Synthesis and biological evaluation of naphthalene, furan and pyrrole based chalcones as cytotoxic and antimicrobial agents

Article abstract of DOI:10.1007/s00044-011-9733-y

Chalcone is an aromatic ketone that forms the central core for a variety of important biological compounds, which are collectively known as chalcones. These show antibacterial, antifungal, antitumour and antiinflammatory properties, and also are intermediates in the biosynthesis of flavonoids, substances widespread in plants with an array of biological activities. These biaryl propenones show potent toxicity to several cancer cell lines and interact with tubulin at its colchicine-binding site. Tubulin binding molecules interfere with the dynamic instability of microtubules and thereby disrupt microtubule inducing cell cycle arrest in the M phase, forming abnormal spindles and finally leading to apoptotic cell death. Basically Chalcones consists of C₆-C₃-C₆ units but in the present study we report the reactions of 1-acetylnaphthalene, 2-acetylfuran and 2-acetylpyrrole with aldehydes, thus getting compounds akin to chalcones. 31 analogues have been synthesised and evaluated for cytotoxic potential against PC-3, OVCAR, IMR-32 and HEP-2. Compound 9 was found to be the most cytotoxic with inhibition ranging from 72 to 88% against the cell lines employed. The synthetics were also evaluated for antimicrobial activity and compound 25 was found to be the most potent. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9733-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2133–2140
DOI 10.1007/s00044-011-9733-y
ORIGINAL RESEARCH
Synthesis and biological evaluation of naphthalene, furan
and pyrrole based chalcones as cytotoxic and antimicrobial agents
•
Abhishek Budhiraja Kanika Kadian Mandeep Kaur
•
•
•
Vikas Aggarwal Atul Garg Sameer Sapra
•
•
•
Kunal Nepali O. P. Suri K. L. Dhar
•
Received: 4 May 2011 / Accepted: 25 June 2011 / Published online: 13 July 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Chalcone is an aromatic ketone that forms the
central core for a variety of important biological com-
pounds, which are collectively known as chalcones. These
show antibacterial, antifungal, antitumour and anti-
inflammatory properties, and also are intermediates in the
biosynthesis of flavonoids, substances widespread in plants
with an array of biological activities. These biaryl prope-
nones show potent toxicity to several cancer cell lines and
interact with tubulin at its colchicine-binding site. Tubulin
binding molecules interfere with the dynamic instability of
microtubules and thereby disrupt microtubule inducing cell
cycle arrest in the M phase, forming abnormal spindles and
finally leading to apoptotic cell death. Basically Chalcones
consists of C6–C3–C6 units but in the present study we
report the reactions of 1-acetylnaphthalene, 2-acetylfuran
and 2-acetylpyrrole with aldehydes, thus getting com-
pounds akin to chalcones. 31 analogues have been syn-
thesised and evaluated for cytotoxic potential against PC-3,
OVCAR, IMR-32 and HEP-2. Compound 9 was found to
be the most cytotoxic with inhibition ranging from 72 to
88% against the cell lines employed. The synthetics were
also evaluated for antimicrobial activity and compound 25
was found to be the most potent.
Keywords Chalcones ꢀ Cytotoxic ꢀ Cancer ꢀ Cell lines
Introduction
In the recent years, there has been a growing interest in
chalcones and their presumed role in the prevention of
various diseases such as cancer, chronic inflammation etc.
The term chalcone refers to the structurally simple and
largest class of plant secondary metabolites, which serve as
defense mechanism in plants to counteract reactive oxygen
species (ROS) to prevent damage by micro-organisms,
insects or herbivores (Vaya et al., 1997).
These flavonoid family compounds display an impres-
sive array of biological activities, amongst which anti-
bacterial (Vibhute and Basser, 2003), anti-fungal (Azad
et al., 2007), antioxidant (Dinkova et al., 2001; Rezk et al.,
2002), antileishmanial (Boeck et al., 2006), anti-malarial
(Lawrence et al., 2006), angiogenesis inhibitor (Nam et al.,
2003), anti-inflammatory (Won et al., 2005; Laskin and
Pendino, 1995), antiviral (Pandey et al., 2004), anti-mitotic
(Edwards et al., 1990), anticancer (Bhat et al., 2005), anti-
invasive (Mukherjee et al., 2001; Modzelewska et al.,
2005) and antiproliferative (Calliste et al., 2001) activities
have been citied in the literature. Chalcones strongly
inhibit the polymerization of tubulin by binding to the
colchicine-binding site (Lawrence et al., 2006).
A. Budhiraja ꢀ K. Kadian ꢀ M. Kaur ꢀ V. Aggarwal ꢀ S. Sapra ꢀ
K. Nepali (&) ꢀ O. P. Suri ꢀ K. L. Dhar (&)
Laboratory for Drug Design, I.S.F. College of Pharmacy,
Moga, Punjab, India
Chemically chalcones are open chain flavonoids in
which the two aromatic rings are joined together by three
carbons, a, b-unsaturated carbonyl system. Fundamentally
they are considered as derivatives of phenyl styryl ketone.
In view of the varied biological and pharmacological
applications, we synthesized some chalcone like, com-
pounds. Generally chalcones contain C6–C3–C6 unit but the
e-mail: Kunal_8855@rediffmail.com; kunalbvk3@gmail.com
K. L. Dhar
e-mail: researchgroupdhar@gmail.com
A. Garg
Department of Pharmaceutical Chemistry, Bharti Institute
of Pharmaceutical Sciences, Ganganagar, Rajasthan, India
123

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Med Chem Res (2012) 21:2133–2140
compounds reported in the present study contain C10–C3–C6
and C5–C3–C6 unit.
cell lines using sulforhodamine B19. The cells were
allowed to proliferate in the presence of test material for
48 h. From the data, it is clear that the compounds 8, 9 and
16 exhibited broad spectrum of cytotoxicity against all the
four cell lines (Table 1). Compound 9 was found to be the
most potent with inhibition ranging from 72 to 88% against
the four different cell lines.
Results and discussion
Synthesis of 1,3-diarylpropenones
Claisen–Schmidt condensation of a series of aryl ketones
(1) with aryl aldehydes (2) in ethanol yielded several
1,3-diarylpropenones (3; 65–94%) (Scheme 1). The prod-
ucts were recrystallized from methanol and characterized by
using spectroscopic techniques such as IR and NMR (Fig. 1).
Biological evaluation of synthesized compounds
for antimicrobial activity
The synthetics were also evaluated for antimicrobial
activity against five reference bacterial strains; Staphylo-
coccus aureus (MTCC 96), Bacillus subtilis (MTCC 2451),
Pseudomonas aeruginosa (MTCC 2642), Escherichia coli
(MTCC 82) and Salmonella typhi (MTCC 1251) and two
fungal strains; Aspergillus niger (MTCC 1344), Candida
albicans (MTCC 3018). The antimicrobial activity of
synthesized compound was determined by observing the
zone of inhibition in comparison to standard antibiotic
(Amoxicillin, Gentamycin) and a standard antifungal
(fluconazole) disc. On this basis, from the data shown in
Table 2, compounds 8 and 9 were found to be the most
potent amongst all test compounds with an MIC value
ranging from 3.9 to 125 lg/ml against the various micro-
bial strains employed.
Biological evaluation of synthesized compounds
for cytotoxic potential
All the synthetics were assayed for in vitro cytotoxicity
against PC-3, OVCAR, IMR-32 and HEP-2 human cancer
CH3
O
H
i
+
A
B
A
B
O
2
1
O
3
Scheme 1 Reagents and conditions: (i) 5% NaOH, ethanol, rt, 1 h,
65–94%.
Fig. 1 Chemical structures of
synthesized compounds.
R2
O
R1
R4
R3
R4
R1
R2
R3
O
R5
O
4, R1 = R2 = R3 = R4
5, R2 = NO2; R1 = R3 = R4 = H
6, R2 + R3 = O-CH2-O; R3 = R4 = H
7, R1 = R2 = Cl; R3 = R4 = H
8, R1 = H; R2 = R3 = R4 = OCH3
9, R1 = R2 = R3 = OCH3; R4 = H
10, R1 = R4 = OCH3; R1 = R3 = H
11, R1 = R4 = H; R2 = R3 = OCH3
12, R1 = R4 = H , R2 =OH, R3 = OCH3
13, R1 = R3 = R4 = H , R2 =Br
17 R1 = R2 = R3= R4 = R5 = H
18, R2+ R3 = O-CH2-O; R1 = R4 = R5 = H
19, R2 = NO2, R1 = R3 = R4 = R5 = H
20, R1 = R4 = OCH3; R2 = R3 = R5 = H
21, R2 = R3 = R4 = OCH3; R1 = R5 = H
22, R2 = R3 = OCH3; R1 = R4 = R5 = H
23, R2 = OH, R3 = OCH3; R1 = R4 = R5 = H
24, R1 = R5 = Cl; R3 = R4 = R5 = H
R2
O
R3
R4
R1
N
H
O
R5
O
14
15, R1 = R2 = R4 = H , R3 = OCH3
25, R1 = R2 = R3 = R4 = R5 = H
O
26, R3 = NO2; R1 = R2 = R4 = R5 = H
27, R2 = NO2, R1 = R3 = R4 = R5 = H
28, R1 = R3 = Cl; R2 = R4 = R5 = H
29, R1 = R2 = OCH3; R3 = R4 = R5 = H
30, R1 = R2 = Cl; R3 = R4 = R5 = H
31, R1 = R5 = Cl; R2 = R3 = R4 = R5 = H
16
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Med Chem Res (2012) 21:2133–2140
2135
(6, 8, 9, 10, 11 and 12). (ii) The prescience of electron
withdrawing substituents at Ring B led to decreased cyto-
toxic potential (5, 7 and 13). (iii) Replacement of ring B
with a heterocyclic ring remarkably reduced the activity
(14). (iv) Replacement of Ring B with another naphthyl
ring drastically increased the cytotoxic potential (16).
Table 1 In vitro cytotoxicity of the compounds 4–31 against human
cancer cell lines at concentration 1 9 10-5 mol
Entry
Prostate
(PC-3)
% Growth inhibition
Ovary
(OVCAR)
Neuroblastoma
(IMR-32)
Liver
(HEP-2)
4
28
16
42
–
21
13
46
11
87
88
52
49
52
14
–
19
11
39
–
27
17
42
9
5
6
Conclusion
7
8
84
81
49
53
47
–
81
75
51
51
61
11
13
36
77
13
16
–
79
72
47
53
57
–
From the data shown in Table 1, it is evident that naphthyl
based chalcones proved to be the most potent cytotoxic.
Thus, it can be concluded that the enhancement of the
electron density in the periphery as in the case of naphthyl
based chalcones prevents the need of electron donating
substituents on Ring A.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
16
33
79
19
21
–
21
29
73
–
31
76
–
Experimental
11
13
–
13
16
29
47
27
19
11
23
13
17
16
33
15
16
All the chemicals used are commercially available and
were used as received. Nuclear magnetic resonance spec-
troscopy was performed using Varian EM-360L and Bruker
AC-300F, 200, 300 and 500 MHz spectrometer with TMS
as an internal standard and the spectra were recorded in
appropriate deuterated solvents, as indicated. IR spectra
were recorded as KBr pellets on Perkin–Elmer 882 spec-
trophotometer model. Mass spectra were recorded on ESI-
esquire 3000 Bruker Daltonics instrument. Melting points
(mp) were determined on a Buchi–Tottoli apparatus and are
23
42
29
21
–
31
49
33
16
–
28
–
23
–
22
11
13
–
18
14
–
14
11
14
–
1
13
24
–
uncorrected. All products reported showed H NMR spec-
31
11
–
28
–
tra in agreement with the assigned structures. Reaction
courses and product mixtures were routinely monitored by
TLC on silica gel (precoated F254 Merck plates).
–
12
‘‘–’’ indicates no activity
General procedure for the synthesis of chalcones
Bold value indicates the best activity of synthetics
Structure activity relationship for cytotoxicity
Aryl ketone (0.003 mol) was taken in a flask (100 ml) and
dissolved in methanol (10 ml). To the solution, substituted
benzaldehyde (0.003 mol) followed by 5% aqueous NaOH
solution (3 ml) was added. The reaction mixture was kept
in stirred condition at room temperature for 15 h. Com-
pletion of reaction was monitored on TLC (20% Ethyl
acetate in toluene). The reaction mixture was poured into
water; precipitated solid was filtered and re-crystallized
from ethanol. The physical data of the synthetics is shown
below:
From the data shown in Table 1, naphthone proved to be
the most potent synthone for cytotoxic activity. The
replacement of naphthyl (ring A) with heterocycles led to
dilution of the activity (compare the compounds 4, 6 and
10 with 17, 18 and 20). The decrease in the cytotoxic
potential was more pronounced with furan than pyrrole
which can be attributed to less aromatic character of the
furan ring (compare the compounds 17, 24 with 25, 31). As
Napthone was found to be the most potent synthone,
emphasis has been laid on SAR studies of Naphthyl based
chalcones and the following conclusions have been
made: (i) The presence of electron donating substituents at
Ring B led to enhanced cytotoxic potential of the synthetics
(E)-1-(naphth-2-yl)-3-phenyl-prop-2-en-1-one (4)
Yield 80%. Mp: 110–113°C. I.R. (KBr, cm-1): 1662, 1604.
1H NMR (CDCl3, 300 MHz): 8.54 (1H, s), 8.10 (1H, dd,
J = 1.8 and 8.7 Hz), 7.85–8.0 (4H, m), 7.66–7.71 (3H, m),
123

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Med Chem Res (2012) 21:2133–2140
Table 2 MIC (lg/ml) of the
compounds against standard
microbial strains.
Diluted
B. subtilis
S. aureus
E. coli
S. typhi
P. aeruginosa
A. niger
C. albicans
solution of
compounds
(lg/ml)
4
–
–
250
125
62.5
31.2
1.9
500
250
125
31.2
3.9
–
–
500
–
–
–
–
–
5
6
125
31.2
3.9
125
62.5
15.6
15.6
250
62.5
125
125
500
–
250
62.5
15.6
7.8
–
–
–
7
250
125
62.5
–
250
125
125
–
8
9
3.9
3.9
15.6
250
125
62.5
250
–
10
125
62.5
31.2
125
250
–
125
62.5
15.6
125
125
–
11
125
250
250
250
–
250
–
500
–
12
13
–
–
14
–
–
15
–
–
–
16
125
250
31.2
125
31.2
31.2
31.2
62.5
125
250
–
62.5
250
62.5
125
62.5
15.6
31.2
31.2
62.5
125
250
125
7.8
125
–
–
250
–
–
–
17
–
–
–
18
125
125
31.2
62.5
15.6
62.5
62.5
500
500
250
15.6
–
125
–
125
125
31.2
15.6
31.2
125
250
–
500
–
–
19
–
20
62.5
31.2
15.6
62.5
125
500
–
125
62.5
125
250
250
–
125
62.5
250
250
250
–
21
22
23
24
25
26
–
–
–
27
250
15.6
–
500
15.6
–
–
500
62.5
–
–
28
31.2
–
125
–
29
–
30
31.2
31.2
0.2
7.8
15.6
15.6
0.25
0.25
–
15.6
31.2
0.2
0.2
–
7.8
31.2
0.3
0.25
–
125
125
–
250
125
–
31
15.6
0.2
Amoxicillin
Gentamycin
Fluconazole
0.3
0.4
–
–
Bold value indicates the best
activity of synthetics
–
–
0.2
0.3
7.53–7.61 (2H, m), 7.44 (3H, m). 13C NMR (CDCl3,
300 MHz): 186.76, 142.21, 135.56, 134. 31, 134.32,
132.45, 129.78, 128.43, 128.31, 128.11, 127.88, 127.76,
126.43, 126.11, 125.54, 124.54. M? at m/z: -258. Anal.
Calcd for C19H14O: C,88.34; H,5.46; O,6.19. Found:
C,88.01;H,5.69.
M? at m/z: -303. Anal. Calcd for C19H13NO3: C,75.24;
H,4.32; N,4.62; O,15.82. Found: C, 75.56; H,4.11; N,4.23.
(E)-3-[benzo(d)1,3-dioxol-5-yl]-1-[naphth-2-yl]prop-2-en-
1-one (6)
Yield 78%. Mp 139–141°C. I.R. (KBr, cm-1): 1655, 1583,
1208. 1H NMR (CDCl3, 300 MHz): 8.53 (1H, s), 8.10 (1H,
dd, J = 1.5 and 18.5 Hz), 7.87–8.01 (3H, m), 7.81 (1H, d,
J = 15.52 Hz), 7.53–7.63 (2H, m), 7.26 (1H, s), 7.24 (1H,
d, J = 1.3 Hz), 7.17 (1H, dd, J = 1.4 and 7.9 Hz), 6.87
(1H, d, J = 8.00 Hz), 6.05 (2H, s). M? at m/z: -302. Anal.
Calcd for C20H14O3: C,79.46; H,4.67; O, 15.88. Found:
C,79.08; H,4.88.
(E)-1-(naphth-2-yl)-3-(3-nitrophenyl)-prop-2-en-1-one (5)
Yield 79%. Mp: 152–157°C. I.R. (KBr, cm-1): 1660, 1606,
1525, 1347. H NMR (CDCl3, 500 MHz): 8.58 (2H, d,
1
J = 2.09), 8.29 (1H, m), 8.13 (1H, dd, J = 1.7 and 8.6 Hz),
8.04 (1H, d, J = 8.00 Hz), 7.80–7.98 (5H, m), 7.59 (3H, m).
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Med Chem Res (2012) 21:2133–2140
2137
(E)-3-(2,3-dichlorophenyl)-1-(naphth-2-yl)-prop-2-en-1-
one (7)
(E)-3-(3-hydroxy-4-methoxyphenyl) -1-(naphth-2-yl)-prop-
2-en-1-one (12)
Yield 65%. Mp 123–127°C. I.R. (KBr, cm-1): 1655, 1592,
747. H NMR (CDCl3, 300 MHz): 8.49 (1H, s), 7.98 (1H,
Yield 65%. Mp 159–161°C. I.R. (KBr, cm-1): 3426, 1662,
1603, 1247; 1H NMR(CDCl3, 300 MHz): 8.49 (1H, s), 7.80
(1H, d, J = 15.3 Hz), 7.52–7.61 (5H, m), 7.18 (1H, d,
J = 15.3 Hz), 6.93–7.10 (4H, m), 3.79 (3H, s). M? at m/z:
-304. Anal. Calcd for C20H16O3: C,78.93; H,5.30; O,
15.77. Found: C,78.61;H, 5.51.
1
d, J = 15.8 Hz), 7.79–7.83 (2H, m), 7.67–7.75 (2H, m),
7.40 (1H, d, J = 15.8 Hz), 7.37 (2H, m), 7.21 (3H, m). M?
at m/z: -326. Anal. Calcd for C19H12Cl2O: C,69.74;
H,3.70; O, 4.89. Found: C,69.38;H,3.41.
(E)-3-(3,4,5-trimethoxyphenyl)-1-(naphth-2-yl)-prop-2-en-
1-one (8)
(E)-3-(3-Bromo-phenyl)-1-naphthalen-2-yl-propenone (13)
Yield 78%. Mp 126–130°C. I.R. (KBr, cm-1): 1662, 1605,
1050. 1H NMR (CDCl3, 200 MHz): 8.58 (2H, s), 8.28 (1H,
d, J = 7.79 Hz), 7.78–8.15 (7H, m), 7.56–7.68 (3H, m).
M? at m/z: -336. Anal. Calcd for C19H13BrO: C,67.67;
H,3.89; O, 4.74. Found: C,67.34; H, 4.29.
Yield 81%. Mp 120–122°C. I.R. (KBr, cm-1): 1650, 1579,
1121; 1H NMR (CDCl3, 200 MHz): 8.52 (1H, s), 7.93 (1H,
d, J = 15.7 Hz), 7.80–7.84 (3H, m), 7.69 (2H, d,
J = 8.1 Hz), 7.54 (1H, d, J = 15.7 Hz), 7.35 (1H, d,
J = 7.8 Hz), 6.50 (2H, s), 3.89 (6H, s), 3.78 (3H, s). M? at
m/z: -348. Anal. Calcd for C22H20O4: C,75.84; H,5.79; O,
18.37. Found: C,75.48;H,6.05.
(E)-3-(furan-2-yl)-1-(naphth-2-yl)-prop-2-en-1-one (14)
Yield 85%. Mp 45–48°C. I.R. (KBr, cm-1): 1676, 1589,
1283. 1H NMR (CDCl3, 300 MHz): 8.51 (1H, s), 7.92 (1H,
d, J = 15.6 Hz), 7.88 (2H, m), 7.81 (1H, d, J = 8.1),
7.64–7.67 (2H, m), 7.54 (1H, d, J = 15.6 Hz), 7.29–7.31
(2H, m), 6.25 (1H, d, J = 3.0 Hz), 6.22 (1H, dd, J = 1.8
and 3.0 Hz). M? at m/z: -248. Anal. Calcd for C17H12O2:
C,82.24; H,4.87; O, 12.89. Found: C,82.55; H,4.54.
(E)-3-(2,3,4-trimethoxyphenyl)-1-(naphth-2-yl)-prop-2-en-
1-one (9)
Yield 82%. Mp 121–124°C. I.R. (KBr, cm-1): 1653, 1556,
1230; 1H NMR (CDCl3, 300 MHz): 8.52 (1H, s), 7.93
(1H, d, J = 15.7 Hz), 7.80–7.84 (3H, m), 7.69 (2H,
d, J = 8.1 Hz), 7.54 (1H, d, J = 15.7 Hz), 7.35 (1H, d,
J = 7.8 Hz), 6.87 (1H, d, J = 8.7 Hz), 6.60 (1H, d,
J = 8.7 Hz), 3.89 (6H, s), 3.78 (3H, s). M? at m/z: -348.
Anal. Calcd for C22H20O4: C,75.84; H,5.79; O, 18.37.
Found: C,75.58;H, 5.41.
(E)-3-(4-methoxyphenyl)-1-(naphth-2-yl)-prop-2-en-1-
one (15)
Yield 79%. Mp 92–95°C. I.R. (KBr, cm-1): 1656, 1596,
1250; 1H NMR (CDCl3, 300 MHz): 8.53 (1H, s), 8.10 (1H,
dd, J = 1.5 and 8.7 Hz), 7.83–8.01 (4H, m), 7.54–7.67
(5H, m), 6.95 (2H, d, J = 8.7 Hz), 3.87 (3H, s). M? at m/z:
-288. Anal. Calcd for C20H16O2: C,83.31; H,5.59;
O,11.10. Found: C,83.01; H,5.24.
(E)-3-(2,5-dimethoxyphenyl)-1-(naphth-2-yl)-prop-2-en-1-
one (10)
Yield 73%. Mp 100–103°C. I.R. (KBr, cm-1): 1655, 1583,
1259. 1H NMR (CDCl3, 200 MHz): 8.54 (1H, s), 7.85–8.09
(5H, m), 7.54–7.62 (3H, m), 7.21–7.26 (2H, m), 6.92 (1H,
d, J = 8.6 Hz), 3.98 (3H, s), 3.95 (3H, s). M? at m/z:
-318. Anal. Calcd for C21H18O3: C,79.22; H,5.70; O,
15.08. Found: C,78.84;H, 6.10.
(E)-3-(naphth-3-yl)-1-(naphth-2-yl)-prop-2-en-1-one (16)
Yield 77%. Mp 206–210°C. I.R. (KBr, cm-1): 1646, 1592;
1H NMR (CDCl3, 300 MHz): 8.59 (1H, s), 8.14 (2H, dd,
J = 1.8 and 8.7 Hz), 7.84–8.08 (8H, m), 7.48–7.65 (5H,
m). M? at m/z: -308. Anal. Calcd for C23H16O: C,89.58;
H,5.23; O, 5.19. Found: C,89.27; H,5.49.
(E)-3-(3,4-dimethoxyphenyl)-1-(naphth-2-yl)-prop-2-en-1-
one (11)
Yield 67%. Mp 101–105°C. I.R. (KBr, cm-1): 1655, 1583,
1259; 1H NMR (CDCl3, 300 MHz): 8.51 (1H, s), 7.94 (1H,
d, J = 15.3 Hz), 7.84–7.87 (2H, m), 7.65–7.71 (2H, m),
7.52 (1H, d, J = 15.3 Hz), 7.31–7.37 (2H, m), 6.70–6.73
(3H, m),3.74 (6H, s). M? at m/z: -318. Anal. Calcd for
C22H20O4: C,79.22; H,5.70; O, 15.08. Found: C,79.46;H,
5.99.
1-(2-Furyl)-3-phenylprop-2-en-1-one (17)
Yield 68%. Mp 87–89°C. I.R. (KBr, cm-1): 1604, 1657. 1H
NMR (CD3OD, 200 MHz): 7.87 (1H, bs), 7.84 (1H, d,
J = 14.6 Hz), 7.73 (3H, m), 7.61 (d, 1H, J = 14.6 Hz),
7.59 (1H, m), 7.44 (2H, m), 6.71 (1H, dd, J = 1.6 and
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1-(2-Furyl)-3-(3-hydroxy-4-methoxyphenyl) prop-2-en-1-
one (23)
3.3 Hz). M? at m/z: -198. Anal. Calcd for C13H10O2:
C,78.77; H,5.09; O, 16.14. Found: C,78.40; H,4.74.
Yield 66%. Mp 144–145°C. I.R. (KBr, cm-1): 1604, 1666,
3386. 1H NMR (CDCl3, 200 MHz): 7.80 (d, 1H,
J = 15.7 Hz), 7.65(bs, 1H), 7.29(m, 3H), 7.15(dd, 1H),
6.88(d, 1H), 6.59(dd, 1H), 3.95(s, 3H). M? at m/z: -244.
Anal. Calcd for C14H12O4: C,68.85; H,4.95; O, 26.20.
Found: C,68.97; H,4.64.
1-(2-Furyl)-3-(3, 4-methylenedioxy phenyl) prop-2-en-1-
one (18)
Yield 69%. Mp 180–182°C. I.R. (KBr, cm-1): 1597, 1663.
1H NMR (CD3OD, 200 MHz): 7.85 (1H, d, J = 1.6 Hz),
7.76 (1H, d, J = 15.6 Hz), 7.56 (1H, d, J = 3.5 Hz), 7.45
(1H, d, J = 15.6 Hz), 7.34 (1H, bs), 7.19 (1H, d,
J = 2.4 Hz), 6.88 (1H, d, J = 8.1 Hz), 6.70 (1H, dd,
J = 1.6 and 3.5 Hz), 6.03 (2H, s). M? at m/z: -242. Anal.
Calcd for C14H10O4: C,69.42; H,4.16; O, 26.42. Found:
C,69.03; H,3.87.
1-(2-Furyl)-3-(2,6-dichlorophenyl) prop-2-en-1-one (24)
Yield 86%. Mp 94–96°C. I.R. (KBr, cm-1): 1604, 1657. 1H
NMR (CDCl3, 200 MHz) 7.87 (1H, bs), 7.81 (1H, d,
J = 15.9 Hz), 7.63 (1H, d, J = 3.6 Hz), 7.55 (3H, m), 7.31
(1H, d, J = 15.9 Hz), 6.71 (1H, dd, J = 1.6 and 3.5 Hz).
M? at m/z: -265. Anal. Calcd for C13H8Cl2O2: C,58.46;
H,3.02; O, 11.98. Found: C,58.10; H,3.36.
1-(2-Furyl)-3-(3-nitrophenyl) prop-2-en-1-one (19)
Yield 73%. Mp 181–183°C. I.R. (KBr, cm-1): 1604, 1656.
1H NMR (DMSO-d6, 500 MHz): 8.72(s, 1H); 8.28 (2H,
m), 7.92 (1H, d, J = 16 Hz), 7.87 (1H, bs), 7.74 (1H, d,
J = 16 Hz), 7.72 (1H, bs), 7.63 (1H, d, J = 3.6 Hz), 6.71
(1H, dd, J = 1.6 and 3.6 Hz). M? at m/z: -243. Anal.
Calcd for C13H9NO4: C,64.20; H,3.73; N,5.76; O, 26.31.
Found: C,63.88; H,3.41; N,6.11.
3-phenyl-1-(1H-pyrrol-2-yl)-propenone (25)
Yield: 71%. Mp 195–197°C. I.R. (KBr, cm-1): 1599, 1643,
3444. H NMR (CD3OD, 200 MHz) 7.76 (2H, bs), 7.45
1
(1H, d, J = 15.4 Hz), 7.24–7.40 (5H, m), 7.19 (1H, d,
J = 15.4 Hz), 6.32 (1H, dd, J = 2.4 and 3.8 Hz). M? at m/
z: -197. Anal. Calcd for C13H11NO: C,79.16; H,5.62;
N,7.10; O, 8.11. Found:C,79.40; H,5.26; N,6.79.
1-(2-Furyl)-3-(2, 5-dimethoxyphenyl) prop-2-en-1-one (20)
Yield 86%. Mp 54–56°C. I.R. (KBr, cm-1): 1583, 1646. 1H
NMR (CD3OD, 200 MHz) 8.16 (1H, d, J = 15.9 Hz, H-3),
7.88 (1H, bs), 7.62 (1H, d, J = 15.9 Hz), 7.56 (1H, bs), 7.43
(1H, m), 7.13 (2H, m), 6.72 (1H, dd, J = 1.6 and 3.6 Hz),
3.88 (6H, s). M? at m/z: -258. Anal. Calcd for C15H14O4:
C,69.76; H,5.46; O, 24.78. Found: C,69.55; H,5.08.
3-(4-nitro-phenyl)-1-(1H-pyrrol-2-yl)-propenone (26)
Yield: 75%. Mp 205–207°C. I.R. (KBr, cm-1): 1340, 1543,
1599, 1643, 3335. 1H NMR (CD3OD, 200 MHz) 8.29 (2H,
d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz), 7.76 (2H, bs),
7.34 (1H, d, J = 15.2 Hz), 7.19 (1H, d, J = 15.2 Hz), 6.34
(1H, dd, J = 2.4 and 3.8 Hz). M? at m/z: -242. Anal.
Calcd for C13H10N2O3: C,64.46; H,4.16; N,11.56; O,
19.82. Found: C,64.06; H,4.52; N,11.20.
1-(2-Furyl)-3-(3, 4, 5-tri methoxy phenyl)-prop-2-en-1-one
(21)
Yield 69%. Mp 149–151°C. I.R. (KBr, cm-1): 1600, 1655.
1H NMR (CD3OD, 200 MHz): 7.87 (1H, s), 7.78 (1H, d,
J = 15.7 Hz), 7.63 (1H, d, J = 3.6 Hz), 7.55 (1H, d,
J = 15.7 Hz), 7.08 (2H, s), 6.71 (1H, dd, J = 1.6 and
3.6 Hz), 3.91 (6H, s), 3.81 (3H, s). M? at m/z: -288. Anal.
Calcd for C16H16O5: C,66.66; H,5.59; O, 27.75. Found:
C,65.28; H,5.80.
3-(3-nitrophenyl)-1-(1H-pyrrol-2-yl)-propenone (27)
Yield: 77%. Mp 204–206°C. I.R. (KBr, cm-1): 1340, 1543,
1601, 1653, 3340. H NMR (DMSO-d6, 200 MHz): 8.72
1
(1H, s), 8.34 (2H, t), 7.92 (1H, dd, J = 16 Hz), 7.74 (1H,
dd, J = 16 Hz), 7.72 (1H, t, J = 8.5 Hz), 7.48 (1H, bs),
7.21 (1H, bs), 6.31 (1H, bs), M? at m/z: -242. Anal. Calcd
for C13H10N2O3: C,64.46; H,4.16; N,11.56; O, 19.82.
Found: C,64.76; H,3.85; N,11.95.
1-(2-Furyl)-3-(3,4-dimethoxyphenyl)-prop-2-en-1-one (22)
Yield 72%. Mp 109–112°C. I.R. (KBr, cm-1): 1597, 1657.
1H NMR (CD3OD, 200 MHz): 7.85 (1H, bs), 7.81 (1H, d,
J = 14.6 Hz), 7.46 (4H, m), 7.02 (1H, d, J = 8.2 Hz), 6.71
(1H, dd J = 1.6 and 3.5 Hz), 3.92 (3H, s), 3.89 (3H, s).
M? at m/z: -258. Anal. Calcd for C15H14O4: C,69.76;
H,5.46; O, 24.78. Found: C,69.97; H,5.67.
3-(2, 4-dichloro-phenyl)-1-(1H-pyrrol-2-yl)-propenone
(28)
Yield: 83%. Mp 172–174°C. I.R. (KBr, cm-1): 1596, 1654,
3334. 1H NMR (CDCl3, 200 MHz) 8.13 (d,1H,
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Med Chem Res (2012) 21:2133–2140
2139
J = 15.6 Hz), 7.69 (1H, d, J = 8.6 Hz), 7.47 (1H, d,
J = 1.9 Hz), 7.30 (3H, m), 7.10 (1H, d, J = 15.6 Hz), 6.37
(1H, bs). M? at m/z: -265. Anal. Calcd for C13H9Cl2NO:
C,58.67; H,3.41; N,5.26; O, 6.01. Found: C,58.31; H,3.01;
N,4.86.
(0.1–100 lM) of test samples made with 1:10 serial dilu-
tions. Four replicate wells were set up for each experi-
mental condition. Test samples were left in contact with the
cells for 48 h under the same conditions. Thereafter, cells
were fixed with 50% chilled TCA and kept at 4°C for 1 h,
washed and air-dried. Cells were stained with sulforhoda-
mine B dye. The adsorbed dye was dissolved in Tris-buffer
and the plates were gently shaken for 10 min on a
mechanical shaker. The optical density (OD) was recorded
on ELISA reader at 540 nm. The cell growth was calcu-
lated by subtracting mean OD value of the respective blank
from the mean OD value of experimental set. Percentage of
growth in the presence of test material was calculated
considering the growth in the absence of any test material
as 100% and in turn percent growth inhibition in presence
of test material was calculated (Monks et al., 2005; Skehan
et al., 1990).
3-(2, 3-dimethoxy-phenyl)-1-(1H-pyrrol-2-yl)-propenone
(29)
Yield: 71%. Mp 107–109°C. I.R. (KBr, cm-1): 1230, 1581,
1647, 3342. H NMR (CDCl3, 200 MHz): 8.11 (1H, d,
1
J = 15.9 Hz), 7.42 (1H, d, J = 15.9 Hz), 7.28 (2H, m),
7.10 (2H, dd, J = 8.2 Hz), 6.96 (1H, d, J = 8.2 Hz), 6.35
(1H, bs), 3.89 (6H, s). M? at m/z: -257. Anal.Calcd for
C15H15NO3: C,70.02; H,5.88; N,5.88; O, 18.66. Found:
C,70.34; H,5.65; N,5.48.
3-(2, 3-dichloro-phenyl)-1-(1H-pyrrol-2-yl)-propenone
(30)
Antimicrobial activity
Yield: 92%. Mp 193–195°C. I.R. (KBr, cm-1): 1579,
1645, 3330. H NMR (CD3OD, 200 MHz) 7.55 (d, 1H,
1
Compounds were tested against seven reference microbial
strains. The standard microbial strains were procured from
the Institute of Microbial Technology, Chandigarh, India.
Antibacterial and antifungal activity of the compounds
were carried out by the disc diffusion method, (1) against
bacterial strains, Staphylococcus aureus (MTCC 96),
Bacillus subtilis (MTCC 2451), Pseudomonas aeruginosa
(MTCC 2642), Escherichia coli (MTCC 82), Salmonella
typhi (MTCC 1251) and two fungal strains; Aspergillus
niger (MTCC 1344), Candida albicans (MTCC 3018). The
antimicrobial activity of synthesized compound was
determined by observing the zone of inhibition in com-
parison to the standard antibiotic (Amoxicillin and Genta-
mycin) disc. Test compounds were dissolved in DMSO to
make a stock solution of 1 mg/ml. The fresh sub culture of
strains in normal saline was added to the sterile assay
medium (Nutrient agar) at 40–45°C and mixed well. The
medium was poured into each of the petridishes. Sterile
discs of diameter 6 mm were placed on the medium. 20 ll
of each test solution was added to the previously marked
discs and the media was allowed to stand for 5 min. The
petridishes were kept aside for 1 h and then incubated at
37°C for 24 h. Zone of inhibition was measured and the
average of the three readings was calculated. DMSO was
kept as negative control. The activity was compared with
standard antibiotics discs. The antifungal activity was
carried in the same way. The fresh sub culture were
inoculated in Saboraud Dextrose agar at 28°C for 48 h and
compared with Fluconazole as standard. The MIC of
compounds was determined by serial tube dilution method.
Different dilutions of test compounds were made from
stock solution and were tested to get the MIC. 1 ml nutrient
J = 15.6 Hz,H-2), 8.06 (d, 1H, J = 15.9 Hz, H-3), 7.55 (d,
1H, J = 15.6 Hz), 7.23 (1H, m), 7.16 (4H, m), 6.32 (dd,1H,
dd, J = 2.6 and 3.7 Hz). M? at m/z: -265. Anal. Calcd for
C13H9Cl2NO: C,58.67; H,3.41; N,5.26; O, 6.01. Found:
C,58.27; H,3.01; N,5.52.
3-(2, 6-dichloro-phenyl)-1-(1H-pyrrol-2-yl)-propenone
(31)
Yield: 94%. Mp 162–164°C. I.R. (KBr, cm-1): 1579, 1655,
3340. 1H NMR (CD3OD, 200 MHz): 7.87 (1H, d,
J = 15.9 Hz), 7.75 (1H, bs), 7.55 (3H, m), 7.31 (1H, d,
J = 15.9 Hz), 7.17 (1H, m), 6.32 (1H, dd, J = 2.4 and
3.8 Hz). M? at m/z: -265. Anal.Calcd for C13H9Cl2NO:
C,58.67;H,3.41; N,5.26; O, 6.01. Found: C,59.03; H,3.68;
N,4.86.
Biology
Cytotoxic activity
The effect of compounds 4–31 on the growth of cancer cell
lines was evaluated according to the procedure adopted by
the National Cancer Institute for in vitro anticancer drug
screening that uses the protein-binding dye sulforhodamine
B to estimate cell growth. Briefly, cells in their log phase of
growth were harvested, counted and seeded (104 cells/well
in 100 ml medium) in 96-well microtitre plates. After 24 h
of incubation at 37°C and 5% CO2 to allow cell attach-
ment, cultures were treated with varying concentrations
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Lawrence NJ, Patterson RP, Li-Ling Ooi, Cook D, Ducki S (2006)
Effects of a-substitutions on structure and biological activity of
anticancer chalcones. Bioorg Med Chem Lett 16:5844–5848
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RS (2005) Anticancer activities of novel chalcones and bis-
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Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D,
Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich
M, Campbell H, Mayo J, Boyd M (2005) Feasibility of a high-
flux anticancer drug screen using a diverse panel of cultured
human tumor cell lines. J Natl Cancer Inst 83:757–766
Mukherjee S, Kumar V, Prasad AK, Raj HG, Bracke ME, Olsen CE,
Jain SC, Parmar VS (2001) Synthetic and Biological activity
evaluation studies on novel 1,3-diarylpropenones. Bioorg Med
Chem Lett 9:337
broth was taken in each test tube and 20 ll of standard
strains were added to previously marked test tubes.
Acknowledgment The authors thank Mr. Parveen Garg, Chairman
of the ISF College of Pharmacy Moga, Punjab for providing the
support and facilities.
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