 132.00, 133.90, 134.18, 136.09, 137.88, 138.16,
142.90, 143.78, 145.37 (–CH=N–), 156.87 (Ar–C), 163.65
(C=O). MS: 412 (M?1).
d ppm: 2.37 (s, 3H, CH3), 5.83 (s, 2H, NH2), 6.57–8.95 (m,
14H, –CH=N ? Ar–H), 11.93 (s, 1H, NH). 13C NMR
(DMSO-d6) d ppm: 21.29 (C-16; CH3), 125.18, 126.33,
127.12, 128.80, 129.72, 131.09, 133.15, 134.70, 135.14,
137.43, 138.35, 139.78, 140.00, 141.12, 142.08, 143.74,
145.35 (–CH=N–), 146.90, 155.19, 157.66 (Ar–C), 163.38
(C=O). MS: 413 (M?1).
(E)-4-chloro-N0-((2-(p-tolylthio)quinolin-3-yl)methylene)
benzohydrazide (4b) Yield 86 %, m.p. 292–294 °C,
anal. calcd. for C24H18ClN3OS (431.94 g/mol): C 66.74, H
4.20, N 9.73 %. Found: C 66.55, H 4.32, N 9.59 %. IR
(KBr, m, cm-1): 3190 (NH str.), 3025 (ArC–H str.), 1690
(E)-4-amino-N0-((2-(p-tolylthio)quinolin-3-yl)methylene)
benzohydrazide (4f) Yield 91 %, m.p. 244–246 °C, anal.
calcd. for C24H20N4OS (412.51 g/mol): C 69.88, H 4.89, N
13.58 %. Found: C 69.65, H 5.01, N 13.71 %. IR (KBr, m,
cm-1): 3190 (NH str.), 3000 (ArC–H str.), 1695 (C=O str.),
1585 (CH=N str.), 793 (C–S–C str.). 1H NMR (DMSO-d6) d
ppm:2.36 (s, 3H, CH3), 5.78 (s, 2H, NH2), 6.60–8.90 (m, 13H,
–CH=N ? Ar–H), 11.77 (s, 1H, NH). 13C NMR (DMSO-d6)
d ppm: 21.37 (C-16; CH3), 125.90, 127.08, 127.83, 128.35,
129.90, 131.00, 132.98, 134.67, 135.42, 137.02, 139.77,
140.19, 141.58, 142.15, 143.60, 145.87 (–CH=N–), 146.53,
156.44 (Ar–C), 163.57 (C=O). MS: 413 (M?1).
1
(C=O str.), 1595 (CH=N str.), 793 (C–S–C str.). H NMR
(DMSO-d6) d ppm: 2.36 (s, 3H, CH3), 7.27–8.96 (m, 14H,
–CH=N ? Ar–H), 12.23 (s, 1H, NH). 13C NMR (DMSO-
d6) d ppm: 20.79 (C-16; CH3), 125.07, 126.15, 128.12,
128.68, 129.44, 131.56, 133.66, 134.05, 136.70, 137.44,
139.99, 140.33, 142.12, 142.78, 143.59, 145.18 (–CH=N–),
146.18, 157.10 (Ar–C), 163.69 (C=O). MS: 432.0 (M?1).
(E)-2-hydroxy-N0-((2-(p-tolylthio)quinolin-3-yl)methylene)
benzohydrazide (4c) Yield 96 %, m.p. 258–260 °C, anal.
calcd. for C24H19N3O2S (413.49 g/mol): C 69.71, H 4.63,
N 10.16 %. Found: C 69.80, H 4.56, N 10.12 %. IR (KBr,
m, cm-1): 3185 (NH str.), 3010 (ArC–H str.), 1690 (C=O
str.), 1585 (CH=N str.), 794 (C–S–C str.). 1H NMR
(DMSO-d6) d ppm: 2.36 (s, 3H, CH3), 6.91–8.89 (m, 14H,
(E)-4-methyl-N0-((6-methyl-2-(p-tolylthio)quinolin-3-yl)meth-
ylene)benzohydrazide (4g) Yield 97 %, m.p. 256–258 °C,
anal. calcd. for C26H23N3OS (425.55 g/mol): C 73.38, H
5.45, N 9.87 %. Found: C 73.21, H 5.67, N 9.72 %. IR
(KBr, m, cm-1): 3180 (NH str.), 3010 (ArC–H str.), 1690
1
(C=O str.), 1595 (CH=N str.), 795 (C–S–C str.). H NMR
123

Med Chem Res
(E)-2-amino-N0-((6-methyl-2-(p-tolylthio)quinolin-3-yl)
methylene)benzohydrazide (4k) Yield 87 %, m.p.
254–256 °C, anal. calcd. for C25H22N4OS (426.53 g/mol):
C 70.40, H 5.20, N 13.14 %. Found: C 70.22, H 5.53, N
13.09 %. IR (KBr, m, cm-1): 3195 (NH str.), 3020 (ArC–H
str.), 1690 (C=O str.), 1590 (CH=N str.), 792 (C–S–C str.).
1H NMR (DMSO-d6) d ppm: 2.35 (s, 3H, CH3), 2.43 (s,
3H, CH3), 5.75 (s, 2H, NH2), 6.58–8.80 (m, 13H, –CH=
N ? Ar–H), 11.90 (s, 1H, NH). 13C NMR (DMSO-d6) d
ppm: 20.68 (C-10; CH3), 21.33 (C-17; CH3), 125.09,
126.17, 127.32, 128.93, 129.35, 131.00, 133.89, 134.53,
135.12, 137.10, 138.24, 139.00, 140.78, 141.48, 142.19,
143.10, 145.42 (–CH=N–), 146.57, 155.11, 157.36 (Ar–C),
163.41 (C=O). MS: 427 (M?1).
(DMSO-d6) d ppm: 2.35 (s, 3H, CH3), 2.38 (s, 3H, CH3),
2.45 (s, 3H, CH3), 7.26–9.07 (m, 13H, –CH=N ? Ar–H),
12.03 (s, 1H, NH). 13C NMR (DMSO-d6) d ppm: 20.67 (C-
10; CH3), 21.20 (C-17; CH3), 21.41 (C-26; CH3), 126.57,
127.00, 128.08, 128.67, 129.49, 130.56, 131.46, 132.93,
133.10, 133.53, 134.81, 136.00, 137.14, 138.05, 141.18,
143.36, 145.12 (–CH=N–), 156.39 (Ar–C), 163.71 (C=O).
MS: 426 (M?1).
(E)-4-chloro-N0-((6-methyl-2-(p-tolylthio)quinolin-3-yl)meth-
ylene)benzohydrazide (4h) Yield 95 %, m.p. 296–298 °C,
anal. calcd. for C25H20ClN3OS (445.96 g/mol): C 67.33,
H 4.52, N 9.42 %. Found: C 67.09, H 4.66, N 9.30 %.
IR (KBr, m, cm-1): 3190 (NH str.), 3020 (ArC–H str.),
1
1690 (C=O str.), 1590 (CH=N str.), 792 (C–S–C str.). H
(E)-4-amino-N0-((6-methyl-2-(p-tolylthio)quinolin-3-yl)
methylene)benzohydrazide (4l) Yield 91 %, m.p. 288–
290 °C, anal. calcd. for C25H22N4OS (426.53 g/mol): C
70.40, H 5.20, N 13.14 %. Found: C 70.21, H 5.34, N
13.27 %. IR (KBr, m, cm-1): 3190 (NH str.), 3015 (ArC–H
str.), 1695 (C=O str.), 1585 (CH=N str.), 793 (C–S–C str.).
1H NMR (DMSO-d6) d ppm: 2.38 (s, 3H, CH3), 2.45 (s,
3H, CH3), 5.94 (s, 2H, NH2), 6.64–8.93 (m, 13H, –CH=
N ? Ar–H), 11.85 (s, 1H, NH). 13C NMR (DMSO-d6) d
ppm: 21.03 (C-10; CH3), 21.29 (C-17; CH3), 125.16,
127.47, 127.91, 128.89, 129.10, 131.14, 132.35, 134.78,
135.31, 137.10, 139.16, 140.00, 141.18, 142.67, 143.36,
145.19 (–CH=N–), 146.77, 156.14 (Ar–C), 163.50 (C=O).
MS: 427 (M?1).
NMR (DMSO-d6) d ppm: 2.37 (s, 3H, CH3), 2.43 (s, 3H,
CH3), 7.25–8.99 (m, 13H, –CH=N ? Ar–H), 12.21 (s,
1H, NH). 13C NMR (DMSO-d6) d ppm: 20.87 (C-10;
CH3), 21.25 (C-17; CH3), 125.15, 127.78, 128.15,
129.77, 130.44, 132.91, 133.00, 134.17, 136.83, 137.25,
139.62, 140.20, 142.02, 142.53, 143.10, 145.52
(–CH=N–), 146.68, 157.53 (Ar–C), 163.51 (C=O). MS:
446 (M?1).
(E)-2-hydroxy-N0-((6-methyl-2-(p-tolylthio)quinolin-3-yl)
methylene)benzohydrazide (4i) Yield 93 %, m.p. 238–
240 °C, anal. calcd. for C25H21N3O2S (427.52 g/mol): C
70.24, H 4.95, N 9.83 %. Found: C 70.20, H 5.13, N
9.66 %. IR (KBr, m, cm-1): 3185 (NH str.), 3000 (ArC–H
str.), 1690 (C=O str.), 1590 (CH=N str.), 790 (C–S–C str.).
1H NMR (DMSO-d6) d ppm: 2.35 (s, 3H, CH3), 2.45 (s,
3H, CH3), 6.99–9.08 (m, 13H, –CH=N ? Ar–H), 12.07 (s,
broad peak, 2H, OH ? NH). 13C NMR (DMSO-d6) d ppm:
20.93 (C-10; CH3), 21.31 (C-17; CH3), 122.18, 125.30,
126.73, 127.09, 128.32, 129.41, 129.72, 130.42, 132.00,
133.15, 134.90, 136.87, 137.15, 138.00, 139.83, 142.17,
143.42, 145.20 (–CH=N–), 155.14, 156.30 (Ar–C), 163.67
(C=O). MS: 428 (M?1).
(E)-4-methyl-N0-((2-(4-chlorophenylthio)quinolin-3-yl)
methylene)benzohydrazide (4m) Yield 86 %, m.p. 290–
292 °C, anal. calcd. for C24H18ClN3OS (431.94 g/mol): C
66.74, H 4.20, N 9.73 %. Found: C 66.53, H 4.05, N
9.92 %. IR (KBr, m, cm-1): 3190 (NH str.), 3015 (ArC–H
str.), 1690 (C=O str.), 1590 (CH=N str.), 795 (C–S–C str.).
1H NMR (DMSO-d6) d ppm: 2.36 (s, 3H, CH3), 7.23–9.05
(m, 14H, –CH=N ? Ar–H), 12.23 (s, 1H, NH). 13C NMR
(DMSO-d6) d ppm: 21.37 (C-24; CH3), 126.78, 127.51,
127.92, 128.09, 129.29, 129.67, 130.65, 131.32, 132.09,
133.16, 134.10, 136.75, 137.45, 138.23, 142.89, 143.31,
145.68 (–CH=N–), 156.77 (Ar–C), 163.50 (C=O). MS: 432
(M?1).
(E)-4-hydroxy-N0-((6-methyl-2-(p-tolylthio)quinolin-3-yl)
methylene)benzohydrazide (4j) Yield 90 %, m.p. 274–
276 °C, anal. calcd. for C25H21N3O2S (427.52 g/mol): C
70.24, H 4.95, N, 9.83 %. Found: C 70.43, H 4.78, N
9.69 %. IR (KBr, m, cm-1): 3190 (NH str.), 3000 (ArC–H
str.), 1695 (C=O str.), 1580 (CH=N str.), 794 (C–S–C str.)
cm-1. 1H NMR (DMSO-d6) d ppm: 2.36 (s, 3H, CH3), 2,45
(s, 3H, CH3), 6.92–9.12 (m, 13H, –CH=N ? Ar–H), 12.15
(s, broad peak, 2H, OH ? NH). 13C NMR (DMSO-d6) d
ppm: 20.89 (C-10; CH3), 21.24 (C-17; CH3), 125.33,
126.89, 127.13, 128.14, 128.67, 129.77, 130.09, 130.45,
132.10, 133.43, 134.16, 135.00, 136.18, 138.23, 142.12,
145.07 (–CH=N–), 155.16, 157.87 (Ar–C), 163.49 (C=O).
MS: 428 (M?1).
(E)-4-chloro-N0-((2-(4-chlorophenylthio)quinolin-3-yl)meth-
ylene)benzohydrazide
(4n) Yield.
89 %,
m.p.
268–270 °C, anal. calcd. for C23H15Cl2N3OS (452.36 g/
mol): C 61.07, H 3.34, N 9.29 %. Found: C 60.89, H 3.08,
N 9.53 %. IR (KBr, m, cm-1): 3195 (NH str.), 3000 (ArC–
H str.), 1695 (C=O str.), 1585 (CH=N str.), 792 (C–S–C
str.). 1H NMR (DMSO-d6) d ppm: 7.25–8.98 (m, 17H, –CH=
N ? Ar–H), 12.25 (s, 1H, NH). 13C NMR (DMSO-d6) d
ppm: 125.30, 126.51, 128.80, 129.17, 129.72, 131.90,
123

Med Chem Res
133.14, 134.10, 136.55, 137.02, 139.00, 140.18, 142.39,
142.80, 143.13, 145.30 (–CH=N–), 146.62, 157.36 (Ar–C),
163.61 (C=O). MS: 452 (M?1).
132.50, 134.13, 135.47, 137.00, 139.52, 140.19, 141.30,
142.81, 143.00, 145.79 (–CH=N–), 146.32, 156.18 (Ar–C),
163.62 (C=O). MS: 433 (M?1).
(E)-2-hydroxy-N0-((2-(4-chlorophenylthio)quinolin-3-yl)meth-
ylene)benzohydrazide (4o) Yield 94 %, m.p.[300 °C, anal.
calcd. for C23H16ClN3O2S (433.91 g/mol): C 63.66, H 3.72,
N 9.68 %. Found: C 63.39, H 3.55, N 9.74 %. IR (KBr, m,
cm-1): 3195 (NH str.), 3005 (ArC–H str.), 1690 (C=O str.),
1580 (CH=N str.), 793 (C–S–C str.). 1H NMR (DMSO-d6) d
ppm: 6.92–8.85 (m, 14H, –CH=N ? Ar–H), 12.23 (s, broad
peak, 2H, OH ? NH). 13C NMR (DMSO-d6) d ppm: 125.15,
126.10, 127.87, 128.19, 128.53, 129.70, 129.98, 130.20,
132.82, 133.16, 134.77, 134.91, 136.43, 138.08, 139.17,
142.32, 143.18, 144.37 (–CH=N–), 155.51, 157.81 (Ar–C),
163.40 (C=O). MS: 434 (M?1).
(E)-4-methyl-N0-((2-(4-chlorophenylthio)-6-methylquinolin-3-
yl)methylene)benzohydrazide (4s) Yield 86 %, m.p.
250–252 °C, anal. calcd. for C25H20ClN3OS (445.96 g/
mol): C 67.33, H 4.52, N 9.42 %. Found: C, 67.56; H, 4.28;
N, 9.31 %. IR (KBr, m, cm-1): 3190 (NH str.), 2995 (ArC–
H str.), 1690 (C=O str.), 1590 (CH=N str.), 791 (C–S–C
str.) cm-1. 1H NMR (DMSO-d6) d ppm: 2.37 (s, 3H, CH3),
2.46 (s, 3H, CH3), 7.28–8.99 (m, 13H, –CH=N ? Ar–H),
12.19 (s, 1H, NH). 13C NMR (DMSO-d6) d ppm: 21.33 (C-
10; CH3), 21.52 (C-25; CH3), 126.34, 126.92, 127.78,
127.86, 128.70, 129.01, 130.36, 132.43, 133.51, 133.62,
134.94, 136.38, 137.12, 138.95, 143.76, 145.39 (–CH=N),
146.62, 156.25 (Ar–C), 163.65 (C=O). MS: 446 (M?1).
(E)-4-hydroxy-N0-((2-(4-chlorophenylthio)quinolin-3-yl)
methylene)benzohydrazide (4p) Yield 87 %, m.p.
262–264 °C, anal. calcd. for C23H16ClN3O2S (433.91 g/
mol): C 63.66, H 3.72, N 9.68 %. Found: C 63.56, H 3.81,
N 9.79 %. IR (KBr, m, cm-1): 3195 (NH str.), 3020 (ArC–
H str.), 1690 (C=O str.), 1595 (CH=N str.), 795 (C–S–C
str.). 1H NMR (DMSO-d6) d ppm: 6.89–8.90 (m, 14H,
–CH=N ? Ar–H), 12.19 (s, broad peak, 2H, OH ? NH).
13C NMR (DMSO-d6) d ppm: 125.71, 126.18, 127.37,
128.00, 128.47, 129.03, 130.18, 130.62, 132.10, 133.29,
134.41, 135.67, 136.18, 138.52, 142.40, 144.25 (–CH=N–),
155.49, 157.15 (Ar–C), 163.67 (C=O). MS: 434 (M?1).
(E)-4-chloro-N0-((2-(4-chlorophenylthio)-6-methylquinolin-
3-yl)methylene)benzohydrazide (4t) Yield 95 %, m.p.
244–246 °C, anal. calcd. for C24H17Cl2N3OS (466.38 g/
mol): C 61.81, H 3.67, N 9.01 %. Found: C 61.93, H 3.70,
N 9.12 %. IR (KBr, m, cm-1): 3190 (NH str.), 3010 (ArC–
H str.), 1690 (C=O str.), 1590 (CH=N str.), 794 (C–S–C
str.). 1H NMR (DMSO-d6) d ppm: 2.39 (s, 3H, CH3),
7.25–8.99 (m, 13H, –CH=N ? Ar–H), 12.20 (s, 1H, NH).
13C NMR (DMSO-d6) d ppm: 21.27 (C-10; CH3), 125.32,
127.81, 128.19, 129.13, 130.33, 132.10, 133.52, 134.19,
136.77, 137.29, 139.11, 140.54, 142.90, 143.53, 144.10,
145.39 (–CH=N–), 146.30, 157.29 (Ar–C), 163.53 (C=O).
MS: 466 (M?1).
(E)-2-amino-N0-((2-(4-chlorophenylthio)quinolin-3-yl)
methylene)benzohydrazide (4q) Yield 90 %, m.p.
296–298 °C, anal. calcd. for C23H17ClN4OS (432.93 g/
mol): C 63.81, H 3.96, N 12.94 %. Found: C 63.57, H 4.08,
N 12.76 %. IR (KBr, m, cm-1): 3190 (NH str.), 3020 (ArC–
H str.), 1695 (C=O str.), 1585 (CH=N str.), 790 (C–S–C
str.). 1H NMR (DMSO-d6) d ppm: 6.33 (s, 2H, NH2),
6.59–8.85 (m, 14H, –CH=N ? Ar–H), 11.83 (s, 1H, NH).
13C NMR (DMSO-d6) d ppm: 125.37, 126.12, 127.74,
128.32, 129.45, 131.10, 133.00, 134.01, 135.19, 137.61,
138.20, 139.17, 140.91, 141.29, 142.43, 143.18, 145.11
(–CH=N–), 146.83, 155.39, 157.59 (Ar–C), 163.48 (C=O).
MS: 433 (M?1).
(E)-2-hydroxy-N0-((2-(4-chlorophenylthio)-6-methylquino-
lin-3-yl)methylene)benzohydrazide (4u) Yield 97 %, m.p.
282–284 °C, anal. calcd. for C24H18ClN3O2S (447.94 g/
mol): C 64.35, H 4.05, N 9.38 %. Found: C 64.41, H 3.91,
N 9.20 %. IR (KBr, m, cm-1): 3190 (NH str.), 3000 (ArC–
H str.), 1690 (C=O str.), 1590 (CH=N str.), 794 (C–S–C
str.). 1H NMR (DMSO-d6) d ppm: 2.43 (s, 3H, CH3),
6.91–9.09 (m, 13H, –CH=N ? Ar–H), 12.11 (s, broad
peak, 2H, OH ? NH). 13C NMR (DMSO-d6) d ppm: 21.39
(C-10; CH3), 122.64, 125.19, 126.00, 127.73, 128.10,
129.53, 129.94, 130.15, 132.29, 133.42, 134.83, 136.64,
137.33, 138.00, 139.15, 142.92, 143.03, 145.27 (–CH=N–),
155.18, 156.62 (Ar–C), 163.60 (C=O). MS: 448 (M?1).
(E)-4-amino-N0-((2-(4-chlorophenylthio)quinolin-3-yl)meth-
ylene)benzohydrazide (4r) Yield 92 %, m.p. 286–288 °C,
anal. calcd. for C23H17ClN4OS (432.93 g/mol): C 63.81, H
3.96, N 12.94 %. Found: C 63.69, H 3.80, N 13.09 %. IR
(KBr, m, cm-1): 3195 (NH str.), 3020 (ArC–H str.), 1690
(E)-4-hydroxy-N0-((2-(4-chlorophenylthio)-6-methylquin-
olin-3-yl)methylene)benzohydrazide (4v) Yield 88 %,
m.p. 270–272 °C, anal. calcd. for C24H18ClN3O2S
(447.94 g/mol): C 64.35, H 4.05, N 9.38 %. Found: C
64.51, H 4.23, N 9.53 %. IR (KBr, m, cm-1): 3195 (NH
str.), 3020 (ArC–H str.), 1695 (C=O str.), 1595 (CH=N
1
(C=O str.), 1590 (CH=N str.), 792 (C–S–C str.). H NMR
(DMSO-d6) d ppm: 5.95 (s, 2H, NH2), 6.54–8.79 (m, 14H,
–CH=N ? Ar–H), 11.77 (s, 1H, NH). 13C NMR (DMSO-
d6) d ppm: 125.67, 127.09, 127.59, 128.14, 129.63, 131.00,
1
str.), 795 (C–S–C str.). H NMR (DMSO-d6) d ppm: 2.36
123

Med Chem Res
Acknowledgments The study was financed by National Natural
Science Foundation of China (No. J1103512).
(s, 3H, CH3), 6.94–9.10 (m, 13H, –CH=N ? Ar–H), 12.07
(s, broad peak, 2H, OH ? NH). 13C NMR (DMSO-d6) d
ppm: 21.31 (C-10; CH3), 125.00, 126.40, 127.18, 128.23,
128.92, 129.10, 130.32, 130.60, 132.15, 133.03, 134.19,
135.00, 136.32, 138.12, 142.09, 145.32 (–CH=N–), 155.19,
157.38 (Ar–C), 163.53 (C=O). MS: 448 (M?1).
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