Synthesis and biological evaluation of some new chalcones containing 2,5-dimethylfuran moiety

Article abstract of DOI:10.1155/2011/582603

A series of new chalcones (3a-g) were prepared by Claisen-Schmidt condensation of 3-acetyl-2,5-dimethylfuran with various substituted aromatic aldehydes in presence of aqueous solution of potassium hydroxide and ethanol at room temperature. The synthesize

Full text of DOI:10.1155/2011/582603

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(2), 541-546
http://www.e-journals.net
Synthesis and Biological Evaluation of Some New
Chalcones Containing 2,5-Dimethylfuran Moiety
S.SRIDHAR*, S.C.DINDA§ and Y.RAJENDRA PRASAD
*Chebrolu Hanumaiah Institute of Pharmaceutical Sciences
Guntur, A.P., India
§School of Pharmaceutical Education and Research
Berhampur University, Berhampur, Orissa, India
University College of Pharmaceutical Sciences
Andhra University, Vishakapatanam, A.P., India
sridhar_pharma24@yahoo.co.in
Received 21 June 2010; Accepted 2 September 2010
Abstract: A series of new chalcones (3a-g) were prepared by Claisen-Schmidt
condensation of 3-acetyl-2,5-dimethylfuran with various substituted aromatic
aldehydes in presence of aqueous solution of potassium hydroxide and ethanol at
room temperature. The synthesized chalcones were characterized by means of their
1
IR, H NMR spectral data and elemental analyses. When these chalcones were
evaluated for antimicrobial and anti-inflammatory activities, some of them were
found to possess significant activity, when compared to standard drugs.
Keywords: Chalcone, Antimicrobial activity, Synthesis, Dimethylfuran moiety.
Introduction
The search for new potent anti-microbial agents with reduced toxicity and lower side effects
is of continuous process. One of the most frequently encountered groups of organic
compounds in medicinal chemistry is chalcones and their derivatives. Chalcone is a generic
term given to compounds bearing the 1,3-diphenylprop-2-en-1-one frame work, which can
be functionalized in the propane chain by the presence olefinic, keto and/or hydroxyl groups
(Figure 1)1. Their bactericidal effect has been related to the ability of the α, β- unsaturated
ketone to undergo a conjugated addition to a nucleophilic group like a thiol group in an
essential protein. In addition, chalcone derivatives showed activity against dermatophytes
only but not against other types of fungi. Chalcones are readily synthesized by the base
catalysed Claisen-Schmidt condensation of an aldehyde and an appropriate ketone in a polar
solvent like ethanol and yields may be variable, ranging2-3 from 5% to 80%. The chalcones
have a diverse range of biological activities, among which antimalarial, antitubercular, anti-
inflammatory, cytotoxic, antioxidant, analgesic, antiviral and antimicrobial4-10 properties
were widely cited.

542
S.SRIDHAR et al.
Figure 1
As shown in scheme 1, chalcones 3(a-g) were synthesized by a base catalyzed
condensation of 3-acetyl-2,5-dimethylfuran and appropriately substituted aldehydes11. The
structures of various synthesized compounds were characterized on the basis of elemental
1
analyses, IR and H NMR spectral data. The compounds were evaluated for their anti-
inflammatory activity by carrageenan induced rat paw oedema method and antimicrobial
activity by agar cup plate method.
Experimental
Melting points were determined on an open capillary melting point apparatus and are
uncorrected. 1H NMR spectra were recorded in CDCl3 on Bruker WM 400 MHz spectrometer
with TMS as internal standard. Infrared spectra were recorded (KBr) on a Perkin-Elmer AC-1
spectrophotometer. Micro analyses were performed on Carlo Erba E–1108 element analyzer
and were with in the 0.4% of the theoretical values. Reaction completion was identified by
TLC using silica gel for TLC (Merck). All the chalcones have been purified by column
chromatography performed on silica gel columns (100-200 mesh, Merck).
General procedure for the synthesis of 1-(2',5'-dimethyl-3'-furyl)-3-(aryl)-2-propen-
1- one (3a-g)
A mixture of 3-acetyl-2,5-dimethylfuran (0.005 mol) (1) and respective aldehyde (0.005 mol)
(2) was stirred in ethanol (7.5 mL) and then an aqueous solution of potassium hydroxide (50%,
7.5 mL) was added to it. The mixture was kept for 24 h and it was acidified with 1:1 HCl and
H2O. Then it was filtered under vacuum and the solid was washed with water, purified by
column chromatography and crystallized from a mixture of ethyl acetate and hexane (Scheme 1).
The physical and spectral data of the chalcones were shown in Table 1 & 2.
O
O
C
CH=CH-Ar
C
CH3
Aq.KOH
Ethanol
OHC-Ar
+
H3
C
CH3
CH3
H3
C
O
O
3(a-g)
3 a-g
1
2
2
1
Scheme 1. Synthesis of chalcones
Where Ar =
OCH
OCH
3
OCH
NH2
Cl
CH3
3
3
3a
3b
3c
3d
Cl
OCH3
Cl
3e
3f
3g

Synthesis and Biological Evaluation of Some New Chalcones
543
Table 1. Physical data of the prepared compounds 3(a-g)
Mol.
Formula
% Calc.
H
% Found
H
S.No.
Ar
C
N
-
C
N
-
3″,4″,5″-
trimethoxyphenyl
C18H20O5 316 154 71 68.34 6.37
68.23 6.28
3a
3b
C15H13ClO2 260 139 68 69.23 5.01
69.25 5.03
4″-chlorophenyl
-
-
C17H19NO2 269 112 73 75.83 7.06 5.20 75.82 7.05 5.22
3c 4″-dimethylaminophenyl
C16H16O2
240 153 75 80.02 6.66
80.04 6.68
61.24 4.06
84.65 5.58
75.02 6.28
-
3d
4″-methylphenyl
-
-
C15H12Cl2O2 294 132 71 61.22 4.08
3e 2″,4″-dichlorophenyl
3f
-
-
C23H18O2
C16H16O3
326 138 78 84.64 5.56
256 87 73 75.01 6.25
9″-anthracenyl
4″-methoxyphenyl
-
-
3g
-
Table 2. Spectral data of the prepared compounds 3(a-g)
IR, υ max, cm-1
S.No
3a
1H NMR (CDCl3), δ ppm
1655 (C=O), 1602 (C=C of
Ar), 1505( CH=CH), 1125
(O-CH3), 1048 (C-O-C)
3.90-3.95 (9H, s, 3x-OCH3), 6.71 (1H, s, C-4'-
H), 7.20 (1H, d, J= 17Hz, -CO-CH=), 7.81 (1H,
d, J= 17Hz, =CH-Ar), 6.90 (2H, s, C-2″-H and
C-6″-H), 2.2(3H,s,Ar-CH3), 2.7(3H,s, Ar-CH3).
6.41 (1H, s, C-4'-H), 7.10 (1H, d, J=17Hz,-CO-
CH=), 7.70 (1H, d,J= 17Hz, =CH-Ar), 7.58 (2H,
d,J= 8Hz, C-3″-H and C-5″-H), 7.40 (2H, d,J=
8Hz, C-2″-H and C-6″-H), 2.3(3H,s, Ar-
CH3),2.6(3H,s, Ar-CH3).
1664 (C=O), 1584 (C=C of
Ar), 1520 (CH=CH), 1060
(C-O), 855 (C-Cl)
3b
3c
1658 (C=O), 1588 (C=C of
Ar), 1502 (CH=CH), 1185
(-N( CH3)2) 1082 (C-O)
3.05 (6H, s, -N(CH3)2), 6.58 (1H, s, C-4'-H), 7.25
(1H, d, J=17Hz, -CO-CH=), 7.87(1H, d, J=17Hz,
-CH=Ar), 6.75(2H,d, J=8.5 Hz, C-2″-H and C-6″-
H), 7.55 (2H,d, J=8.5Hz, C-3″-H andC-5″-H),
2.05 (3H,s, Ar-CH3), 2.5(3H,s, Ar-CH3).
2.60 (3H, s, Ar-CH3), 6.30 (1H, s, C-4'-H), 7.23
(1H, d, J=17Hz, -CO-CH=), 7.77 (1H, d, J=
17Hz, -CH=Ar), 7.56 (2H, d, J=9Hz,C-3″-H and
C-5″H), 7.3 (2H, d, J=9Hz, C-2″-H and C-6″-
H), 2.3(3H,s, Ar-CH3), 2.4(3H,s, Ar-CH3).
6.3 (1H,s,C-4'-H), 7.1 (1H, d, J=17Hz, -CO-CH=),
7.99 (1H, d, J=17Hz, =CH-Ar), 7.3 (1H, d, J=8Hz,
C-6″-H), 7.4(1H,s,C-3″-H), 7.6(1H,d, J=9HZ,
C-5″-H), 2.3(3H,s, Ar-CH3), 2.6(3H,s, Ar-CH3).
6.20 (1H, s, C-4'-H), 7.36 (1H, d, J=17Hz, -CO-
CH=), 7.68 (1H, d, J=17Hz, =CH-Ar), 7.50-8.90
(9H, Ar-H), 2.3(3H,s, Ar-CH3), 2.7(3H,s, Ar-CH3).
3.85 (3H, s, OCH3), 6.3 (1H, s, C-4'-H), 6.9 (1H,
d, J=17Hz, -CO-CH=), 7.1-7.6 (4H, m, C-2″, 3″,
5″and 6″-H), 7.7 (1H, d, J=17Hz, =CH-Ar),
2.3(3H,s, Ar-CH3), 2.5(3H,s, Ar-CH3).
1641 (C=O), 1583 (C=C of
Ar), 1505 (CH=CH), 1076
(C-O)
3d
3e
1648 (C=O), 1609 (C=C of
Ar), 1510 (CH=CH), 1080
(C-O), 868 (C-Cl)
1633 (C=O), 1591 (C=C of
Ar), 1506 (CH=CH), 1070
(C-O)
3f
1664 (C=O), 1585 (C=C of
Ar), 1505 (CH=CH), 1133
(O-CH3), 1055 (C-O-C)
3g
Anti-inflammatory activity
Spraygue-dawley rats (M/S Gosh Enterprises, Calcutta, West Bengal, India) of either sex
weighing between 180-200 g were used in the experiment. 1% carrageenan sodium gel was
prepared with saline water for producing inflammation and gel of 1% sodium CMC was
prepared with saline water for suspending the test compounds and standard drug.

544
S.SRIDHAR et al.
Rats were divided into nine groups of five animals each. Inflammation was induced by
injecting 0.05 mL of 1% carrageenan subcutaneously into the sub plantar region of the right
hind paw and 0.05 mL of saline was injected into the sub plantar region of the left hind paw
for all groups. 1% sodium CMC gel (1 mL/kg) was given to group-I used as carrageenan
treated control and the standard drug aceclofenac (2 mg/kg) was administered to group-II.
The groups III-IX treated with compounds 3(a-g) (10 mg/kg). All the doses were
administered orally. Anti-inflammatory activity was evaluated by measuring carrageenan
induced paw oedema12,13. The thickness of raw paw was measured before carrageenan
injection and after carrageenan injection at time intervals 0.5,1,2,3,4 and 6 h using Zeitlin
constant loaded lever method14. The percentage increase of paw oedema thickness was
calculated15. The results and statistical analysis of anti-inflammatory activity of aceclofenac
and the compounds tested were shown in Table 3.
Table 3. Anti-inflammatory activity of chalcones 3 (a-g)
% inhibition SEM at various time intervals
Compound
0.5 h
1.0 h
2.0 h
3.0 h
4.0 h
6.0 h
20.58 0.91
31.65 1.01
59.84 1.53
69.13 1.25 76.55 1.98 85.15 2.22
3a
3b
3c
3d
24.19 0.78* 42.57 0.99* 65.47 1.65* 79.87 1.66* 89.28 2.01 97.28 1.99
21.10 0.65 41.46 1.12* 53.13 1.36* 72.91 1.67 82.65 2.32 72.55 2.32
17.13 0.75* 28.02 0.89 42.37 1.45* 67.81 1.33* 78.74 1.88 82.70 2.53
24.78 0.77* 37.37 0.92* 51.11 1.35 62.35 1.81* 84.10 2.95 87.30 3.25
3e
23.01 0.65* 36.25 1.23* 57.10 1.48
21.68 0.88 34.11 1.02* 57.45 1.43
78.14 1.59 80.10 2.32 85.15 2.31
76.16 1.53 82.46 1.95 89.52 2.35
58.10 1.52 77.83 1.68 77.19 1.97
3f
3g
Aceclofenac
28.0 2.0
20.16 0.90
43.85 0.97
*
All values are represented as mean SEM (n=6). P<0.01 compared to reference standard Aceclofenac
Student’s t-test. Dosage: Aceclofenac-2 mg/kg and test compounds-10 mg/kg body weight of rat
Antimicrobial activity
Cup plate method16,17 using Mueller-Hinton agar medium was employed to study the
preliminary antibacterial activity of (3a-g) against B. subtilis, B. pumilis, S. aureus, E. coli and
P. vulgaris. The agar medium was purchased from HI-media Laboratories Ltd., Mumbai,
India. Preparation of nutrient broth, subculture, base layer medium, agar medium and peptone
water was done as per the standard procedure. Each test compound (5 mg) was dissolved in
5 mL of dimethyl sulfoxide. Benzylpenicillin was employed as reference standard (1000 µg/mL)
to compare the results. The pH of the all the test solutions and control was maintained at 2-3 by
using conc. HCl, because the compounds were not diffused through agar medium at pH below
3. All the compounds were tested at a concentration of 0.05 mL (50 µg) and 0.1 mL (100 µg)
level and DMSO as control did not show any inhibition.
Same cup plate method using PDA (Potato-Dextrose-Agar) medium was employed to
study the preliminary antifungal activity of (3a-g) against A. niger, C. albicans and
R. oryzae. The PDA medium was purchased from HI-media Laboratories Ltd., Mumbai,
India. Preparation of nutrient broth, subculture, base layer medium and PDA medium was
done as per the standard procedure. Each test compound (5 mg) was dissolved in 5 mL of
dimethyl sulfoxide. Fluconazole employed as reference standard (1000 µg/mL) to compare
the results. The pH of the all the test solutions and control was maintained at 2-3 by using
conc. HCl, because the compounds were not diffused through agar medium at pH below 3.
All the compounds were tested at a concentration of 0.05 mL (50 µg) and 0.1 mL (100 µg)
level and DMSO as control did not show any inhibition.
The cups each of 7 mm diameter were made by scooping out medium with a sterilized
cork borer in a Petri dish which was streaked with the organisms. The solutions of each test

Synthesis and Biological Evaluation of Some New Chalcones
545
compound, control and reference standards (0.05 and 0.1 mL) were added separately in the
cups and Petri dishes were subsequently incubated at 37 1 0C for 24 h for antibacterial activity
and kept aside at room temperature for 48 h for antifungal activity. Zone of inhibition
produced by each compound was measured in mm and the results are presented in Table.4
for antibacterial activity and in Table.5 for antifungal activity.
Table 4. Antibacterial activity of chalcones 3(a-g)
Zone of inhibition, in mm
Quantity in µg/mL
Compound
50 100
50
09
17
18
19
14
18
20
30
-
100 50
100
11
23
23
19
21
21
22
29
-
50
100
12
15
23
19
16
17
17
26
-
50
13
14
21
17
11
16
13
27
-
100
08
18
26
18
14
20
16
31
-
12
15
16
20
11
14
19
11
21
18
23
13
16
22
32
-
10
20
23
16
14
23
24
31
-
08
18
20
11
17
14
18
26
-
11
14
18
18
12
15
16
24
-
3a
3b
3c
3d
3e
3f
3g
Benzylpenicillin 27
Control
-
Table 5. Antifungal activity of chalcones 3(a-g)
Zone of inhibition, in mm
Quantity in µg/mL
Compound
A. niger
50
C. albicans
R. oryzae
100
100
20
21
23
17
17
20
20
27
-
50
17
15
24
16
20
22
21
23
-
100
21
20
25
21
22
20
22
27
-
50
17
15
16
13
13
14
15
21
-
16
17
17
14
15
18
17
23
-
19
18
18
18
16
19
18
26
-
3a
3b
3c
3d
3e
3f
3g
Fluconazole
Control
Results and Discussion
The results of anti-inflammatory activity revealed that the compounds (3a-g) exhibited
moderate to considerable activity when compared to reference standard aceclofenac. In
addition, it was found that 3b showed maximum activity and this may be due to presence of
chloro group at 4th position on aromatic ring-B of chalcone. Moreover, it was also observed
that the compounds 3e and 3g, carrying 2,4-dichlorophenyl and 4-methoxy phenyl rings as
ring-B of chalcone, respectively, showed remarkable activity.
Compounds (3a-g) showed significant antibacterial activity at both 0.05 mL (50 µg) and
0.1 mL (100 µg) concentration levels when compared with standard drug benzylpenicillin.
However, the chalcones 3b, 3c and 3g were found to be more potent on all the bacterial
strains. Compounds (3a-g) also showed significant antifungal activity at both 0.05 mL (50 µg)
and 0.1 mL (100 µg) concentration levels when compared with standard drug fluconazole.
Compounds 3c and 3g showed maximal antifungal activity. The results clearly revealed the
contribution of electron withdrawing groups and electron releasing groups on the aromatic
ring in enhancing the antibacterial and antifungal activity.

546
S.SRIDHAR et al.
Acknowledgment
The authors are thankful to Dr. Trimurtulu, Vice-President, Laila Impex Industries Ltd.,
Vijayawada, India for providing IR, 1H NMR and elemental analyses data.
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