Synthesis, characterization, and antimicrobial activity of some new coumarin derivatives

Article abstract of DOI:10.1007/s00044-011-9553-0

A number of new [(4-methyl-2-oxo-2H-chromen- 7-yl)amino]methylcoumarins (5a-c), benzofuran (6), and benzoxazol (7) were synthesized through the reaction of 7-amino-4-methylcoumarin (1) with a number of organic halides. In addition, series of N-substituted 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (11a-h) and (12a-d) were prepared from the reaction of 2-[(4-methyl-2- oxo-2H-chromen-7-yl)oxy]acetohydrazide (8) with corresponding heteroaryl/alkyl halides (2-4, 9, and 10). The synthesized compounds were characterized by elemental analysis and by spectroscopic techniques such as ¹H-NMR, ¹³C-NMR, and mass spectrometry and were tested for their in vitro antimicrobial activity. The newly synthesized compounds exerted significant inhibitory activity against the growth of tested bacterial strains and a few of them are found to be potent antimicrobial agents. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9553-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:468–476
DOI 10.1007/s00044-011-9553-0
ORIGINAL RESEARCH
Synthesis, characterization, and antimicrobial activity of some
new coumarin derivatives
•
Asma’a A. Al-Rifai Mikdad T. Ayoub
•
•
•
Ashok K. Shakya Kayed A. Abu Safieh
Mohammad S. Mubarak
Received: 9 September 2010 / Accepted: 5 January 2011 / Published online: 18 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A number of new [(4-methyl-2-oxo-2H-chro-
men-7-yl)amino]methylcoumarins (5a–c), benzofuran (6),
and benzoxazol (7) were synthesized through the reaction of
7-amino-4-methylcoumarin (1) with a number of organic
halides. In addition, series of N-substituted 2-[(4-methyl-2-
oxo-2H-chromen-7-yl)oxy]acetohydrazide (11a–h) and
(12a–d) were prepared from the reaction of 2-[(4-methyl-2-
oxo-2H-chromen-7-yl)oxy]acetohydrazide (8) with corre-
sponding heteroaryl/alkyl halides (2–4, 9, and 10). The
synthesized compounds were characterized by elemental
analysis and by spectroscopic techniques such as 1H-NMR,
13C-NMR, and mass spectrometry and were tested for their in
vitro antimicrobial activity. The newly synthesized com-
pounds exerted significant inhibitory activity against the
growth of tested bacterial strains and a few of them are found
to be potent antimicrobial agents.
Introduction
Coumarins form an important class of benzopyrones sev-
eral derivatives of which are found in nature (Borges et al.,
2005). Recently, many of the isolated prenyloxycoumarins
were shown to exhibit in vitro and in vivo remarkable anti-
tumorial, anti-inflammatory, and anti-viral effects (Curini
et al., 2006). In addition, coumarins and related derivatives
have continued to attract attention for their interesting
biological activities. Their anticoagulant, antithrombiot-
ics, antifungal, antiinflammatory, and antiviral activities
including human immunodeficiency virus activities are
well known (Al-Zghoul et al., 2005).
The natural occurrence, antimicrobial, antiinflamma-
tory, anticancer, and other properties of different couma-
rins have been recently reviewed (Kulkarni et al., 2006).
Kalkhambkar et al. (2008) have quite recently prepared a
series of new fluorinated coumarins and 1-aza coumarins
and studied their antimicrobial, antiinflammatory, and
analgesic activities. They discovered that these newly
synthesized compounds exhibit moderate analgesic and
excellent inflammatory and potential anti-bacterial and
anti-fungal activities compared to other halogenated com-
pounds. In addition, interest in coumarins and 1-aza cou-
marins as antibiotics is due to recent observations that these
compounds are potent inhibitors of bacterial DNA gyrase
(Kalkhambkar et al., 2008).
Keywords 7-Amino-4-methylcoumarin Á
Acetohydrazide Á Spectral analysis Á Antimicrobial activity
A. A. Al-Rifai Á M. T. Ayoub Á K. A. Abu Safieh
Department of Chemistry, Faculty of Science,
The Hashemite University, Zarqa 13115, Jordan
Similarly, the biological importance of substituted cou-
marins and acetohydrazide stimulated an intensive research
work for the synthesis of many members of this class of
compounds (Maczynski et al., 2008; Mubarak and Ayoub,
2007). Among the various coumarin derivatives, 7-substi-
tuted coumarins constitute an important group of com-
pounds that show various bioactivities along with other
applications (Kuznetsova et al., 2003). Moreover, 7-amino
A. K. Shakya
Faculty of Pharmacy and Medical Sciences,
Al-Ahliyya Amman University, Amman, Jordan
M. S. Mubarak (&)
Department of Chemistry, The University of Jordan,
Amman 11942, Jordan
e-mail: mmubarak@ju.edu.jo
123

Med Chem Res (2012) 21:468–476
469
4-methyl coumarin is also used as laser dye and inter-
mediate for the synthesis of bioactive compounds
(Nowakowska et al., 2001) and the 4-methylcoumarin
derivatives present in various naturally occurring com-
pounds, are known to exhibit a wide range of biological
and pharmaceutical activities (Ramesh and Raghunathan,
2008). In addition, coumarin moieties containing hydrazide
and sulfonamide groups act as anti-malarial, antiviral
activity, anti-HIV, and anticancer agents (Havaldar and
Patil, 2008; Hwu et al., 2008; Azizian et al., 2008; Geor-
gieva et al., 2007).
oxo-2H-chromen-7-yl)oxy]acetohydrazide. The antibacte-
rial activity of these newly synthesized compounds was
evaluated.
Results and discussion
Chemistry
The key starting material, 7-amino-4-methylcoumarin (1)
was synthesized according to published procedures (Pozd-
nev, 1990) through the reaction of m-aminophenol, methoxy-
carbonyl chloride, and acetoacetic ester, using concentrated
sulfuric acid. Compound 1 was reacted with 4-(bromo-
methyl)-2H-chromen-2-one (2a–c), 3-bromomethyl-6-meth-
oxy-benzofuran-2-carboxylic acid ethyl ester (3), and 2-
chlorobenzoxazole (4) in the presence of dry DMF to afford
the substituted [(4-methyl-2-oxo-2H-chromen-7-yl)amino]
methylcoumarins (5a–c), ethyl-6-methoxy-3-{[(4-methyl-2-
oxo-2H-chromen-7-yl)amino]methyl}-1-benzofuran-2-car-
boxylate (6) and 7-[(1,3-benzoxazol-2-yl)amino]-4-methyl-
2H-chromen-2-one (7), respectively, in good yields
In view of the wide continued interest in the activity
spectrum and profile of coumarins (Kontogiorgis and
Hadjipavlou-Litina 2003; Satyanarayana et al., 2008;
Burbuliene et al., 2005; Brzozowski et al., 2007), and in
continuation of our work in the synthesis of new compounds
of pharmacological and biological interest (Al-Zghoul et al.,
2005; Salih et al., 2006; Salih et al., 2007; Al-Soud et al.,
2008; Abu-Shaireh et al., 2009, Saadeh et al., 2010), we
report, herein, on the synthesis and characterization of
some newly substituted [(4-methyl-2-oxo-2H-chromen-7-yl)
amino]methylcoumarins and N-substituted 2-[(4-methyl-2-
Scheme 1 Synthesis of
compounds 5a–c, 6, and 7
123

470
Med Chem Res (2012) 21:468–476
(Scheme 1). Purity of the prepared compounds was checked
by TLC and their structures were confirmed by means of 1H
NMR, 13C NMR, mass spectrometry, IR, and elemental
analysis; the spectral data are in total agreement with the
proposed structures. All the compounds were screened for
anti-bacterial activities.
by the addition of hydrazine hydrate (Satyanarayana et al.,
2008).
1H-NMR and 13C-NMR spectra of all prepared com-
pounds are in total agreement with the suggested struc-
1
tures; the H NMR spectra of compounds (5a–c, 6, and
7), (11a–h), and (12a–d) showed signals corresponding to
hydrazide, sulfonamide, aromatic, and NH protons. DEPT
experiments were employed to differentiate between
secondary and quaternary carbons from primary and ter-
tiary carbons. Moreover, the infrared spectra of the pre-
pared compounds showed characteristics of absorption
bands of NH group in addition to other absorptions cor-
related to the assigned structures. Mass spectral data of
the synthesized compounds are also in total agreement
with the assigned structures and show the expected
molecular ions, M? as suggested by their molecular
formulas.
Since many benzenesulfonohydrazide derivatives dis-
play a variety of interesting activities as antibacterial agents
(Salih et al., 2007), it was of interest to react the parent
2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide
(8) with appropriate benzene sulfonyl chlorides (9a–h)
and aryl halides (10a–d) to obtain new N-substituted 2-
[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazides
(11a–h) and (12 a–d) (Scheme 2). Compound 8 itself was
prepared according to published procedures outlined by
Satyanarayana et al. that involves reacting 7-hydroxy-4-
methylcoumarin with ethyl chloroacetate in DMF followed
O
O
O
O
HO
O
O
H2NHN
1) ClCH2COOEt / DMF
2) NH2NH2 hydrate
CH3
CH3
(8)
R2
R2
R3
R1
O
R3
R1
H
N
Dry DMF
O
O
O
S
N
H
(8)
O2
SO2Cl
CH3
(9a-h)
(11a-h)
a
b
c
d
H
H
F
e
f
H
H
g
h
R1
R2
R3
H
H
H
H
NO2
H
H
H
H
H
H
NO2
H
H
CH3
H
Cl Br
CF3
O
O
O
O
O
H
N
O
O
O
H2NHN
Ar-X
(X = Cl or Br)
Dry DMF
Ar
N
H
CH3
CH3
(8)
(10a-d)
(12a-d)
a
b
c
d
MeO
O
O
Me
O
O
N
O
N
Ar =
Cl
-
-
CH2
CH2
Scheme 2 Synthesis of compounds 11a–h and 12a–d
123

Med Chem Res (2012) 21:468–476
Biological activity
471
Table 2 Minimum inhibitory concentrations (lg/ml) for the synthe-
sized compound (5a, 5c, 6, 11b, 11d-h, and 12c) against K. pneu-
moniae, E. coli, and S. aureus
Antibacterial activity
SN Compound
K. pneumoniae
E. coli
S. aureus
Minimum inhibitory concentration (lg/ml)
A numberofthe newly synthesized compounds werescreened
for their antibacterial activity against Gram-negative micro-
organism (K.pneumoniae and E.coli) and Gram-positive
bacteria (Staphylococcus aureus). In vitro antibacterial
screening of the compounds 5a, 5c, 6, 11b, 11d–h, and 12c
indicates that all of them produce antibacterial activity
against Gram-negative microorganism (K.pneumoniae and
E.coli) and Gram-positive bacteria (Staphylococcus aureus)
in general (Table 1). Results (Tables 1, 2) reveal that these
compound have significant influence on antibacterial profile
of Gram-negative bacteria. The compounds also showed
moderate to good inhibitory results against Gram-positive
bacteria. The Minimum inhibitory concentrations of the
synthesized compounds ranged from 22.9 to 57.8 lg/ml
against K. pneumoniae and 24.1–98.4 lg/ml against E.coli.
The MIC values were more than 85 lg/ml against Staphy-
lococcus aureus (Table 2). Compounds 5a, 5c, 11b, 11d,
11f, and 11h showed good antibacterial activity while
compounds 6, 11e, 11g, and 12c showed moderate antibac-
terial activity against Gram-positive microorganism as
compared to ciprofloxacin. It is generally assumed that the
more lipophilic compound can penetrate better the lipophilic
cell membrane of Gram-positive bacteria, while less lipo-
philic compound are more liable to penetrate the cell wall of
Gram-negative bacteria. It has been noted that the com-
pounds which are less lipophilic (lower log P values,
Table 1) in nature are more effective against Gram-negative
microorganism, on the other hand, these compounds are less
effective against Gram-positive microorganism. In the
1
5a
22.9
46.4
25.8
49.2
48.3
27.7
42.6
52.0
44.5
57.8
1.3
45.9
46.4
51.6
98.4
24.1
55.3
42.6
26.0
44.5
28.9
0.6
91.9
92.8
2
5c
3
6
[100
98.4
4
11b
5
11d
96.6
6
11e
[100
85.1
7
11f
8
11g
[100
89.1
9
11h
10
11
12c
[100
0.6
Ciprofloxacin
Ph–SO2–NH–NH–CO–O series, compounds with electron-
withdrawing groups have more activity than compounds
with electron-donating functional groups. In the case of
amino-coumarin series, it was noted that the introduction of
o-bromo group, reduces the antibacterial activity against
Gram-negative microorganism; this could be due to changes
in the lipophilicity of the compound. Compound 5c is more
lipophilic than compound 5a (Table 1). Isosteric replace-
ment (benzofuran instead of coumarin), does not reduce the
antibacterial activity significantly.
Conclusions
We reported on the synthesis and characterization of new
coumarin derivatives and new N-substituted 2-[(4-methyl-
Table 1 In-vitro antibacterial activity of compounds (5a, 5c, 6, 11b, 11d–h, and 12c) at 50 lg/ml concentration
Sn
Compound
Log P (c Log P)a
Gram negative
Gram positive
K. pneumoniae
E. coli
S. aureus
Diameter of inhibition zone in mm at 50 lg/ml
1
5a
1.03 (1.88)
1.34 (2.74)
0.56 (3.31)
1.79 (2.65)
1.52 (2.30)
2.00 (2.87)
2.27 (3.02)
1.34 (1.90)
2.36 (3.04)
2.55 (3.92)
20
14
14
10
12
10
11
14
15
13
20
12
11
11
11
12
12
12
13
13
13
22
10
10
11
10
9
2
5c
3
6
4
11b
5
11d
6
11e
9
7
11f
14
10
11
10
24
8
11g
9
11h
10
11
12c
Ciprofloxacin (1.0 lg/ml)
Note: diameter of wells = 6 mm
a
Log P (cLog P) were calculated using CambridgeSoft Chem Draw Ultra Ver. 8.0
123

472
Med Chem Res (2012) 21:468–476
General procedure for preparation of compounds (5a–c, 6,
and 7)
2-oxo-2H-chromen-7-yl)oxy]acetohydrazide. The antimi-
crobial activity showed that the synthesized compounds
exerted significant inhibitory activity against the growth of
tested bacterial strains and a few of them are potent anti-
microbial agents.
A mixture of 7-amino-4-methylcoumarin (1) (0.25 g, 1.43
mmol) and corresponding halides (2a–c, 3, and 4) (1.43
mmol) in dry DMF (5–10 ml) was heated at 70°C for
5–15 h depending on the halide. Disappearance of the
starting material and completion of the reaction were
confirmed by TLC. The reaction mixture was poured onto
crushed ice (100 ml) and stirred for 10 min. The precipi-
tate was filtered, washed with cold water, and recrystal-
lized from ethanol to give the desired products (5a-c, 6,
and 7).
Experimental
Chemistry
All reagents were used as received from commercially
sources without further purification. Progress of reactions
was monitored by thin layer chromatography (TLC) using
glass plates pre-coated with silica gel (E. Merck Kiesegel
60 F254 layer thickness 0.25 mm). Melting points of the
newly synthesized compounds were determined with a
7-Methoxy-4-{[(4-methyl-2-oxo-2H-chromen-7-
yl)amino]methyl}-2H-chromen-2-one (5a)
1
Stuart melting point apparatus and were uncorrected. H
Yield = 0.292 g (56.3%), mp = 268–270°C. 1H NMR
(DMSO-d6): d 7.79 (d, J = 8.7 Hz, 1H), 7.44 (d,
J = 8.7 Hz, 1H), 7.21(t, J = 5.4 Hz, 1H), 6.99 (dd, J =
2.5, 8.7 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.68 (dd,
J = 2.1, 8.7 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 6.08 (s,
1H), 5.92 (s, 1H), 4.62 (d, J = 5.4 Hz, 2H), 3.83 (s, 3H),
2.28 (s, 3H). 13C NMR (DMSO-d6): d 162.97, 161.06,
160.74, 155.97, 155.54, 154.19, 153.92, 152.25, 126.73,
126.49, 112.70, 111.74, 110.87, 110.09, 108.98, 108.71,
101.37, 97.65, 56.47, 43.11, 18.52. IR (KBr): 1710, 3381,
1614, 1291 cm-1. HRMS m/z: calcd for C21H17NO5 [M]?
363.11067, found 363.11122. Anal. Calcd for C21H17NO5:
C, 69.41; H, 4.72; N, 3.85. Found: C, 69.53; H, 4.96; N,
3.47.
and 13C NMR spectra were recorded with the aid of Bru-
ker-DPX 300 MHz spectrometers and are reported in ppm
(d) relative to TMS as an internal standard and with
DMSO-d6 as solvent. Infrared (IR) spectra were recorded
as KBr discs on a Nicolet-MAGNA-IR-560 instrument.
High resolution mass spectral data were acquired with
a Brucker APEX (IV) mass spectrometer (Bremen,
Germany). Elemental analyses were obtained using a
Eurovector Euro EA3000, CHNS-O elemental analyzer.
7-Amino-4-methylcoumarin (1)
The title compound was synthesized according to pub-
lished procedure by reacting m-aminophenol (22.0 g, 202
mmol) and methoxycarbonyl chloride (18.0 ml, 234
mmol), followed by the addition of acetoacetic ester
(25.0 ml) and concentrated sulfuric acid. The reaction
mixture was then filtered to give 7-amino-4-methylcoum-
arin (1), mp 224–226°C (28.5 g, 80% yield), [lit., 222–
223°C, Pozdnev (1990)].
7-Methyl-4-{[(4-methyl-2-oxo-2H-chromen-7-
yl)amino]methyl}-2H-chromen-2-one (5b)
Yield = 0.298 g (60.1%), mp = 216–219°C. 1H NMR
(DMSO-d6): d 7.77 (d, J = 8.0 Hz, 1H), 7.44 (d,
J = 8.7 Hz, 1H), 7.23 (br s, 1H), 7.23 (d, J = 2.8 Hz, 1H),
7.21 (dd, J = 2.8, 8.0 Hz, 1H), 6.68 (dd, J = 1.9, 8.7 Hz,
1H), 6.48 (d, J = 1.9 Hz, 1H), 6.18 (s, 1H), 5.92 (s, 1H),
4.64 (d, J = 4.6 Hz, 2H), 2.39 (s, 3H), 2.27 (s, 3H). 13C
NMR (DMSO-d6): d 161.04, 160.53, 155.98, 154.15,
153.74, 153.67, 152.22, 143.49, 126.71, 125.91, 125.09,
117.13, 115.91, 111.23, 110.87, 110.13, 108.74, 97.69,
43.09, 21.57, 18.51. IR (KBr) 1707, 3375, 1616, 1266,
2-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide
(8)
This compound was synthesized according to the procedure
outlined by Satyanarayana et al. (2008), which involved
the reaction of 7-hydroxy-4-methylcoumarin (0.057 mol,
10.0 g) and ethylchloroacetate, followed by the addition of
hydrazine hydrate (0.014 mol). The reaction mixture was
filtered to give 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]-
acetohydrazide (8), mp 203–205°C (Yield 90%), [lit.
202–204°C, (Satyanarayana et al., 2008)].
3071 cm-1
.
HRMS m/z: calcd for C21H17NO4Na
[M ? Na]? 370.10553, found 370.10498. Anal. Calcd for
C21H17NO4: C, 72.61; H, 4.93; N, 4.03. Found: C, 72.53;
H, 4.53; N, 4.08.
123

Med Chem Res (2012) 21:468–476
473
3-Bromo-7-methoxy-4-{[(4-methyl-2-oxo-2H-chromen-7-
yl)amino]methyl}-2H-chromen-2-one (5c)
N-Substituted-2-[(4-methyl-2-oxo-2H-chromen-7-yl)
oxy]acetohydrazide (11a–h)
Yield = 0.359 g (56.8%), mp = 252–254°C. 1H NMR
(DMSO-d6): d 7.74 (d, J = 8.2 Hz, 1H), 7.45 (d,
J = 8.7 Hz, 1H), 7.04 (dd, J = 2.3, 8.21 Hz, 1H), 6.99 (t,
J = 2.5 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.65 (dd,
J = 1.8, 8.7 Hz, 1H), 6.58 (d, J = 1.8 Hz, 1H), 5.94 (s,
1H), 4.63 (d, J = 2.5 Hz, 2H), 3.83 (s, 3H), 2.28 (s, 3H).
13C NMR (DMSO-d6): d 163.14, 161.09, 157.18, 156.03,
154.19, 154.08, 152.12, 150.39, 127.59, 126.64, 113.56,
112.38, 111.09, 110.93, 110.09, 108.73, 101.32, 97.46,
56.62, 44.97, 18.53. IR (KBr): 1706, 3303, 1621, 1284,
3080, 631 cm-1. HRMS m/z: calcd for C21H15Br NO5
[M - H]? 440.01336, found 440.01391. Anal. Calcd for
C21H16BrNO5: C, 57.03; H, 3.65; N, 3.17. Found: C, 56.43;
H, 3.26; N, 3.31.
General procedure
A
mixture of substituted sulfonyl chloride (9a–h)
(1.37 mmol) and 2-[(4-methyl-2-oxo-2H-chromen-7-
yl)oxy]acetohydrazide (8) (0.34 g, 1.37 mmol) was stirred
at room temperature in (5–10 ml) dry DMF in the presence
of TEA as base. The progress of reaction and disappear-
ance of the starting material was monitored by TLC. The
reaction mixture was poured onto crushed ice (100 ml) and
stirred for 10 min. The precipitate was collected by suction
filtration, washed with cold water and further purified by
crystallization from ethanol to give compounds (11a–h).
2-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]-N-
(phenylsulfonyl)acetohydrazide (11a)
Yield = 0.198 g (37%), mp = 195–196°C. 1H NMR
(DMSO-d6): d 10.21 (br s, 1H), 9.85 (br s, 1H), 7.66 (m,
5H), 7.50 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H),
6.77 (s, 1H), 6.19 (s, 1H), 4.57 (s, 2H), 2.36 (s, 3H). 13C
NMR (DMSO-d6): d 166.56, 161.07, 160.55, 154.94,
153.84, 139.37, 133.54, 129.37, 128.07, 126.91, 114.16,
113.00, 111.98, 101.96, 66.24, 18.61. IR (KBr): 1724,
3308, 1618, 1206, 3061, 1686 cm-1. HRMS m/z: calcd for
C18H15N2O6S [M-H]? 387.06508, found 387.06563. Anal.
Calcd for C18H16N2O6S: C, 55.66; H, 4.15; N, 7.21. Found:
C, 56.04; H, 4.42; N, 7.67.
Ethyl-6-methoxy-3-{[(4-methyl-2-oxo-2H-chromen-7-
yl)amino]methyl}-1-benzofuran -2-carboxylate (6)
Yield = 0.253 g (43.4%), mp = 164–167°C. 1H NMR
(DMSO-d6): d 7.80 (d, J = 8.7 Hz, 1H), 7.38 (d,
J = 8.7 Hz, 1H), 7.32 (t, J = 5.9 Hz, 1H), 7.25 (d,
J = 2.1 Hz, 1H), 6.92 (dd, J = 2.1, 8.7 Hz, 1H), 6.63 (dd,
J = 2.1, 8.7 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 5.87 (s,
1H), 4.81 (d, J = 5.9 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H),
3.77 (s, 3H), 2.23 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C
NMR (DMSO-d6): d 161.07, 160.99, 159.95, 155.96,
155.89, 154.15, 152.42, 140.48, 127.61, 126.65, 123.34,
120.66, 114.17, 110.58, 109.68, 108.38, 97.05, 96.32,
61.57, 56.26, 37.45, 18.47, 14.67. IR (KBr): 1712, 3370,
2-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]-N-[(4-methyl
phenyl)sulfonyl]acetohydrazide (11b)
1624, 1272, 3078 cm-1
.
HRMS m/z: calcd for
C23H21NO6Na [M ? Na]? 430.12666, found 430.12611.
Anal. Calcd for C23H21NO6: C, 67.80; H, 5.20; N, 3.44.
Found: C, 67.34; H, 6.15; N, 3.78.
Yield = 0.196 g (35.6%), mp = 217–218°C. 1H NMR
(DMSO-d6): d 10.32 (br., 1H), 9.84 (br., 1H), 7.73 (d,
J = 7.8 Hz, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.28 (d,
J = 7.8 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H),
6.20 (s, 1H), 4.57 (s, 2H), 2.31 (s, 3H), 2.24 (s, 3H). 13C
NMR (DMSO-d6): d 166.45, 161.09, 160.55, 154.95,
153.85, 143.81, 136.40, 129.81, 128.15, 126.89, 114.14,
113.05, 111.97, 101.95, 66.18, 21.49, 18.61. IR (KBr):
1737, 3291, 1613, 1285, 3076, 1690, 1334 cm-1. HRMS
m/z: calcd for C19H18N2NaO6S [M ? Na]? 425.07832,
found 425.07778. Anal. Calcd for C19H18N2O6S: C, 56.71;
H, 4.51; N, 6.96. Found: C, 56.65; H, 4.81; N, 6.29.
7-[(1,3-Benzoxazol-2-yl)amino]-4-methyl-2H-chromen-2-
one (7)
Yield = 0.239 g (57.2%), mp = 335–336°C. 1H NMR
(DMSO-d6): d 11.16 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H),
7.73 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 1.8, 8.7 Hz, 1H),
7.20 (m, 4H), 6.21 (s, 1H), 2.37 (s, 3H). 13C NMR (DMSO-
d6): d 160.58, 157.66, 154.60, 153.72, 147.44, 142.58,
126.67, 124.78, 122.88, 117.66, 114.46, 112.18, 109.78,
104.39, 18.54. IR (KBr): 1686, 3253, 1596, 1271, 3077,
2-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]-N-[(2-nitro
phenyl)sulfonyl]acetohydrazide (11c)
1567 cm-1
.
HRMS m/z: calcd for C17H12N2O3Na
[M ? Na]? 315.07456, found 315.07401. Anal. Calcd for
C17H12N2O3: C, 69.86; H, 4.14; N, 9.58. Found: C, 70.01;
H, 4.39; N, 10.04.
Yield = 0.212 g (35.7%), mp = 203–205°C. 1H NMR
(DMSO-d6): d 10.58 (br s, 1H), 10.27 (br s, 1H), 8.02 (d,
J = 7.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.79 (m, 2H),
123

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Med Chem Res (2012) 21:468–476
7.64 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 2.0, 8.2 Hz, 1H),
6.79 (d, J = 2.0 Hz, 1H), 6.19 (s, 1H), 4.63 (s, 2H), 2.36 (s,
3H). 13C NMR (DMSO-d6): d 167.06, 161.02, 160.53,
154.92, 153.82, 148.15, 135.16, 132.96, 132.23, 131.35,
126.92, 124.87, 114.19, 112.92, 112.01, 102.04, 66.23,
18.60. IR (KBr): 1700, 3299, 1614, 1281, 3171, 1683,
1352, 1542 cm-1. HRMS m/z: calcd for C18H14N3O8S [M -
H]? 432.05016, found 432.05071. Anal. Calcd for
C18H15N3O8S: C, 49.88; H, 3.49; N, 9.70. Found: C, 50.31;
H, 3.63; N, 9.11.
114.13, 112.89, 112.00, 101.94, 66.04, 18.68. IR (KBr):
1733, 3324, 1621, 1307, 3054, 1696, 656 cm-1. HRMS
m/z: calcd for C18H16BrN2O6S [M ? H]? 466.99124,
found 466.99070. Anal. Calcd for C18H15BrN2O6S: C,
46.27; H, 3.24; N, 5.99. Found: C, 47.04; H, 3.67; N,
6.06.
2-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]-N-[(3-nitro
phenyl)sulfonyl]acetohydrazide (11 g)
Yield = 0.330 g (55.6%), mp = 247–249°C. 1H NMR
(DMSO-d6): d 10.60 (br s, 1H), 10.50 (br s, 1H), 8.47 (s,
1H), 8.43 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H),
7.79 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 6.83
(dd, J = 2.3, 8.7 Hz, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.21
(s, 1H), 4.57 (s, 2H), 2.36 (s, 3H). 13C NMR (DMSO-d6): d
166.94, 160.87, 160.54, 154.87, 153.85, 147.99, 141.22,
134.26, 131.45, 128.16, 126.93, 122.92, 114.19, 112.75,
112.04, 101.97, 66.21, 18.64. IR (KBr): 1729, 3309, 1616,
1280, 3080, 1710, 1533 cm-1. HRMS m/z: calcd for
C18H16N3O8S [M ? H]? 434.06581, found 434.06526.
Anal. Calcd for C18H15N3O8S: C, 49.88; H, 3.49; N, 9.70.
Found: C, 50.09; H, 3.40; N, 9.68.
N-[(4-Flouro phenyl)sulfonyl]-2-[(4-methyl-2-oxo-2H-
chromen-7-yl)oxy]acetohydrazide (11d)
Yield = 0.312 g (55.9%), mp = 238–240°C. 1H NMR
(DMSO-d6): d 10.45 (br s, 1H), 10.09 (br s, 1H), 7.81 (m,
2H), 7.64 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 8.7 Hz, 2H),
6.85 (dd, J = 2.2 Hz, 8.84 Hz, 1H), 6.78 (d, J = 2.2 Hz,
1H), 6.21 (s, 1H), 4.57 (s, 2H), 2.36 (s, 3H). 13C NMR
(DMSO-d6): d 166.63, 163.42, 160.99, 160.54, 154.89,
153.87, 135.64, 131.30, 126.93, 116.69, 114.12, 112.95,
111.98, 101.91, 66.13, 18.64. IR (KBr): 1735, 3318, 1622,
1307, 3057, 1686, 1078 cm-1. HRMS m/z: calcd for
?
C18H16FN2O6S [M ? H] 407.07131, found 407.07076.
Anal. Calcd for C18H15FN2O6S: C, 53.20; H, 3.72; N, 6.89.
Found: C, 52.81; H, 4.07; N, 6.46.
2-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]-N-{[4-
(triflouromethyl)phenyl]sulfonyl}acetohydrazide (11 h)
N-[(4-Chloro phenyl)sulfonyl]-2-[(4-methyl-2-oxo-2H-
chromen-7-yl)oxy]acetohydrazide (11e)
Yield = 0.378 g (60.4%), mp = 245–247°C. 1H NMR
(DMSO-d6): d 10.52 (br s, 1H), 10.35 (br s, 1H), 7.97
(d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.65 (d,
J = 8.8 Hz, 1H), 6.86 (d, J = 2.3, 8.8 Hz, 1H), 6.79 (d,
J = 2.3 Hz, 1H), 6.21 (s, 1H), 4.59 (s, 2H), 2.36 (s, 3H).
13C NMR (DMSO-d6): d 166.82, 160.95, 160.54, 154.89,
153.86, 143.51, 129.52, 129.08, 126.94, 126.51, 114.13,
112.91, 111.98, 101.92, 66.04, 18.62. IR (KBr): 1736,
3328, 1623, 1306, 3049, 1702, 1164 cm-1. HRMS m/z:
calcd for C19H16F3N2O6S [M ? H]? 457.06812, found
457.06757. Anal. Calcd for C19H15F3N2O6S: C, 50.00; H,
3.31; N, 6.14. Found: C, 50.45; H, 3.01; N, 6.45.
Yield = 0.347 g (59.8%), mp = 236–238°C. 1H NMR
(DMSO-d6): d 10.47 (br s, 1H), 10.18 (br s, 1H), 7.75 (d,
J = 8.5 Hz, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.55 (d,
J = 8.5 Hz, 2H), 6.85 (dd, J = 2.2, 8.8 Hz, 1H), 6.79
(d, J = 2.2 Hz, 1H), 6.21 (s, 1H), 4.58 (s, 2H), 2.37 (s,
3H). 13C NMR (DMSO-d6): d 166.66, 160.98, 160.56,
154.89, 153.88, 138.43, 138.21, 130.07, 129.51, 126.95,
114.12, 112.92, 111.99, 101.93, 66.05, 18.66. IR (KBr):
1734, 3324, 1625, 1307, 3055, 1699, 832 cm-1. HRMS
m/z: calcd for C18H16ClN2O6S [M ? H]? 423.04176,
found 423.04121. Anal. Calcd for C18H15ClN2O6S: C,
51.13; H, 3.58; N, 6.63. Found: C, 51.63; H, 3.86; N, 6.96.
General procedure for preparation of compounds (12a–d)
N-[(4-Bromo phenyl)sulfonyl]-2-[(4-methyl-2-oxo-2H-
chromen-7-yl)oxy]acetohydrazide (11f)
A mixture of 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]
acetohydrazide (8) (0.34 g, 1.37 mmol) and other required
reactants (10a–d) (1.37 mmol) in dry DMF (5–10 ml) and
TEA was heated at 70°C. Completion of the reaction was
checked by TLC. The reaction mixture was poured onto
crushed ice (100 ml) and stirred for 10 min. The precipitate
was collected by suction filtration, washed with cold water
and further purified by crystallization from ethanol to give
the desired products (12a–d).
Yield = 0.378 g (58.9%), mp = 234–235°C. 1H NMR
(DMSO-d6): d 10.48 (br s, 1H), 10.18 (br s, 1H), 7.67
(d, J = 5.4 Hz, 2H), 7.64 (d, J = 5.4 Hz, 2H), 7.64 (d,
J = 8.7 Hz, 1H), 6.84 (dd, J = 2.3, 8.7 Hz, 1H), 6.79
(d, J = 2.3 Hz, 1H), 6.21 (s, 1H), 4.59 (s, 2H), 2.37 (s,
3H). 13C NMR (DMSO-d6): d 166.68, 160.97, 160.56,
154.89, 153.87, 138.64, 133.07, 130.48, 127.49, 126.94,
123

Med Chem Res (2012) 21:468–476
475
N-[(7-Methoxy-2-oxo-2H-chromen-4-yl)methyl]-2-[(4-
methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (12a)
N-1,3-Benzoxazol-2-yl-2-[(4-methyl-2-oxo-2H-chromen-7-
yl)oxy]acetohydrazide (12d)
Yield = 0.278 g (44.6%), mp = 219–222°C. 1H NMR
(DMSO-d6): d 9.60 (br s, 1H), 7.86 (d, J = 6.5 Hz, 1H),
7.44 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 6.5 Hz, 1H), 6.78
(d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 6.32 (s, 1H), 6.12 (s,
1H), 4.54 (s, 1H), 4.27 (s, 2H), 3.81 (s, 3H), 3.26 (d,
J = 6.7 Hz, 2H), 2.31 (s, 3H). 13C NMR (DMSO-d6): d
166.68, 162.63, 160.63, 160.36, 155.40, 154.66, 153.46,
151.56, 127.03, 126.69, 114.10, 112.71, 112.34, 112.08,
111.81, 102.10, 101.09, 67.08, 56.93, 56.34, 18.52. IR
(KBr): 1724, 3298, 1615, 1284, 3077, 1699 cm-1. HRMS
m/z: calcd for C23H20N2O7Na [M ? Na]? 459.11682,
found 459.11627. Anal. Calcd for C23H20N2O7: C, 63.30;
H, 4.62; N, 6.42. Found: C, 63.46; H, 5.14; N, 7.11.
Yield = 0.291 g (58.1%), mp = 239–241°C. 1H NMR
(DMSO-d6): d 9.80 (br s, 1H), 7.42 (d, J = 7.7 Hz, 1H),
7.16 (d, J = 7.7 Hz, 1H), 7.12 (s, 1H), 7.09 (m, 4H), 6.23
(s, 1H), 4.81 (s, 2H), 2.38 (s, 3H). 13C NMR (DMSO-d6): d
167.74, 163.40, 162.62, 161.05, 160.62, 155.04, 153.95,
148.67, 127.01, 124.57, 121.81, 116.99, 114.21, 113.31,
112.00, 109.72, 102.15, 66.74, 18.68. IR (KBr): 1705,
3238, 1611, 1281, 3055, 1656 cm-1. HRMS m/z: calcd for
C19H15N3O5Na [M ? Na]? 388.09094, found 388.09039.
Anal. Calcd for C19H15N3O5: C, 62.46; H, 4.14; N, 11.50.
Found: C, 62.87; H, 4.34; N, 11.07.
Biological evaluation
Antibacterial studies
N-[(7-Methyl-2-oxo-2H-chromen-4-yl)methyl]-2-[(4-
methyl-2-oxo-2H-chromen-7-yl)oxy]acetohydrazide (12b)
The synthesized compounds were dissolved to prepare a
stock solution of 5 mg/ml using DMSO. All the chemical
compounds were tested for antibacterial activity against
human pathogens Gram-negative (K. pneumoniae, E. coli.)
and Gram-positive bacteria (Staphylococcus aureus). The
minimal inhibitory concentration (MICs) of the chemical
compound assays were carried out as described by
Foroumadi et al. (2003a, b) with minor modification.
Ciprofloxacin was used as reference antibacterial agent.
Determination of inhibition zones (agar diffusion
method): a drop of bacteria was added to sterile nutrient
agar (20 ml), poured into a plate (9 cm in diameter) and
allowed to solidify to obtain the seeded agar. The final
concentration of the microorganisms in the agar plate was
1–4 9 105 cfu ml-1 (checked by viable counting in nor-
mal saline). Aliquots of 50 ll of the freshly prepared
solutions of the synthesized compounds (50 lg/ml) were
poured in wells (6 mm in diameter). Plates were then
incubated at 37°C for 24 h. The zones of inhibition were
determined as the diameter of the zone of inhibition around
the well solution for each compound at its saturated con-
centration (Table 1). Solvent (DMSO) was included in
every experiment of determining zones of inhibition as a
control to ensure that it has no effect on the bacterial
growth. Each experiment was done in duplicate.
Yield = 0.303 g (50.5%), mp = 215–217°C. 1H NMR
(DMSO-d6): d 9.70 (br s, 1H), 7.81 (d, J = 8.6 Hz, 1H),
7.42 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.10 (s,
1H), 6.77 (dd, J = 2.3, 8.6 Hz, 1H), 6.69 (d, J = 2.3 Hz,
1H), 6.43 (s, 1H), 6.12 (s, 1H), 4.55 (s, 2H), 4.30 (d,
J = 6.0 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H). 13C NMR
(DMSO-d6): d 166.73, 160.66, 160.42, 154.68, 153.63,
153.34, 151.39, 143.06, 126.65, 125.61, 125.55, 116.92,
116.20, 114.13, 114.01, 112.23, 112.05, 102.20, 67.17,
56.85, 21.51, 18.45. IR (KBr): 1717, 3272, 1619, 1282,
3070, 1693 cm-1. HRMS m/z: calcd for C23H20N2O6Na
[M ? Na] ? 443.12191, found 443.12136. Anal. Calcd for
C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C, 66.55;
H, 5.66; N, 7.46.
N-(8-Chloroquinolin-4-yl)-2-[(4-methyl-2-oxo-2H-
chromen-7-yl)oxy]acetohydrazide (12c)
Yield = 0.309 g (55.0%), mp = 290–292°C. 1H NMR
(DMSO-d6): d 11.23 (br s, 1H), 8.63 (d, J = 6.8 Hz, 1H),
8.57 (d, J = 9.1 Hz, 1H),8.12 (d, J = 8.4 Hz,1H), 7.81
(dd, J = 8.4, 9.1 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.09
(d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 6.8 Hz,
1H), 6.23 (s, 1H), 4.99 (s, 2H), 2.38 (s, 3H). 13C NMR
(DMSO-d6): d 167.47, 161.02, 160.56, 156.54, 155.02,
153.90, 144.73, 139.68, 138.74, 128.11, 127.14, 125.79,
120.39, 114.30, 113.05, 112.10, 102.22, 99.75, 66.82,
18.68. IR (KBr): 1767, 3209, 1614, 1281, 3085, 1698,
Determination of minimum inhibitory concentration,
MIC, (serial dilution method): stock solutions were pre-
pared by dissolving each pure compound (5 mg) in 1 ml of
DMSO, then 1 ml of the compound stock solution was
added to nutrient broth (4 ml). Progressive two fold serial
dilutions of the stock solutions were made in nutrient broth
starting from *1000 lg/ml concentrations in the first test
tubes and ending with a concentration of 1.9 lg/ml. The
standardization of bacterial test suspension was carried out
816 cm-1
. HRMS m/z: calcd for C21H16ClN3O4Na
[M ? Na]? 432.07270, found 432.07215. Anal. Calcd for
C21H16ClN3O4: C, 61.54; H, 3.94; N, 10.25. Found: C,
61.95; H, 3.33; N, 10.37.
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