Synthesis of 3-methylflavones and their antioxidant and antibacterial activities

Article abstract of DOI:10.1007/s00044-011-9725-y

An attempt was made to synthesise newer 3-methylflavones with various substitution on the ring A and B of 2-phenylchromen-4-one. They were evaluated for antioxidant activity and antibacterial activity against the Gram-positive and Gram-negative bacteria.

Full text of DOI:10.1007/s00044-011-9725-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1991–1996
DOI 10.1007/s00044-011-9725-y
ORIGINAL RESEARCH
Synthesis of 3-methylflavones and their antioxidant
and antibacterial activities
•
•
•
B. S. Jayashree Afroze Alam Yogendra Nayak
D. Vijay Kumar
Received: 2 November 2009 / Accepted: 21 June 2011 / Published online: 9 July 2011
Ó Springer Science+Business Media, LLC 2011
Abstract An attempt was made to synthesise newer
3-methylflavones with various substitution on the ring A
and B of 2-phenylchromen-4-one. They were evaluated
for antioxidant activity and antibacterial activity against
the Gram-positive and Gram-negative bacteria. Five test
compounds exhibited DPPH radical scavenging activity
with IC50 below 100 lg/ml, and the same test compounds
exhibited 50–100% growth inhibition in Gram-positive
bacteria against standard Amoxicillin.
et al., 2007; Jung et al., 2006; Cushnie and Lamb 2005).
The antibacterial mechanisms of action of selected flavo-
noids including robinetin, myricetin, apigenin, rutin,
galangin, 2,4,20-trihydroxy-50-methyl chalcone and lon-
chocarpol A have been proved and elucidated (Plaper et al.,
2003). For example, the activity of quercetin (3,30,40,5,7-
pentahydroxy flavone) has been at least partially attributed
to the inhibition of DNA gyrase. It has also been proposed
that sophoraflavone-G and (-)-epigallocatechin gallate
inhibit cytoplasmic membrane function and energy
metabolism. This group of compounds represent novel
leads, and future studies may allow the development of a
pharmacologically acceptable antimicrobial class of agents.
Eventhough, natural flavonoids are highly potent, they
show certain limitations as far as their stability, solubility
characteristics and kinetics are concerned. Hence, these
vast literatures prompted us to modify the benzopyrone
ring to explore the biological activities associated with this
nucleus (Jayashree et al., 2007). In the present study,
3-methyl flavone with various substitutions on the ring A
and B were synthesised and explored for their antioxidant
and antibacterial activities.
Keywords 3-Methylflavone ꢀ Antioxidant ꢀ Antibacterial
Introduction
Flavonoids are polyphenolic compounds widely distributed
in plants. Majority of the flavonoids studied, selectively
react with free radicals and anti-inflammatory activity
´
(Amic et al., 2007; Pietta, 2000; Kim et al., 2004; Aron and
´
Kennedy, 2008; Gonzalez-Gallego et al., 2007; Tipoe
et al., 2007; Es-Safi et al., 2007). They are also reported
to exhibit antimicrobial, antihypertensive, antiplatelet,
gastroprotective, antitumor, antiallergic and antidiabetic
activities (Cazarolli et al., 2008; Li et al., 2005; Holt et al.,
2006; Zayachkivska et al., 2005; Li et al., 2007; Kawai
Experimental
The chemicals used were of Analytical reagent (AR) and
Laboratory reagent (LR) grade, purchased from Loba
Chemicals, Qualigens, NR Chemicals, Lancaster, Sigma,
Reachem, SD Fine Chemicals Ltd., Merck and Hi-Media.
Melting points were determined using melting point
apparatus (Shital Scientific industries, Mumbai, India) and
were found uncorrected. The reactions were monitored by
TLC, and the Rf values were determined on pre-coated
TLC plates using the solvent system n-hexane: ethyl
B. S. Jayashree (&) ꢀ A. Alam ꢀ D. Vijay Kumar
Department of Pharmaceutical Chemistry,
Manipal College of Pharmaceutical Sciences,
Manipal 576104, India
e-mail: jesolar2001@yahoo.co.in
Y. Nayak
Department of Pharmacology,
Manipal College of Pharmaceutical Sciences,
Manipal 576104, India
123

1992
Med Chem Res (2012) 21:1991–1996
General procedure for the synthesis
acetate (9:1). kmax, 2max for the synthesised test compounds
were established by UV–visible spectrometer (Shimadzu
UV–Vis Spectrophotometer UV-1650 PC, Shimadzu Cor-
poration, Japan) in methanol (HPLC grade) as explained in
the article (Beckett and Stenlake 2005). The influence of
substituent on the synthesised flavones was determined by
partition coefficient using classical shake flask method
(Selassie 2003; Taylor 2005). The FTIR studies were done
using Shimadzu FTIR 8310 (Shimadzu Corporation,
of 3-methylflavones
The chalcones synthesised above were further cyclised by
oxidation with iodine by Algar Flynn Oymeda method. To
a solution of 0.01 M of chalcone (C 1–20) in a 50 ml of
DMSO taken in a 100 ml round bottom flask, fitted with
reflux condenser, and a catalytic amount of iodine was
added. The reaction mixture was refluxed for 3–4 h and
kept overnight. The precipitate was neutralised with
sodium thiosulphate, filtered, washed with water, dried and
was recrystallised with absolute ethanol (for synthetic
details see Fig. 1).
1
Japan). H NMR was carried out by the instrument NMR
(AMX 400, Bruker AXS Analytical Instruments. New
Delhi, India), and the mass spectral studies were done
using GC–MS (Shimadzu GCMS QP5050, Shimadzu
Corporation, Japan).
DPPH radical scavenging activity
General procedure for the synthesis of substituted
3-methylchalcones (C 1–20) (Fig. 1)
Antioxidant activity of the test compounds was determined
by diphenylpicrylhydrazyl (DPPH) radical scavenging
method as described earlier (Rajakumar and Rao 1995).
Different aliquots of the test compound (10–1000 lg/ml) in
methanol were mixed with 1 mM of methanolic DPPH
solution to a final volume of 2.0 ml, incubated for 20 min
at room temperature and absorbance was measured at
517 nm. Blank was carried out in the same manner without
the test compounds, and ascorbic acid was taken as the
standard. The experiment was performed in triplicate and
To a solution of 0.01 M o-hydroxy propiophenone in 10 ml
of 40% KOH in ethanol, 0.01 M of substituted benzalde-
hyde was added and the mixture was stirred for 48–72 h.
The coloured solution was poured into crushed ice, and
acidified with 1 N HCl. The precipitate obtained was
washed with cold water, filtered, dried and recrystallised
with absolute ethanol.
Fig. 1 Scheme for synthesis of
3-methylflavones by Algar
Flynn Oymeda method
R3
R1
OH
O
R2
R4
+
CH3
Compound R1
R2
R3
R4
OHC
1
2
3
H
H
H
H
H
H
H
H
H
N(CH3)2
CH3
H
EtOH
40% KOH
R4
R3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
OH
H
H
H
H
OCH3
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
OCH3
H
N(CH3)2
H
H
OCH3
OH
Cl
NO2
H
Cl
F
Br
H
CH3
Cl
H
H
H
H
Br
H
H
H
H
F
H
OCH3
H
R1
OH
R2
CH3
O
(C 1 - 20)
R3
B
I2 / DMSO
R2
R4
R1
O
C
H
H
H
H
A
CH3
H
H
O
OH
H
3-Methylflavones (1 - 20)
123

Med Chem Res (2012) 21:1991–1996
1993
ꢀ
ꢁ
the percentage radical scavenging was determined as
100 ꢂ ODnegativecontrol ꢁ ODtest
=
ꢀ
ꢁ
follows
h
ODnegativecontrol ꢁ ODpositivecontrol
ðAbsorbance of blank ꢁ Absorbance of testÞ=
i
The IC50 was calculated using the Microsoft excel.
Results and discussion
Absorbance of blank ꢂ 100
2-Hydroxy propiophenone was refluxed with different
substituted benzaldehyde in aqueous alkali media gave
corresponding chalcones in the range of 70–80% yield. The
chalcones were further cyclised by oxidation with iodine in
DMSO to respective 3-methylflavones and were synthes-
ised following Algar Flynn Oymeda method as shown in
the Fig. 1 (compound 1–20). All the synthesised test
compounds were purified by recrystallisation with metha-
nol (yield &60%), melting point was determined and their
Antibacterial activity
The synthesised test compounds were evaluated for their
antibacterial activity by agar diffusion method against six
species of bacteria namely Gram-positive bacteria such as
Staphylococcus aureus, Bacillus subtilis, Bacillus cereus;
and Gram-negative bacteria such as Escherichia coli,
Pseudomonas aeruginosa and Klebsiella pneumonia (Atta-
ur-Rahman et al., 2001). The organisms were initially
cultured in Luria Broth media overnight to a stationary
growth phase, and subcultured after dilution to obtain
optical density at OD600 to &1.200 ll of this culture
medium was placed into 96-well plate, and test compounds
were added to a final concentration of 100 lg/100 ll. The
OD600 was measured before and after the incubation for
24 h at 37°C. Amoxicillin was used as positive control.
The percentage inhibition of the bacterial growth was
obtained by the following equation
1
structures were confirmed by FTIR, HNMR and GCMS
studies.
kmax and 2max of all the compounds were determined
using UV spectrophotometer in methanol (HPLC grade).
The kmax of all the synthesised test compounds were found
to be in the range of 225–347 nm as shown in Table 1. The
2max of all the synthesised test compounds were found to
be in the range of 6.621 9 103 to 8.44 9 104 as shown in
Table 1. Partition coefficient of all the synthesised com-
pounds was determined to know the influence of substitu-
tions on 3-methylflavones by classical shake flask method
using n-Octanol and phosphate buffer. The partition
Table 1 Physical constants of
3-methylflavones synthesised
Compound
Yield (%)
M. formula
C18O2NH17
M. wt
mp (°C)
kmax
2max
Rfa
LogP
1
72
80
55
65
72
90
85
60
45
85
72
88
90
85
72
65
60
60
65
60
280
252
237
294
252
272.5
268
253
304
283
316
272.5
256
316
268
256
252
268
268
253
120–125
125–132
110–112
160–170
117–120
95–100
90–95
338.0
339.0
298.4
339.0
253.2
282.4
312.0
225.0
273.4
235.0
282.4
281.8
285.0
278.8
275.0
292.4
323.6
347.4
341.9
312.8
1.026 9 104
1.524 9 104
6.621 9 103
1.707 9 104
1.663 9 104
5.450 9 104
8.764 9 104
8.496 9 104
3.155 9 104
7.785 9 104
1.344 9 104
1.689 9 104
9.587 9 103
1.203 9 104
2.048 9 104
1.944 9 104
2.378 9 104
2.405 9 104
1.340 9 104
2.620 9 104
0.53
0.44
0.33
0.83
0.45
0.57
0.38
0.86
0.53
0.33
0.53
0.44
0.33
0.83
0.45
0.77
0.55
0.54
0.56
0.43
1.57
1.34
1.01
1.22
1.33
1.03
1.36
0.93
1.66
1.20
0.96
1.03
1.10
1.05
1.16
0.94
1.62
1.12
1.61
0.91
2
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
17O2H14
3
16O2H12
4
16O3NH17
17O2H14
5
6
16O2H11Cl
17O3H14
7
8
17O3H12
105–108
160–170
65–75
9
17O3H13Cl
16O4NH11
16O2H11Br
16O3H11Cl
10
11
12
13
14
15
16
17
18
19
20
80–85
70–75
16O2H11
F
90–95
16O2H11Br
17O3H14
120–125
85–90
16O2H11
17O2H14
17O3H14
17O3H14
16O3H12
F
139–142
105–110
129–132
121–125
115–120
a
Solvent system—
n-hexane:ethyl acetate (9:1)
123

1994
Med Chem Res (2012) 21:1991–1996
Table 2 DPPH radical scavenging activity
Table 3 Percentage inhibition of bacterial growth
Compound Gram-positive microbes Gram-negative microbes
Compound
IC50 values (lg/ml)
S.a
B.s
B.c
E.c
P.a
K.p
1
104.16
102.04
106.38
58.82
2
1
58
60
47
55
53
57
66
74
65
77
81
74
73
58
59
55
76
61
43
70
55
38
44
50
49
25
46
56
46
60
39
68
81
82
63
26
69
59
74
83
50
62
80
57
50
60
68
81
90
89
80
85
75
62
50
60
80
51
65
50
51
42
41
29
40
51
41
47
28
31
34
33
31
27
34
47
50
52
50
38
46
43
48
51
52
44
46
37
28
57
42
47
48
51
51
47
56
45
59
43
50
60
75
50
40
59
60
80
87
85
78
81
70
72
41
52
70
62
40
70
3
2
4
3
5
156.25
192.30
100.00
104.00
80.64
4
6
5
7
6
8
7
9
8
10
131.57
70.42
9
11
10
11
12
13
14
15
16
17
18
19
20
12
98.04
13
113.64
111.11
200.00
208.30
250.00
142.86
156.25
79.37
14
15
16
17
18
19
20
Ascorbic acid
17.60
Amoxicillin was used as positive control. The percentage inhibition of
bacterial growth was obtained by the equation
coefficient values were found to be in the range of
0.912–1.66 as shown in Table 1.
100 9 [ODnegative control - OD test]/[OD negative control - ODpositive control
]
S.a Staphylococcus aureus, B.s Bacillus subtilis, B.c Bacillus cereus,
E.c Escherichia Coli, P.a Pseudomonas aeruginosa, K.p Klebsiella
pneumonia
DPPH radical scavenging activity
All the synthesised test compounds were screened for their
antioxidant activity by DPPH radical scavenging assay.
Ascorbic acid was taken as the positive control. The 50%
inhibitory concentrations expressed as IC50 is shown in the
Table 2. The test compounds, such as 4, 9, 11, 12 and 20
showed the IC50 at 58.82, 80.64, 70.42, 98.04 and
79.37 lg/ml, respectively. However, the remaining test
compounds showed the IC50 values above 100 lg/ml.
S. aureus, and 80% against B. cereus. Whereas, compounds
such as 8, 10 and 12 exhibited inhibition at the range of
80–90% against B. cereus and K. pneumonia. Further,
compounds such as 13, 14 and 20 exhibited activity at 81, 82
and 83% respectively against B. subtilis, and compounds 3
and 17 were effective against B. cereus at 80% each. How-
ever, compound 9 is effective against K. pneumonia at 87%.
It is evident from the data that all the test compounds were
active against all Gram-positive organisms selected in the
range of 50–100% as compared with that of the standard as
shown in Table 3. However, out of the three Gram-negative
organism selected, all the test compounds showed activity
only against K. pneumonia, in the range of 50–90%.
Antibacterial activity
The synthesised test compounds were evaluated for their
antibacterial activity by agar diffusion method against
Gram-positive and Gram-negative organisms. Results were
expressed as percentage inhibition as shown in the Table 3.
The test compound 9 showed the activity against B. cereus at
90% inhibition when compared with that of the standard
Amoxicillin. Further, compounds such as 3, 8, 9, 10, 11, 12,
13, 14, 17 and 20 have exhibited activity against four species
of organism except E. coli and P. aeruginosa, in the range of
80–90% as compared with that of the standard Amoxicillin.
However, compound 11 exhibited activity at 81% against
Spectral data of the synthesised compounds
3-Methyl-2-(40-methylphenyl) benzopyron-4-one (2)
IR (KBr) cm-1: 3178 (ArC-H), 2813 (C–H), 1680 (C=O),
1
1570 (C=C); H NMR (400 MHz, CDCl3): d 2.1 (3H, s,
123

Med Chem Res (2012) 21:1991–1996
1995
3-Methyl-2-(40-fluorophenyl) benzopyron-4-one (13)
3-CH3), 2.5 (3H, s, H-40-CH3), 7.6 (2H, d, H-30/50), 7.70
(1H, t, H-7), 7.75 (1H, d, H-5), 7.8 (2H, d, H-20/60), 8.0
(1H, t, H-6), 8.1 (1H, d, H-8); GCMS: m/e 252 (M??2);
MF: C17H14O2; mw: 252.
IR (KBr) cm-1: 3041(ArC-H), 2762 (C–H), 1639 (C=O),
1
1467 (C=C), 1014 (C–F); H NMR (400 MHz, CDCl3): d
8.26 (2H, d, H-30/50), 7.68 (1H, d, 5H), 7.64 (1H, d, H-8),
7.46 (2H, d, H-20/60), 7.42 (1H, t, H-7), 7.26 (1H, t, H-6),
2.2 (3H, s, CH3); GCMS: m/e 255 (M??1); MF:
C16O2H11F; mw: 256.
3-Methyl-7-hrdoxy-2-(40 N,N-dimethylphenyl)
benzopyron-4-one (4)
IR (KBr) cm-1: 3390 (O–H), 3100 (ArC-H), 2800 (C–H),
1612 (C=O), 1561 (C=C), 1312 (C–N); 1H NMR
(400 MHz, CDCl3): d 11.48 (1H, s, –OH), 8.3 (1H, d, H-6),
7.82 (1H, s, H-8), 7.75 (1H, d, 5H), 7.58 (2H, d, -20,60),
7.47 (2H, d, H-30,50), 2.2 (9H, s, –CH3, –N(CH3)2); GCMS:
m/e 295 (M?); MF: C16H17NO3; mw: 294.
3-Methyl-2-(40-bromophenyl) benzopyron-4-one (14)
IR (KBr) cm-1: 3090 (ArC-H), 2854 (C–H), 1639 (C=O),
1
1419 (C=C), 543 (C–Br); H NMR (400 MHz, CDCl4): d
8.27 (1H, d, H-5), 8.23 (1H, t, H-7), 8.1 (2H, d, H-3’/5’),
7.76 (2H, d, H-2’/6’), 7.38 (1H, t, H-6), 7.29 (1H, d, H-8),
2.2 (3H, s, H–CH3); GCMS: m/e 316 (M??1); MF:
C16O2H11Br; mw: 256.
3-Methyl-2-(40-methoxyphenyl) benzopyron-4-one (7)
IR (KBr) cm-1: 3080 (ArC-H), 2716 (C–H), 1637 (C=O),
3-Methyl-7-methoxy-2-phenyl benzopyron-4-one (15)
1
1467(C=C), 1140 (C–O); H NMR (400 MHz, CDCl3): d
8.1 (1H, d, H-8), 7.9 (2H, d, H-30/50), 7.7 (1H, t, H-7), 7.4
(1H, t, H-6), 7.1 (1H, d, H-5), 6.9 (2H, d, H-2’/6’), 3.4 (3H,
s, H-40–OCH3), 2.5 (3H, s, H–3CH3); GCMS: m/e 268
(M??2); MF: C17O3H14; mw: 268.
IR (KBr) cm-1: 3110 (ArC-H), 2726 (C–H), 1650 (C=O),
1
1469 (C=C), 1200 (C–F); H NMR (400 MHz, CDCl3): d
7.67 (1H, d, H-5), 7.25-7.43 (5H, m, Ar-H), 7.25 (1H, s,
H-8), 6.4 (1H, d, H-6), 3.83 (3H, s, H-OCH3), 2.9 (3H, s,
H-CH3); GCMS: m/e 268 (M??2); MF: C17O3H14; mw:
268.
3-Methyl-7-methoxy-2-(4’-chlorophenyl) benzopyron-
4-one (9)
3-Methyl-2-(2’-florophenyl) benzopyron-4-one (16)
IR (KBr) cm-1: 3110 (ArC-H), 2750 (C–H), 1658 (C=O),
1
1460 (C=C), 1200 (C–O); H NMR (400 MHz, CDCl3): d
1H NMR (400 MHz, CDCl3): d 8.27 (1H, d, H-5), 7.6–7.7
(3H, m, H-6/7/8), 7.39–7.5 (4H, m, Ar-H-2’/3’/4’/5’), 2.2
(3H, s, H–CH3); GCMS: m/e 254 (M?); MF: C16O2H11F;
mw: 256.
8.1 (2H, d, H-30,50), 8.0 (1H, d, 5H), 7.5 (2H, d, H-20,60),
7.4 (1H, d, 6H), 7.2 (1H, s, H-8), 3.9 (3H, s, H–OCH3),
2.8 (3H, s, H–CH3); GCMS: m/e 301(M??1); MF:
C17O3H13Cl; mw: 304.
3-Methyl-2-(40-nitrophenyl) benzopyrone 4-one (10)
Conclusion
IR (KBr) cm-1: 3115 (ArC-H), 2770 (C–H), 1650 (C=O),
Test compounds such as 4, 9, 11, 12 and 20 showed DPPH
radical scavenging activity comparable to that of the
standard ascorbic acid. All the test compounds were active
against Gram-positive organisms in the range of 50–100%.
However, they are not active against Gram negative. This
study overlay the newer 3-methylflvones for antioxidant
and antibacterial activities.
1
1490 (C=C), 1312 (C–N); H NMR (300 MHz, DMSO): d
2,43 (3H, s, 3-CH3), 3.06 (6H, m, N(CH)2), 7.25–8.06 (8H,
m, Ar–H); GCMS: m/e 283 (M??2); MF: C16O4NH11;
mw: 283.
3-Methyl-2-(4’-chlorophenyl) benzopyron-4-one (12)
IR (KBr) cm-1: 3025 (ArC-H), 2805 (C–H), 1645 (C=O),
1450 (C=C), 1150 (C–Cl); 1H NMR (400 MHz, CDCl3):, d
8.1 (1H, d, H-8), 7.8 (1H, t, H-6), 7.7 (2H, d, H-30/50), 7.5
(2H, d, H-20/60), 7.4 (2H, t, H-7), 7.1 (1H, d, H-5), 2.5 (3H,
s, H-3–CH3); GCMS: m/e 273 (M??2); MF: C16O2H11Cl;
mw: 272.5.
Acknowledgments The authors thank Karnataka State Council for
Science and Technology (KSCST) Bangalore – India for financial
support, and Manipal College of Pharmaceutical Sciences, Manipal
University – India for all the research facilities.
Conflict of interest Authors do not have conflict of interest in
connection with the submitted article.
123

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