Synthesis and biologic activities of some novel heterocyclic chalcone derivatives

Article abstract of DOI:10.1007/s00044-012-0401-7

We synthesized 36 chalcone-like (E)-3-(substitutedphenyl)-1-hetrylprop-2- en-1-ones by condensing 2-acetylfuran/2-acetylpyrrole with substituted benzaldehydes under basic conditions. Of the 36 molecules synthesized, 10 are new to the literature. Bio-evalu

Full text of DOI:10.1007/s00044-012-0401-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3969–3983
DOI 10.1007/s00044-012-0401-7
ORIGINAL RESEARCH
Synthesis and biologic activities of some novel heterocyclic
chalcone derivatives
•
Punita Sharma Suresh Kumar Furquan Ali Sumati Anthal
•
•
•
•
•
•
Vivek K. Gupta Inshad A. Khan Surjeet Singh Payare L. Sangwan
•
•
Krishan A. Suri Bishan D. Gupta Devinder K. Gupta Prabhu Dutt
•
•
•
•
Ram A. Vishwakarma Naresh K. Satti
Received: 5 July 2012 / Accepted: 6 December 2012 / Published online: 18 December 2012
ꢀ Springer Science+Business Media New York 2012
Abstract We synthesized 36 chalcone-like (E)-3-(substi-
tutedphenyl)-1-hetrylprop-2-en-1-ones by condensing 2-acet-
ylfuran/2-acetylpyrrole with substituted benzaldehydes under
basic conditions. Of the 36 molecules synthesized, 10 are new
to the literature. Bio-evaluation studies of these molecules
revealed that compounds 5, 9, 15, 25, and29 were potent NorA
efflux pump inhibitors against Staphylococcus aureus by
reducing MIC of ciprofloxacin fourfold, while compounds 11,
21, 25, and 26 showed promising anticancer activity in all four
tested cancer cell lines (HL-60, MOLT-4, PC-3, and HeLa).
Compound 25 emerged as a very good potentiator of cipro-
floxacin against multidrug resistant S. aureus and also showed
promising anticancer activity. The present communication
describes syntheses, bio-evaluation, and structure-related
activity of the (E)-3-(substitutedphenyl)-1-hetrylprop-2-en-
1-ones.
Keywords Chalcone ꢀ
(E)-3-(substitutedphenyl)-1-hetrylprop-2-en-1-ones ꢀ
NorA efflux pump inhibitors ꢀ Staphylococcus aureus ꢀ
Docking study
Introduction
Chalcones are an important class of secondary metabolites
which are precursors of many naturally occurring plant
pigments (Wong, 1968). These small molecules are also used
as starting materials in the synthesis of UV absorption filters
in polymers, photorefractive polymers, photosensitizers in
color films, sweeteners in food technology, and in holo-
graphic recording technology. They have significant com-
mercial applications in medical therapy due to the wide range
of valuable biologic activities which include antimutagenic,
antibacterial, antiviral, anti-inflammatory, anti-ulcerative,
P. Sharma ꢀ P. L. Sangwan ꢀ K. A. Suri ꢀ
B. D. Gupta ꢀ D. K. Gupta ꢀ P. Dutt ꢀ R. A. Vishwakarma ꢀ
N. K. Satti (&)
Natural Product Chemistry Division, CSIR-Indian Institute
of Integrative Medicine, Canal Road, Jammu 180001, India
e-mail: nksatti@rediffmail.com
´
hepatoprotective, and anticancer activities (Forejtnıkov
S. Kumar
Cancer Pharmacology Division, CSIR-Indian Institute
of Integrative Medicine, Canal Road, Jammu 18000, India
et al., 2005). Chalcones, considered as the precursors of
flavonoids and isoflavones, are also known to be effective
¨
antimicrobial agents (Tsukiyama et al., 2002; Friss-Moller
et al., 2002; Fukai et al., 2002; Kromann et al., 2004; Hatono
et al., 2000; Nielsen et al., 2005; Bremner and Meyer, 1998;
Belofsky et al., 2004; Mustafa et al., 2003; Joshi et al., 2001).
Recently, bacterial resistance to antimicrobic agents has
resulted in serious public health problems. Several different
mechanisms have been put forward for the development of
bacterial resistance. In one of these mechanisms, access of
the antibiotic into the cell is prevented or reduced by
decreasing the transport of the antibiotic into the cell or by
F. Ali ꢀ I. A. Khan
Clinical Microbiology Division, CSIR-Indian Institute
of Integrative Medicine, Canal Road, Jammu 180001, India
S. Anthal ꢀ V. K. Gupta
Department of Physics, University of Jammu,
Jammu 180006, India
S. Singh
Pharmacology Division, CSIR-Indian Institute of Integrative
Medicine, Canal road, Jammu 18000, India
123

3970
Med Chem Res (2013) 22:3969–3983
increasing the efflux of the drug from the cell to the outside
medium by efflux pumps. Efflux pumps are found in both
Gram-positive and -negative pathogens and some of these
drug pumps confer multiple-drug resistance (MDR), and
the NorA protein of Staphylococcus aureus is one of such
pumps (Prasad et al., 2007; Memurry et al., 1980). NorA is
a member of the major facilitator superfamily (MFS) of
transport proteins, one of the most studied MDR pumps. Its
substrates include antimicrobial agents such as ciproflox-
acin and norfloxacin and dyes like ethidium bromide and
acriflavine (Li and Nikaido, 2004). Chalcones have been
found to potentiate the activity of berberine, erythromycin,
and tetracycline, demonstrating a mode of action consistent
with inhibition of the NorA MDR efflux pump in S. aureus
(Poole, 2005).
Results and discussion
Chemistry
In the present investigation, 36 chalcone-like molecules viz
(E)-3-(substitutedphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-
ones (1–20) and (E)-3-(substitutedphenyl)-(1-furan-2-yl)
prop-2-en-1-ones (21–36) have been synthesized by Clais-
en–Schmidt’s condensation of 2-acetylfuran/2-acetylpyrrol
with substituted benzaldehydes under basic conditions
(Scheme 1). The synthesized chemical entities (1–36) with
diversification in chemical structures are shown in Table 1.
All the compounds were chemically characterized based
on their spectral and physical data. A literature search
revealed that out of 36 molecules synthesized, compounds
5, 6, 7, 9, 13, 14, 27–29, and 36 are new to the literature.
The structure of compound 9 was further confirmed by
X-ray analysis of single crystal. The crystal used for data
collection was of the dimension 0.3 9 0.2 9 0.1 mm. The
cell dimensions were determined by least-square fit of
angular settings of 2,440 reflections in the h range
2.59ꢁ–27.45ꢁ, Table 2. Selected bond distances and bond
angles are listed in Table 3. An ORTEP view of compound
9 with atomic labeling is shown in Fig. 1 (Radwan and
Abbas, 2009).
Cancer is the second leading cause of human death in the
developing as well as advanced countries. Among naturally
occurring chalcones and their synthetic analogs (Achanta
et al., 2006; Romagnoli et al., 2008; Echeverria et al., 2009;
Szliszka et al., 2010; Ilango et al., 2010), several com-
pounds have been found to have cytotoxic activity (anti-
mitotic, a cell growth inhibitor) toward cultured tumor cells.
Chalcones are also known to possess antioxidant character
at various extents. Activated macrophages play a key role in
inflammatory responses and release a variety of mediators
including nitric oxide (NO). NO is a potent vasodilator that
facilitates leukocytic migration and formation of edema
as well as leukocytic activity and cytokine production
(Belofsky et al., 2004).
The geometry of the molecule was calculated using the
WinGX and PARST software (Farrugia, 1997, 1999). Bond
lengths and bond angles of the title molecule show a fair
amount of agreement with some related molecules (Nardelli,
1995; Li, 2008; Tang et al., 2008). The six C–C bond lengths
Keeping in view the wide range of activities of the
chalcones, many research groups have synthesized these
molecules (Bandgar et al., 2010; Rateb and Zohdi, 2009;
Bsasaif et al., 2005). We designed and synthesized a
number of chalcone-like molecules in which one of the
phenyl rings (ring-B) has been replaced by a heterocyclic
ring (pyrrole/furan ring) for bio-evaluation of their bioen-
hancing, anticancer, anti-inflammatory, and antioxidant
activities. In this communication, we report the preparation
of (E)-3-(substitutedphenyl)-1-hetrylprop-2-en-1-ones with
chemical diversification and identification of potent lead
molecules along with structure activity relationship of
these analogs.
˚
in the phenyl ring lie in the range 1.381(4)–1.408(3) A. The
bond angles in the phenyl ring vary from 116.4(2)ꢁ to
122.7(2)ꢁ with an average of 120.0(2)ꢁ. In the title molecule,
the bond lengths N10–C50 and N10–C20 are 1.345(3) and
˚
˚
1.378(3) A, respectively. The C1=O1 distance [1.241(3) A]
is significantly longer than those usually observed for car-
bonyl bonds, probably because atom O1 is involved in
intramolecular C–HꢀꢀꢀO hydrogen bond (Table 4).
The pyrrole and phenyl rings are perfectly planar
0
˚
˚
(maximum deviations: 0.006(2) A for C5 and 0.010(2) A
for C100). Different to most substituted chalcones, the
molecule of the title compound is non-planar with a
Scheme 1 Synthesis of (E)-3-
(substitutedphenyl)-1-
hetrylprop-2-en-1-ones by
Claisen–Schmidt condensation
of 2-acetyl furan/2-
acetylpyrrole with substituted
R2
O
R1
R3
R4
O
OH-
+
H
A
X
B
X
R
O
R5
benzaldehydes. Substituents of
X=NH or O
aldehyde and products (1–36)
are provided in Table 1
1-20, X=NH
21-36, X=O
123

Med Chem Res (2013) 22:3969–3983
3971
Table 1 Synthesis of (E)-3-(substitutedphenyl)-1-hetrylprop-2-en-1-ones
Entry
Substitutions
Yield (%)
Reaction time (h)
m.p. (ꢁC)
X
R1
R2
R3
R4
R5
1
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
68.8
72.72
77.27
58.33
45.45
66.66
74.16
63.25
62.50
37.57
72.58
70.00
71.0
87.5
90
15
15
18
15
15
15
15
18
15
15
18
24
15
48
24
15
18
20
20
22
48
16
15
15
18
18
24
48
15
12
24
15
15
15
10
18
195.8
205.3
205.7
172.4
107.2
193.7
162.2
148.5
133.9
139.6
116.0
203.8
128.7
228.5
116.0
178.5
105.1
137.2
166.4
153.4
96.4
2
H
H
NO2
H
3
H
NO2
H
H
H
4
Cl
OCH3
Cl
Cl
H
Cl
H
5
OCH3
Cl
H
H
H
6
H
H
7
H
H
8
OCH3
H
H
H
9
Br
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
a
H
F
H
H
H
Cl
H
H
H
N(CH3)2
H
H
OCH3
Cl
Cl
H
H
H
H
H
NO2
H
H
H
H
Br
H
87.5
95
OCH3
H
H
OCH3
OCH3
H
H
H
95
H
OCH3
a
OCH3
a
H
95
H
H
65
Cl
Br
H
H
H
H
86.13
70
O
H
H
H
60.8
O
H
F
H
90
114.2
–
O
H
H
Cl
H
95
O
H
H
N(CH3)2
H
96
88.9
O
H
NO2
H
H
H
H
H
72.5
55.5
90
181.2
87.5
O
H
H
O
Cl
OCH3
H
H
NO2
H
184.9
67.5
O
OCH3
a
H
a
75
O
H
67
180
O
H
OCH3
H
OCH3
NO2
Br
H
43
109.5
230.6
131.6
82.5
O
H
H
80
O
H
H
H
89
O
H
H
OCH3
OCH3
H
H
90
O
H
OCH3
H
OCH3
OCH3
67
149.6
54
O
OCH3
30
R2R3 = (–O–CH2–O–)
Biologic evaluation
dihedral angle of 35.16 (8)ꢁ between the pyrrole and phe-
nyl rings (Jasinski et al., 2009). The angles between the
mean plane of the prop-2-en-1-one group and the mean
planes of the pyrrole and phenyl rings are 15.7 (1) and
30.7(1)ꢁ, respectively. In the crystal structure, intermolec-
ular N10–H10ꢀꢀꢀO1 hydrogen bond links the molecules into
centrosymmetric dimers (Fig. 2). Dimers are arranged in a
manner to form layers (Fig. 3). Within the layers, the
dimers are arranged parallel to each other.
In vitro combination study of ciprofloxacin
with molecules (1–36)
The MIC of the compounds (1–36) was determined to use
these molecules at a concentration devoid of antibacterial
activity, a prerequisite of any compound to be used as safe
efflux pump inhibitors (EPIs). The compounds (1–36) were
123

3972
Med Chem Res (2013) 22:3969–3983
Table 2 Crystal data and other
experimental details of
compound (9)
CCDC number
776070
Crystal description
Crystal size
Yellow plate
0.3 9 0.2 9 0.1 mm
Empirical formula
Formula weight
C
13H10BrNO
276.13
˚
Radiation, Wavelength
Unit cell dimensions
Mo Ka, 0.71073 A
a = 31.524(11), b = 7.266(2),
˚
c = 10.000(3) A, b = 93.171(9)
Crystal system
Monoclinic
Space group
C2/c
3
˚
Unit cell volume
No. of molecules per unit cell (Z)
Temperature
2286.9(13) A
8
100(2) K
3.571 mm-1
Absorption coefficient
F(000)
1104
h range for entire data collection
Reflections collected/unique
Reflections observed [I [ 2r(I)]
Refinement
2.88ꢁ \ h \ 28.36ꢁ
6,806/2,673
2,029
Full-matrix least-squares on F2
No. of parameters refined
Final R-factor
185
0.0343
wR(F2)
0.0879
Weight
1/[r2(F2o) ? (0.0493P)2 ? 0.0000P]
where P = [F2o ?2Fc2]/3
1.000
Goodness-of-fit
(D/r)max
-0.001 (for 9 Br1)
-3
˚
Final residual electron density
-0.643 \ Dq \ 0.597eA
Table 3 Selected bond lengths
˚
Br1–C200
1.905(2)
1.482(3)
1.345(3)
120.8(2)
110.4(2)
121.7(2)
116.5(2)
O1–C1
1.241(3)
1.340(4)
1.378(3)
119.3(2)
106.3(2)
108.3(2)
(A) and bond angles (ꢁ) for
C1–C2
N10–C50
C2–C3
N10–C20
non-hydrogen atoms (e.s.d.s are
given in parentheses)
O1–C1–C2
C50–N10–C20
N10–C20–C1
C300–C200–Br1
C3–C2–C1
N10–C20–C30
N10–C50–C40
studied in combination with ciprofloxacin (standard drug)
and bio-evaluated against NorA over expressing S. aureus
1199B (Bandgar et al., 2010; Kaatz et al.,1993, 1999).
Along with these synthetic molecules, two known EPIs
namely reserpine and verapamil were also used for the
comparative studies (Kaatz and Seo, 1995; Neyfakh
et al.,1993). Ciprofloxacin alone showed MIC at 8 lg/mL
against NorA over expressing S. aureus 1199B. Among the
library of 36 molecules used in combination with cipro-
floxacin and tested against S. aureus 1199B, only com-
pounds 5, 9, 10, 15, 17, 18, 25, 29, and 33 could reduce the
MIC of the drug (Table 5) and rest of the molecules failed
to potentiate the antibacterial activity of the drug. How-
ever, the compounds 5, 15, 29, 25, and 33 showed the
Fig. 1 ORTEP view of the molecule (9) with displacement ellipsoids
drawn at 50 % probability level. H atoms are shown as small spheres
of arbitrary radii. The broken lines show the intramolecular C–HꢀꢀꢀO,
C–HꢀꢀꢀBr hydrogen bonds
123

Med Chem Res (2013) 22:3969–3983
3973
Table 4 Hydrogen-bonding
geometry (e.s.d.s in
parentheses)
˚
D–H(A)
˚
˚
D–HꢀꢀꢀA
HꢀꢀꢀA(A)
DꢀꢀꢀA(A)
D–HꢀꢀꢀA(ꢁ)
C3–H3ꢀꢀꢀBr1
C3–H3ꢀꢀꢀO1
N10–H10 ꢀꢀꢀO1i
1.00(2)
1.00(2)
0.74(3)
2.76(2)
2.43(2)
2.11(3)
3.187(3)
2.798(3)
2.824(3)
106(1)
101(2)
162(3)
Symmetry code: (i) 1/2 - x,
1/2 - y, 2 - z
most active compound in this study, which showed four-
fold reduction in the MIC of ciprofloxacin at 12.5 lg/mL
conc. against S. aureus 1199B.
Anticancer activity
Among the currently identified antitumor agents, chalcones
represent an important class of molecules that are abundant
in edible plants. The anticancer activity of certain chal-
cones is believed to be a result of binding to tubulin
and preventing it from polymerizing into microtubules
(Lawrence et al., 2006). The prepared synthetics (1–36)
were also evaluated for their anticancer activity against
four different cancer cell lines (HL-60, MOLT-4, PC-3,
and HeLa). Out of 36, 14 molecules showed significant
anticancer activity (Table 6). Compound 25 having
–N(CH3)2 substitution at ring A (R3) was the most active.
Compounds 11, 21, and 24 having chloro substitution at
different positions in ring A of (E)-3-(substitutedphenyl)-1-
hetrylprop-2-en-1-ones also showed promising anticancer
activity.
Fig. 2 A plot of two molecules of the compound (9) showing the
intermolecular N–HꢀꢀꢀO hydrogen bonds (dashed lines)
Compounds 2, 3, and 26 having nitro substitution in ring
A also exhibited promising anticancer activity, while
compounds 14 and 28 having both nitro and chloro sub-
stitutions in ring A of (E)-3-(substitutedphenyl)-1-hetryl-
prop-2-en-1-ones were less active. Compounds without any
modification in these rings did not show any anticancer
activity (1 and 27).
Anti-inflammatory and antioxidant activity
Anti-inflammatory and antioxidant activities of all the
synthesized molecules were determined using carrageenan-
induced inflammation and DPPH methods, respectively.
Out of the 36 synthetics tested, except compound 31 which
showed mild anti-inflammatory activity at 100 mg/kg p.o.
(23 % inhibition), others were devoid of activity (data not
shown).
Molecular docking study
Fig. 3 Appearance of layers of dimers of the compound (9) that are
hydrogen bonded
A flexible docking study was performed in order to ratio-
nalize the observed cytotoxic activity of compound 25.
GOLD software was employed for this purpose and Gold-
score was used to score the binding conformations. The
coordinates of the colchicine-binding site of tubulin receptor
fourfold reduction of MIC of ciprofloxacin and the rest of
the active compounds indicated a twofold reduction in the
MIC of ciprofloxacin. Compound 25 was found to be the
123

3974
Med Chem Res (2013) 22:3969–3983
Table 5 Ciprofloxacin activity
against S. aureus 1199B in
combination with (E)-3-
Compound
MECa of compounds
MICb of ciprofloxacin (lg/mL)
Without EPI
With EPI
Fold reduction
(substitutedphenyl)-1-
hetrylprop-2-en-1-ones (1–36)
1
[50
[50
[50
[50
25
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
2
8
8
8
2
4
8
8
8
8
2
8
4
4
8
8
8
8
8
8
2
8
8
8
2
8
8
8
4
8
8
8
8
4
0
0
0
0
4
0
0
0
4
2
0
0
0
0
4
0
2
2
0
0
0
0
0
0
4
0
0
0
4
0
0
0
2
0
0
0
0
2
2
3
4
5
6
[50
[50
[50
25
7
8
9
10
25
11
[50
[50
[50
[50
25
12
13
14
15
16
[50
25
17
18
25
19
[50
[50
[50
[50
[50
[50
12.5
[50
[50
[50
25
20
21
22
23
24
25
26
27
28
29
30
[50
[50
[50
25
31
32
33
34
[50
[50
[50
25
35
a
36
Minimum effective
concentration
Reserpine
Verapamil
b
Minimum inhibitory
concentration
50
were obtained from a protein data bank (PDB ID: 1SA0)
(Ravelli et al., 2004) on which docking was performed. To
validate the docking procedure for the prediction of the
correct binding mode of ligands at the colchicine-binding
site, colchicine was extracted from the original crystal
structure (1SA0) and re-docked using GOLD. The highest
scoring conformation was selected and compared with
The best binding conformation of the compound 25 in a
colchicine-binding site was selected based on the GOLD
score and visual inspection. In the binding conformation,
compound 25 fits well in the binding cavity of colchicine
(Fig. 4). Oxygen of the furan ring is involved in an
important hydrogen bonding interaction with Met 259,
which acts as an anchor to hold the compound in the cavity.
Moreover, phenyl ring of compound 25 finds optimum
˚
crystal structure conformation based on RMSD (0.72 A).
123

Med Chem Res (2013) 22:3969–3983
3975
Hela
Table 6 List of IC50 values
(lM) of active compounds in
four human cancer cell lines
Compounds
HL-60
PC-3
MOLT-4
1
[100
14
[100
13
[100
15
[100
26
2
3
20
23
22
32
4
22
22
13
26
8
16
24
28
30
9
42
44
38
44
11
14
16
21
24
25
26
27
28
33
13
18
22
25
38
55
42
68
32
44
49
[100
26
12
14
25
19
29
23
38
12
13
12
20
14
14
18
22
100
58
[100
62
[100
72
[100
[100
[100
48
58
62
and anti-inflammatory activities. The result of this study
finds compound 25 as the lead molecule for the develop-
ment of improved therapeutic agents designed to fight
cancer as well as a NorA EPI.
Experimental
Materials and methods
Reagents for chemical synthesis were obtained from
Sigma-Aldrich. The solvents used in reactions were dis-
tilled and dried before use. Reactions were monitored by
TLC on 0.25-mm silica gel 60 F254 plates (E. Merck) using
UV light, or ceric ammonium sulfate solution for visuali-
zation of the spots. Melting points were recorded on Buchi-
510 instrument and elemental analyses were performed on
Fig. 4 Docking conformation of compound 25 at colchicine-binding
site of tubulin receptor
1
Elementar vario EL-III. H NMR and 13C NMR spectra
position over the Lys254 and Leu255, and the dimethyl
amine is present in vicinity of the Asn101 and Asn249.
were recorded on Bruker DPX 200/400/500 instruments
using CD3OD/CDCl3/DMSO-d6 as the solvent with TMS
as the internal standard. Mass spectra were recorded on
ESI-esquire 3000 Bruker Daltonic’s instrument and IR
spectra were recorded on Bruker Vector 22 instruments.
X-ray intensity data were collected at 100 K on Bruker
CCD area-detector diffractometer equipped with graphite
monochromated Mo Ka radiation.
Conclusion
Preparations of a series of chalcone-like derivatives, having
a B ring either as pyrrole or furan, and their biologic
activities are described. Compounds 11, 21, 25, and 26
were found to have good anticancer activity in all four
tested cancer cell lines (HL-60, MOLT-4, PC-3, and
HeLa), while compounds 5, 9, 10, 15, 17, 18, 25, 29, and
33 were identified as EPIs against S. aureus. Compounds
with methoxy substitution did not reveal any significant
activity. Molecules 1–36 possess insignificant antioxidant
General procedure for synthesis of chalcone-like (E)-3-
(substitutedphenyl)-1-hetrylprop-2-en-1-ones (1–36)
2-Acetylpyrrole/2-acetylfuran (4 mmol) was taken in a
flask (100 mL) and dissolved in 10 mL methanol. Substi-
tuted benzaldehyde (4 mmol) was added to the solution
123

3976
Med Chem Res (2013) 22:3969–3983
(E)-3-(2,4-Dichloro-phenyl)-1-(1H-pyrrol-2-yl)prop-2-en-
1-one (4) MS: M? at m/z 266. Anal. Calcd for C13H9
Cl2NO: C, 58.67; H, 3.41; N, 5.26 %. Found: C, 58.76; H,
followed by 10 % aqueous NaOH solution (2 mL), and the
reaction mixture was kept in stirred condition at 15–20 ꢁC
until completion of the reaction. Progress of the reaction
was monitored by TLC (7:3, n-hexan:acetone). Spots on
TLC were visualized by spraying with 2 % ceric ammo-
nium sulfate spray reagent followed by heating the plate at
120 ꢁC. After completion of the reaction, the mixture was
diluted with distilled water and allowed to stand at room
temperature for precipitation. Precipitated solid was filtered
and recrystallized from EtOH/EtOAc. The melting point,
reaction time, and yield of the products are shown in
Table 1. The purity of products was monitored on TLC
(30 % acetone in n-hexane). Spectral data and elemental
analysis of synthesized molecules are given below.
1
4.45; N, 5.38 %. H NMR (200 MHz, DMSO-d6): d 6.37
(bs, 1H, H-40), 7.10 (d, 1H, J = 15.60 Hz, H-2), 7.30 (m,
3H, H-500, H-600 and H-30), 7.47 (d, 1H, J = 1.9 Hz, H-300),
7.69 (d, 1H, J = 8.60 Hz, H-50), 8.13 (d, 1H, J =
15.60 Hz, H-3), 10.50 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6): 178.10 (C-1), 140.38 (C-3), 135.81 (C-400),
133.65 (C-200), 133.03 (C-20), 131.84 (C-300), 131.23 (C-100),
130.27 (C-600), 128.59 (C-50), 127.89 (C-500), 126.21 (C-30),
122.59 (C-2),115.89 (C-40).
(E)-3-(2,3-Dimethoxy-phenyl)-1-(1H-pyrrol-2-yl)prop-2-
en-1-one (5) MS: M? at m/z 257. Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44 %. Found: C,
70.16; H, 4.92; N, 5.47 %. 1H NMR (200 MHz, CDCl3): d
3.89 (s, 6H, 2 9 OCH3), 6.35 (bs, 1H, H-40), 6.96 (d, 1H,
J = 8.22 Hz, H-400), 7.10 (m, 2H, H-500 and H-600), 7.28 (m,
2H, H-30 and H-50), 7.42 (d, 1H, J = 15.90 Hz, H-2), 8.11
(d, 1H, J = 15.90 Hz, H-3), 10.25 (s, 1H, NH). 13C NMR
(125 MHz, DMSO-d6): 178.10 (C-1), 162.49 (C-300),
159.40 (C-200), 145.34 (C-3), 135.98 (C-20), 129.32 (C-50),
125.88 (C-30), 123.24 (C-500), 122.09 (C-2), 120.00 (C-600),
116.77 (C-100), 115.87 (C-400), 109.94 (C-40), 55.95
(OCH3)2.
(E)-3-Phenyl-1-(1H-pyrrol-2-yl)prop-2-en-1-one (1) MS:
M? at m/z 197. Anal. Calcd for C13H11NO: C, 79.16; H,
1
5.62; N, 7.10 %. Found: C, 79.28; H, 5.60; N, 7.25 %. H
NMR (200 MHz, CD3OD): d 6.32 (dd, 1H, J = 2.4 Hz and
3.8 Hz, H-40), 7.19 (d, 1H, J = 15.0 Hz, H-2), 7.34 (m,
5H, H-200, H-300, H-400, H-500and H-600), 7.45 (d, 1H,
J = 15.0 Hz, H-3), 7.76 (bs, 2H, H-30 and H-50), 10.65
(s,1H, NH). 13C NMR (100 MHz, CD3OD) : d 178.81
(C-1), 140.94 (C-3), 133.12 (C-100), 131.35 (C-20), 130.21
(C-300and C-500), 130.12 (C-400), 127.98 (C-50), 126.08
(C-200and C-600), 125.90 (C-30), 121.88 (C-2), 111.43 (C-40).
(E)-3-(2,3-Dichloro-phenyl)-1-(1H-pyrrol-2-yl)prop-2-en-
1-one (6) MS: M? at m/z 266. Anal. Calcd for
C13H9Cl2NO: C, 58.67; H, 3.41; N, 5.26 %. Found: C,
(E)-3-(4-Nitro-phenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(2) MS: M? at m/z 242. Anal. Calcd for C13H10N2O3: C,
64.46; H, 4.16; N, 11.56 %. Found: C, 64.57; H, 4.14; N,
11.67 %. MS. 1H NMR (200 MHz, DMSO-d6): d 6.34 (dd,
1H, J = 2.4 and 3.8 Hz, H-40), 7.19 (d, 1H, J = 15.2 Hz,
H-2), 7.34 (d, 1H, J = 15.2 Hz, H-3), 7.76 (bs, 2H,
H-30and H-50), 7.79 (d, 2H, J = 8.8 Hz, H-200 and H-600),
8.79 (d, 2H, J = 8.8 Hz, H-300and H-500), 9.50 (s,1H, H-10,
NH). 13C NMR (100 MHz, DMSO-d6): 178.10 (C-1),
162.49, (C-400), 142.46 (C-3), 140.18 (C-20), 133.15 (C-100),
128.42 (C-200 and C-600), 128.02 (C-50), 125.73 (C-30),
120.6 (C-2), 120.58 (C-300and C-500), 111.97 (C-40).
1
59.72; H, 4.48; N, 5.37 %. H NMR (200 MHz, CD3OD):
d 6.32 (dd, 1H, J = 2.62 and 3.74 Hz, H-40), 7.16 (m, 4H,
H-30, H-400, H-500and H-600), 7.23 (m, 1H, H-50), 7.55 (d,
1H, J = 15.90 Hz, H-2), 8.06 (d, 1H, J = 15.90 Hz, H-3),
10.52 (s, 1H, NH). 13C-NMR (125 MHz, CD3OD): d
178.28 (C-1), 140.92 (C-3), 135.92 (C-100), 135.07 (C-300),
133.42 (C-20), 131.92 (C-400), 130.21 (C-500), 129.37 (C-200),
128.01 (C-50), 126.52 (C-600), 125.95 (C-30), 122.09 (C-2),
113.05 (C-40).
(E)-3-(2,6-Dichloro-phenyl)-1-(1H-pyrrol-2-yl)prop-2-en-
1-one (7) MS: M? at m/z 266. Anal. Calcd for
C13H9Cl2NO: C, 58.67; H, 3.41; N, 5.26 %. Found: C,
(E)-3-(3-Nitrophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(3) MS: M? at m/z 242. Anal. Calcd for C13H10N2O3: C,
64.46; H, 4.16; N, 11.56 %. Found: C, 64.38; H, 4.70; N,
1
1
59.79; H, 3.18; N, 5.23 %. H-NMR (200 MHz, CD3OD):
11.67 %. H NMR (200 MHz, DMSO-d6): d 6.31 (bs, 1H,
d 6.32 (dd, 1H, J = 2.41 Hz and 3.89 Hz, H-40), 7.17 (m,
1H, H-30), 7.31 (d, 1H, J = 15.98 Hz, H-2), 7.55 (m, 3H,
H-300, H-400 and H-500), 7.75 (bs, 1H, H-50), 7.87 (d, 1H,
J = 15.98 Hz, H-3), 10.25 (s, 1H, H-10,NH). 13C NMR
(125 MHz, CD3OD): d 179.91 (C-1), 140.59 (C-3), 136.05
(C-100), 133.16 (C-200 and C-600), 132.82 (C-20), 131.5 (C-
400), 128.52 (C-50), 127.19 (C-300 and C-500), 126.05 (C-30),
122.12 (C-2), 112.25 (C-40).
H-40), 7.21(bs, 1H, H-30),7.48 (bs, 1H, H-50), 7.72 (dd,
J = 8.52 Hz and 8.04 Hz, H-500), 7.74 (dd, 1H,
J = 16.00 Hz, H-2), 7.92 (dd, 1H, J = 16 Hz, H-3), 8.28
(m, 2H, H-400 and H-600), 8.72 (s, 1H, H-200), 9.65 (s, 1H,
H-10, NH). 13C NMR (125 MHz, DMSO-d6): 178.10 (C-1),
149.46 (C-300), 140.29 (C-3), 135.18 (C-100), 133.87 (C-600),
132.15 (C-20), 129.42 (C-500), 128.19 (C-50), 125.73 (C-30),
122.19 (C-2), 122.92 (C-200), 120.69 (C-400), 112.91(C-40).
123

Med Chem Res (2013) 22:3969–3983
3977
(C-300and C-500), 129.09 (C-200and C-600), 125.85(C-30),
122.57 (C-2) and 111.03 (C-40).
(E)-3-(3-Methoxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-
one (8) MS: M? at m/z 227. Anal. Calcd for C14H13NO2:
C, 73.99; H, 5.77; N, 6.16 %. Found: C, 74.02; H, 5.81; N,
5.27 %. 1H NMR (400 MHz, CDCl3): d 3.84 (s, 3H,
OCH3), 6.33 (m, 1H, H-40), 6.94 (dd, 1H, J = 8.00 Hz and
2.04 Hz, H-400), 7.04 (m, 1H, H-30), 7.10 (d, 1H,
J = 2.04 Hz, H-200), 7.26 (d, 1H, J = 7.79 Hz, H-600), 7.44
(dd, 1H, J = 8.00 Hz and 7.79 Hz, H-500), 7.32 (d, 1H,
J = 16.00 Hz, H-2), 7.64 (d, 1H, J = 1.6 Hz, H-50), 7.79
(d, 1H, J = 16.00 Hz, H-3), 10.55 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3): 179.06 (C-1), 159.94 (C-300), 142.21,
(C-3), 136.46 (C-100), 133.16 (C-20), 129.90 (C-50), 125.97
(C-30), 122.47 (C-500), 120.99, (C-2) 116.99 (C-600), 115.95
(C-400), 113.47 (C-40), 110.94 (C-200) and 55.34 (OCH3).
(E)-3-(4-Dimethylaminophenyl)-1-(1H-pyrrol-2-yl)prop-2-
en-1-one (12) MS: M? at m/z 240. Anal. Calcd for
C15H16N2O: C, 74.97; H, 6.71; N, 11.66 %. Found: C,
1
75.85; H, 6.78; N, 11.68 %. H NMR (500 MHz, CDCl3):
d 3.05 (s, 6H, –N(CH3)2), 6.33 (m, 1H, H-40), 6.70 (d, 2H,
J = 8.8 Hz, H-300 & H-500), 7.03 (m, 1H, H-30), 7.05 (m,
1H, H-50), 7.17 (d, 1H, J = 15 Hz, H-2), 7.54 (d, 2H,
J = 8.8 Hz, H-200 and H-600), 7.79 (d, 1H, J = 15.5, H-3),
9.55 [s, 1H, H-10 (–NH)]. 13C NMR (125 MHz, CDCl3): d
179.35 (C-1), 151.85 (C-400), 143.07 (C-3), 133.58 (C-20),
130.15 (C-200 and C-600), 124.54 (C-50), 122.89 (C-100),
116.90 (C-30), 115.26 (C-2), 111.89 (C-300 and C-500),
110.62 (C-40), 40.14 (–N(CH3)2).
(E)-3-(2-Bromophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(9) MS: M? at m/z 276. Anal. Calcd for C13H10BrNO: C,
73.99; H, 5.77; N, 6.16 %. Found: C, 74.12; H, 5.78; N,
5.17 %. 1H NMR (400 MHz, CDCl3): d 6.35 (m, 1H,
H-40), 7.09 (m, 1H, H-400), 7.17 (m, 1H, H-30), 7.28 (d, 1H,
J = 16.00 Hz, H-2), 7.35 (d, 1H, J = 8.70 Hz, H-600), 7.40
(d, 1H, J = 1.68 Hz, H-50), 7.62 (dd, 1H, J = 8.70 Hz and
1.60 Hz, H-500), 7.74 (dd, 1H, J = 8.70 Hz and 1.60 Hz,
H-300), 8.18 (d, 1H, J = 16.00 Hz, H-3), 10.5 (bs, 1H, NH).
13C NMR (100 MHz, CDCl3): 178.59 (C-1), 140.61 (C-3),
135.21 (C-100), 133.48 (C-400), 132.98 (C-20), 131.00 (C-300),
127.82 (C-600), 127.64 (C-500), 126.17 (C-50), 125.74 (C-2),
125.04 (C-30), 117.01 (C-200) and 111.04 (C-40).
(E)-3-(2,6-Dimethoxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-
1-one (13) MS: M? at m/z 257. Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44 %. Found: C,
70.16; H, 5.92; N, 6.55 %. 1H NMR (500 MHz, CDCl3): d
3.82 (s, 6H, (–OCH3)2), 6.35 (m, 1H, H-40), 6.91 (d, 1H,
J = 16.48 Hz, H-2), 6.94 (dd, 1H, J = 3.02 Hz and
5.9 Hz, H-30), 7.07 (m, 2H, H-300 and H-500), 7.16 (t, 1H,
J = 3.2 Hz, H-50), 7.42 (d, 1H, J = 16.48 Hz, H-3), 8.08
(dd, 1H, J = 8.00 Hz, H-400), 9.65 (s, 1H, NH). 13C NMR
(125 MHz, CDCl3): d 178.56 (C-1), 150.87 (C-200and
C-600), 143.48 (C-3), 135.76 (C-400), 133.17 (C-20), 129.80
(C-50), 125.96 (C-30), 123.87(C-2), 111.98 (C-40), 110.60
(C-100), 109.98 (C-300 and C-500), 55.95 (OCH3), 55.56
(OCH3).
(E)-3-(4-Fluorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(10) MS: M? at m/z 215. Anal. Calcd for C13H10FNO: C,
72.55; H, 4.68; N, 6.51 %. Found: C, 72.65; H, 4.72; N,
6.59 %. 1H NMR (400 MHz, CDCl3): d 6.34 (m, 1H,
H-40), 7.06 (d, 1H, J = 2.03 Hz, H-30), 7.10 (m, 2H, H-300
and H-500), 7.16 (m, 1H, H-50), 7.30 (d, 1H, J = 15.66 Hz,
H-2), 7.59 (m, 2H, H-200 and H-600), 7.80 (d, 1H,
(E)-3-(2-Chloro-5-nitrophenyl)-1-(1H-pyrrol-2-yl)prop-2-
en-1-one (14) MS: M? at m/z 276.5. Anal. Calcd for
C13H9ClN2O3: C, 56.43; H, 3.28; N, 10.13 %. Found: C,
1
56.56; H, 3.32; N, 10.43 %. H NMR (500 MHz, DMSO-
13
d6): d 6.33 (m, 1H, H-40), 7.25 (s, 1H, H-30), 7.55 (s, 1H,
H-50), 7.84 (d, 1H, J = 8.8 Hz, H-300), 7.90 (d, 1H,
J = 15.5 Hz, H-2), 8.02 (d, 1H, J = 15.5 Hz, H-3), 8.22
(dd, 1H, J = 2.5 and 8.0 Hz, H-400), 8.93 (d, 1H,
J = 2.5 Hz, H-600). 13C NMR (125 MHz, DMSO-d6): d
176.70 (C-1), 146.85 (C-500), 140.14 (C-3), 134.01 (C-100),
133.41 (C-200), 132.80 (C-20), 131.30 (C-300), 128.32 (C-50),
127. 31 (C-600), 125.19 (C-30), 122.77 (C-2), 118.72 (C-400),
110.39 (C-40).
J = 15.66 Hz, H-3), 10.62 (bs, 1H, NH). C NMR
(100 MHz, CDCl3): 178.81 (C-1), 165.10 (C-400), 145.01
(C-3), 135.94 (C-20), 133.12 (C-100), 130.21 (C-200), 130.21
(C-600), 126.08 (C-50), 121.90 (C-30), 121.88 (C-2), 116.81
(C-300), 116.11 (C-500).
(E)-3-(4-Chlorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(11) MS: M? at m/z 213.5. Anal. Calcd for C13H10ClNO:
C, 67.39; H, 4.35; N, 6.05 %. Found: C, 67.34; H, 4.38; N,
6.13 %. 1H NMR (400 MHz, CDCl3): d 6.36 (m, 1H,
H-40), 7.07 (m, 1H, H-30), 7.12 (m, 1H, H-50), 7.31 (d, 1H,
J = 15.69 Hz, H-2), 7.54 (d, 2H, J = 8.0 Hz, H-300 and
H-500), 7.59 (d, 2H, J = 8 Hz, H-200 and H-600), 7.75 (d, 1H,
J = 15.6 Hz, H-3), 9.73 [bs, 1H, H-10 (NH)]. 13C NMR
(100 MHz, CDCl3): 178.67 (C-1), 140.79 (C-3), 136.04 (C-
400), 133.56 (C-100), 133.08 (C-20), 132.94 (C-50), 129.17
(E)-3-(2-Chlorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(15) MS: M? at m/z 231.5. Anal. Calcd for C13H10ClNO:
C, 67.39; H, 4.35; N, 6.05 %. Found: C, 67.55; H, 4.36; N,
6.08 %. 1H NMR (500 MHz, CDCl3): d 6.35 (m, 1H,
H-40), 7.10 (m, 1H, H-400), 7.11 (s, 1H, H-500), 7.18 (s, 1H,
H-30), 7.30 (m, 2H, H-300 and H-600), 7.34 (d, 1H,
123

3978
Med Chem Res (2013) 22:3969–3983
J = 15.8 Hz, H-2), 7.74 (m, 1H, H-50), 8.23 (1H, d,
J = 15. 8 Hz, H-3), 10.59 (bs, 1H, NH). 13C NMR
(125 MHz, CDCl3): d 178.68 (C-1), 138.04 (C-3), 135.32
(C-100), 133.36 (C-20), 133.00 (C-200), 130.86 (C-400), 130.22
(C-300), 127.70 (C-600), 127.02 (C-50), 126.32 (C-500), 124.77
(C-30), 117.15 (C-2), 111.02 (C-40).
C15H15NO3: C, 70.02; H, 5.88; N, 5.44 %. Found: C,
1
70.12; H, 5.92; N, 5.51 %. H NMR (500 MHz, DMSO-
d6): d 3.86 (s, 6H, (OCH3)2), 6.27 (d, 1H, J = 2.45 Hz,
H-40), 7.01 (d, 1H, J = 8.35 Hz, H-500), 7.15 (s, 1H, H-200)
7.35 (dd, 1H, J = 1.83 and 8.35 Hz, H-600), 7.38 (m, 1H,
H-300), 7.48 (d, 1H, J = 1.74 Hz, 50), 7.56 (d, 1H,
J = 15.84 Hz, H-2), 7.64 (1H, d, J = 15.84 Hz, H-3),
10.55 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6): d
177.83 (C-1), 150.68 (C-300), 148.8 (C-400), 140.98 (C-3),
133.07 (C-20), 127.60 (C-100), 125.94 (C-50), 123.07 (C-30),
120.60 (C-2), 116.96 (C-600), 111.44 (C-500), 110.50 (C-40),
109.88 (C-200), 55.59 (OCH3), 55.45 (OCH3).
(E)-3-(4-Bromophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(16) MS: M? at m/z 276. Anal. Calcd for C13H10BrNO:
C, 56.55; H, 3.65; N, 5.07 %. Found: C, 56.59; H, 3.68; N,
1
5.17 %. H NMR (500 MHz, DMSO-d6): d 6.31 (m, 1H,
H-40), 7.21 (dd, 1H, J = 1.47 and 0.56 Hz, H-30), 7.42 (dd,
1H, J = 1.11 and 2.6 Hz, H-50), 7.64 (d, 1H,
J = 15.76 Hz, H-2), 7.65 (d, 2H, J = 8.36 Hz, H-200 and
H-600), 7.76 (d, 1H, J = 15.7 Hz, H-3), 7.83 (d, 2H,
J = 8.36 Hz, H-300 and H-500), 10.59 (bs, 1H, NH). 13C
NMR (125 MHz, DMSO-d6): d 177.49 (C-1), 139.28
(C-3), 134.08 (C-100), 132.91 (C-20), 131.74 (C-300and
C-500), 130.35 (C-200and C-600), 126.60 (C-50), 123.75
(C-30), 123.29 (C-400), 117.62 (C-2), 110.22 (C-40).
(E)-3-(Benzo[d][1,3]dioxol-6-yl)-1-(1H-pyrrol-2-yl)prop-
2-en-1-one (20) MS: M? at m/z 242. Anal. Calcd for
C14H11NO3: C, 69.70; H, 4.60; N, 5.81 %. Found: C,
1
69.79; H, 4.67; N, 5.89 %. H NMR (500 MHz, CDCl3):
6.03 (s, 2H, O–CH2–O), 6.35 (m, 1H, H-40), 6.98 (m, 1H,
H-30), 7.13 (d, 1H, J = 8.04 Hz, H-50), 7.18 (d, 1H,
J = 15.62 Hz, H-2), 7.74 (d, 1H, J = 15.62 Hz, H-3)
10.55 (s, 1H, NH). 13C NMR (125 MHz, CDCl3) 177.89
(C-1), 152.59 (C-300), 152.09 (C-400), 52.05 (C-200), 140.9
(C-3), 133.24 (C-20), 128.28 (C-50), 126.29 (C-30), 123.95,
(C-500), 123.05 (C-2), 120.89 (C-600), 118.52 (C-100), 115.92
(C-40), 102.61 (OCO).
(E)-3-(2,4-Dimethoxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-
1-one (17) MS: M? at m/z 257. Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44 %. Found: C,
1
70.12; H, 5.91; N, 5.51 %. H NMR (500 MHz, DMSO-
d6): d 3.84 (s, 6H, (–OCH3)2), 6.26 (m, 1H, H-40), 6.63 (m,
2H, H-300 and H-500), 7.14 (m, 1H, H-30), 7.27 (dd, 1H,
J = 1.05 and 2.5 Hz, H-50), 7.54 (d, 1H, J = 15.77 Hz,
H-2), 7.37 (d, 1H, J = 8.52 Hz, H-600), 7.92 (d, 1H,
J = 15.77 Hz, H-3), 10.55 (s, 1H, NH) .13C NMR
(125 MHz, DMSO-d6): d 178.10 (C-1), 162.49 (C-400),
159.46 (C-2000), 135.18 (C-3), 133.15 (C-20), 129.42 (C-50),
125.73 (C-3 ), 120.06 (C-600), 116.47 (C-2), 115.97 (C-400),
109.91 (C-100), 106.09 (C-500), 98.16 (C-300), 55.86 (OCH3),
55.71 (OCH3).
(E)-3-(2-Chlorophenyl)-1-(furan-2-yl)prop-2-en-1-one
(21) MS: M? at m/z 232.5. Anal. Calcd for C13H9ClO2:
C, 67.11; H, 3.90 %. Found: C, 67.20; H, 3.89 %. 1H NMR
(400 MHz, CDCl3): d 6.61 (dd, 1H, J = 1.8 & 3.5 Hz,
H-40), 7.21(m, 3H, H-40’, H-500 and H-30), 7.37 (m, 2H,
H-30’, H-60’), 7.58 (d, 1H, J = 16.04 Hz, H-2), 7.78 (bs,
1H, H-50), 7.95 (d, 1H, J = 16.04 Hz, H-3). 13C NMR
(100 MHz, CDCl3): d 177.25 (C-1), 153.63 (C-20), 149.82
(C-50), 140.23 (C-3), 133.25 (C-200), 133.07 (C-100), 132.05
(C-400), 131.83 (C-300), 128.52 (C-600), 127.76 (C-500),
122.52 (C-2), 122.12 (C-30), 112.6 (C-40).
(E)-13-(4-Methoxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-
one (18) MS: M? at m/z 228. Anal. Calcd for
C14H13NO2: C, 73.99; H, 5.77; N, 6.11 %. Found: C,
74.03; H, 5.80; N, 6.15 %. 1H NMR (500 MHz, CDCl3): d
3.90 (s, 3H, –OCH3), 6.35 (m, 1H, H-40), 6.94 (d, 2H,
J = 8.76 Hz, H-300 and H-500), 7.06 (m, 1H, H-30), 7.09 (m,
1H, H-50), 7.25 (d, 1H, J = 15.67, H-2), 7.60 (d, 2H,
J = 8.76 Hz, H-200 and H-600), 7.81 (d,1H, J = 15.67, H-3),
10.59 (s, 1H, NH). 13C NMR (125 MHz, CDCl3): d 178.28
(C-1), 163.48 (C-400), 136.21 (C-3), 133.49 (C-20), 131.92
(C-20 and C-600), 128.56 (C-100), 127.58 (C-50), 125.98 (C-
30), 120.06 (C-2), 118.89 (C-300 and C-500), 115.82 (C-40),
55.71 (OCH3).
(E)-3-(2-Bromophenyl)-1-(furan-2-yl)prop-2-en-1-one
(22) MS: M? at m/z 277. Anal. Calcd for C13H9BrO2: C,
1
56.34; H, 3.27 %. Found: C, 56.42; H, 3.29 %. H-NMR
(400 MHz, DMSO-d6): d 6.60 (m, 1H, H-40), 7.35 (m, 1H,
H-30), 7.44 (d, 1H, J = 16.01 Hz, H-2), 7.55 (m, 4H, H-300,
H-400, H-500 and H-600), 7.66 (m, 1H, H-50), 7.84 (d, 1H,
J = 16.01 Hz, H-3). 13C NMR (100 MHz, DMSO-d6): d
177.73 (C-1), 153.62 (C-20), 146.63 (C-50), 142.53 (C-3),
135.80 (C-100), 133.66 (C-400), 132.21 (C-300), 129.87 (C-
600), 129 0.04 (C-500), 124.89 (C-200), 121.71 (C-2),121.24
(C-30), 112.66 (C-40).
(E)-3-(3,4-Dimethoxyphenyl)-1-(1H-pyrrol-2-yl)prop-2-
en-1-one (19) MS: M? at m/z 258. Anal. Calcd for
(E)-3-(4-fluorophenyl)-1-(furan-2-yl)prop-2-en-1-one
(23) MS: M? at m/z 216. Anal. Calcd for C13H9FO2: C,
123

Med Chem Res (2013) 22:3969–3983
3979
1
1
72.22; H, 4.20 %. Found: C, 73.38; H, 4.19 %. H-NMR
(500 MHz, CDCl3): d 6.59 (m, 1H, H-40), 7.09 (d, 1H,
J = 8.62 Hz, H-300), 7.11 (d, 1H, J = 8.62 Hz, H-500), 7.34
(d, 1H, J = 3.52 Hz, H-30), 7.38 (d, 1H, J = 15.76 Hz,
H-2), 7.62 (d, 1H, J = 8.62 Hz, H-200), 7.63 (d, 1H,
J = 8.62 Hz, H-600), 7.65 (d, 1H, J = 1.64 Hz, H-50), 7.83
(d, 1H, J = 15.76 Hz, H-3). 13C NMR (500 MHz, CDCl3):
d 177.81 (C-1), 165.08 (C-400), 153.61 (C-20), 146.60 (0C0 -
50), 142.63 (C-3), 130.98 (C-100), 130.42 (C-200 and C-6 ),
120.84 (C-2), 120.83 (C-30), 116.20 (C-300 and C-500),
112.62 (C-40).
5.09 %. Found: C, 78.81; H. 5.11 %. H NMR (400 MHz,
CDCl3): d 6.62 (m, 1H, H-40), 7.38 (dd, 1H, J = 1.4 Hz
and 3.2 Hz, H-30), 7.45 (d, 1H, J = 2.0 Hz, H-50), 7.47 (m,
2H, H-300, H-500), 7.48 (d, 1H, J = 16.02 Hz, H-2), 7.68 (m,
3H, H-400, H-200 and 600), 7.92 (d, 1H, J = 16.02 Hz,
H-3).13C NMR (100 MHz, CDCl3): d 178.00 (C-1), 153.71
(C-20), 146.54 (C-40), 143.97 (C-3), 134.73 (C-100), 130.61
(C-400), 128.95 (C-300and C-500), 128.53 (C-200 and C-600),
121.18 (C-2), 117.52 (C-30), 112.55 (C-40).
(E)-3-(2-Chloro-5-nitrophenyl)-1-(furan-2-yl)-prop-2-
en-1-one (28) MS: M? at m/z 277.5. Anal. Calcd for
C13H8ClNO4: C, 56.23; H, 2.90; N, 5.04 %. Found: C,
56.37; H, 2.95; N, 5.14 %. 1H NMR (500 MHz, CDCl3): d
6.66 (m, 1H, H-40), 7.45 (d, 1H, J = 3.5 Hz, H-30), 7.58
(d, 1H, J = 15.02 Hz, H-2), 7.65 (d, 1H, J = 8.32 Hz,
H-300), 7.73 (d, 1H, J = 1.24 Hz, H-50), 8.17 (m, 1H,
H-400), 8.21 (d, 1H, J = 15.7 Hz, H-3), 8.63 (d,
J = 2.62 Hz, 1H, H-600). 13C NMR (125 MHz, CDCl3): d
176.97 (C-1), 153.22 (C-20), 147.39 (C-50), 146.78 (C-500),
141.89 (C-3), 137.26 (C-200), 134.62 (C-100), 132.40 (C-300),
126.13 (C-600), 125.20 (C-400), 122.58 (C-30), 118.83 (C-2),
113.30 (C-40).
(E)-3-(4-chlorophenyl)-1-(furan-2-yl)prop-2-en-1-one
(24) MS: M? at m/z 232.5. Anal. Calcd for C13H9ClO2:
C, 67.11; H, 3.90 %. Found: C, 67.28; H, 3.88 %. 1H NMR
(200 MHz, CD3OD): d 6.63 (m, 1H, H-400), 7.28 (m, 5H,
H-200, 300, 500, 600 and 300), 7.43 (d, 1H, J = 15.78 Hz, H-2),
7.72 (d, 1H, J = 1.64 Hz, H-50), 7.79 (d, 1H,
J = 15.78 Hz, H-3). 13C NMR (100 MHz, CD3OD): d
177.86 (C-1), 152.91 (C-20), 148.53 (C-50), 144.65 (C-3),
134.34 (C-40), 134.02 (C-10) 129.18 (C-200 and C-600),
130.67(C-300 and 500), 120.89 (C-30), 120.08 (C-2), 111.92
(C-40).
(E)-3-(4-Dimethylaminophenyl)-1-(furan-2-yl)prop-2-en-
1-one (25) MS: M? at m/z 241. Anal. Calcd for
C15H15NO2: C, 67.11; H, 3.90 %. Found: C, 67.18; H,
(E)-3-(2, 3-Dimethoxy-phenyl)-1-(furan-2-yl)prop-2-en-1-
one (29) MS: M? at m/z 258. Anal. Calcd for C15H14O4:
C, 69.76; H, 5.46 %. Found: C, 69.98; H, 6.60 %. 1H NMR
(400 MHz, CDCl3): d 3.81 (s, 6H, 2 9 –OCH3), 6.61 (m,
1H, H-40), 7.00 (m, 1H, H-500), 7.21 (d, 1H, J = 8.00 Hz,
H-600), 7.29 (d, 1H, J = 3.5 Hz, H-30), 7.42 (d, 1H,
J = 15.67 Hz, H-2), 7.65 (d, 1H, J = 8.00 Hz, H-400), 7.73
(d, 1H, J = 1.23 Hz, H-50), 8.21 (d, 1H, J = 15.67 Hz,
H-3). 13C NMR (100 MHz, CDCl3): d 176.19 (C-1),
153.22 (C-20), 148.56 (C-5000), 147.39 (C-300), 145.05 (C-200),
141.45 (C-3), 122.85 (C-5 ), 121.58 (C-2), 120.66 (C-600),
122.02 (C-30), 118.84 (C-100), 113.30 (C-400), 113.04 (C-40),
55.96 (200-OCH3), 55.34 (30’-OCH3).
1
3.85 %. H NMR (400 MHz, DMSO-d6): d 3.43 [s, 6H,
N(CH3)2], 6.72 (m, 1H, H-40), 6.78 (d, 2H, J = 8.02 Hz,
H-300 and H-500), 7.40 (d, 1H, J = 15.07 Hz, H-2), 7.63 (d,
1H, J = 2.01 Hz, H-30), 7.65 (d, 1H, J = 15.07 Hz, H-3),
7.67 (d, 2H, J = 8.02 Hz, H-200 and H-600), 7.94 (m, 1H,
H-50). 13C NMR (100 MHz, DMSO-d6): d 177.18 (C-1),
153.90 (C-20), 152.49 (C-50), 147.96 (C-400), 144.36 (C-3),
131.13 (C-200 and C-600), 122.18 (C-100), 118.36 (C-2),
116.41 (C-30), 112.99 (C-40), 112.22 (C-300 and C-500),
40.38 (CH3)2.
(E)-3-(3-Nitrophenyl)-1-(furan-2-yl)-prop-2-en-1-one
(26) MS: M? at m/z 211. Anal. Calcd for C13H9NO2: C,
64.20; H, 3.73; N, 5.76 %. Found: C, 64.28; H, 3.75; N,
(E)-3-(Benzo[d][1,3]dioxol-6-yl)-1-(furan-2-yl)prop-2-en-
1-one (30) MS: M? at m/z 242. Anal. Calcd for
C14H10O4: C, 69.42; H, 4.16 %. Found: C, 69.65;
1
1
5.86 %. H NMR (400 MHz, DMSO-d6): d 6.80 (bs, 1H,
H,4.26 %. H NMR (400 MHz, CDCl3): d 6.03 (s, 2H,
H-40), 6.98 (d, 1H, J = 15.82 Hz, H-2), 7.74 (m, 1H, H-30),
7.57 (m, 1H, H-500), 7.78 (m, 3H, H-3, H-600, H-50), 8.26 (m,
2H, H-400 and H-200). 13C NMR (100 MHz, DMSO-d6): d
176.2 (C-1), 152.71 (C-20), 148.77 (C-30), 148.36 (C-300),
140.32 (C-3), 136.28 (C-100), 134.89 (C-600), 130.31 (C-500),
124.62 (C-2 and C-200), 122.86 (C-30), 120.37 (C-400),
112.75 (C-40).
–OCH2O–), 6.70 (dd, 1H, J = 1.62 and 3.55 Hz, H-40),
6.88 (d, 1H, J = 8.05 Hz, H-500), 7.19 (d, 1H, J = 1.46 Hz,
H-200), 7.34 (bs, 1H, H-600), 7.45 (d, 1H, J = 15.61 Hz,
H-2), 7.56 (d, 1H, J = 3.55 Hz, H-30), 7.76 (d, 1H,
J = 15.61 Hz, H-3), 7.85 (d, 1H, J = 1.62 Hz, H-50). 13C
NMR (100 MHz, CDCl3): d 177.29 (C-1), 153.29 (C-20),
149.82 (C-50), 149.25 (C-300), 148.73 (C-400), 140.52 (C-3),
123.52 (C-500), 122.24 (C-2), 121.82 (C-30), 120.25 (C-600),
116.92 (C-100), 113.26 (C-200), 112.83 (C-40), 102.54
(OCH2O–).
(E)-3-(Phenyl)-1-(furan-2-yl)prop-2-en-1-one (27) MS :
M? at m/z 198. Anal. Calcd for C13H10O2: C, 78.77; H.
123

3980
Med Chem Res (2013) 22:3969–3983
(E)-3-(3,4-Dimethoxyphenyl)-1-(furan-2-yl)prop-2-en-1-one
(31) MS: M? at m/z 258. Anal. Calcd for C15H14O4: C,
(E)-3-(3,4,5-Trimethoxyphenyl)-1-(furan-2-yl)prop-2-en-1-
one (35) MS: M? at m/z 288. Anal. Calcd for C16H16O5:
C, 66.66; H, 5.59 %. Found: C, 69.76; H, 5.56 %. 1H NMR
(200 MHz, CDCl3): d 3.81 (s, 3H, –OCH3), 3.91 (s, 6H,
2 9 –OCH3), 6.71 (dd, 1H, J = 1.63 and 3.58 Hz, H-40),
7.08 (s, 2H, H-200 and H-600), 7.55 (d, 1H, J = 15.67 Hz,
H-2), 7.63 (d, 1H, J = 3.58 Hz, H-30), 7.78 (d, 1H,
J = 15.67 Hz, H-3), 7.87 (bs, 1H, H-50). 13C NMR
(100 MHz, CDCl3): d 177.82 (C-1), 162.34 (C-300and
C-500), 153.63 (C-20), 149.38 (C-50), 140.59 (C-3), 140.13
(C-400), 129.56 (C-100), 122.56 (C-2), 121.89 (C-30), 113.23
(C-40), 110.6 (C-200and C-600), 56.52(OCH3), 56.23
(OCH3)2.
1
69.76; H, 5.46 %. Found: C, 69.88; H, 6.51 %. H NMR
(500 MHz, CDCl3): d 3.89 (s, 3H, -OCH3), 3.92 (s, 3H,
–OCH3), 6.71 (dd, 1H, J = 1.65 and 3.51 Hz, H-40), 7.02
(d, 1H, J = 8.24 Hz, H-500), 7.46 (m, 4H, H-30, H-200, H-600
and H-2), 7.81 (d, 1H, J = 14.60 Hz, H-3), 7.85 (bs, 1H,
H-50). 13C NMR (125 MHz, CDCl3): 178.43 (C-1), 154.196
(C-20), 151.86 (C-50), 149.57 (C-30’), 148.67 (C-400), 144.49
(C-3), 128.07 (C-100), 123.76 (C-2), 119.34 (C-30), 117.55
(C-600), 112.88 (C-500), 114.4 (C-40), 110.42 (C-200), 56.36
(OCH3)2.
(E)-3-(4-Nitrophenyl)-1-(furan-2-yl)prop-2-en-1-one (32)
MS: M? at m/z 243 Anal. Calcd for C13H9NO4: C,
64.20; H, 3.74; N, 5.76 %. Found: C, 64.31; H, 3.78; N,
(E)-3-(2,5-Dimethoxyphenyl)-1-(furan-2-yl)prop-2-en-1-one
(36) MS: M? at m/z 258. Anal. Calcd for C15H14O4: C,
1
69.76; H, 5.46 %. Found: C, 69.88; H, 5.51 %. H NMR
1
5.87 %. H NMR (400 MHz, DMSO-d6): d 6.83 (m, 1H,
(200 MHz, CDCl3): d 3.88 (s, 6H, 2 9 –OCH3), 6.72 (dd,
1H, J = 1.58 and 3.61 Hz, H-40), 7.13 (m, 2H, H-300 and
H-400), 7.43 (m, 1H, H-600), 7.56 (bs, 1H, H-30), 7.62 (d, 1H,
J = 15.93 Hz, H-2), 7.88 (bs, 1H, H-50), 8.16 (d, 1H,
J = 15.93 Hz, H-3).13C NMR (100 MHz, CDCl3): d 177.45
(C-1), 162. 43 (C-500), 162.03 (C-200), 153.23 (C-20), 149.82
(C-500), 140.25 (C-3), 121.46 (C-2), 121.35 (C-30), 116.25
(C-1 ’), 115.26 (C-300), 115.03 (C-400), 112.39 (C-40), 111.37
(C-600), 55.93 (OCH3), 55.23 (OCH3).
H-40), 7.82 (d, 1H, J = 15.18 Hz, H-2), 7.90 (d, 1H,
J = 3.8 Hz, H-30), 8.11 (d, 1H, J = 1.6, H-50), 8.14 (d, 2H,
J = 8.8 Hz, H-200 & H-600), 8.20 (d, 1H, J = 15.18 Hz,
H-3), 8.29 (d, 2H, J = 8.8 Hz, H-300 and H-500). 13C NMR
(100 MHz, DMSO-d6): d 176.14 (C-1), 152.7 (C-20),
148.94 (C-50), 148.08 (C-400), 140.88 (C-3), 139.99 (C-100),
129.76 (C-200and C-600), 125.89 (C-2), 123.93 (C-300 and
C-500), 120.51 (C-30), 112.87 (C-40).
X-ray studies
(E)-3-(4-Bromophenyl)-1-(furan-2-yl)prop-2-en-1-one (33)
MS: M? at m/z 277 Anal. Calcd for C13H9BrO2: C,
1
The crystal of compound 9 used for data collection was of the
dimension 0.3 9 0.2 9 0.1 mm. X-ray intensity data of
6,806 reflections (of which 2,673 were unique) were col-
lected. The cell dimensions were determined by least-square
fit of angular settings of 2,440 reflections in the h range
2.59ꢁ–27.45ꢁ. The structure was solved by direct methods
using SHELXS97 (Hijova, 2006). All the hydrogen atoms
were located on a difference electron density map and their
positional and isotropic thermal parameters were included in
the refinement. The final refinement cycles converged to an
R = 0.0343 and wR(F2) = 0.0879 for the observed data
0.59. The crystallographic data are summarized in Table 2.
CCDC-776070 contains the supplementary crystallographic
data for this paper.
56.34, 3.27, H, 5.46 %. Found: C, 56.49, H, 3.29 %. H
NMR (400 MHz, CDCl3): d 6.60 (m, 1H, H-40), 7.35 (dd,
1H, J = 1.6 & 3.2, H-30), 7.44 (d, 1H, J = 16 Hz, H-2),
7.5 (dd, 2H, J = 8.02 Hz and 1.63 Hz, H-200 and H-600),
7.66 (m, 1H, H-50), 7.72 (dd, 2H, J = 8.02 Hz and
1.63 Hz, H-30’ and H-500), 7.84 (d, 1H, J = 16 Hz, H-3).
13C NMR (100 MHz, CDCl3): d 177.73 (C-1), 153.62
(C-20), 146.63 (C-50), 142.53 (C-3), 133.66 (C-100), 132.21
(C-300 and 500), 129.87 (C-200 and 600), 124.89 (C-400), 121.71
(C-2), 117.68 (C-30), 112.66 (C-40).
(E)-3-(4-Methoxyphenyl)-1-(furan-2-yl)prop-2-en-1-one (34)
MS: M? at m/z 228. Anal. Calcd for C14H12O3: C, 73.67;
H, 5.30 %. Found: C, 73.81; H, 5.34 %. 1H NMR
(400 MHz, CDCl3): d 3.83 (s, 3H, –OCH3), 6.58 (dd,
J = 1.68, 2.01 Hz, 1H, H-40), 6.92 (m, 2H, H-300 and
H-500), 7.30 (d, 1H, J = 4.4 Hz, H-30), 7.32 (d,
J = 16.0 Hz, H-2), 7.60 (m, 2H, H-200 and H-600), 7.63 (m,
In vitro combination (EPI) study of ciprofloxacin
in combination with compounds
The ciprofloxacin/compounds’ combination studies were
performed on S. aureus 1199B in Mueller–Hinton broth
(Difco). The MIC of ciprofloxacin was determined in the
presence of increasing concentrations of compounds by the
broth checkerboard method in microtiter plates (Lawrence
et al., 2006). The twofold serial dilutions of ciprofloxacin
13
1H, H-50), 7.84 (d, 1H, J = 16 Hz, H-3). C NMR
(100 MHz, CDCl3): d 178.16 (C-1), 161.76 (C-400), 153.86
(C-20), 146.32 (C-50), 143.82 (C-3), 130.34 (C-200 and
C-600), 127.48 (C-100), 118.85 (C-2), 117.35 (C-30), 114.43
(C-300 and C-500), 112.4 (C-40), 55.41 (OCH3).
123

Med Chem Res (2013) 22:3969–3983
3981
ranging from 0.03 to 16 lg/mL were tested in combination
with compounds at seven different concentrations
(0.78–50 lg/mL). The final bacterial inoculum of 5 9 105
cfu/mL was added to each well. The plates were incubated
for 18 h at 37 ꢁC and the wells were assessed visually for
growth. The minimum concentration of compounds that
produced the maximal reduction in the MIC of ciproflox-
acin was determined. The minimal effective concentration
(MEC) was determined to be the minimal concentration of
EPI that produced the maximal reduction in substrate MIC.
No further decrease in substrate MIC was observed at EPI
concentrations greater than the MEC (Sheldrick, 1997).
house. They were fed with a pellet diet and water ad libi-
tum during the course of experimentation. The light cycle
was automatically controlled for a 12-h light and dark cycle
(on at 7.00 a.m. and off at 7.00 p.m.). Room temperature
was regulated at 26 1 ꢁC. The animals were housed in
such conditions for 3–4 days prior to the experimentation
for acclimatization.
Preparation of test material
The test material was prepared freshly as fine homogenized
suspension in 2 % gum acacia (w/v) for administration.
Anticancer activity
Carrageenan-induced inflammation assay
Cell culture, growth conditions, and treatment
Edema was induced in groups of four rats by injecting
100 lL of 1 % (w/v) freshly prepared carrageenan solution
in normal saline into the sub-planter region of the left hind
paw, while the right paw received an equal volume of
normal saline. Test compounds were administered orally
45 min. before carrageenan injection at 100 mg/kg. The
volume of the paw was measured immediately and 4 h
after carrageenan injection with a volume differential meter
model 7101, Ugo Basile (Italy). Percent inhibition of the
test compound was calculated.
All the cancer cell lines (HL-60, MOLT-4, PC-3, and
HeLa) were obtained from the National Cancer Institute
(NCI), Bethesda, USA. The cells were grown in RPMI-
1640 medium supplemented with 10 % heat inactivated
fetal bovine serum (FBS), penicillin (100 units/mL),
streptomycin (100 lg/mL), L-glutamine (0.3 mg/mL),
pyruvic acid (0.11 mg/mL), and 0.37 % NaHCO3. Cells
were grown in CO2 incubator (Thermocon Electron Cor-
poration, USA) at 37 ꢁC in an atmosphere of 95 % air and
5 % CO2 with 98 % humidity. Compounds (1–36) were
dissolved in DMSO and delivered to cell culture in a
complete medium.
Statistical evaluation
The numerical values were expressed as Mean SEM of
the difference between the vehicle control and treatment
groups, unless otherwise specified.
Cell proliferation assay
HL-60 and MOLT-4 cells were plated in 96-well plates at the
density of 15,000 cells per well/200 lL of the medium.
Adherent cells (PC-3 and HeLa)were treated whenthey were
75 % confluent in 96-well plates. Cultures were treated
with four different concentrations (1 lm, 10 lm, 30 lm,
and 100 lm) of compounds (1–36) for 48 h to determine
IC50 values. 20lL of MTT (3-(4,5-dimethylthiazole-2-yl)-
2,5-diphenyltetrazolium bromide) of concentration (2.5 mg/
mL) was added to each well and incubated at 37 ꢁC for 3 h.
The plates were centrifuged at 2,000 rpm for 15 min, and the
supernatant was discarded and the MTT formazan crystals
were dissolved in 150 lL of DMSO. Plates were shaken on a
shaker for 3 min and then incubated at 37 ꢁC for 5 min. The
OD measured at 570 nm.
In vitro antioxidant activity (DPPH method)
Test solution was prepared by dissolving DPPH solution
45 lg/mL in methanol, while samples were prepared in
D.W. (distilled water)/methanol/PBS. Standard ascorbic
acid was prepared (Ascorbic acid 10 mg/mL or 1 mg/mL
stock solution dissolved in distilled water). The free radical
scavenging activity of EPA was measured in terms of the
hydrogen donating or radical scavenging ability using the
stable radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). 0.
1 mM solution of DPPH in ethanol was used. For the assay,
the reaction mixture contained 10 lL of the test drug in
990 lL of DPPH solution in 48-well microtiter plates and
incubated at room temperature for 30 min (Lee and Chung).
Absorbance was measured at 517 nm in an ELISA reader
(Thermo multiscan spectrum). The capacity to scavenge
DPPH radical was calculated. DPPH was dissolved in
methanol and sonicated for 5 min to obtain the stable free
radical DPPH•. The test compounds were diluted in different
concentrations with the DPPH• solution in a 48-well
microplate. Ascorbic acid was used as control in each series.
Anti-inflammatory activity
Animal
Wistar rats (12–16-week old, weighing between 130 and
150 mg) were housed in polycarbonate cages in the animal
123

3982
Med Chem Res (2013) 22:3969–3983
Fukai T, Marumo A, Kaitou K, Kanda T, Terada S, Nomura T (2002)
Anti-Helicobacter pylori flavonoids from licorice extract. Life
Sci 71:1449–1463
Hatano T, Shintani Y, Aga Y, Shiota S, Tsuchiya T, Yoshida T (2000)
Phenolic constituents of licorice. viii. Structures of glicophenone
and glicoisoflavanone, and effects of licorice phenolics on
methicillin-resistant Staphylococcus aureus. Chem Pharm Bull
48:1286–1292
The compounds 1–36 were tested in triplicate at different
concentrations, such that a 50 % fall in absorbance of the
DPPH• could be calculated. The absorbance of the reaction
mixture was measured after 20-min incubation at room
temperature using a microplate ELISA reader at 517 nm.
The IC50 of each sample was determined and compared with
standard ascorbic acid.
Hijova E (2006) Bioavailability of chalcones. Bratisl Lek Listy
107:80–84
Ilango K, Valentina P, Saluja G (2010) Synthesis and In vitro anti-
cancer activity of some substituted Chalcone derivatives. Res J
Pharm Biol Chem Sci 1:354–359
Jasinski JP, Butcher RJ, Narayana B, Veena K, Yathirajan HS (2009)
(2E)-1-(3-Chlorophenyl)-3-(4-chlorophenyl)prop-2-en-1-one.
Acta Cryst E65:2641–2642
Joshi AS, Li XC, Nimrod AC, ElSohly HN, Walker LA, Clark AM
(2001) Dihydrochalcones from Piper longicaudatum. Planta
Med 67:186–188
Kaatz GW, Seo SM (1995) Inducible NorA-mediated multidrug
resistance in Staphylococcus aureus. Antimicrob Agents Che-
mother 39:2650–2655
Molecular modeling
The coordinates of tubulin complexed with colchicine were
obtained from a protein data bank (PDB entry: 1SA0). The
structure of compound 25 was drawn in MOE and sub-
jected to energy minimization using MMFF94x force field.
The ligands were docked at the colchicine-binding site of
tubulin using the GOLD 4.0.1. Gold performs genetic
algorithm-based ligand docking to optimize the confor-
mation of the ligand at the receptor-binding site. It utilizes
GOLD score fitness function to evaluate the various con-
formations of the ligand at the binding site and comprises
four components: protein–ligand hydrogen bond energy,
protein–ligand vander Waals (vdw) energy, ligand internal
energy, and ligand torsional strain energy.
Kaatz GW, Seo SM, Ruble CA (1993) Efflux-mediated fluoroquin-
olone resistance in Staphylococcus aureus. Antimicrob Agents
Chemother 37:1086–1094
Kaatz GW, Seo SM, Foster T (1999) Introduction of a norA promoter
region mutation into the chromosome of a fluoroquinolone-
susceptible strain of Staphylococcus aureus using plasmid
integration. Antimicrob Agents Chemother 43:2222–2224
Kromann H, Larsen M, Boesen T, SchØnning K, Nielsen SF (2004)
Synthesis of prenylated benzaldehydes and their use in the
synthesis of analogues of licochalcone A. Eur J Med Chem
3:1000–9993
References
Lawrence NJ, Patterson RP, Ooi LL, Cook D, Ducki S (2006) Effects
of alpha-substitutions on structure and biological activity of
anticancer chalcones. Bioorg Med Chem Lett 16:5844–5848
Li DQ (2008) 3-(4-Methoxyphenyl)-1-(2-pyrrolyl)prop-2-en-1-one.
Acta Cryst E64:1920
Li XZ, Nikaido H (2004) Efflux-mediated drug resistance in bacteria.
Drugs 64:159–204
Memurry LM, Petrucci REJ, Levy SB (1980) Active efflux of
tetracycline encoded by four genetically different tetracycline
resistance determinants in Escherichia coli. Proc Natl Acad Sci
77:3974–3977
Mustafa K, Kjaergaard HG, Perry NB, Weavers RT (2003) Hydrogen-
bonded rotamers of 20,40,60-trihydroxy-30-formyldihydrochal-
cone, an intermediate in the synthesis of a dihydrochalcone
from Leptospermum recurvum. Tetrahedron 59:6113–6120
Nardelli M (1995) PARST95 - an update to PARST: a system of
Fortran routines for calculating molecular structure parameters
from the results of crystal structure analyses. J Appl Cryst
28:659
Neyfakh AA, Borsch CM, Kaatz GW (1993) Fluoroquinolone
resistance protein NorA of Staphylococcus aureus is a multidrug
efflux transporter. Antimicrob Agents Chemother 37:128–129
Nielsen SF, Larsen M, Boesen T, SchØnning K, Kromann H (2005)
Cationic chalcone antibiotics. Design, synthesis, and mechanism
of action. J Med Chem 48:2667–2677
Achanta G, Modzelewska A, Feng L, Khan SR, Huang P (2006) A
Boronic-chalcone derivative exhibits potent anticancer activity
through inhibition of the proteasome. Mol Pharmacol 70:426–433
Bandgar BP, Gawande SS, Bodade RG, Totre JV, Khobragade CN
(2010) Synthesis and biological evaluation of simple methoxy-
lated chalcones as anticancer, anti-inflammatory and antioxidant
agents. Bioorg Med Chem 18:1364–1370
Belofsky G, Percivill D, Lewis K, Tegos GP, Ekart J (2004) Phenolic
metabolic of Dalea versicolor that enhance antibiotic activity
against multi-drug resistant bacteria. J Nat Prod 67:481–484
Bremner PD, Meyer JJ (1998) Pinocembrin chalcone: an antibacterial
compound from Helichrysum trilineatum. Planta Med 64:777
Bsasaif SA, Sobahi TR, Khalil AK, Hassan MA (2005) Stereoselective
crossed-aldol condensation of hetarylmethyl ketones with aro-
matic aldehydes in water: synthesis of (2E)-3-Aryl-1-hetarylprop-
2-en-1-ones. Bull Korean Chem Soc 26:1677–1681
Echeverria C, Santibanez JF, Donoso-Tauda O, Escobar CA, Tagle
RR (2009) Structural antitumoral activity relationships of
synthetic chalcones. Int J Mol Sci 10:221–231
Farrugia LJ (1997) ORTEP-3 for Windows—a version of ORTEP-III
with a Graphical User Interface (GUI). J Appl Cryst 30:565
Farrugia LJ (1999) WinGX suite for small-molecule single-crystal
crystallography. J Appl Cryst 32:837–838
´
´
´
´
´
´
Poole KJ (2005) Efflux-mediated antimicrobial resistance. J Antimic-
rob Chemother 56:20–51
Prasad YR, Kumar PR, Ramesh B (2007) Synthesis and antidepres-
sant activity of some new 3-(200-hydroxy naphthalen-100-yl)-5-
phenyl-2-Isoxazolines. Int J Chem Sci 5:542–548
Forejtnıkova H, Lunerova K, Kubınova R, Jankovska D, Marek R,
´
´
Kares R, Suchy V, Vondracek J, Machala M (2005) Chemopro-
tective and toxic potentials of synthetic and natural chalcones and
dihydrochalcones in vitro. Toxicology 208:81–93
¨
Friss-Moller A, Chen M, Fuursted K, Christensen SB, Kharazmi A
Radwan MAA, Abbas EMH (2009) Synthesis of some pyridine,
thiopyrimidine, and isoxazoline derivatives based on the pyrrole
moiety. Monatsh Chem 140:229–233
(2002) In vitro antimycobacterial and antilegionella activity of
licochalcone A from Chinese licorice roots. Planta Med 68:416–
419
123

Med Chem Res (2013) 22:3969–3983
3983
Rateb NM, Zohdi HF (2009) Atom-efficient, solvent-free, green
synthesis of chalcones by grinding. Synth Commun 39:
2789–2794
Szliszka E, Czuba ZP, Mazur B, Sedek L, Paradysz A, Krol W (2010)
Chalcones enhance TRAIL-induced apoptosis in prostate cancer
cells. Int J Mol Sci 11:1–13
Ravelli RBG, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A
(2004) Insight into tubulin regulation from a complex with
colchicine and a stathmin-like domain. Nature 428:198
Romagnoli R, Baraldi PG, Carrion MD, Cara CL, Cruz-Lopez O,
Preti D (2008) Design, synthesis, and biological evaluation of
thiophene analogues of chalcones. Bioorg Med Chem 16:5367–
5376
Tang SP, Kuang DZ, Feng YL, Li W, Chen ZM (2008) 3-[4-
(Dimethyl-amino)phenyl]-1-(2-pyrrolyl)prop-2-en-1-one. Acta
Cryst E64:1123
Tsukiyama RI, Katsura H, Tokuriki N, Kobayashi M (2002) Antibac-
terial activity of Licochalcone A against spore-forming bacteria.
Antimicrob Agents Chemother 46:1226–1230
Wong E (1968) The role of chalcones and flavanones in flavonoid
biosynthesis. Phytochemistry 7:1751–1758
Sheldrick GM (1997) SHELX97 University of Gottingen, Germany
123