Synthesis, characterization and antimicrobial studies of some new quinoline incorporated benzimidazole derivatives

Article abstract of DOI:10.1016/j.ejmech.2012.05.027

Two new series of quinoline incorporated benzimidazole derivatives (4a-i and 8a-f) were synthesized from substituted aniline and isatin through multi-step reaction. 6-substituted-4-carboxyquinolines (3a,b and 7) were synthesized by multi component one pot

Full text of DOI:10.1016/j.ejmech.2012.05.027

European Journal of Medicinal Chemistry 54 (2012) 900e906
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, characterization and antimicrobial studies of some new quinoline
incorporated benzimidazole derivatives
B. Garudachari a, M.N. Satyanarayana b, B. Thippeswamy c, C.K. Shivakumar c, K.N. Shivananda d,
,
Gurumurthy Hegde e, Arun M. Isloor a
*
a Medicinal Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Mangalore 575 025, India
b Department of Physics, National Institute of Technology Karnataka, Surathkal, Mangalore 575 025, India
c Department of P.G. Studies and Research in Microbiology, Jnanasahyadri, Kuvempu University, Shankaraghatta 577 451, India
d Schulich Faculty of Chemistry, Technion Israel Institute of Technology, Haifa, Israel
e Faculty of Industrial Science and Technology, Universiti Malaysia Pahang, LebuhrayaTunRazak, 26300, Gambang, Kuantan, Paghang Darul Makmur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new series of quinoline incorporated benzimidazole derivatives (4aei and 8aef) were synthesized
from substituted aniline and isatin through multi-step reaction. 6-substituted-4-carboxyquinolines (3a,b
and 7) were synthesized by multi component one pot reactions (via Doebner reaction and Pfitzinger
reaction respectively) and the targeted benzimidazole derivatives were obtained by the reaction of 6-
substituted-4-carboxyquinolines (3a,b and 7) with substituted aromatic diamines in acidic media. All
the newly synthesized compounds were characterized by IR, NMR mass spectral study and also by C, H, N
analyses. The final compounds were screened for their in-vitro antibacterial and antifungal activity by
well plate method (zone of inhibition). The results revealed that, compounds 4c, 4d, 8c and 8d showed
significant antibacterial activity. The compound 8b was found to be potent antifungal agent. 4a, 8a and 8f
showed moderate to good antimicrobial activity as compared to the standard drugs against all tested
microbial strains.
Received 20 October 2011
Received in revised form
17 May 2012
Accepted 22 May 2012
Available online 1 June 2012
Keywords:
Benzimidoquinolines
Antibacterial studies
Antifungal studies
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
anti-inflammatory [9,10], antimicrobial and antiviral [11e13]
agents. The fused heterocyclic rings which include Saquinavir
In recent years, the mounting threat of bacterial resistance has
heightened the urgency to discover and develop anti-ineffective
agents with novel mechanism of action and enhanced activity
profile. Clinical use of potent drugs is limited in many cases due to
their systemic side effects. To overcome the clinical limitation,
considerable research efforts have been directed to the discovery of
high potency local antimicrobial agents with reduced or without
systemic adverse effects.
The development of potent and effective antimicrobial agent is
most important to overcome the emerging multi-drug resistance
strains of bacteria and fungi such as Methicillin resistant Staphy-
lococcus aureus (MRSA) [1,2]. The heterocyclic compounds play an
important role in developing new antimicrobial, anticancer, anti-
malarial, anticonvulsant agents. Recent observations suggested
that, quinolines and substituted benzimidazoles have wide range of
applications in the field of pharmaceuticals as antimalarial [3,4],
anti-tuberculosis [5], antitumour [6,7], anticancer [8], analgesic,
(antiviral), Aripiprazole (antipsychotic), are some of drugs which
contain quinoline as a core moiety (Figs. 1 and 2).
Azole class of drugs particularly fused imidazoles occupy
prominent place in medicinal chemistry because of their broad
spectrum of pharmacological activities such as anti-inflammatory,
analgesic, anticancer, antiulcer, antimicrobial, antiviral, pesticidal,
cytotoxicity and anti-arrhythmic [14e17] activities. Omeprazole,
Mebendazole, Pimobendan and Albendazole are well-known drugs
in the market which contain fused imidazoles as active core moiety.
Literature review revealed that, insertion of pharmacophore at
position 4 of quinoline with substituted amines enhances its anti-
tuberculosis, antimicrobial activity [18]. Substituted quinolines at
2 and 3 positions with various benzimidazole derivatives showed
excellent pharmacological properties like antimicrobial, antifungal
and antitumour activities [19,20]. Prompted by these observations
and in continuation of our research on biologically active hetero-
cycles [21e24], we hereby report the synthesis of some new
benzimidazole derivatives containing substituted quinoline
nucleus. These compounds were evaluated for their antimicrobial
properties.
* Corresponding author. Tel.: þ91 824 2474000; fax: þ91 824 2474033.
E-mail address: isloor@yahoo.com (A.M. Isloor).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.05.027

B. Garudachari et al. / European Journal of Medicinal Chemistry 54 (2012) 900e906
901
pathway has been summarized in Schemes 1 and 2. Newly
synthesized compounds were characterized by IR, NMR, mass
spectral and C, H, N elemental analyses.
Formation of 6-substituted-4-carboxyquinolines (3a, b and 7)
was confirmed by recording their IR, 1H NMR, 13C NMR and mass
spectra. The formation of quinoline acid (3a) was confirmed by the
peak at 3330 cmꢀ1 in IR spectrum which is due to the eOH
stretching of carboxylic acid. Band at 1718 cmꢀ1 is due to C]O
stretch of acid group. The 1H NMR spectrum of 3a showed a singlet
N
Cl
N
O
Cl
N
H
O
Fig. 1. Structure of Aripiprazole (antipsychotic).
at
d
d
13.77 corresponds to acid eOH proton of quinoline. A singlet at
8.49 is due to quinoline-3H proton, 4-fluorophenyl aromatic
7.02e8.25 further confirmed the
protons appeared as multiplet at
d
structure of the compound. The mass spectrum of 3a showed
molecular ion peak at m/z ¼ 302 (M þ 1), which is in agreement
with the molecular formula C16H9ClFNO2.
Formation of 4-(1H-benzimidazol-2-yl)-6-chloro-2-(4-fluoro-
phenyl)quinoline (4a) was confirmed by the presence of absorp-
tion peak at 3356 cmꢀ1 in IR spectrum which is due to eNH
stretching of benzimidazole. Band at 1621 and 1597 is due to C]N
and C]C of benzimidazole respectively. The 1H NMR spectrum of
Fig. 2. Structure of Saquinavir (antiviral).
compound 4a showed broad singlet at
which is due to benzimidazole eNH. Singlet at
quinoline-3H, multiplet at 7.66e7.77 is due to aromatic protons of
benzimidazole ring and multiplet at 7.28e7.47 is due to protons of
d
13.35 (D2O exchangeable)
d
8.67 is due to
2. Results and discussion
d
d
2.1. Chemistry
4-fluorophenyl moiety conformed the structure. The mass spectrum
of 4a showed molecular ion peak at m/z ¼ 374 (M þ 1), which is in
agreement with the molecular formula C22H13ClN3. Similarly the
spectral values for all the compounds and C, H, N analyses are pre-
sented in the experimental part and the characterization data are
provided in Table 1.
6-Substituted-4-carboxyquinolines (3a, b) were synthesized by
Doebner reaction using substituted aniline (1), 4-
fluorobenzaldehyde (2), pyruvic acid and catalytic amount of tri-
fluoroacetic acid in ethanol media. The versatile Pfitzinger reaction
was utilized to synthesize 4-carboxyquinoline (7) in satisfactory
yields by reacting isatin (5) with a-methylketone (6) in aqueous
ethanol [25e27]. The targeted quinoline incorporated benzimid-
azole derivatives (4aei and 8aef) were synthesized by reacting 6-
2.2. Antimicrobial studies
substituted-4-carboxyquinolines (3a,
b and 7) with various
2.2.1. Antibacterial studies
aromatic-1,2-diamines in polyphosphoric acid media. The crude
products were purified by column chromatography. The reaction
The newly synthesized compounds (4aei and 8aef) were
screened for their in-vitro antibacterial activity against S. aureus,
R2
X
R1
O
OH
O
R
R
N
NH
pyruvic acid
Ethanol, TFA
Aromatic-1,2-diamine
+
NH2
F
R
N
PPA
F
1
2
3a,b
N
F
4a-i
Where R= H, Cl, F; R1= Cl, F; R2= H, Cl; X= CH, N
Scheme 1. Synthetic route for the compounds 4aei.
R2
R1
O
OH
X
O
O
N
NH
33% KOH
Ethanol
Aromatic-1,2-diamine
PPA
O
+
N
F
N
H
F
5
6
N
7
F
8a-f
Scheme 2. Synthetic route for the compounds 8aef.

902
B. Garudachari et al. / European Journal of Medicinal Chemistry 54 (2012) 900e906
Table 1
Characterization data of the compounds 4aei and 8aef.
Comp. No
R
R1
R2
X
Mol. Wt
Mol. Formula
22H13ClN3
C22H12Cl2FN3
C21H12ClFN4
C22H11Cl3FN3
C22H13F2N3
M.p. (ꢁC)
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
8a
8b
8c
8d
8e
8f
Cl
Cl
Cl
Cl
F
F
F
F
F
H
H
H
H
H
H
H
Cl
H
Cl
H
Cl
H
Cl
F
H
Cl
H
Cl
F
H
H
H
Cl
H
H
H
Cl
H
H
H
H
Cl
H
H
H
H
N
H
H
H
N
H
H
H
H
N
H
H
H
373.82
408.26
374.80
442.70
373.81
391.80
358.34
426.25
375.35
339.38
408.26
340.35
408.26
357.36
369.39
C
241e241
197e198
266e267
165e166
218e219
139e139
132e133
108e109
97e98
164e165
234e235
128e129
205e206
77e78
60
50
58
40
54
52
51
42
40
78
65
68
57
55
25
C22H12ClF3N3
C21H12F2N4
C22H11Cl2F2N3
C22H12F3N3
C22H14FN2
C22H13ClFN3
C21H13FN4
C22H12Cl2FN3
C
22H13ClF2N3
OMe
C23H16FN3O
74e75
Escherichia coli, Xanthomonas sp. and Salmonella sp. (recultured)
using Ciprofloxacin as standard by well plate method (zone of
inhibition) [28,29]. The test compounds were dissolved in dime-
Aspergillus terreus and Penicillium sp. (recultured) were used to
investigate the activity. The test compounds were dissolved in
dimethylsulfoxide (DMSO) at concentrations of 6.25 and 12.5
mL.
mg/
thylsulfoxide (DMSO) at concentrations of 6.25 and 12.5 mg/mL.
The antibacterial screening revealed that, few of the tested
compounds showed good inhibition against various tested micro-
bial strains compared to the standard drug. Among the synthesized
compounds, 4c and 8d showed significant antibacterial activity
against E. coli and S. aureus. Compound 8c is found to be more
potent against S. aureus. Compounds 4d and 8d exhibited excellent
antibacterial activity against Salmonella and Xanthomonas sp.
respectively. Remaining compounds showed moderately good
antibacterial activity against all the tested bacterial strains than
compared to standard drug Ciprofloxacin. Compounds 4c and 8c
contain fused pyridine ring in benzimidazole moiety and a 4-
fluorophenyl group on second position of quinoline ring which
has accounted for the enhanced activity. Compounds 4d and 8d
contain two chlorine atoms on benzimidazole ring and 4-
fluorophenyl group on second position of quinoline ring which
are responsible for the moderately good inhibition. Results of
antibacterial studies have been presented in Table 2.
The result indicated that, among the tested compounds, 8b
showed significant antifungal activity against A. niger and A. flavus
compared to standard drug Flucanazole. Compounds 4a, 8a and 8f
were active against A. terreus and Penicillium sp. fungal strains
respectively. The enhanced activity of the compound 8b may be due
to the presence of a chlorine atom on benzimidazole ring and 4-
fluorophenyl group on second position of quinoline ring. All other
compounds showed less inhibition against all the tested micro
organisms as compared to the standard drug. Table 3 depicts the
antifungal screening results of the final compounds.
3. Conclusion
Two new series of quinoline incorporated benzimidazole
derivatives (4aei and 8aef) were synthesized, characterized by IR,
NMR, mass spectra and C, H, N analyses. Final compounds were
investigated for their in-vitro antimicrobial and antifungal activities
by well plate method. Among the screened samples, 4c, 4d, 8c and
8d showed excellent inhibition of bacterial growth. Compound 8b
showed significant inhibition of fungal strain as compared with
standard drug Fluconazole.
2.2.2. Antifungal studies
The in-vitro antifungal activities of newly synthesized
compounds (4aei and 8aef) were determined by well plate
method [30,31]. In this work Aspergillus niger, Aspergillus flavus,
Table 2
Antibacterial activity of the compounds 4aei and 8aef.
Zone of inhibition in mm (mean ꢂ S.D.) n ¼ 3
Compound No.
Staphylococcus aureus
Escherichia coli
Xanthomonas sp
Salmonella sp
Concn. ( g/mL)
m
6.25
12.5
6.25
12.5
6.25
12.5
6.25
12.5
Standard Ciprofloxacin
Control
4a
4b
4c
4d
4e
18 ꢂ 0.87
20 ꢂ 0.50
19 ꢂ 1.00
21 ꢂ 0.50
18 ꢂ 0.50
22 ꢂ 0.50
19 ꢂ 0.50
31 ꢂ 0.50
00
00
00
00
00
00
00
00
12 ꢂ 0.50
16 ꢂ 1.00
14 ꢂ 0.50
10 ꢂ 0.50
14 ꢂ 1.00
12 ꢂ 0.50
12 ꢂ 0.50
14 ꢂ 0.50
12 ꢂ 0.50
12 ꢂ 1.00
12 ꢂ 1.00
16 ꢂ 1.00
12 ꢂ 0.50
10 ꢂ 1.00
12 ꢂ 0.50
13 ꢂ 1.00
16 ꢂ 0.50
18 ꢂ 1.00
12 ꢂ 0.50
15 ꢂ 0.50
12 ꢂ 0.50
12 ꢂ 1.00
15 ꢂ 0.50
12 ꢂ 0.50
13 ꢂ 1.00
13 ꢂ 0.50
16 ꢂ 1.00
16 ꢂ 0.50
16 ꢂ 0.50
12 ꢂ 0.50
01 ꢂ 0.50
12 ꢂ 0.50
16 ꢂ 0.50
12 ꢂ 0.50
10 ꢂ 0.50
10 ꢂ 0.50
01 ꢂ 0.50
01 ꢂ 0.50
16 ꢂ 0.50
11 ꢂ 1.00
01 ꢂ 0.50
14 ꢂ 0.50
12 ꢂ 0.50
10 ꢂ 0.50
12 ꢂ 0.50
13 ꢂ 0.50
12 ꢂ 0.50
16 ꢂ 0.50
17 ꢂ 0.50
15 ꢂ 0.50
11 ꢂ 0.50
13 ꢂ 0.50
12 ꢂ 0.50
16 ꢂ 0.50
16 ꢂ 0.50
16 ꢂ 0.87
14 ꢂ 0.50
16 ꢂ 0.50
11 ꢂ 0.50
14 ꢂ 0.87
01 ꢂ 0.50
01 ꢂ 0.50
15 ꢂ 1.00
14 ꢂ 0.50
14 ꢂ 0.50
11 ꢂ 0.50
15 ꢂ 0.50
12 ꢂ 0.50
01 ꢂ 0.50
11 ꢂ 0.50
15 ꢂ 0.50
10 ꢂ 0.50
20 ꢂ 1.00
01 ꢂ 0.50
12 ꢂ 0.50
10 ꢂ 0.50
10 ꢂ 0.50
16 ꢂ 0.50
16 ꢂ 0.50
14 ꢂ 0.50
12 ꢂ 0.50
16 ꢂ 0.50
16 ꢂ 0.50
14 ꢂ 0.50
12 ꢂ 0.50
15 ꢂ 0.50
14 ꢂ 0.50
22 ꢂ 0.50
13 ꢂ 0.50
14 ꢂ 0.50
01 ꢂ 0.50
10 ꢂ 0.50
9 ꢂ 0.50
20 ꢂ 0.50
15 ꢂ 0.50
01 ꢂ 0.50
13 ꢂ 0.50
9 ꢂ 0.50
9 ꢂ 0.50
9 ꢂ 0.50
9 ꢂ 0.50
9 ꢂ 0.50
11 ꢂ 0.50
10 ꢂ 0.50
10 ꢂ 1.00
9 ꢂ 0.50
13 ꢂ 0.50
20 ꢂ 0.50
28 ꢂ 0.50
15 ꢂ 0.50
11 ꢂ 0.50
13 ꢂ 0.50
12 ꢂ 0.50
13 ꢂ 0.50
15 ꢂ 0.50
17 ꢂ 0.50
12 ꢂ 0.50
12 ꢂ 0.50
11 ꢂ 0.50
11 ꢂ 0.50
4f
4g
4h
4i
8a
8b
8c
8d
8e
8f

B. Garudachari et al. / European Journal of Medicinal Chemistry 54 (2012) 900e906
903
Table 3
Antifungal activity of the compounds 4aei and 8aef.
Zone of inhibition in mm (mean ꢂ S.D.) n ¼ 3
Compound No.
Concn. ( g/mL)
Aspergillus niger
Aspergillus flavus
Penicillium sp.
Aspergillus terreus
m
6.25
12.5
6.25
12.5
6.25
12.5
6.25
12.5
Standard Flucanazole
Control
4a
4b
4c
4d
4e
14 ꢂ 0.50
18 ꢂ 1.00
15 ꢂ 0.50
20 ꢂ 0.50
19 ꢂ 0.50
21 ꢂ 0.50
16 ꢂ 0.50
18 ꢂ 0.50
00
00
00
00
00
00
00
00
10 ꢂ 1.00
01 ꢂ 1.00
12 ꢂ 0.50
12 ꢂ 1.00
10 ꢂ 0.50
01 ꢂ 0.50
11 ꢂ 1.00
10 ꢂ 1.00
10 ꢂ 0.50
11 ꢂ 1.00
15 ꢂ 1.00
14 ꢂ 1.00
10 ꢂ 0.50
01 ꢂ 0.50
10 ꢂ 1.00
12 ꢂ 0.50
10 ꢂ 0.50
14 ꢂ 0.50
12 ꢂ 1.00
12 ꢂ 1.00
10 ꢂ 0.50
13 ꢂ 0.50
13 ꢂ 0.50
17 ꢂ 0.50
12 ꢂ 1.00
18 ꢂ 1.00
16 ꢂ 1.00
12 ꢂ 0.50
14 ꢂ 1.00
12 ꢂ 0.50
01 ꢂ 0.50
01 ꢂ 0.50
01 ꢂ 0.50
13 ꢂ 0.50
01 ꢂ 0.50
01 ꢂ 0.50
11 ꢂ 0.50
12 ꢂ 1.00
01 ꢂ 0.50
11 ꢂ 1.00
11 ꢂ 0.50
01 ꢂ 0.50
10 ꢂ 1.00
01 ꢂ 0.50
01 ꢂ 0.50
01 ꢂ 0.50
17 ꢂ 1.00
10 ꢂ 0.50
13 ꢂ 0.50
10 ꢂ 0.50
10 ꢂ 0.50
14 ꢂ 0.50
15 ꢂ 0.50
01 ꢂ 0.50
12 ꢂ 0.50
16 ꢂ 0.50
11 ꢂ 0.50
10 ꢂ 0.50
14 ꢂ 0.50
10 ꢂ 1.00
16 ꢂ 0.50
12 ꢂ 1.00
01 ꢂ 0.50
12 ꢂ 0.50
12 ꢂ 0.50
15 ꢂ 1.00
14 ꢂ 0.87
01 ꢂ 1.00
13 ꢂ 0.50
15 ꢂ 0.87
12 ꢂ 0.50
16 ꢂ 0.50
12 ꢂ 0.50
12 ꢂ 0.50
16 ꢂ 0.50
18 ꢂ 0.50
17 ꢂ 0.50
13 ꢂ 1.00
19 ꢂ 0.50
12 ꢂ 1.00
17 ꢂ 0.50
15 ꢂ 0.50
12 ꢂ 0.50
13 ꢂ 1.00
17 ꢂ 0.50
12 ꢂ 0.50
17 ꢂ 0.50
12 ꢂ 1.00
15 ꢂ 0.50
18 ꢂ 1.00
13 ꢂ 0.50
9 ꢂ 0.50
9 ꢂ 0.50
9 ꢂ 0.50
9 ꢂ 0.50
10 ꢂ 0.87
10 ꢂ 0.50
01 ꢂ 0.50
10 ꢂ 0.50
12 ꢂ 0.50
10 ꢂ 0.87
9 ꢂ 0.50
10 ꢂ 0.50
12 ꢂ 0.50
12 ꢂ 0.50
14 ꢂ 0.50
9 ꢂ 1.00
15 ꢂ 0.50
10 ꢂ 0.50
9 ꢂ 1.00
14 ꢂ 0.50
15 ꢂ 0.50
09 ꢂ 0.50
9 ꢂ 0.50
14 ꢂ 0.50
16 ꢂ 1.00
10 ꢂ 0.50
11 ꢂ 0.50
12 ꢂ 0.50
13 ꢂ 0.50
4f
4g
4h
4i
8a
8b
8c
8d
8e
8f
The enhanced antibacterial activity of compounds 4c, 8c is due
to the presence of fused pyridine ring in benzimidazole moiety as
well as 4-fluorophenyl group on second position of quinoline ring.
The presence of two chlorine atoms on benzimidazole ring along
with 4-fluorophenyl group on second position of quinoline ring is
the reason for enhanced activity of 4d and 8d. The compound 8b
contains a chlorine atom on benzimidazole ring and 4-fluorophenyl
group on second position of quinoline which is responsible for the
enhanced antifungal activity.
trifluoroacetic acid (1 mL) were then added to the reaction mass
and further refluxed for 12 h. After completion of the reaction, the
reaction mixture was poured into ice-cold water. The solid product
obtained was filtered, washed with water and recrystallized using
ethanol.
4.2.1. 6-Chloro-2-(4-fluorophenyl)quinoline-4-carboxylic acid (3a)
Yield: 15.20 g, 64.4%; M.p: 210e211 ꢁC; IR (KBr nmax cmꢀ1):
3384 (OeH-str), 3062, 2983 (CeH-str), 1718 (C]O); 1H NMR
As regards the relationships between the structure of the
heterocyclic scaffold and the detected antimicrobial properties, it
showed varied pharmacological activity. Probably in this case the
nature of the heterocyclic ring is not so important for antimicrobial
activity. Moreover, the presence of different substituents causes
a certain change of activity. It can be concluded that the combi-
nation of two different heterocyclic moieties namely quinoline and
benzimidazole has enhanced the biological activity and hence they
are ideally suited for father notifications to obtain more efficient
antimicrobial compounds.
(400 MHz, DMSO-d6): d 6.98e7.25 (m, 4H, 4-fluorophenyl), 8.49
(d, J ¼ 8.2 Hz, 2H, quinoline), 8.53 (s, 1H, quinoline), 8.74 (m, 1H,
quinoline), 14.77 (s, 1H, COOH); MS: m/z ¼ 302 (M þ 1); Anal.
calcd. For C16H9ClFNO2: C, 67.70; H, 3.01; N, 4.64. Found: C, 67.68;
H, 3.00; N, 4.67%.
4.2.2. 6-Fluoro-2-(4-fluorophenyl)quinoline-4-carboxylic acid (3b)
Yield: 9.5 g, 36.8%; M.p: 187e188 ꢁC; IR (KBr nmax cmꢀ1): 3400
(OeH-str), 3068, 2981 (CeH-str), 1681 (C]O); 1H NMR (400 MHz,
DMSO-d6): d6.90e8.18 (m, 4H, 4-fluorophenyl), 8.49e8.53 (m, 2H,
quinoline), 8.54 (s, 1H, quinoline), 8.54 (m, 1H, quinoline), 14.10 (s,
1H, COOH); MS: m/z ¼ 385; Anal. calcd. For C16H9F2NO2: C, 67.37; H,
3.18; N, 4.91. Found: C, 67.70; H, 3.16; N, 4.68%.
4. Experimental
4.1. Chemistry
All the chemicals were purchased from Sigma Aldrich, Merck and
S. D. Fine chemicals-India. Commercial grade solvents were used and
were distilled before use. Melting points were determined by open
capillarymethodandwereuncorrected. TheIRspectra(inKBrpellets)
were recorded on a JASCO FT/IR-4100 spectrophotometer and Bruker
(400 MHz) spectrometer was used to record 1H NMR and 13C NMR
spectra (DMSO-d6) using TMS as internal standard. Chemical shift
4.3. Preparation of 2-(4-fluorophenyl)quinoline-4-carboxylic acid (7)
A mixture of isatin (5) (10.0 g, 0.067 mol), 100 mL 33% alcoholic
potassium hydroxide solution and 4-fluoroacetophenone (6)
(10.32 g, 0.074 mol) were refluxed for 48 h. After completion of
reaction, the reaction mass was concentrated by distillation and the
residue obtained was acidified with 15% acetic acid. The solid
precipitated was filtered, washed with 5% acetic acid, ethanol,
hexane and crystallized in methanol.
values were given in d (ppm) scales. The mass spectra were recorded
on LCeMS-Agilent 1100 series and elemental analysis was performed
on a Flash EA 1112 series CHNS-O Analyzer. The completion of the
reactions was checked by thin layer chromatography (TLC) on silica
gel coated aluminium sheets (silica gel 60 F254).
Yield: 11.30 g, 62.2%; M.p: 155e156 ꢁC; IR (KBr nmax cmꢀ1): 3400
(OeH-str), 3051, 2989 (CeH-str), 1703 (C]O); 1H NMR (400 MHz,
DMSO-d6):
d 7.09e7.64 (m, 2H, 4-fluorophenyl), 7.68e7.88 (m, 2H,
quinoline), 8.76 (d, J ¼ 8.3 Hz, 2H, 4-fluorophenyl), 8.34 (m, 1H,
4.2. General procedure for the synthesis of 6-substituted-4-
carboxyquinoline (3aeb)
quinoline), 8.45 (s, 1H, quinoline), 8.59e8.61 (m, 1H, quinoline),
14.11 (s, 1H, COOH); 13C NMR (100 MHz, DMSO-d6):
d 167.4, 167.2,
162.2, 160.8, 147.9, 134.0, 131.3, 131.0, 130.5, 129.8, 129.6, 129.5,
129.3, 125.6, 123.1, 114.2; MS: m/z ¼ 268 (M þ 1); Anal. calcd. For
C16H9ClFNO2: C, 71.91; H, 3.77; N, 5.24. Found: C, 72.10; H, 2.98; N,
5.23%.
An equimolar mixture of 4-substituted aniline (1) (10.0 g,
0.078 mol), 4-fluorobenzaldehyde (2) (9.72 g, 0.078 mol) in ethanol
(100 mL) were refluxed for 1 h, pyruvic acid (10.30 g, 0.117 mol) and

904
B. Garudachari et al. / European Journal of Medicinal Chemistry 54 (2012) 900e906
4.4. General method for the preparation of 4-substituted
benzimidoquinoline (4aei and 8aef)
4.4.6. 4-(5-Chloro-1H-benzimidazol-2-yl)-6-fluoro-2-(4-fluorop
henyl)quinoline (4f)
IR (KBr nmax cmꢀ1): 3354 (eNH stretching for benzimidazole
A mixture of 6-substituted-4-carboxyquinoline (3a,b and 7)
(0.01 mol), aromatic-1,2-diamine (0.01 mol) and fresh poly-
phosphoric acid (PPA) (2 mL) were heated to 250 ꢁC for 2 h. The
reaction mixture was then poured into 20 mL of 30% sodium
carbonate solution in water. The solid product obtained was filtered
and dried. The crude products were purified by column chroma-
tography using pet ether and ethyl acetate (9:1) as the eluent.
ring), 3020, 2979 (CeH-str), 1603 (C]N), 1507 (C]C); 1H NMR
(400 MHz, DMSO-d6):
d 7.34e7.70 (m, 4H, 4-fluorophenyl),
8.26e8.28 (m, 1H, quinoline), 8.47 (s, 1H, quinoline), 8.49 (d,
J ¼ 8.5 Hz, 2H, benzimidazole), 8.76 (s, 1H, benzimidazole),
9.42e9.45 (m, 2H, quinoline), 13.45 (s, 1H, eNH, D2O-exchangeble);
MS: m/z ¼ 392 (M þ 1). Anal. calcd. For C22H12ClF2N3; Calc: C, 67.44;
H, 3.09; N, 10.72; found: C, 67.42; H, 3.08; N, 10.75%.
4.4.1. 4-(1H-Benzimidazol-2-yl)-6-chloro-2-(4-fluorophenyl)
quinoline (4a)
4.4.7. 6-Fluoro-2-(4-fluorophenyl)-4-(1H-imidazo[4,5]pyridin-2-
yl)quinoline (4g)
IR(KBrnmax cmꢀ1):3356(eNHstretchingforbenzimidazolering),
IR (KBr nmax cmꢀ1): 3403 (eNH stretching for benzimidazole
3087, 2927 (CeH-str), 1621 (C]N), 1597 (C]C); 1H NMR (400 MHz,
ring), 3028, 2921 (CeH-str), 1623 (C]N), 1540 (C]C); 1H NMR
DMSO-d6):
d 7.28e7.46 (m, 2H, 4-fluorophenyl), 7.67e7.73 (m, 2H,
(400 MHz, DMSO-d6):
d 7.39e7.48 (m, 4H, 4-fluorophenyl),
benzimidazole), 7.75e7.88(m, 2H, 4-fluorophenyl), 8.18(d, J ¼ 8.2Hz,
2H, quinoline), 8.44e8.48 (m, 2H, benzimidazole), 8.63 (s, 1H, quin-
oline), 9.46 (s, 1H, quinoline), 13.45 (s, 1H, eNH, D2O-exchangeble);
MS: m/z ¼ 374 (M þ 1). Anal. calcd. For C22H13FN3; Calc: C, 70.69; H,
3.51; N, 11.24; found: C, 70.70; H, 3.50; N, 11.26%.
7.50e7.53 (m, 2H, quinoline), 7.83e7.85 (m, 1H, quinoline),
8.28e8.48 (m, 2H, benzimidazole), 8.51 (s, 1H, quinoline),
9.38e9.43 (m, 1H, benzimidazole), 13.73 (s, 1H, eNH, D2O-
exchangeble); MS: m/z ¼ 359 (M þ 1). Anal. calcd. For C21H12F2N4;
Calc: C, 70.39; H, 3.38; N, 15.65; found: C, 70.41; H, 3.35; N, 15.66%.
4.4.2. 6-Chloro-4-(5-chloro-1H-benzimidazol-2-yl)-2-(4-fluorop
henyl)quinoline (4b)
4.4.8. 4-(5,6-Dichloro-1H-benzimidazol-2-yl)-6-fluoro-2-(4-fluor
ophenyl)quinoline (4h)
IR (KBr nmax cmꢀ1): 3342 (eNH stretching for benzimidazole
IR (KBr nmax cmꢀ1): 3355 (eNH stretching for benzimidazole
ring), 3082, 2935 (CeH-str), 1597 (C]N), 1556 (C]C); 1H NMR
ring), 3057, 2932 (CeH-str), 1660 (C]N), 1539 (C]C); 1H NMR
(400 MHz, DMSO-d6):
d 7.45e7.87 (m, 4H, 4-fluorophenyl), 7.90 (d,
(400 MHz, DMSO-d6):
d 7.38e7.83 (m, 4H, 4-fluorophenyl), 8.26 (s,
J ¼ 8.2 Hz, 2H, benzimidazole), 8.45 (s, 1H, quinoline), 8.72 (s, 1H,
benzimidazole), 8.72 (s, 1H, quinoline), 8.69 (s, d ¼ 8.2 Hz, 2H,
quinoline), 13.44 (s, 1H, eNH, D2O-exchangeble); MS: m/z ¼ 409
(M þ 1). Anal. calcd. For C22H12Cl2FN3; Calc: C, 64.72; H, 2.96; N,
10.29; found: C, 64.75; H, 2.99; N, 10.20%.
1H, quinoline), 8.46e8.48 (m, 2H, quinoline), 8.75e8.76 (m, 1H,
quinoline), 9.42 (s, 1H, benzimidazole), 9.46 (s, 1H, benzimidazole),
13.42 (s, 1H, eNH, D2O-exchangeble); MS: m/z ¼ 427 (M þ 1). Anal.
calcd. For C22H11Cl2F2N3; Calc: C, 61.99; H, 2.60; N, 9.86; found: C,
61.98; H, 2.55; N, 9.89%.
4.4.3. 6-Chloro-2-(4-fluorophenyl)-4-(1H-imidazo[4,5]pyridin-2-
yl)quinoline (4c)
4.4.9. 6-Fluoro-4-(5-fluoro-1H-benzimidazol-2-yl)-2-(4-fluorophe
nyl)quinoline (4i)
IR (KBr nmax cmꢀ1): 3400 (eNH stretching for benzimidazole
IR (KBr nmax cmꢀ1): 3400 (eNH stretching for benzimidazole
ring), 3057, 2929 (CeH-str), 1592 (C]N), 1538 (C]C); 1H NMR
ring), 3057, 2928 (CeH-str), 1584 (C]N), 1540 (C]C); 1H NMR
(400 MHz, DMSO-d6):
d 7.45e7.90 (m, 4H, 4-fluorophenyl),
(400 MHz, DMSO-d6):
d 7.17e7.73 (m, 4H, 4-fluorophenyl),
8.48e8.55 (m, 2H, benzimidazole), 8.73 (s, 1H, quinoline), 8.82 (s,
1H, quinoline), 9.62e9.66 (m, 1H, benzimidazole), 9.84 (d,
J ¼ 8.2 Hz, 2H, quinoline),13.59 (s,1H, eNH, D2O-exchangeble); MS:
m/z ¼ 375 (M þ 1). Anal. calcd. For C21H12ClFN4; Calc: C, 67.30; H,
3.23; N, 14.95; found: C, 67.34; H, 3.26; N, 14.93%.
7.98e8.28 (m, 2H quinoline), 8.45e8.48 (m, 2H, benzimidazole),
8.74 (s, 1H, quinoline), 9.33e9.40 (m, 2H, benzimidazole), 13.53 (s,
1H, eNH, D2O-exchangeble); MS: m/z ¼ 375 (M þ 1). Anal. calcd.
For C22H12F3N3; Calc: C, 70.40; H, 3.22; N, 11.20; found: C, 70.45; H,
3.20; N, 11.23%.
4.4.4. 6-Chloro-4-(5,6-dichloro-1H-benzimidazol-2-yl)-2-(4-fluoro
phenyl)quinoline (4d)
4.4.10. 4-(1H-Benzimidazol-2-yl)-2-(4-fluorophenyl)quinoline (8a)
IR (KBr nmax cmꢀ1): 3396 (eNH stretching for benzimidazole
ring), 3055, 2986 (CeH-str), 1619 (C]N), 1594 (C]C); 1H NMR
IR (KBr nmax cmꢀ1): 3362 (eNH stretching for benzimidazole
ring), 3054, 2911 (CeH-str), 1627 (C]N), 1550 (C]C); 1H NMR
(400 MHz, DMSO-d6):
d 7.30e7.36 (m, 2H, 4-fluorophenyl),
(400 MHz, DMSO-d6):
d 7.47e7.90 (m, 4H, 4-fluorophenyl), 8.22 (s,
7.38e7.47 (m, 2H, benzimidazole), 7.70e7.89 (m, 2H, quinoline),
7.90e8.19 (m, 2H, benzimidazole), 8.44e8.48 (m, 2H, quinoline),
8.72 (s, 1H, quinoline), 13.43 (s, 1H, eNH, D2O-exchangeble); MS:
m/z ¼ 340 (Mþ1). Anal. calcd. For C22H14FN3; Calc: C, 77.86; H, 4.16;
N, 12.38; found: C, 77.89; H, 4.14; N, 12.40%.
1H, quinoline), 8.45 (s, 1H, quinoline), 8.48 (d, J ¼ 8.3 Hz, 2H,
quinoline), 9.58 (s, 1H, benzimidazole), 9.61 (s, 1H, benzimidazole),
13.46 (s, 1H, eNH, D2O-exchangeble); MS: m/z ¼ 444 (M þ 1). Anal.
calcd. For C22H11Cl3FN3; Calc: C, 59.69; H, 2.50; N, 9.49; found: C,
59.71; H, 2.51; N, 9.55%.
4.4.11. 4-(5-Chloro-1H-benzimidazol-2-yl)-2-(4-fluorophenyl)
quinoline (8b)
4.4.5. 4-(1H-Benzimidazol-2-yl)-6-fluoro-2-(4-fluorophenyl)
quinoline (4e)
IR (KBr nmax cmꢀ1): 3325 (eNH stretching for benzimidazole
IR (KBr nmax cmꢀ1): 3409, (eNH stretching for benzimidazole
ring), 3066, 2928 (CeH-str), 1601 (C]N), 1508 (C]C); 1H NMR
ring), 3066, 2925 (CeH-str), 1605 (C]N), 1552 (C]C); 1H NMR
(400 MHz, DMSO-d6):
d 7.30e7.73 (m, 4H, 4-fluorophenyl),
(DMSO-d6) d: 7.28e7.47 (m, 4H, 4-fluorophenyl), 7.66e7.75e7.81
7.76e8.44 (m, 4H, quinoline), 8.45e8.48 (m, 2H, benzimidazole),
8.63 (s, 1H, quinoline), 9.46 (s, 1H, benzimidazole), 13.35 (s, 1H,
eNH, D2O-exchangeble); MS: m/z ¼ 374 (M þ 1). Anal. calcd. For
C22H13ClFN3; Calc: C, 70.69; H, 3.51; N, 11.24; found: C, 70.67; H,
3.53; N, 11.25%.
(m, 2H, benzimidazole), 7.82e7.86 (m, 2H, benzimidazole),
8.45e8.47 (m, 2H, quinoline), 8.76 (s, 1H, quinoline), 9.33e9.40 (m,
1H, quinoline),13.53 (s,1H, eNH, D2O-exchangeble); MS: m/z ¼ 358
(M þ 1). Anal. calcd. For C22H13F2N3; Calc: C, 73.94; H, 3.67; N,11.76;
found: C, 73.97; H, 3.68; N, 11.77%.

B. Garudachari et al. / European Journal of Medicinal Chemistry 54 (2012) 900e906
905
4.4.12. 2-(4-Fluorophenyl)-4-(1H-imidazo[4,5]pyridin-2-yl)
4.6. Antifungal studies
quinoline (8c)
IR (KBr nmax cmꢀ1): 3400 (eNH stretching for benzimidazole
Antifungal studies of newly synthesized compounds (4aei and
8aef) were carried out against A. niger, A. flavus, A. terreus (NCIM
1325) and Penicillium sp. (recultured). Sabourands agar media was
ring), 3021, 2925 (CeH-str), 1660 (C]N), 1539 (C]C); 1H NMR
(400 MHz, DMSO-d6): d 7.39e7.77 (m, 4H, 4-fluorophenyl), 7.91e8.31
(m, 2H, benzimidazole), 8.49e8.52 (m, 4H, quinoline), 8.74 (s, 1H,
quinoline), 9.48 (m, 1H, benzimidazole), 13.63 (s, 1H, eNH, D2O-
exchangeble); MS: m/z ¼ 341 (M þ 1). Anal. calcd. For C21H13FN4;
Calc: C, 74.11; H, 3.85; N, 16.46; found: C, 74.15; H, 3.82; N, 16.47%.
prepared by dissolving peptone (10 g), D-glucose (40 g) and agar
(20 g) in distilled water (1000 mL) and adjusting the pH to 5.7.
Normal saline was used to make a suspension of spore of fungal
strains for lawning. A loopful of particular fungal strain was
transferred to 3 mL saline to get a suspension of corresponding
species. Twenty millilitres of agar media was poured into each
petri dish. Excess of suspension was decanted and plates were
dried by placing in incubator at 37 ꢁC for 1 h. Using a puncher,
wells were made on the seeded agar plates. The different
concentrations of the test compounds in DMSO were added into
each labelled well. A control was also prepared for the plates in
the same way using solvent DMSO. The petri dishes were prepared
in triplicates and maintained at 25 ꢁC for 72 h. Antifungal activity
was determined by measuring the diameter of inhibition zone.
Activity of each compound was compared with flucanazole as
standard. Zones of inhibition (mm) were determined for
compounds (4aei and 8aef).
4.4.13. 4-(5,6-Dichloro-1H-benzimidazol-2-yl)-2-(4-fluorophenyl)
quinoline (8d)
IR (KBr nmax cmꢀ1): 3453 (eNH stretching for benzimidazole
ring), 3102, 3015 (CeH-str), 1622 (C]N), 1539 (C]C); 1H NMR
(400 MHz, DMSO-d6):
d 7.45e7.76 (m, 4H, 4-fluorophenyl),
7.88e8.47 (m, 4H, quinoline), 8.65 (s, 1H, quinoline), 9.36 (s, 1H,
benzimidazole), 9.38 (s, 1H, benzimidazole), 13.66 (s, 1H, eNH,
D2O-exchangeble); MS: m/z ¼ 409 (M þ 1). Anal. calcd. For
C22H12Cl2FN3; Calc: C, 64.72; H, 2.96; N, 10.29; found: C, 64.70; H,
2.92; N, 10 35%.
4.4.14. 4-(5-Fluoro-1H-benzimidazol-2-yl)-2-(4-fluorophenyl)
quinoline (8e)
IR (KBr nmax cmꢀ1): 3444 (eNH stretching for benzimidazole
Acknowledgements
ring), 3057, 2919 (CeH-str), 1568 (C]N), 1539 (C]C); 1H NMR
(400 MHz, DMSO-d6):
d 7.46e7.77 (m, 4H, 4-fluorophenyl),
AMI thanks Department of Atomic Energy, Board for Research
in Nuclear Sciences, Government of India for the ‘Young Scien-
tist’ award. AMI and SMN thanks Department of Information &
technology, Government of India, New Delhi for the financial
support.
7.87e8.20 (m, 4H, quinoline), 8.46e8.49 (m, 1H, benzimidazole),
8.64 (s, 1H, quinoline), 9.39e9.44 (m, 2H, benzimidazole), 13.53 (s,
1H, eNH, D2O-exchangeble); 13C NMR (100 MHz, DMSO-d6):
d
165.53, 162.67, 155.20, 149.05, 130.74, 130.15, 130.08, 130.00,
127.91, 127.19, 126.68, 124.16, 119.84, 118.74, 116.45, 116.23. MS:
m/z ¼ 358 (M þ 1). Anal. calcd. For C22H13F2N3; Calc: C, 73.94; H,
3.67; N, 11.76; found: C, 73.97; H, 3.65; N, 11.77%.
References
[1] T. Chua, C.L. Moore, M.B. Perri, S.M. Donabedian, W. Masch, D. Vager,
S.L. Davis, K. Lulek, B. Zimnicki, M.J. Zervos, J. Clin. Microbiol. 46 (2008)
2345e2352.
[2] D.T.W. Chu, J.J. Plattner, L. Katz, J. Med. Chem. 39 (1996) 3853e3874.
[3] K. Kaur, M. Jain, R.P. Reddy, R. Jain, Eur. J. Med. Chem. 45 (2010) 3245e3264.
[4] P. Nasveld, S. Kitchener, Trans. R. Soc. Trop. Med. Hyg. 99 (2005) 2e5.
[5] S. Eswaran, A.V. Adhikari, I.H. Chowdhury, N.K. Pal, K.D. Thomas, Eur. J. Med.
Chem. 45 (2010) 3374e3383.
[6] L.C. Chou, M.T. Tsai, M.H. Hsu, S.H. Wang, T.D. Way, C.H. Huang, H.Y. Lin, K. Qian,
Y. Dong, K.H. Lee, L.J. Huang, S.C. Kuo, J. Med. Chem. 53 (2010) 8047e8058.
[7] M. Yamato, Y. Takeuchi, K. Hashigaki, Y. Ikeda, M.R. Chang, K. Takeuchi,
M. Matsushima, T. Tsuruo, T. Tashiro, J. Med. Chem. 32 (1989) 1295e1300.
[8] Y.L. Chen, H.M. Hung, C.M. Lu, K.C. Li, C.C. Tzeng, Bioorg. Med. Chem. 12 (2004)
6539e6546.
4.4.15. 2-(4-Fluorophenyl)-4-(6-methoxy-1H-benzimidazol-2-yl)
quinoline (8f)
IR (KBr nmax cmꢀ1): 3359 (eNH stretching for benzimidazole
ring), 3015, 2924 (CeH-str), 1660 (C]N), 1540 (C]C); 1H NMR
(400 MHz, DMSO-d6):
d 4.01 (s, 3H, eOCH3), 7.41e7.77 (m, 4H, 4-
fluorophenyl), 7.89e8.18 (m, 2H, benzimidazole), 8.20e8.41 (m, 3H,
quinoline), 8.51 (s, 1H, benzimidazole), 9.06 (s, 1H, quinoline),
9.46e9.49 (m, 1H, quinoline), 13.36 (s, 1H, eNH, D2O-exchangeble);
MS: m/z ¼ 370 (M þ 1). Anal. calcd. For C23H16FN3O; Calc: C, 74.78;
H, 4.37; N, 11.38; found: C, 74.75; H4.39; N, 11.39%.
[9] M. Gaba, D. Singh, S. . Si ngh, V. Sharma, P. Gaba, Eur. J. Med. Chem. 45 (2010)
2245e2249.
[10] K.C.S. Achar, K.M. Hosamani, H.R. Seetharamareddy, Eur. J. Med. Chem. 45
(2010) 2048e2054.
4.5. Antibacterial studies
[11] R.V. Shingalapur, K.M. Hosamani, R.S. Keri, Eur. J. Med. Chem. 44 (2009)
4244e4248.
[12] P.R. Vachharajani, M.J. Solanki, G.G. Dubal, V.H. Shah, Der Pharma Chemica 3
(2011) 280e285.
[13] S. Eswaran, A.V. Adhikari, N.S. Shetty, Eur. J. Med. Chem. 44 (2009) 4637e4647.
[14] J. Mann, A. Baron, Y.O. Boahen, E. Johansson, G. Parkinson, L.R. Kelland,
S. Neidle, J. Med. Chem. 44 (2001) 138e144.
[15] D.A. Horton, G.T. Bourne, M.L. Smythe, Chem. Rev. 103 (2003) 893e930.
[16] S.M. Sondhi, S. Rajvanshi, M. Johar, N. Bharti, A. Azam, A.K. Singh, Eur. J. Med.
Chem. 37 (2002) 835e843.
[17] A. Gellis, H. Kovacic, N. Boufatah, P. Vanelle, Eur. J. Med. Chem. 43 (2008)
1858e1864.
[18] S. Eswaran, A.V. Adhikari, R.A. Kumar, J. Med. Chem. 45 (2010) 957e966.
[19] D. Mungra, M. Patel, R. Patel, Med. Chem. Res. 20 (2011) 782e789.
[20] N. Perin, L. Uzelac, I. Piantanida, G.K. Zamola, M. Kralj, M. Hranjec, Bioorg.
Med. Chem. 19 (2011) 6329e6339.
[21] A.M. Isloor, B. Kalluraya, M. Rao, J. Saudi Chem. Soc. 4 (3) (2000) 265e270.
[22] A.M. Isloor, B. Kalluraya, P. Shetty, Eur. J. Med. Chem. 44 (2009)
3784e3787.
[23] A.M. Vijesh, A.M. Isloor, V. Prabhu, S. Ahmad, S. Malladi, Eur. J. Med. Chem. 45
(2010) 5460e5464.
The in-vitro antibacterial activity of newly synthesized
compounds 4aei and 8aef were evaluated for their antibacterial
against S. aureus, E. coli, Xanthomonas sp. and Salmonella sp.
bacterial strains by well plate method. A number of antimicrobial
discs were placed on the agar for the purpose of producing zones of
inhibition in the bacterial lawn. 15e20 mL of agar media were
poured into each petri dish. Agar containing plates were dried by
placing in a laminar air flow at 37 ꢂ 2 ꢁC for an hour. Using an agar
punch, wells were made on the seeded agar plates and minimum
inhibitory concentrations of the test compounds in dimethylsulf-
oxide (DMSO) were added into each labelled wells. A control was
also prepared for the plates in the same way using solvent DMSO.
The Petri dishes were prepared in triplicate and maintained at
37 ꢂ 2 ꢁC for 24e48 h. Activities were determined by measuring the
diameter of inhibition zone (mm). Ciprofloxacin was used as stan-
dard. Experiments were triplicates and standard deviation was
calculated.
[24] B. Chandrakantha, P. Shetty, V. Nambiyar, N. Isloor, A.M. Isloor, Eur. J. Med.
Chem. 45 (2010) 1206e1210.

906
B. Garudachari et al. / European Journal of Medicinal Chemistry 54 (2012) 900e906
[25] A.V. Ivachtchenko, A.V. Khvat, V.V. Kobak, V.M. Kysil, C.T. Williams, Tetrahe-
dron Lett. 45 (2004) 5473e5476.
[28] B.A. Arthington-Skaggs, M. Motley, D.W. Warnock, C.J. Morrison, J. Clin.
Microbiol. 38 (2000) 2254e2260.
[26] A. Zarghi, R. Ghodsi, E. Azizi, B. Daraie, M. Hedayati, O.G. Dadrass, Bioorg. Med.
Chem. 17 (2009) 5312e5317.
[29] L. Rocha, A. Marston, O. Potterat, M.A.C. Kaplan, H. Stoeckli-Evans,
K. Hostettmann, Phytochemistry 40 (5) (1995) 1447e1452.
[27] K.A. Metwally, L.M.A. Aziz, E.S.M. Lashine, M.I. Husseinyb, R.H. Badawya,
Bioorg. Med. Chem. 14 (2006) 8675e8682.
[30] D.J.Mac. Lowry, M.J. Jaqua, S.T. Selepak, Appl. Microbiol. 20 (1970) 46e53.
[31] A.Portillo,R.Vila,B.Freixa,T.Adzet,S.Can-igueral,J.Ethnopharmacol.76(1)(2001)93e98.