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0974-360X (Online)
RESEARCH ARTICLE
Synthesis and
Antimicrobial Activity of Some New Chalcones Containing Benzofuran and
Benzofuran Schiff Bases
Lunkad A.S.*, Kothawade S.N., Jadhav D.V.,
Chaudhari P.S., Bornare S.P.
SCSSS’s Sitabai
Thite College of Pharmacy, Shirur (Ghodnadi), Dist-Pune.
*Corresponding Author E-mail: amit.lunkad15@gmail.com
Benzofuran nucleus frequently
occurs in natural products. In the present course of study an attempt is made
for synthesis of new Benzofuran derivatives. 5-chloro-2-hydroxy acetophenone 2
was prepared by the Fries rearrangement with anhydrous aluminium chloride at
1300c for 3 hrs. The compound 2 was treated with chloroacetone in presence of
anhydrous acetone and potassium carbonate gave 5-chloro-3-methyl-2-acetyl
Benzofuran 3. Compound 3 underwent condensation with aromatic aldehyde and
aromatic amines to furnished chalcone and Schiff derivatives 4a-e and 5a-e
respectively. The synthesized compounds were screened for their antimicrobial
activities.
KEYWORDS: 5-chloro-2-hydroxy acetophenone, Chalcone, Schiff
base, Antimicrobial activity.
INTRODUCTION:
Heterocyclic synthesis has emerged as powerful technique
for generating new molecules useful for drug discovery1.
Heterocyclic compounds provide scaffolds on which pharmacophore can arrange to
yield potent and selective drugs2. Chalcones, the bichromophoric
molecules constitute an important class of naturally occurring flavonoids
exhibiting a wide spectrum of biological activities3. The compounds
with backbone of chalcones have been reported to exhibit a wide variety of
pharmacological effects including anticancer, anti-inflammatory, antioxidant,
antifungal, antiviral, antimalerial and antimicrobial activities4.
In recent years, Schiff bases are reported to exhibit
broad- spectrum of chemotherapeutic properties such as anti-viral5,6,
anti-tubercular7, antifungal and antibacterial activities8.
MATERIALS AND METHODS:
All chemicals were purchased from the commercial supplier.
Melting points were determined with open capillary and are uncorrected. IR
spectra were recorded in KBr pellets by using JASCO FT-IR 300E
spectrophotometer. 1H NMR spectra were recorded on a Bruker-400 MHz
spectrometer using TMS as an internal standard. UV spectra were recorded on
Jasco V-530 UV- Visible spectrometer.
EXPERIMENTAL:
Preparation
of 5-Chloro-2-hydroxy acetophenone (2):
A mixture
of p-chlorophenyl acetate (0.025 moles) and anhydrous aluminium chloride (8g)
was heated initially 1200C and slowly the temperature raised to 1600C.
The heating continued for 3 hrs, the reaction mixture was cooled and decomposed
in ice cold water containing conc. hydrochloric acid. The solid separated was
collected and crystallized from ethanol. Yield 85.68%, m.p. 54-550C
(lit 540C).
Preparation of 5-Chloro-3-methyl-2-acetylbenzofuran (3):
To a solution of 5-chloro-2-hydroxy acetophenone 1 (0.05
mole) anhydrous acetone (70 ml), chloroacetone (0.05 moles) and anhydrous
potassium carbonate (15g) were added. The reaction mixture heated under gentle
reflux for 12 hrs. Then it was cooled, potassium salts were filtered off,
washed with acetone. The excess of acetone was removed under reduced pressure
and resulting oil solidified on cooling. The solid obtained was collected and
crystallized from benzene. Yield 78.77%, m.p. 1020C.
General Procedure for formation of
1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-prop-2-en-1-one Derivative (4a-e):
A mixture of 5-chloro-3-methyl-2-acetyl benzofuran (0.01
mole) and different aromatic aldehyde (0.01 mole) was dissolved in ethanol (15
ml).The clear solution was cooled in an ice bath at 0-50C compound
crystallize. To this solution aq. NaOH (2 ml, 70%) was added drop wise with
stirring for 2-3 hr. stirring continued and then left overnight. The reaction
mixture was poured into excess of ice-water and carefully acidified with HCl.
After 25 min. the chalcone which separated as a bright orange color solid and
the filter and washed with water. Dried and recrystallized by suitable solvent.
General Procedure for formation of N-[1-(5-chloro-3-methyl-1-benzofuran-2-yl)
ethylidene] Derivative (5a-e):
A mixture of 5-chloro-3-methyl-2-acetyl benzofuran (0.01
moles) was dissolved in 10ml of n-butanol under heating then different primary
aromatic amine (0.03 moles) was added. The reaction mixture was refluxed for
2hrs and then the solvent was removed under vacuum. The residue was triturated
with 20ml of ethanol until a precipitate formed which was filtered and purified
by crystallization from ethanol.
Scheme:
Table I- Characterization data of compounds 4a-e and 5a-e
|
Compound
|
R
|
% Yield
|
M.P. 0C
|
Absorption
(λmax nm)
|
Molecular
formula
|
|
4a
|
-NO2(m)
|
63.28
|
120
|
330
|
C18H12O4NCl
|
|
4b
|
-NO2(o)
|
62.56
|
116
|
332
|
C18H12O4NCl
|
|
4c
|
-OH(p)
|
74.48
|
118
|
356
|
C18H13O3Cl
|
|
4d
|
-CH3(p)
|
78.01
|
92
|
346
|
C19H15O2Cl
|
|
4e
|
-Cl (p)
|
61.45
|
130
|
334
|
C18H12O2Cl2
|
|
5a
|
-NO2(m)
|
62.88
|
120
|
326
|
C17H13 ClN2O3
|
|
5b
|
-Cl (m)
|
84.33
|
110
|
328
|
C17H13 Cl2NO
|
|
5c
|
-Cl (o)
|
83.33
|
90
|
328
|
C17H13 Cl2NO
|
|
5d
|
-CH3(o)
|
71.11
|
88
|
326
|
C18H16 ClNO
|
|
5e
|
-H
|
67.71
|
90
|
330
|
C17H14 ClNO
|
(2E)-1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-(3-nitrophenyl)
prop-2-en-1-one (4a)
FTIR (KBr cm-1): 1700 (-C=O
of α, β- unsaturated ketone), 2908 (-CH of CH3), 728
(Ar-H)
1H NMR DMSO δ (ppm): 7.5 (s, 3H
of Benzofuran), 7.64 and 7.67 (s, H of ethylene), 2.2 (s, 3H of CH3)
(2E)-1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (4c)
FTIR (KBr cm-1): 1670 (-C=O
of α, β- unsaturated ketone), 2356 (-CH of CH3), 3343
(OH), 728 (Ar-H)
1H NMR DMSO δ (ppm): 7.5 (s, 3H
of Benzofuran), 7.64 and 7.67 (s, H of ethylene), 2.2 (s, 3H of CH3),
6.5 (s, H of OH)
(2E)-1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-(4-methylphenyl)prop-2-en-1-one
(4d)
FTIR (KBr cm-1): 1654 (-C=O
of α, β- unsaturated ketone), 2908 (-CH of CH3), 728
(Ar-H)
1H NMR DMSO δ (ppm): 7.5 (s, 3H
of Benzofuran), 7.64 and 7.67 (s, H of ethylene), 2.35 (s, 3H of CH3)
N-[1-(5-chloro-3-methyl-1-benzofuran-2-yl)
ethylidene]-4-nitroaniline (5a):
FTIR (KBr cm-1): 1573 (-C=N
str), 748 (C-Cl)
1H NMR DMSO δ (ppm): 7.5 (s, 3H
of Benzofuran), 8.2 (m, Aryl-H), 2.5 (s, 3H of CH3)
Antimicrobial activity:
All the newly synthesized compounds were screened for
antimicrobial activity against both gram positive S.aureus and negative E.coli
bacteria and antifungal activity against C.albicans
and A.flavus according to cup plate
method at a concentration of 0.005 mol/ml. Streptomycin and Gresofulvin were
used as standard for comparison of antibacterial and antifungal activity.
Solvent dimethyl formamide (DMF) was used as control. The results of activity
are given in Table II and Table III.
Table II: Antibacterial activity
|
Sr. No.
|
Compound
|
Mean Zone of Inhibition (in mm)
|
|
Staphylococcus
aureus
|
Escherichia
Coli
|
|
50 μg
|
100 μg
|
50 μg
|
100 μg
|
|
1
|
Procaine Penicillin
|
19
|
23
|
-
|
-
|
|
2
|
Strptomycin
|
-
|
-
|
20
|
24
|
|
3
|
4a
|
13
|
15
|
6
|
12
|
|
4
|
4b
|
12
|
14
|
7
|
11
|
|
5
|
4c
|
13
|
15
|
8
|
10
|
|
6
|
4d
|
12
|
14
|
8
|
9
|
|
7
|
4e
|
14
|
16
|
11
|
12
|
|
8
|
5a
|
13
|
16
|
8
|
12
|
|
9
|
5b
|
12
|
18
|
7
|
11
|
|
10
|
5c
|
11
|
17
|
7
|
11
|
|
11
|
5d
|
10
|
13
|
8
|
10
|
|
12
|
5e
|
9
|
12
|
8
|
12
|
|
|
|
|
|
|
|
Table III: Antifungal activity
|
Sr. No.
|
Compound
|
Mean Zone of Inhibition (in mm)
|
|
Candida
aibicans
|
Asperagillus
flavus
|
|
50 μg
|
100 μg
|
50 μg
|
100 μg
|
|
1
|
Griseofulvin
|
21
|
24
|
21
|
24
|
|
2
|
4a
|
12
|
15
|
19
|
22
|
|
3
|
4b
|
11
|
13
|
18
|
20
|
|
4
|
4c
|
15
|
17
|
9
|
12
|
|
5
|
4d
|
13
|
14
|
8
|
9
|
|
6
|
4e
|
14
|
16
|
11
|
12
|
|
7
|
5a
|
10
|
11
|
11
|
16
|
|
8
|
5b
|
14
|
15
|
16
|
19
|
|
9
|
5c
|
12
|
14
|
15
|
17
|
|
10
|
5d
|
10
|
11
|
11
|
14
|
|
11
|
5e
|
9
|
11
|
10
|
12
|
|
|
|
|
|
|
|
RESULTS AND DISCUSSION:
All the newly synthesized Benzofuran derivatives were
screened for In-vitro antibacterial against S.
aureus and E. coli at a concentration of 50 μg
and 100 μg Compounds 4e, 5b have shown high activity against S. aureus and
Compounds 4e and 5a exhibited high activity against E. coli. Remaining
compounds possess moderate and weak activity against both bacteria.
Compounds 4c, 4e, 5b possess very good activity against
fungi C. aibicans and compounds 4a,
4b, 5b, 5c shown high activity against A.
flavus and remaining compounds exhibited either moderate or weak activity
against both fungi.
ACKNOWLEDGEMENTS:
The authors are thankful to the Principal, Sitabai Thite
College of pharmacy, Shirur for providing laboratory facilities. Authors are
also thankful to the Garware Institute of research, University of Pune for
providing 1H NMR.
REFERENCES:
1) Hermakens P.H.,
Ottenheijm H. C., Rees D. C. Solid-phase organic reactions II: A review of
literature. Nov. 95 – Nov. 96. Tetrahedron 1997; 53: 5643.
2) Gordon E, Barrett R. W., Power W. J.,
FoderS. P., Applications of combinatorial technologies to drug discovery. 2.
Combinatorial organic synthesis library screening strategies; and future
directions J. Med. Chem 1994: 37: 1485.
3) Patil C.B., Mahajan S. K. and Katti S. A.
Chalcone: A versatile molecule, J. Pharm Sci. Res. 2009, 1 (3), 11-22.
4) Ramakrishna A., Sirisha V., Jose M. A.,
Narasimharao B., Deepthi B., Ramankumar P., Soumya M. and Ramanamma T., Indian
Drugs April 2011, 48(04), 25-29.
5) D. Sriram, Y. Perumal, Curr. Med. Chem.
2003, (10), 1689.
6) M. C. Pirrung, S. V. Pansare, K.D. Sarma,
K.A. Keith, E.R. Kern., J. Medi. Chem. 48 (2005) 3045.
7) D. Sriram, P. Yogeeswari, G. Gopal, Eur. J.
Med. Chem., 40(2005) 1373.
8) D. Patel, P. Kumari, N, Patel, Arch. Appl.
Sci. Res. 2 (2010) 68.