Synthesis, antioxidant, and antibacterial studies of phenolic esters and amides of 2-(1-benzofuran-2-yl) quinoline-4-carboxylic acid

Article abstract of DOI:10.1007/s00044-012-0117-8

A new series of phenolic esters 2(a-j) and amides 3(a-c) of 2-(1-benzofuran-2-yl) quinoline-4-carboxylic acid were synthesized by the reaction of 2-(1-benzofuran-2-yl)-quinoline-4-carboxylic acid (1) with various substituted phenols and secondary amines using ethyl-(N′,N′- dimethylamino)propyl carbodiimide hydrochloride (EDC.HCl) as a coupling agent. The newly synthesized compounds were evaluated for in vitro antioxidant and antibacterial activity. Among all tested compounds 2a, 2c, 2e, and 2h showed good chelating ability with Fe⁺² ions, whereas compounds 2g and 2j exhibited good scavenging activity with DPPH free radicals. Concerning antibacterial activities compounds 2a, 2b, 2c, and 2h were found to be equipotent to ampicillin against Enterococcus sp and Staphylococcus aureus, while compound 2e is found to be as potent as ampicillin against Pantoea Dispersa and Ochrobactrum sp. amide derivatives 3(a-c) were found to be less potent when compared to standard.

Full text of DOI:10.1007/s00044-012-0117-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0117-8
ORIGINAL RESEARCH
Synthesis, antioxidant, and antibacterial studies of phenolic esters
and amides of 2-(1-benzofuran-2-yl) quinoline-4-carboxylic acid
•
Sheelavanth Shankerrao Yadav D. Bodke
•
Sundar S. Mety
Received: 4 January 2012 / Accepted: 22 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A new series of phenolic esters 2(a–j) and
amides 3(a–c) of 2-(1-benzofuran-2-yl) quinoline-4-
carboxylic acid were synthesized by the reaction of
2-(1-benzofuran-2-yl)-quinoline-4-carboxylic acid (1) with
various substituted phenols and secondary amines using
ethyl-(N0,N0-dimethylamino)propyl carbodiimide hydro-
chloride (EDC.HCl) as a coupling agent. The newly syn-
thesized compounds were evaluated for in vitro antioxidant
and antibacterial activity. Among all tested compounds 2a,
2c, 2e, and 2h showed good chelating ability with Fe?2
ions, whereas compounds 2g and 2j exhibited good scav-
enging activity with DPPH free radicals. Concerning
antibacterial activities compounds 2a, 2b, 2c, and 2h were
found to be equipotent to ampicillin against Enterococcus
sp and Staphylococcus aureus, while compound 2e is found
to be as potent as ampicillin against Pantoea Dispersa and
Ochrobactrum sp. amide derivatives 3(a–c) were found to
be less potent when compared to standard.
Introduction
Antioxidants are gaining a lot of importance as universal
remedy for a wide range of lifestyle-related diseases like
early aging, cancer, diabetes, cardiovascular, and other
degenerative diseases etc. owing to our deskbound way of
life and stressful existence. Added to these are the harmful
effects of pollution and exposure to carcinogenic chemicals.
All these can cause accumulation of harmful free radicals.
The main characteristic of an antioxidant is its ability to
entrap free radicals. Highly reactive free radicals and oxygen
species are present in biological systems from a wide variety
of sources. These free radicals may oxidize nucleic acids,
proteins, lipids or DNA and can initiate degenerative dis-
ease (Jung et al., 1999; Pietta et al., 1998). Antioxidant
compounds like phenolic acids, polyphenols, and flavo-
noids scavengefree radicals such as peroxide, hydroperoxide
or lipid peroxyl and thus inhibit the oxidative mecha-
nisms that lead to degenerative diseases (Van Acker et al.,
1996).
Keywords Phenyl 2-(1-benzofuran-2-yl) quinoline-4-
carboxylate ꢀ Antioxidant activity ꢀ Antibacterial activity
2-Heteroarylbenzofuran ring systems are widely distrib-
uted in nature and have been reported to possess antioxidant,
antiviral, and antifungal activities (Fuganti and Serra, 1998;
Abdel-Wahab et al., 2009; Akgul and Anil, 2003; Venkatesh
and Bodke, 2010; Ahmad et al., 2006; Kirilmis et al., 2008;
Manna and Agrawal, 2009). Kapche et al. (2009) isolated
prenylated 2-aryl benzofuran derivatives from Morus mes-
ozygia plant and these compounds found to possess potent
antioxidant property. Many researchers have demonstrated
the efficient scavenging ability of 3-arylbenzofuranone
derivatives on both carbon and oxygen centered radicals and
are widely used as excellent antioxidants for polymers (Xin
et al., 2006; Solera, 1998; Pospisil and Nespurek, 1995;
Michele and Paul, 2002; Peter et al., 1995; Michael et al.,
2002). Benzofuran derivative extracted from yeast was
S. Shankerrao ꢀ Y. D. Bodke (&)
Department of P.G. Studies and Research in Industrial
Chemistry, School of Chemical Sciences, Kuvempu University,
Jnana Sahyadri, Shankarghatta 577 451, Shivamogga Dist,
Karnataka, India
e-mail: ydbodke@gmail.com
S. S. Mety
Department of Botany, Gulbarga University, Jnana Ganga,
Gulbarga 585 106, Karnataka, India
123

Med Chem Res
shown to protect in vitro the erythrocytes of vitamin E
deficient rats from hemolysis (Jinno and Otsuka, 1999).
Cinchophen (2-phenyl quinoline-4-carboxylic acid) was
first synthesized by Doebner and Giesecke in 1887 and was
introduced into the therapeutic application by Weintraub in
1911 as a uricosuric agent in the treatment of gout. Later,
cincophen and its numerous derivatives have been found to
possess wide range of physiological functions such as uri-
cosuric, analgesic, antiinflammatory etc. (Mishra et al.,
1988; Short and Bauer, 1957). Merely few reports were
found about synthesis of 2-(benzofuran-2-yl) quinoline-4-
carboxylic acid (Chatterjea, 1955; Bisagni et al., 1955;
Ardashev and Gaidzhurova, 1968); further this moiety was
not exploited till now to get new compounds except one
molecule methyl 2-(2-(benzofuran-2-yl) quinoline-4-car-
boxamido)-2-phenyl acetate [I] which was reported as a
potent Selective Non-Peptide antagonists of Human neu-
rokinin-3 receptor (Giardina et al., 1997). Therefore, to
exploit further in the present investigation
organisms agar-well diffusion method and minimum inhib-
itory concentration (MIC) was determined by serial broth-
dilution method.
Results and discussion
Chemistry
The key intermediate 2-(1-Benzofuran-2-yl) quinoline-4-
carboxylic acid (1) was synthesized by Pfitzinger method
(Ardashev and Gaidzhurova, 1968) which involves the
reaction of 2-acetyl benzofuran with isatin under basic
condition. Compound (1) upon reaction with different
substituted phenols using EDC.HCl as a coupling reagent
in the presence of catalytic amount of dimethyl ammonium
pyridine furnished corresponding phenyl 2-(1-benzofuran-
2-yl) quinoline-4-carboxylate derivatives 2(a–j). In the
same way when piperidine, morpholine, and 2-methyl
R
COOMe
O
N
O
NH
O
O
N
N
N
O
O
O
[I]
[II]
[III]
we are reporting the synthesis and characterization hitherto
unknown 2-(1-benzofuran-2-yl) quinoline-4-substituted
derivatives containing 2-(benzofuran-2yl) quinoline as a
pharmacophore; phenyl carboxylates [II] 2(a–j) and tertiary
amides [III] 3(a–c). Further it comprises the evaluation of
antioxidant activity using two models namely DPPH free
radical scavenging assay, which is more efficient and reli-
able; another model is iron chelating assay, it is important
because in earlier reports it is mentioned that common
antioxidants inactivate ROS (reactive oxygen species) only
after they have been formed, but iron chelators are able to
preventtheir formation. Iron can redox-cycle between its two
states—Fe2? and Fe3?—and acts as a catalyst for hydroxyl
radical formation (Fenton and Haber–Weiss reactions). Iron
chelation is considered to be an important tool to decrease
anthracycline cardiotoxicity as documented by the beneficial
effect of dexrazoxane (Schroeder and Hasinoff, 2002) as
imidazole were made to react with compound 1 under same
reaction condition, it furnished the corresponding tertiary
amides 3a–c (Scheme 1). The structures of newly synthe-
1
sized compounds were confirmed by H NMR, 13C NMR,
and Mass Spectral data. The characterization data of the
newly synthesized compounds are given in Table 1.
Antioxidant activity
Chelating ability of metal ion
Initially ferrozine quantitatively forms complex with Fe?2
ions present in the solution. In the presence of chelating
agent, the initial complex was competitively destroyed and
hence resulting in the reduction in red color. The reduction
in color allows for estimation of the ability of test com-
pounds to form stable complex by chelating with metal
ions. The results of chelating ability of different esters with
Fe?2 were shown in Fig. 1. The range and mean of Fe?2
chelating capacities varied significantly among different
ˇ
ˇ
ˇ
˚
well as other chelators of iron (Simunek et al., 2005; Sterba
et al., 2006). Further the new compounds were investigated
for antibacterial potency against four selected causative
123

Med Chem Res
Scheme 1 Synthesis of esters
2a–j and amides 3a–c of 2-(1-
benzofuran-2-yl) quinoline-4-
carboxylic acid
HO
O
O
O
1) 33% potash / reflux
2) Dil.HCl
+
N
O
O
N
H
O
(1)
R2
R3
R4
R1
O
HO
O
OH
R4
R1
R2
O
EDC.HCl / DCM
DMAP
+
O
N
N
R3
O
2(a-j)
(1)
O
N
N
H
O
N
3a
HO
O
O
N
N
N
NH
DCM
DMAP
EDC.HCl
+
N
O
N
O
(1)
3b
O
O
N
O
N
H
O
N
3c
compounds on the basis of substitution on the molecules
(Fig. 1). Phenyl ester 2a and para substituted phenyl esters,
2c, 2e, and 2h have showed good chelating ability. When
phenyl ring replace with bulkier rings like 1-nephthol, 2i
and 2-nephthol, 2j, respectively exhibited decreasing trend
in chelating ability.
shown in Fig. 2. The lone pair electrons present on the
ring heteroatom may be responsible for blocking the
DPPH free radical by donating electron pair and hence
fading the color. From the Fig. 2, it is clear that 2j and 2g
have showed excellent scavenging activity, whereas
compound 2i, 2d, and 2c showed moderate activity.
Further the IC50 values of compounds showing good
scavenging activity were determined and the results are
shown in Table 2. The results reveal that compound 2j
and 2g, respectively showed lower concentration of 15.6
and 24.3 lg/mL.
Scavenging effect on DPPH
The radical scavenging activities of synthesized com-
pounds were carried out using methanolic solution of the
stable free radical, DPPH. The freshly prepared DPPH
solution exhibits a deep purple color with the absorption
maximum at 517 nm. This purple color generally fades
when antioxidant is present in the medium. The results
of DPPH scavenging activities of different esters were
Antibacterial activity
The experiment designed to investigate the antibacterial
potency of the phenolic esters and tertiary amides of
123

Med Chem Res
% yield
Table 1 Characterization data of compounds 2(a–j) and 3(a–c)
Comp. code
R1
R2
R3
R4
Molecular formula
Melting point (°C)
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
C24H15NO3
C25H17NO3
C25H17NO3
137
142
173
181
202
168
190
163
218
182
124
165
104
72
85
89
70
68
68
65
80
84
86
73
78
75
CH3
H
H
CH3
H
Cl
C
C
C
C
C
C
C
C
C
C
24H14NO3Cl
24H14NO3Cl
24H13NO3Cl2
24H12NO3Cl3
24H14NO2Br
28H17NO3
H
Cl
Cl
Cl
Br
Cl
2g
2h
2i
Cl
H
1-Naphathol
2-Naphathol
Piperdine
Morpholine
2j
28H17NO3
3a
3b
3c
23H20N2O2
22H18N2O3
22H15N3O2
2-Methyl imidazole
Fig. 1 Ferrous ion chelating
activity of test compounds
100.00
90.00
80.00
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
Std*
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
100
200
400
600
Concentration in µg
2-(benzofuran-2-yl) quinoline-4-carboxylic acid against
selected species Pantoea dispersa, Ochrobacterium species,
Entercoccus species, and staphylococcus aureus. The pre-
liminary test was done using agar-well diffusion method;
further the antibacterial potency of the compounds was
quantified by determining MIC using serial broth-dilution
method. The results are presented in Table 3. The obtained
data revealed that all tested compounds were inhibited the
growth of the tested micro-organisms in vitro showing MIC
values ranging from 0.5 and 0.06 mg mL-1. Among phe-
nolic esters 2(a–j), the compounds 2a, 2b, 2c, and 2h against
S. aureus; compound 2c and 2h against Entercoccus sp.;
compound 2a and 2d against Ochrobacterium species and
compound 2d against Pantoea dispersa have showed MIC’s
at lowest concentration of 0.06 mg/mL, respectively and
these results are comparable with the standard ampicillin
MIC’s values. All other compounds showed varying degrees
of MIC values from 0.12 to above 0.5 mg/mL. Among ter-
tiary amides 3(a–c), compound 3c showed the MIC of
0.12 mg/mL against Entercoccus species and compounds 3a
showed MIC of 0.25 mg/mL against Pantoea dispersa,
Ochrobacterium species. From the results it is evident that on
varying the functionalities on the phenyl ring of ester group
2(a–j) has shown modest effect on the antibacterial potency.
On substituting methyl group on ortho and para position in
2b, 2c, respectively retained the activity without much var-
iation. Among chloro substituted derivatives, o-chloro
substituted derivative 2d found to be less active than para
chloro derivative 2e, further declining trend in activity was
found in 2,4-dichloro, 2,4,6-trichloro substituted derivatives
2g, 2h, respectively. When phenyl ring was replaced with
bulkier 1-naphthol and 2-naphthol ring system in compound
2i, 2j, respectively showed decrease in activity. From the
results it clearly indicates that by increasing the bulkiness of
the phenyl ring either by increasing the number of substitu-
tion 2(f–g) or by replacing phenyl ring with other bulkier
rings 2(i–j) leads to the decrease in activity. All tertiary
amide derivatives piperdanyl, morpholinyl, and 2-methyl
imidazolyl 3(a–c) showed low activity against all tested
organisms.
123

Med Chem Res
Fig. 2 DPPH free radical
scavenging activity of test
compounds
100
90
80
70
60
50
40
30
20
10
0
DPPH
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
0
5
10
15
20
25
30
Time in min
Table 2 IC50 values of DPPH scavenging activity
Experimental
Compound
DPPH (IC50) (lg/mL)
All the chemicals used were of analytical grade. Melting
points were determined in open capillary and are uncor-
rected. Purity of the compounds was checked by TLC on
2c
2d
2g
2i
49.5 0.4*
ꢁ100
1
24.34 0.1*
45.6 0.5*
15.6 0.18*
silica gel. H NMR spectra were recorded on a Bruker
supercon FT NMR (400 MHz) spectrometer in CDCl3 or
DMSO-d6 and TMS as an internal standard. The chemical
shifts are expressed in d units. Mass spectra were recorded on
a JEOL SX 102/DA-6000 (10 kV) FAB mass spectrometer.
2j
* Each value represents the mean value of three determina-
tions standard deviation. * P B 0.05
Table 3 Zone of inhibition and MIC values of compounds 2(a–j) and 3(a–c)
Zone of inhibition in mm (1 mg/mL)
Minimum inhibitory concentration (MIC mg/mL)
Compound
Pantoea
Ochrobactrum
Enterococcus S. aureus Pantoea Ochrobactrum Enterococcus S. aureus
dispersa 100 lL sp 100 lL
sp 100 lL
100 lL
dispersa sp
sp
0.12
2a
2b
2c
2d
2e
2f
18
19
13
16
18
16
14
14
15
12
10
15
13
16
18
20
14
17
14
12
15
11
12
09
12
11
21
12
16
19
10
14
11
10
16
13
10
07
09
13
24
16
17
19
12
17
14
12
18
14
12
11
08
10
20
0.12
0.12
0.25
0.12
0.06
0.12
0.25
0.5
0.06
0.06
0.06
0.06
0.5
0.025
0.06
0.25
0.06
0.12
0.5
0.06
0.06
0.5
0.12
0.25
0.5
0.12
0.25
0.5
2g
2h
2i
0.25
0.5
0.06
0.5
0.06
0.25
0.5
0.12
0.25
2j
[0.5
[0.5
0.25
[0.5
3a
3b
3c
[0.5
[0.5
[0.5
[0.5
0.25
0.25
0.06
[0.5
[0.5
0.5
0.12
0.06
Std Ampicillin 20
0.06
0.06
123

Med Chem Res
(m, 5H), 2.51 (s, 3H, CH3). 13C-NMR (CDCl3, 100.5 MHz):
164.47(1C), 156.82(1C), 155.2(1C), 149.45(1C), 149.24(1C),
147.8(1C), 138.72(1C), 135.6(1C), 134.54(1C), 131.44(1C),
130.48(1C), 130.10(1C), 129.85(1C), 129.01(1C), 128.17(1C),
127.50(1C), 127.22(1C), 126.58(1C), 125.33(1C), 123.8
(1C), 123.3(1C), 121.90(1C), 120.82(1C), 102.7(1C) and
18.52(1C). MS: m/z = 379(M?), 380 (M?1).
General method of synthesis of 2-(1-benzofuran-2-yl)
quinoline-4-carboxylic acid (1)
The compound (1) was synthesized by literature method
(Chatterjea, 1955; Bisagni et al., 1955; Ardashev and Gaidz-
hurova, 1968); with slight modification. After completion of
the reaction, the reaction mixture was cooled to room tem-
perature, diluted with water, and extracted with ethyl acetate
to suspend impurities in organic layer. Then aqueous layer
was acidified with dilute hydrochloric acid. The resulting
yellowsolidmasswasfilteredanddriedtogetpurecompound.
The melting point was 243–246 °C (literature 248–50 °C).
4-Methylphenyl 2-(1-benzofuran-2-yl)quinoline-4-
carboxylate (2c)
1H-NMR (CDCl3, 400 MHz): 8.79 (s, 1H) 8.70–8.72 (d,
J = 8,1H),8.24–8.27(d,J = 12,1H),8.05(s, 1H),7.93–7.97
(t, 1H), 7.79–7.84 (t, 3H), 7.46–7.50 (m, 1H), 7.35–7.40 (m,
5H) 2.51 (s, 3H, CH3). 13C-NMR (CDCl3, 100.5 MHz):
164.47(1C), 156.82(1C), 155.2(1C), 149.24(1C), 148.4(1C),
147.8(1C), 138.72(1C), 135.6(1C), 135.2(1C), 134.54(1C),
130.48(1C), 130.10(1C), 129.01(2C), 128.17(1C), 127.50
(1C), 127.22(1C), 123.8(1C), 123.3(1C), 121.60(2C),
120.82(1C), 111.5(1C), 102.7(1C) and 24.52(1C). MS: m/z =
379(M?), 380 (M?1).
2-(Benzofuran-2-yl) quinoline-4-carboxylic acid (1)
IR (KBr) (v, cm-1), IR 3426.9 (OH), 1702.1 (C=O), 1599,
1510, 1246. 1H NMR (DMSO-d6, 400 MHz): 14.15 (s, 1H,
COOH), 8.70–8.72 (d, J = 8.4, 1H Ar–H), 8.48 (s, 1H
quinoline 3C–H), 8.18–8.20 (d, J = 8.4, 1H Ar–H),
8.014–8.018(d, J = 16, 1H, Ar–H),7.78–7.82(q, 2H, Ar–H),
7.72–7.77 (t, 1H, Ar–H), 7.45–7.49 (t, 1H,Ar–H), 7.34–7.38
(t, 1H, Ar–H). MS: m/z = 290.1 (M?1), 291.1 (M?2).
2-Chlorophenyl 2-(1-benzofuran-2-yl) quinoline-4-
carboxylate (2d)
General method for synthesis of compounds 2(a–j)
1H-NMR (CDCl3, 400 MHz): 8.85–8.87 (t, J = 8, 2H),
8.29–8.31 (d, J = 8, 1H), 7.82–7.86 (t, 1H), 7.67–7.73 (q, 1H),
7.79–7.84 (t, 4H), 7.39–7.45 (m, 3H), 7.30–7.35 (m, 2H). 13C-
NMR (CDCl3, 100.5 MHz): 164.17(1C), 155.82(1C), 155.2
(1C), 149.35(1C), 149.24(1C), 147.8(1C), 138.72(1C), 135.6
(1C), 134.54(1C), 131.44(1C), 130.48(1C), 130.10(1C), 129.
85(1C), 129.01(1C), 128.17(1C), 127.50(1C), 127.22(1C),
126.58(1C), 125.33(1C), 123.80(1C), 123.3(1C), 121.90(1C),
120.82(1C) and 102.7(1C) MS: m/z = 400.62 (M?1).
An equimolar mixture of 2-(1-benzofuran-2-yl)quinoline-4-
carboxylic acid 0.578 g (2 mmol) and various phenols were
taken in 10 ml of dichloromethane. To that 0.768 g (4 mmol)
of EDC.HCl and catalytic amount of dimethylaminopyridine
is added and the reaction mixture was stirred at room tem-
perature for about 10 h. After completion of the reaction, the
solvent was evaporated to dryness and the resulting product
quenched with water, filtered, dried, and recrystallized from
diethyl ether to furnish compounds 2(a–j).
Phenyl 2-(1-benzofuran-2-yl) quinoline-4-carboxylate (2a)
4-Chlorophenyl 2-(1-benzofuran-2-yl) quinoline-4-
carboxylate (2e)
1H-NMR (CDCl3, 400 MHz): 8.81 (s, 1H) 8.71–8.73 (d,
J = 8, 1H), 8.25–8.27 (d, J = 8, 1H), 8.03 (s, 1H), 7.93–7.97
(t, 1H), 7.79–7.84 (t, 3H), 7.46–7.50 (m, 5H), 7.35–7.41
(t, 2H). 13C-NMR (CDCl3, 100.5 MHz): 164.75(1C), 156.77
(1C), 156.2(1C), 150.57(1C), 149.39(1C), 138.67(1C), 134.
64(1C), 130.45(1C), 130.06(1C), 129.82(2C), 129.69(1C),
128.97(1C), 128.12(1C), 127.48(1C), 126.38(1C), 125.28
(1C), 124.09(1C), 123.3(1C), 123.56(1C), 122.34(1C), 121.
63(2C) and 120.84(1C) MS: m/z = 366.12 (M?1).
1H-NMR (CDCl3, 400 MHz): 8.87–8.90 (t, J = 12, 2H),
8.29–8.31 (d, J = 8, 1H), 7.82–7.86 (t, 1H), 7.67–7.73 (q, 1H),
7.79–7.84 (t, 4H), 7.39–7.45 (m, 3H), 7.30–7.35 (m, 2H). 13C-
NMR (CDCl3, 100.5 MHz): 164.80(1C), 156.82(1C), 155.2
(1C), 149.24(1C), 148.4(1C), 147.8(1C), 138.72(1C), 135.6
(1C), 135.2(1C), 134.54(1C), 131.48(1C), 130.10(1C),
129.02(2C), 128.17(1C), 127.50(1C), 127.22(1C), 123.8(1C),
123.2(1C), 123. 01(2C), 120.82(1C), 111.5(1C) and 102.7(1C)
MS: m/z = 399.04 (M?), 400.65 (M?1).
2-Methylphenyl 2-(1-benzofuran-2-yl)quinoline-4-
carboxylate (2b)
2,4-Dichlorophenyl 2-(1-benzofuran-2-yl)quinoline-4-
carboxylate (2f)
1H-NMR (CDCl3, 400 MHz): 8.79 (s, 1H) 8.70–8.72 (d,
J = 8, 1H), 8.25–8.27 (d, J = 8, 1H), 8.05 (s, 1H), 7.93–7.96
(t, 1H), 7.78–7.83 (t, 3H), 7.46–7.50 (m, 1H), 7.35–7.40
1H-NMR (CDCl3, 400 MHz: 8.84–8.87 (t, J = 12, 2H),
8.29–8.31 (d, J = 8, 1H), 7.82–7.87 (t, 1H), 7.67–7.74
123

Med Chem Res
(q, 4H), 7.60 (s, 1H), 7.40–7.43 (m, 2H) 7.27–7.34 (m, 2H).
13C-NMR (CDCl3, 100.5 MHz): 164.32, 157.45, 149.59,
149.22, 138.12, 134.79, 131.48, 131.33, 130.29, 129.12,
129.61, 128.82, 126.54, 126.34, 125.78, 124.58, 122.43 and
121.19. MS: m/z = 434.17 (M?), 435.12 (M?1).
(t, 3H) 7.40–7.43 (t, 1H) 7.27–7.34 (q, 1H). 13C-NMR
(CDCl3, 100.5 MHz): 165.10(1C), 156.82(1C), 155.2(1C),
150.24(1C), 148.4 (1C), 147.8(1C), 138.72(1C), 135.6(1C),
135.2(1C), 134.7(1C), 133.48(1C), 132.7(1C) 130.10(1C),
129.8(1C), 129.1 (1C), 127.50(1C), 127.22(1C), 126.7(1C),
126.32(2C), 125.1(1C), 123.8(1C), 123.2(1C), 121.7(1C),
121.1(1C), 117.5(1C),111.5(1C), 109.5(1C) and 102.7(1C)
MS: m/z = 416.10 (M?1).
2,4,6-Trichlorophenyl 2-(1-benzofuran-2-yl)quinoline-4-
carboxylate (2g)
1H-NMR (CDCl3, 400 MHz: 8.85–8.87 (t, J = 8, 2H),
8.30–8.32 (d, J = 8,1H), 7.82–7.87 (t, 1H),7.67–7.74(q, 4H),
7.60 (s, 1H), 7.40–7.44 (m, 1H) 7.27–7.34 (m, 2H). 13C-NMR
(CDCl3, 100.5 MHz): 164.80(1C), 156.82(1C), 155.2(1C),
150.24(1C), 148.4(1C), 147.8(1C), 138.72(1C), 135.6(1C),
135.2(1C), 134.54(1C), 133.48(1C), 132.7(2) 130.10(1C),
128.8(2C) 128.17(1C), 127.50(1C), 127.22(1C), 123.8(1C),
123.2(1C), 123. 01(1C), 111.5(1C) and 102.7(1C) MS:
m/z = 471.34 (M?2).
[2-(1-Benzofuran-2-yl) quinolin-4-yl](piperidin-1-yl)
methanone (3a)
1H-NMR (CDCl3, 400 MHz): 8.16–8.18 (d, J = 8, 1H),
8.10 (s, 1H), 7.94 (s, 1H), 7.86–7.90 (q, 1H), 7.78–7.82
(q, 3H), 7.68–7.72 (t, 1H), 7.44–7.50 (q, 1H), 7.33–7.37
(t, 1H), 3.84–3.88 (m, 1H), 3.71–3.76 (m, 1H), 3.13–3.16
(t, 2H), 1.65–1.71 (m, 4H), 1.44–1.48 (q, 1H), 1.32–1.37
(q, J = 20, 1H). 13C-NMR (CDCl3, 100.5 MHz): 172.31(1C),
156.86(1C), 155.23(1C), 149.92(1C), 146.8(1C), 146.4(1C),
130.42(1C), 129.21(1C), 128.4(1C), 128.0(1C) 124.7(1C),
123.84(1C), 123.32(1C), 121.72(1C), 120.76(1C), 117.4(1C),
111.58(1C), 102.711(1C), 35.1(2C), 25.73 (2C), and
24.5(1C) MS: m/z = 357.41 (M?1).
4-Bromophenyl 2-(1-benzofuran-2-yl) quinoline-4-
carboxylate (2h)
1H-NMR (CDCl3, 400 MHz): 8.85–8.89 (t, 2H), 8.28–8.31
(d, J = 12, 1H), 7.82–7.86 (t, 1H), 7.67–7.73 (q, 1H),
7.79–7.84 (t, 4H), 7.39–7.45 (m, 3H), 7.30–7.35 (m, 2H).
13C-NMR (CDCl3, 100.5 MHz): 164.80(1C), 156.82(1C),
155.2(1C), 150.24(1C), 148.4(1C), 147.8(1C), 138.72(1C),
135.6(1C), 135.2(1C), 134.54(1C), 131.48(2C), 130.10
(1C), 129.02(1C), 128.17(1C), 127.50(1C), 127.22(1C),
123.8(1C), 123.2(1C), 123.01(2C), 119.82(1C), 111.5(1C)
and 102.7(1C) MS: m/z = 445.01 (M?1).
[2-(1-Benzofuran-2-yl) quinolin-4-yl](morpholin-4-yl)
methanone (3b)
1H-NMR (CDCl3, 400 MHz): 8.76 (s, 1H) 8.14–8.17 (q,
2H), 7.81–7.83 (d, J = 8, 1H), 7.75–7.79 (m, 1H),
7.78–7.81 (d, J = 12, 1H), 7.58–7.61 (q, 1H), 7.55–7.56
(d, J = 4, 1H), 7.50–7.54 (m, 1H), 6.46–6.49 (q, 1H),
3.85–3.91(m, 4H), 3.19–3.26 (m, 4H). 13C-NMR (CDCl3,
100.5 MHz): 168.9(1C), 156.8 (1C), 155. 32 (1C), 149.92
(1C), 146.8(1C), 146.4(1C), 130.42(1C), 129.21(1C),
128.4(1C), 128.0(1C), 124.7(1C), 123.84(1C), 123.32(1C),
121.72(1C), 120.76(1C), 117.54(1C), 111.58(1C), 102.711
(1C), 65.8(2C), and 46.1(2C), MS: m/z = 359 (M?1).
Naphthalen-1-yl 2-(1-benzofuran-2-yl) quinoline-4-
carboxylate (2i)
1H-NMR (CDCl3, 400 MHz: 8.90–8.92 (d, J = 8, 1H),
8.84 (s, 1H), 8.30–8.32 (d, J = 8, 1H), 7.99–8.01 (d, J =
8, 1H),7.84–7.92 (q, 4H), 7.67–7.75 (q, 4H), 7.49–7.56 (t,
3H) 7.40–7.43 (t, 1H) 7.27–7.34 (q, 1H). 13C-NMR (CDCl3,
100.5 MHz): 165.10(1C), 156.82(1C), 155.2(1C), 150.
24(1C), 148.4(1C), 147.8(1C), 138.72(1C), 135.6(1C),
135.2(1C), 134.7(1C), 133.48(1C), 132.7(1C) 130.10(1C),
[2-(1-Benzofuran-2-yl) quinolin-4-yl](2-methyl-1H-
imidazol-1-yl) methanone (3c)
1H-NMR (CDCl3, 400 MHz): 8.74 (s, 1H), 8.27–8.29 (d,
J = 12, 1H) 8.16–8.20 (q, 2H), 7.97 (s, 1H), 7.82–7.84 (m,
1H), 7.78–7.81 (d, J = 12, 1H), 7.59–7.62 (d, J = 12, 1H),
7.56–7.58 (q, 1H), 7.54–7.55 (m, 2H), 6.80–6.85 (q, 2H),
2.83 (s, 1H, –CH3). 13C-NMR (CDCl3, 100.5 MHz):
167.82(1C), 158.6(1C), 155.3(1C), 149.92(1C), 146.8(1C),
146.4(1C), 135.2(1C), 132.4(1C), 130.42(1C), 129.21(1C),
128.4(1C), 128.0(1C), 124.7(1C), 123.84(1C), 123.32(1C),
121.72(1C), 120.76(1C), 117.4(1C), 115.6(1C), 111.5(1C),
108.3, 106.6, 102.7(1C), and 17.4(1C) MS: m/z = 354.31
(M?1).
128.8(2C)
128.17(1C),
127.50(1C),
127.22(1C),
126.32(2C), 125.1(1C), 123.8(1C), 123.2(1C), 123.01(1C),
121.7(1C), 121.1(1C), 111.5(1C), 109.5(1C) and 102.7
(1C) MS: m/z = 416.10 (M?1).
Naphthalen-2-yl 2-(1-benzofuran-2-yl) quinoline-4-
carboxylate (2j)
1H-NMR (CDCl3, 400 MHz: 8.89–8.92 (d, J = 12, 1H),
8.86 (s, 1H), 8.30–8.32 (d, J = 8, 1H), 7.99–8.01 (d, J =
8, 1H), 7.86–7.92 (q, 4H), 7.67–7.75 (q, 4H), 7.49–7.56
123

Med Chem Res
Antioxidant activity
Antibacterial activity
Chelating effects on ferrous ions
The bacterial strains were obtained from the laboratory
stock culture from the Department of biochemistry Gul-
barga University, Gulbarga. All synthesized compounds
were dissolved in dimethyl formamide (DMF) to prepare
chemicals stock solution at the concentration of 1 mg/mL.
The antibacterial activity was carried out by agar-well
diffusion method which is a simple susceptibility screening
method. Each microorganism was suspended in nutrient
broth and diluted approximately colony forming unit (cfu)/
mL. They were ‘‘flood-inoculated’’ onto the surface of
nutrient agar and then dried. Five millimeter diameter wells
were cut from the agar using a sterile cork-borer; 100 lL of
the test compound solution were delivered into the wells.
The plates were incubated for 24 h at 35 °C. Antibacterial
activity was evaluated by measuring the zone of inhibition
against the test organism. Ampicillin was used as standard
drug and dimethyl formamide is used as solvent control.
The chelating effect was determined according to the
method of Decker and welch (1990), (Nevcihan et al.,
2010). In brief, 2 mL of different concentrations (0.5–
2.0 mg/mL) of the compound in methanol was added to a
solution of 2 mM FeCl2 (0.05 mL). The reaction was ini-
tiated by the addition of 5 mM ferrozine (0.2 mL) and total
volume was adjusted to 5 mL with methanol. Then, the
mixture was shaken vigrously and left at room temperature
for 10 min. Absorbance of the solution was measured
spectrophotometrically at 562 nm. The inhibition percent-
age of ferrozine-Fe?2 complex formation was calculated
using the formula given below.
ÂÀ
Á
Ã
Metal chelating effect ð%Þ ¼ Acontrol ꢂ Asample = Acontrol
ꢃ 100
where Acontrol is the absorbance of control (the control
contains FeCl2 ferrozine complex formation molecules)
and Asample is the absorbance of test compound. Ascorbic
acid is used as control.
Determination of the MICs
MIC was determined by micro-broth dilution technique
using nutrient broth. Serial twofold dilutions ranging from
1,000 to 0.031 mg/mL were prepared in media. The inoc-
ulum was prepared using a 4–6 h old broth culture of each
bacterium and diluted in broth media to give a final con-
centration of 5 9 105 cfu/mL of bacteria in the test tray.
The trays were covered and placed in plastic bags to pre-
vent evaporation and are incubated at 35 °C for 18–20 h.
The MIC was defined as the lowest concentration of the
compound giving complete inhibition of visible growth.
Scavenging effect on DPPH
The hydrogen atoms or electrons donation ability of the
corresponding test compounds and standard compound
were measured from the bleaching of purple colored
methanol solution of DPPH. The effect of methanolic
solution of the test compounds on DPPH radical was
estimated according to Kerby and Schimdt (1997). In brief,
0.004 % DPPH radical solution in methanol was prapared
and then 4 mL of this solution was mixed with 1 mL of
various concentrations (1 mg/mL) of the test compounds in
methanol. Finally, the samples were incubated for 30 min
in dark at room temperature and scavenging capacity was
read spectrophotometrically by monitoring the decrease in
absorbance at 517 nm. Inhibition of free radical DPPH in
percent (1 %) was calculated in following way.
Acknowledgments The authors are thankful to IISc Bangalore for
providing spectral data. One of the authors (Sheelavanth S) is thankful
to DST-Govt. of India, for awarding Inspire fellowship.
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