Synthesis and biological evaluation of β-chloro vinyl chalcones as inhibitors of TNF-α and IL-6 with antimicrobial activity

Article abstract of DOI:10.1016/j.ejmech.2010.01.050

A series of β-chloro vinyl chalcones have been synthesized by Claisen-Schmidt condensation. β-chloro vinyl aldehyde has been synthesized by the Vilsmayer-Hack formylation reaction. The structures of the newly synthesized compounds were confirmed by ¹H NMR, IR and Mass spectral analysis. All the compounds were evaluated for their anti-inflammatory activity (against TNF-α and IL-6) and antimicrobial (antibacterial and antifungal) activity. Compounds 5a, 5d, 5e, 5g and 5i exhibited promising activity against IL-6 with 58-83% inhibition at 10 μM concentration. None of the compound was found to be cytotoxic in CCK-8 cells at 10 μM concentration. Whereas compounds 5b, 5d, 5e and 5i showed very good antibacterial activity and compounds 5a, 5b, 5e and 5i showed good antifungal activity.

Full text of DOI:10.1016/j.ejmech.2010.01.050

European Journal of Medicinal Chemistry 45 (2010) 2629–2633
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and biological evaluation of
b-chloro vinyl chalcones as inhibitors of
TNF- and IL-6 with antimicrobial activity
a
,
b
,
b
b
c
Babasaheb P. Bandgar a , Sachin A. Patil , Balaji L. Korbad , Shivraj H. Nile ,
*
Chandrahase N. Khobragade c
a Organic Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur 413255, India
b Organic Chemistry Research laboratory, School of chemical sciences, Swami Ramanand Teerth Marathwada University, Nanded 431606, India
c Biochemistry Research Laboratory, School of Life Sciences, Swami Ramanand Teerth Marathwada University, Nanded 431 606, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of b-chloro vinyl chalcones have been synthesized by Claisen–Schmidt condensation. b-chloro
Received 29 October 2009
Received in revised form
19 January 2010
Accepted 21 January 2010
Available online 28 January 2010
vinyl aldehyde has been synthesized by the Vilsmayer–Hack formylation reaction. The structures of the
newly synthesized compounds were confirmed by 1H NMR, IR and Mass spectral analysis. All the
compounds were evaluated for their anti-inflammatory activity (against TNF-
crobial (antibacterial and antifungal) activity. Compounds 5a, 5d, 5e, 5g and 5i exhibited promising
activity against IL-6 with 58–83% inhibition at 10 M concentration. None of the compound was found to
be cytotoxic in CCK-8 cells at 10 M concentration. Whereas compounds 5b, 5d, 5e and 5i showed very
a and IL-6) and antimi-
m
m
Keywords:
good antibacterial activity and compounds 5a, 5b, 5e and 5i showed good antifungal activity.
Ó 2010 Elsevier Masson SAS. All rights reserved.
b
-Chloro vinyl chalcones
Anti-inflammatory activity
TNF-
IL-6
a
Antibacterial activity
Antifungal activity
1. Introduction
are proteins (Etanercept, Infliximab, Adalimumab and Anakinra)
that display adverse effects such as aplastic anemia, pancytopenia,
Inflammation is the complex process due to which it causes
a large number of diseases, amongst this some commonest are
rheumatoid arthritis (RA), inflammatory bowel disease, psoriasis
vasculitis, demyelination and congestive heart failure [10], while
the IL-6 inhibitors can be used in Alzheimer’s disease, psychiatric
disorders, cancer, diabetes, and depression [11–13].
and multiple sclerosis [1,2]. Tumour necrosis factor-alpha (TNF-
a
)
Amongst pro-inflammatory cytokines the IL-6, is a pleiotropic
cytokine that is abundant in both the synovium and serum of RA
patients and induces a broad range of cellular and physiological
responses during the inflammation reaction. It is a multifunctional
cytokine produced by a variety of cells in response to infection,
trauma, or immunological challenge. It plays a key role in the
regulation of inflammation, immune responses, the acute-phase
reaction, and hematopoiesis, exerting its effects at the systemic
and local tissue levels and across a range of cell types. It appears to
be the central mediator of anemia of chronic disease in a range of
inflammatory diseases, including end-stage renal disease and
rheumatoid arthritis [14]. Till-date, designing the IL-6 inhibitory
agents has remained a significant hope in the mainstream of anti-
inflammatory drug development.
and Interleukin-6 (IL-6) are two major multifunctional pro-
inflammatory mediators of a variety of autoimmune diseases such
as pain and joint destruction characteristics of RA [3]. The inhibition
of release of cytokines becomes a major focus of current drug
development and an important method for evaluating the bioac-
tivity of drugs [4]. It is a key cytokine in the inflammation cascade,
causing the production and/or release of other cytokines and agents.
Over-expression of TNF-a is responsible for a number of path-
ological conditions like Crohn’s disease, ulcerative colitis [5], dia-
betes [6], multiple sclerosis [7], atherosclerosis [8] and stroke [9]. In
spite of enormous efforts, no small molecule has yet been approved
to specifically inhibit TNF-a activity. TNF-a inhibitor drugs in clinics
Chalcones are the main precursors for the biosynthesis of
flavonoids and are present in variety of plant species such as
fruits, vegetables, spices, tea and soy based foodstuff. Chalcones
* Corresponding author. Tel./fax: þ91 217 2351300.
E-mail address: bandgar_bp@yahoo.com (B.P. Bandgar).
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.01.050

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B.P. Bandgar et al. / European Journal of Medicinal Chemistry 45 (2010) 2629–2633
isolated from natural products are known to possess several
important activities including antifungal [15], leishmanicidal [16]
and anti-malarial [17]. Synthesis of chalcones from substituted
acetophenones and benzaldehydes makes them an attractive
drug scaffold, so they have been shown to display interesting
biological activities including antimitotic [18], anti-inflammatory
[19], cytotoxic [20], anticancer [21–23], anti-tubercular [24],
cardiovascular [25] and hyperglycemic agents [26]. It is well
known that 20-hydroxychalcones were shown to possess anti-
inflammatory agents involved in inhibition of cell migration
3. Biological evaluation
All the synthesized compounds were evaluated for anti-
inflammatory and antimicrobial activity. Anti-inflammatory
activity against TNF-a and IL-6 at 10 mM concentration. Inhibitory
activity results are summarized in Table 2. Dexamethasone was
used as a reference compound. Compounds 5b, 5d, 5e, 5f, 5h and 5j
shown 13–18% inhibition at 10
mM, while none of the compounds
showed significant TNF- inhibitory activity.
a
All the synthesized compounds were shown moderate to good
and inhibition of TNF-
investigation reveals that no endeavor was proposed the
synthesis of -chloro vinyl chalcones to verify the effects on the
biological activity. Thus, we investigated that 2-hydroxy -chloro
and IL-6 with anti-
a
synthesis in mouse [27]. The literature
IL-6 inhibitory activity. Compounds 5a, 5d, 5e, 5g and 5i showed
promising activity against IL-6 with inhibition 58–83% at 10
concentration. Compounds 5b, 5c, 5g, 5h, 5j and 5k showed 31–45%
inhibition of IL-6 at 10 M. All compounds did not show significant
toxicity at 10 M.
mM
b
b
m
vinyl chalcones are the inhibitors of TNF-
microbial activity.
a
m
3.1. Assay for TNF-a and IL-6 inhibition
2. Chemistry
Pro-inflammatory cytokine production by lipopolysaccharide
(LPS) in THP-1 cells was measured according to the method
described by Hwang et al., 1933 [31]. Briefly, THP-1 cells were
cultured in RPMI 1640 culture medium (Gibco BRL, Pasley, UK)
containing 100 U/mL penicillin and 100 mg/mL streptomycin
(100ꢀ solution, Sigma Chemical Co. St. Louis, MO) containing 10%
fetal bovine serum (FBS, JRH). Cells were differentiated with
phorbol myristate acetate (PMA, Sigma). Following cell plating, the
test compounds or vehicle (0.5% DMSO) was added to each well and
the plate was incubated for 30 min at 37 ꢁC. Finally, LPS (Escher-
ichia coli0127:B8, Sigma Chemical Co., St. Louis, MO) was added, at
Compounds described in this study were prepared using
a straight forward chemistry (Scheme 1). Xanthoxyline 2 was
synthesized following the method described in the literature with
minor modifications [28].
b-Chloro vinyl aldehyde (4) was
synthesized following the method described in the literature with
minor modifications [29]. (2E,4Z)-5-Chloro-1-(2-hydroxy-4,6-
dimethoxyphenyl)-5-phenylpenta-2,4-dien-1-one (5) was prepared
by the Claisen–Schmidt condensation between 2-hydroxy-4,6-
dimethoxy acetophenone (2) and various b-chloro vinyl aldehydes
(4) in alkaline medium furnished the desired derivatives with
minor modifications to previously described method [30] Table 1.
The desired derivatives were obtained in 55% yield after purifica-
tion. All synthesized compounds were characterized by using IR, 1H
NMR and mass spectra.
a final concentration of 1
24 h, 5% CO2. Supernatants were harvested and assayed for TNF-
and IL-6 by ELISA as described by the manufacturer (BD Biosci-
ences). The cells were simultaneously evaluated for cytotoxicity
m
g/mL. Plates were incubated at 37 ꢁC for
a
O
O
O
a
O
O
O
OH
1
2
R2
R2
Cl
O
R3
R3
R4
CHO
b
R4
R5
R5
3
4
R2
O
O
Cl
R2
O
O
Cl
R3
R4
R3
R4
OHC
c
+
O
OH
O
OH
2
5
R5
R5
4
Scheme 1. Synthetic route used for the synthesis of b b-chloro vinyl aldehydes,
-chloro vinyl chalcones: (a) AlCl3, CH3COCl, Dry ether, 0 ꢁC, 48 h rt, (b) DMF, POCl3, 0 ꢁC–80 ꢁC, 1 h, (c)
NaOH, EtOH, H2O, rt, 60–65%.

B.P. Bandgar et al. / European Journal of Medicinal Chemistry 45 (2010) 2629–2633
2631
Table 1
The antibacterial screening data revealed that compounds 5a,
5b, 5d, 5e, 5i and 5j showed very good activity, almost equal to that
of standard drugs, whereas all other tested compounds showed
moderate to good antibacterial activity.
Substitution pattern of chalcones studied for the TNF-
activity
a
, IL-6 and antimicrobial
O
O
Cl
R2
R3
R4
3.3. Antifungal studies
Newly synthesized compounds were screened for their anti-
fungal activity against Aspergillus fumigatus (NCIM 902), Aspergillus
niger (NCIM 545), Trichoderma viride (TT), Candida albicans (NCIM
3100) and Penicillium chrysogenum (NCIM 707). Antifungal activity
was assessed by disc diffusion method in a modified condition
[34,35]. Fluconazole (200 mg/disc) was used as standard fungicide.
Potato dextrose agar (PDA) was used as basal medium for test fungi.
Glass petridishes used were sterilized. Sterilized melted PDA
medium (w45 ꢁC) was poured at the rate of 15 mL into each pet-
ridish (90 mm). After solidification of the medium, small portions
of the mycelium of each fungus were spread carefully over the
centre of each PDA plate with the help of sterilized needles. Thus,
each fungus was transferred to a number of PDA plates, which were
then incubated at (25 ꢂ 2) ꢁC and ready for use after five days of
incubation.
O
OH
R5
Entry
R2
R3
R4
R5
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
Cl
H
H
H
H
OMe
H
Cl
H
H
H
H
Cl
H
H
H
H
OMe
H
Br
H
H
Cl
F
H
H
H
H
H
H
H
OMe
H
OMe
OMe
H
Cl
5j
H
OMe
Me
H
H
H
5k
Prepared discs of samples were placed gently on solidified agar
plates, freshly seeded with the test organisms with sterile forceps. A
control disc was also placed on the test plates to compare the effect
of the test samples and to nullify the effect of solvent respectively.
The plates were then kept in a refrigerator at 4 ꢁC for 24 h so that
the materials had sufficient time to diffuse over a considerable area
of the plates. After this, the plates were incubated at 37 ꢂ 5 ꢁC for
72 h. Dimethyl sulphoxide (DMSO) was used as solvent to prepare
desired solutions (10 mg/mL) of the compounds initially and also to
maintain proper control. The results of the antifungal studies are
given in Table 4.
using CCK-8 from Dojindo Laboratories. Percent inhibition of
cytokine release compared to the control was calculated.
3.2. Antibacterial studies
The newly synthesized compounds were screened for their
antibacterial activity against Bacillus subtilis (NCIM 2546), Escher-
ichia coli (NCIM 2065), Staphylococcus aureus (NCIM 2120), Klebsi-
ella pneumoniae (NCIM 5082), and Proteus vulgaris (NCIM 2813)
bacterial strains by disc diffusion method [32,33]. Disc measuring
6.25 mm in diameter was punched from Whatmann no.1 filter
paper. Batches of 100 discs were dispensed to each screw capped
bottles and sterilized by dry heat at 140 ꢁC for an hour. The test
compounds were prepared with different concentrations using
dimethylsulfoxide. 1 mL containing 100 times the amount of
chemical in each disc was added to each bottle, which contains 100
discs. The discs of each concentration were placed in triplicate in
nutrient agar medium seeded with fresh bacterial culture sepa-
rately and incubated at 37 ꢁC for 24 h. Penicillin and Gentamycin
were used as standard drugs. Solvent and growth controls were
prepared and kept. Zones of inhibition and minimum inhibitory
concentrations (MICs) were noted. The results of antibacterial
studies are given in Table 3.
The antifungal screening data revealed that compounds 5a, 5b,
5d, 5e, 5i and 5j showed very good activity almost equal to that of
standard drugs, whereas all other tested compounds showed
moderate to good fungal activity.
4. Conclusion
A new series of
b-chloro vinyl chalcones exhibiting anti-
inflammatory and antimicrobial activity were synthesized. From
the results of the tested compounds, 5a, 5b, 5d, 5e, 5f, 5h and 5i
showed promising activity against IL-6. None of the compound was
Table 3
Antibacterial activity of
b-chloro vinyl chalcones.
Table 2
Compound Bacillius
Esherichia Staphylococcus Klebsiella
Proteus
Antiinflammatory (TNF-alpha, IL-6) inhibitory activity of
b-chloro vinyl chalcones.
no.
subtilis
coli
aureus
pneumoniae valgaris
5a
5b
5c
5d
5e
5f
5g
5h
5i
18 (25)
16 (50)
12 (100) 16 (50)
20 (25)
22 (25)
–
15 (50)
14 (50)
14 (50)
16 (50)
–
18 (25)
14 (50)
–
20 (25)
18 (25)
–
18 (25)
14 (50)
–
12 (100)
20 (25)
18 (25)
15 (50)
18 (25)
17 (50)
–
Compound
% Inhibition at 10 mM
TNF-a
IL-6
Cytotoxicity
5a
5b
5c
5d
5e
5f
5g
5h
5i
08
17
00
13
16
18
00
13
00
17
11
69
58
43
31
74
83
78
33
45
67
36
39
90
26
24
00
23
26
15
00
17
00
19
21
00
15 (50)
16 (50)
–
–
–
14 (50)
12 (100)
10 (100)
18 (25)
21 (25)
–
–
14 (50)
–
13 (100)
–
–
17 (50)
15 (50)
–
22 (25)
24 (25)
19 (25)
16 (50)
15 (50)
20 (25)
18 (25)
15 (50)
18 (25)
14 (50)
21 (25)
22 (25)
19 (25)
19 (25)
–
22 (25)
18 (25)
5j
5k
A
5j
5k
DMS
B
‘‘d’’ Indicates bacteria are resistant to the compounds at concentrations >100 mg/mL;
MIC values are given in brackets; MIC (mg/mL) ¼ minimum inhibitory concentra-
tion, i.e., concentration to completely inhibit bacterial growth; zone of inhibition is
expressed in mm. A ¼ Penicillin, B ¼ Gentamycin.
The results summarized are the mean values of n ¼ 2, DMS ¼ Dexamethasone,
ND ¼ Not Determined, NR ¼ Not Reactive.

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B.P. Bandgar et al. / European Journal of Medicinal Chemistry 45 (2010) 2629–2633
Table 4
(m, 2H, Ar-H), 6.93 (m, 2H, Ar-H), 6.09 (s, 1H, Ar-H), 5.93 (s, 1H, Ar-H),
3.88 (s, 3H, OCH3), 3.83 (s, 3H, OCH3). MS: m/z 379 (M þ 1).
Antifungal activity of b-chloro vinyl chalcones.
Compound Aspergillus Aspergillus Trichoderma Candida
Penicillium
no.
fumigatus
niger
viridie
albicans
chrysogenum
5.1.3. (2E,4Z)-5-Chloro-5-(3-chlorophenyl)-1-(2-hydroxy-4,6-
dimethoxyphenyl)penta-2,4-dien-1-one (5c)
5a
5b
5c
5d
5e
5f
5g
5h
5i
20 (25)
14 (50)
–
17 (25)
14 (50)
–
10 (100)
14 (50)
17 (50)
10 (100)
16 (50)
20 (25)
14 (50)
16 (50)
–
16 (50)
17 (25)
16 (50)
–
16 (50)
10 (100)
–
16 (50)
20 (25)
18 (25)
14 (50)
–
15 (50)
16 (50)
–
10 (100)
14 (50)
18 (25)
13 (100)
16 (50)
22 (25)
14 (25)
–
–
12 (100) 12 (100)
10 (100) 14 (50)
–
–
12 (100) 15 (50)
10 (100) 17 (25)
–
13 (100) 17 (25)
18 (25) 22 (25)
18 (25)
16 (50)
–
Yield (35%), IR (KBr, cmꢃ1) 3618 (OH), 3031 (Ar-H), 1619 (C]O),
1595 (C]C). 1H NMR (CDCl3,
d): 14. 83 (s, 1H, OH), 8.01 (dd, 1H,
Ar-H, J ¼ 10.4 Hz and 10.4 Hz), 7.62 (m, 2H, Ar-H), 7.58 (d, 1H, Ar-H,
J ¼ 10.4 Hz), 7.52 (m, 1H, Ar-H), 7.55 (m, 1H, Ar-H), 7.01 (d, 1H, Ar-H,
J ¼ 10.8 Hz), 6.09 (s, 1H, Ar-H), 5.98 (s, 1H, Ar-H), 3.95 (s, 3H, OCH3),
3.96 (s, 3H, OCH3). MS: m/z 379 (M þ 1).
–
14 (50)
5j
5k
A
–
5.1.4. (2E,4Z)-5-Chloro-5-(4-chlorophenyl)-1-(2-hydroxy-4,6-
dimethoxyphenyl)penta-2,4-dien-1-one (5d)
Yield (30%), IR (KBr, cmꢃ1) 3648 (OH), 3012 (Ar-H), 1617 (C]O),
‘‘d’’ Indicates bacteria are resistent to the compounds at concentrations >100 mg/mL;
MIC values are given in brackets; MIC (mg/mL) ¼ minimum inhibitory concentration,
i.e., concentration to completely inhibit fungal growth; zone of inhibition is
expressed in mm. A ¼ Fluconazole.
1592 (C]C). 1H NMR (CDCl3,
d): 14.19 (s, 1H, OH), 7.95 (dd, 1H, Ar-H,
J ¼ 12.8 Hz and 10.8 Hz), 7.61 (m, 2H, Ar-H), 7.57 (d, 1H, Ar-H,
J ¼ 12.8 Hz), 7.53 (d, 2H, Ar-H), 7.01 (d, 1H, Ar-H, J ¼ 10.8 Hz), 6.09
(s, 1H, Ar-H), 5.98 (s, 1H, Ar-H), 3.96 (s, 3H, OCH3), 3.95 (s, 3H,
OCH3). MS: m/z 379 (M þ 1).
found to be active against TNF-a. The screening result of antimi-
crobial study of the 11 compounds reveals that only six compounds
showed good antibacterial and antifungal activity. Compounds
having bromo, chloro, fluoro substitution at ortho and para position
found to be favorable for both antibacterial and antifungal
screening. However the
one of the scaffolds for design and development of anti-
5.1.5. (2E,4Z)-5-Chloro-5-(4-fluorophenyl)-1-(2-hydroxy-4,6-
dimethoxyphenyl)penta-2,4-dien-1-one (5e)
Yield (30%), IR (KBr, cmꢃ1) 3648 (OH), 3012 (Ar-H), 1617 (C]O),
b-chloro vinyl chalcones are considered as
1592 (C]C). 1H NMR (CDCl3,
d): 14.21 (s, 1H, OH), 7.93 (dd,1H, Ar-H,
J ¼ 10.8 Hz and 12.8 Hz), 7.70 (d, 2H, Ar-H, J ¼ 8 Hz), 7.50 (d, 1H, Ar-
H, J ¼ 12.8 Hz), 7.11 (d, 2H, Ar-H, J ¼ 8 Hz), 7.07 (d, 1H, Ar-H,
J ¼ 10.8 Hz), 6.01 (s, 1H, Ar-H), 5.99 (s, 1H, Ar-H), 3.90 (s, 3H,
OCH3), 3.98 (s, 3H, OCH3). MS: m/z 363 (M þ 1).
inflammatory (TNF-a and IL-6) and antimicrobial agents.
5. Experimental
IR spectra were recorded on FT-IR Shimadzu 8300 spectropho-
tometer in KBr pellet and 1H NMR spectra were recorded on
a Bruker 300 MHz spectrometer in CDCl3 using tetramethylsilane as
5.1.6. (2E,4Z)-5-Chloro-1-(2-hydroxy-4,6-dimethoxyphenyl)-5-
(4-methoxyphenyl)penta-2,4-dien-1-one (5f)
Yield (30%), IR (KBr, cmꢃ1) 3648 (OH), 3012 (Ar-H), 1617 (C]O),
1592 (C]C). 1H NMR (CDCl3,
d): 14.21 (s, 1H, OH), 7.98 (dd,1H, Ar-H,
internal standard and chemical shifts are reported in d units and the
coupling constants (J) are reported in hertz. Mass spectra were
obtained with a Shimadzu LCMS-2010EV. TLC was performed on
aluminium-backed silica plate with visualization by UV-light and
column chromatography using silica gel (mesh size 100–200).
J ¼ 10.8 Hz and 12.8 Hz), 7.69 (d, 2H, Ar-H, J ¼ 8 Hz), 7.47 (d, 1H, Ar-
H, J ¼ 12.8 Hz), 6.93 (d, 2H, Ar-H, J ¼ 8 Hz), 6.92 (d, 1H, Ar-H,
J ¼ 10.8 Hz), 6.01 (s, 1H, Ar-H), 5.99 (s, 1H, Ar-H), 3.92 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3). MS: m/z 375 (M þ 1).
5.1. Procedure for the preparation of (2E,4Z)-5-chloro-1-
(2-hydroxy-4,6-dimethoxyphenyl)-5-phenylpenta-2,4-dien-1-one (5)
5.1.7. (2E,4Z)-5-Chloro-1-(2-hydroxy-4,6-dimethoxyphenyl)-5-
(2,4-dimethoxyphenyl)penta-2,4-dien-1-one (5g)
Yield (30%), IR (KBr, cmꢃ1) 3648 (OH), 3012 (Ar-H), 1617 (C]O),
To a mixture of 1-(2-hydroxy-4,6-dimethoxyphenyl)ethanone
1592 (C]C). 1H NMR (CDCl3,
d): 14.19 (s, 1H, OH), 7.95 (dd, 1H, Ar-H,
(2) (1 mmol) in ethanol (15 mL) was added NaOH (0.1 g, 2–3 drops
of water) and stirred for 5 min. Then, added the purified b-chloro
J ¼ 10.8 Hz and 12.8 Hz), 7.44 (m, 2H, Ar-H), 7.37 (d, 1H, Ar-H,
J ¼ 12.8 Hz), 7.19 (m, 1H, Ar-H), 6.83 (d, 1H, Ar-H, J ¼ 10.8 Hz), 6.00
(s, 1H, Ar-H), 5.92 (s, 1H, Ar-H), 3.99 (s, 3H, OCH3), 3.92 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 3.90 (s, 3H, OCH3). MS: m/z 405 (M þ 1).
vinyl aldehydes and stirred the reaction mixture at room temper-
ature. After completion of reaction (TLC), reaction mixture was
poured over crushed ice and acidified with acetic acid. The
precipitated solid was filtered, washed with water and oven dried.
It was column purified by column chromatography using silica gel
mesh size, 100–200 and elution with petroleum ether.
5.1.8. (2E,4Z)-5-Chloro-1-(2-hydroxy-4,6-dimethoxyphenyl)-5-
(3,5-dimethoxyphenyl)penta-2,4-dien-1-one (5h)
Yield (30%), IR (KBr, cmꢃ1) 3648 (OH), 3012 (Ar-H), 1617 (C]O),
1592 (C]C). 1H NMR (CDCl3,
d): 14.19 (s, 1H, OH), 7.95 (dd, 1H, Ar-H,
5.1.1. (2E,4Z)-5-(4-Bromophenyl)-5-chloro-1-(2-hydroxy-4,6-
dimethoxyphenyl)penta-2,4-dien-1-one (5a)
J ¼ 10.8 Hz and 12.8 Hz), 7.44 (m, 2H), 7.37 (d, 1H, Ar-H, J ¼ 12.8 Hz),
7.19 (m, 1H, Ar-H), 6.83 (d, 1H, Ar-H, J ¼ 10.8 Hz), 5.99 (s, 1H, Ar-H),
5.92 (s, 1H, Ar-H), 3.99 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3). MS: m/z 405 (M þ 1).
Yield (39%), IR (KBr, cmꢃ1) 3559 (OH), 3017 (Ar-H), 1615 (C]O),
1597 (C]C). 1H NMR (CDCl3,
d) 14.18 (s, 1H, OH), 7.86 (d, 1H, Ar-H,
J ¼ 14 Hz), 7.79 (d, 1H, Ar-H, J ¼ 14 Hz), 7.34 (d, 1H, Ar-H, J ¼ 8 Hz),
7.29–7.23 (m, 4H, Ar-H), 6.09 (s, 1H, Ar-H), 5.94 (s, 1H, Ar-H), 3.93
(s, 3H, OCH3), 3.85 (s, 3H, OCH3). MS: m/z 424 (M þ 1).
5.1.9. (2E,4Z)-5-Chloro-5-(2,4-dichlorophenyl)-1-(2-hydroxy-4,6-
dimethoxyphenyl)penta-2,4-dien-1-one (5i)
Yield (30%), IR (KBr, cmꢃ1) 3648 (OH), 3012 (Ar-H), 1617 (C]O),
5.1.2. (2E,4Z)-5-Chloro-5-(2-chlorophenyl)-1-(2-hydroxy-4,6-
dimethoxyphenyl)penta-2,4-dien-1-one (5b)
1592 (C]C). 1H NMR (CDCl3,
d): 14. 20 (s, 1H, OH), 7.96 (dd, 1H, Ar-
H, J ¼ 10.8 Hz and 12.8 Hz), 7.61 (m, 1H, Ar-H), 7.64 (d, 1H, Ar-H,
J ¼ 12.8 Hz), 7.38 (m, 2H, Ar-H), 7.01 (d, 1H, Ar-H, J ¼ 10.8 Hz), 6.09
(s, 1H, Ar-H), 5.99 (s, 1H, Ar-H), 3.90 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3). MS: m/z 414 (M þ 1).
Yield (39%), IR (KBr, cmꢃ1)3618(OH),3018(Ar-H),1626(C]O),1589
(C]C). 1H NMR (CDCl3,
7.78 (d, 1H, Ar-H, J ¼ 12 Hz and 10 Hz), 7.69 (d,1H, Ar-H, J ¼ 10 Hz), 7.11
d
) 14.83 (s,1H, OH), 7.91 (d,1H, Ar-H, J ¼ 12 Hz),

B.P. Bandgar et al. / European Journal of Medicinal Chemistry 45 (2010) 2629–2633
2633
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5.1.10. (2E,4Z)-5-Chloro-1-(2-hydroxy-4,6-dimethoxyphenyl)-5-p-
tolylpenta-2,4-dien-1-one (5j)
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Yield (30%), IR (KBr, cmꢃ1) 3648 (OH), 3012 (Ar-H), 1617 (C]O),
1592 (C]C). 1H NMR (CDCl3,
d): 14.23 (s, 1H, OH), 7.97 (dd,1H, Ar-H,
J ¼ 10.8 Hz and 12.8 Hz), 7.67 (d, 2H, Ar-H, J ¼ 8 Hz), 7.41 (d, 1H, Ar-
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J ¼ 10.8 Hz), 6.00 (s, 1H, Ar-H), 5.99 (s, 1H, Ar-H), 3.94 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3). MS: m/z 359 (M þ 1).
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5.1.11. (2E,4Z)-5-Chloro-1-(2-hydroxy-4,6-dimethoxyphenyl)-5-
(3-methoxyphenyl)penta-2,4-dien-1-one (5k)
Yield (30%), IR (KBr, cmꢃ1) 3648 (OH), 3012 (Ar-H), 1617 (C]O),
1592 (C]C). 1H NMR (CDCl3,
d): 14. 21 (s, 1H, OH), 7.98 (dd, 1H, Ar-
H, J ¼ 10.8 Hz and 12.8 Hz), 7.68 (d, 2H, Ar-H, J ¼ 8 Hz), 7.47 (d, 1H,
Ar-H, J ¼ 12.8 Hz), 6.93 (d, 2H, Ar-H, J ¼ 8 Hz), 6.92 (d, 1H, Ar-H,
J ¼ 10.8 Hz), 6.01 (s, 1H, Ar-H), 5.99 (s, 1H, Ar-H), 3.92 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 3.85 (S, 3H, OCH3). MS: m/z 375 (M þ 1).
Acknowledgement
The authors are thankful to Mr. Mahesh Nambiar and Mrs. Asha
Almeida, Piramal Life Sciences Ltd., Mumbai for screening of the
compounds against TNF-a and IL-6 and Council of Scientific and
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Chem. 10 (2002) 2795.
Industrial Research (CSIR), New Delhi, for financial assistance
[Project No. 01(2023)/05/EMR-II]. SAP thanks to CSIR for Senior
Research Fellowship.
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