Synthesis and evaluation of antioxidant activity of 2-styrylchromones

Article abstract of DOI:10.1007/s00044-012-0069-z

Antioxidants are emerging as potential prophylactic and therapeutic agents which scavenge free radicals otherwise reactive oxygen species and prevent the damage caused by them. Free radicals have been associated with pathogenesis of various disorders like

Full text of DOI:10.1007/s00044-012-0069-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:753–757
DOI 10.1007/s00044-012-0069-z
ORIGINAL RESEARCH
Synthesis and evaluation of antioxidant activity
of 2-styrylchromones
•
Shrinivas P. Pawar Dasharath D. Kondhare
•
P. K. Zubaidha
Received: 21 August 2011 / Accepted: 19 April 2012 / Published online: 4 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Antioxidants are emerging as potential prophy-
lactic and therapeutic agents which scavenge free radicals
otherwise reactive oxygen species and prevent the damage
caused by them. Free radicals have been associated with
pathogenesis of various disorders like cancer, diabetes,
cardiovascular diseases, autoimmune diseases, neurodegen-
erative disorders and are implicated in aging. Chromones
and their derivatives display important biological activities
such as anti-tumor, anti-hepatotoxic, anti-inflammatory,
anti-spasmolytic, oestrogenic and antibacterial activities, in
particular the antioxidant behavior of these compounds
continue to draw attention of researchers. In the present
communication a series of halo substituted 2-styrylchro-
mones 4a–4k were prepared and tested for the antioxidant
activity by using DPPH (1, 1 diphenyl 2, picryl hydrazyl)
method, and among the synthesized compounds 4e and 4h
shows strong antioxidant activity while remaining com-
pounds show antioxidant activity in the normal range.
therapeutic agents in many diseases. The discovery of the
role of free radicals in cancer, diabetes cardiovascular dis-
eases, autoimmune diseases neurodegenerative disorders
aging and other diseases has led to medical revolution that is
a promising a new paradigm of healthcare. Traditionally,
herbal medicines with antioxidant properties have been used
for various purposes and epidemiological data also points at
widespread acceptance and use of these agents. The global
market of antioxidants is increasing rapidly, because of the
increased health risk in a constantly polluting environment.
Further application of these agents in cosmetics has fuelled
extensive research in search for novel anti oxidants of ther-
apeutic significance. Free radicals are highly reactive mol-
ecules or chemical species containing unpaired electrons that
cause oxidative stress, which is defined as ‘‘an imbalance
between oxidants and antioxidants in favor of the oxidants,
potentially leading to damage’’ (Sies, 1997). Oxidative stress
can damage lipids, proteins, enzymes, carbohydrates and
DNA in cells and tissues, resulting in membrane damage,
fragmentation or random cross linking of molecules like
DNA, enzymes and structural proteins and even lead to cell
death induced by DNA fragmentation and lipid peroxidation
(Beckman and Ames, 1998). The consequences of oxidative
stress is the molecular basis in the development of cancer,
neurodegenerative disorders, cardiovascular diseases, dia-
betes and autoimmune disorders.
Keywords Antioxidants ꢀ Pathogenesis ꢀ Synthesis ꢀ
2-Styrylchromones ꢀ Halo substituted
Introduction
In the recent years antioxidants have gained a lot of
importance because of their potential as prophylactic and
Chromones and their derivatives of different oxidation
level are well known naturally occurring oxygen-containing
heterocyclic compounds which perform important biologi-
cal functions in nature. It is known that certain natu-
ral and synthetic derivatives possess important biological
activities, such as anti-tumor, anti-hepatotoxic, anti-inflam-
matory, anti-spasmolytic, oestrogenic and antibacterial
activities and in particular the antioxidant behavior of these
compounds is the matter of immense interest (McClure,
S. P. Pawar
School of Pharmacy, S.R.T.M. University, Nanded, India
D. D. Kondhare ꢀ P. K. Zubaidha (&)
School of Chemical Sciences, S.R.T.M. University,
Nanded, India
e-mail: pzubaidha20001@yahoo.co.in
123

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Med Chem Res (2013) 22:753–757
catalytic amount of Iodine. The reaction proceeds smoothly to
afford the corresponding flavones in good yield.
O
O
Antioxidant activity
The newly synthesized 2-styrylchromones 4a–4k have
been tested for the antioxidant activity by DPPH method
and ascorbic acid was used as standard for comparison of
antioxidant activity. The results are presented in Table 1.
The antioxidant values are taken in the term of % RSA
(Radical scavenging activity). The synthesized compounds
show antioxidant activity in the range of 60–71 %. The
compounds 4e and 4h shows significant antioxidant
activity 71.40 and 71.11 % respectively, while remaining
compounds show normal antioxidant behavior, from these
results it is apparent that introduction of functional groups
such as iodo/chloro/OH/OCH3/CH3 significantly increased
antioxidant activity in comparison to unsubstituted styryl
chromone.
Fig. 1 Molecular scaffold of 2-styrylchromone
1975; Atassi et al., 1985; Middleton and Kandaswami, 1994;
Bruneton, 1999; Harborne and Williams, 2000). 2-Sty-
rylchromones are one of the scarcest classes of natural
chromones. Hormothamnione 1 and 6-desmethoxyhor-
mothamnione 2 are the first and to the best of our knowledge
the only naturally occurring styrylchromones isolated from
the marine crytophyte Chrysophaeum taylori. (Gerwick
et al., 1986; Gerwick, 1989). Hormathamnione 1 is excep-
tionally cytotoxic to P388 lymphocytic leukemia and HL-60
promyelocytic leukemia cell lines in vitro and appears to be a
selective inhibitor of RNA synthesis. (Gerwick et al., 1986)
while 6-Desmethoxyhormothamnione 2 showed cytotoxic-
ity to 9 KB cell lines (Gerwick, 1989). The pharmacological
profile and their presence in low concentration in natural
sources prompted us to synthesise these compounds and
study their antioxidant activity (Fig. 1).
In conclusion the present paper describes facile syn-
thesis of substituted styryl chromones from easily available
starting material using molecular iodine as catalyst. The
study clearly indicates that substitution with halogens on
aromatic nucleus enhance antioxidant activity.
OH
OH
OCH3
OCH3
H3CO
H
O
O
H3CO
H3CO
O
O
OH
OH
OCH3
OCH3
OH
OH
2
1
6-Desmethoxyhormothamnione
Hormothamnione
Results and discussion
Experimental section
Chemistry
All melting points were determined on a Thomas-Hoover
1
Unimelt apparatus and are uncorrected. H NMR spectra
The synthetic route of the desired 2-styrylchromones is sum-
marized in Scheme 1. This two-step approach involves an
Aldol reaction followed by an oxidative cyclization. The Base-
catalyzed Aldol reactionofcinnamaldehydeswith20-hydroxy-
acetophenones in ethanolic solution afforded (E, E)-20-
hydroxycinnamylidene-acetophenones. Second step involves
oxidative cyclization of (E, E)-20-hydroxycinnamylidene-
acetophenones into (E)-2-styrylchromones. In DMSO usning
were recorded on a Varian Gemini Spectrometer 300 MHz.
IR spectra were recorded on Nicolet Fourier Transform
spectrometer. Mass spectra were obtained on a 7070H or
VG Auto spec Mass spectrometer using LSIMS technique.
Thin-layer chromatography (TLC) was performed on GF-
25U (Anal. Tech) plates and silica gel glass-backed plates.
Routine column chromatography was conducted using
silica gel 60–120 mesh.
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Med Chem Res (2013) 22:753–757
755
R1
R2
OH
O
R5
R5
R1
R2
OH
O
ethanol
NaOH
O
CH3
R3
R4
H
R4
R3
3a-i
1
2
DMSO
I2
R5
R1
R2
O
R4
R3
O
4a-i
4a: R1 = I, R2 = Cl, R3, R4, R5 = H; 4b: R1 = I, R2 = Cl, R3, R4 = H, R5 = OCH3; 4c: R1, R4 = H, R2 = Br, R5 = OCH3,
4d: R1 = I, R2, R3, R4, R5 = H; 4e: R1 = I, R2 = Cl, R4 = CH3, R3, R5 = H; 4f: R1 = I, R2, R3, R4 = H, R5 = OCH3; 4g:
R1 = I, R2, R3, R5 = H, R4 = CH3; 4h: R1, R2, R4 = H, R3 = OH, R5 = OCH3; 4i: R1, R2, R3, R5 = H R4 = CH3 ; 4j: R1,
R2, R3, R4, R5 = H; 4k: R1 = I, R2 = Cl, R3, R4, R5 = H.
Scheme 1 Synthesis of studied 2-Styrylchromones
Table 1 Antioxidant activity of synthesized 2-styrylchromones
mixture was stirred for 12-h at room temperature. The
reaction progress was monitored by TLC. After completion
of reaction it was poured into water and acidified with dil.
HCl, and was filtered to obtain the product. The product
was washed with cold water, and recrystallized using
ethanol.
Compounds
Antioxidant activity
Mean % RSA
4a
4b
4c
4d
4e
4f
67.18
69.12
60.94
64.96
71.40
66.75
69.59
71.11
65.81
64.43
67.48
The above product in DMSO was refluxed in the presence
of catalytic amount of iodine for 0.5 h; progress of reaction
was monitored by TLC. After completion of reaction,
workup with water followed by sodium thiosulphate wash
afforded the desired Styrylchromone in good yield. The
product was purified by recrystallisation from ethanol.
4g
4h
4i
4j
(E)-6-chloro-7-iodo-2-styryl-4H-chromen-4-one (4a)
4k
Yield: 65 %; mp 175–177 °C. IR (KBr cm-1): 3072, 3035,
3000, 1710, 1680, 1591, 1515, 1442, 1427, 1365, 1332,
1280, 972, 686, 600. 1HNMR (400 MHz, CDCl3):
d = 6.32 (1H, s, =CH), 6.68 (1H, d, J = 16.0 Hz, =CH),
7.26–7.61 (5H, m, Ar), 7.76 (1H, d, J = 16 Hz, =CH),
d 8.07 (1H, s), d 8.13 (1H, s). 13C NMR (100 MHz, CDCl3):
d = 85.7, 109.3, 114.5, 116.9, 125.1, 125.5, 127.4, 129.6,
132.4, 135.7, 138.4, 153.2, 161.5, 162.9, 175.6. EI MS: m/
z (rel.abund. %) 408 (M?, 100), 410 (M2?, 33).
Synthesis of halogenated 2-styrylchromones
General procedure
To the aqueous solution of NaOH (2.5 equiv.) in ethanol at
0–5 °C, halogenated 2-hydroxyacetophenone (1 mmol) 1
was added and stirred for 10 min. After 10 min substituted
cinnamaldehyde (1 mmol) 2 was added and the resulting
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Med Chem Res (2013) 22:753–757
(E)-2-(4-methoxystyryl)-6-chloro-7-iodo-4H-chromen-
4-one (4b)
NMR (100 MHz, CDCl3): d = 14.1, 85.7, 107.6, 124.5,
125.4, 127.7, 128.4, 128.5, 129.7, 131.5, 135.8, 135.9, 142.6,
153.4, 164.9, 176.9. EI MS: m/z (rel.abund. %) 422 (M?,
100), 424 (M2?, 33).
Yield: 59 %; mp 188–190 °C. IR (KBr cm-1) 3070, 3065,
3030, 2810, 1721, 1717, 1689, 1650, 1600, 1548, 1508,
1
1442, 1425, 1363, 1250, 1172, 1100, 1031, 670, 550. H
(E)-2-(4-methoxystyryl)-7-iodo-4H-chromen-4-one (4f)
NMR (400 MHz, CDCl3): d = 3.86 (3H, s, OCH3), 6.27
(1H, s, =CH), 6.62 (1H, d, J = 16.0 Hz, =CH), 6.94 (2H, d,
J = 7.6 Hz), 7.54 (2H, d, J = 8.0 Hz), 7.75 (1H, d,
J = 16.0 Hz), 8.05 (1H, s), 8.11 (1H, s). 13C NMR
(100 MHz, CDCl3): d = 55.4, 85.6, 109.2, 114.4, 116.8,
125.0, 125.5, 127.4, 129.6, 131.4, 138.7, 142.4, 153.2,
161.4, 162.8, 176.6. EI MS: m/z (rel.abund. %) 438 (M?,
100), 440 (M2?, 33).
Yield: 60 %; mp 174-176 °C. IR (KBr cm-1): 3052, 2995,
2966, 2952, 2812, 1648, 1598, 1541, 1512, 1436, 1419,
1357, 1253, 1174, 1031, 974, 833, 813. 1H NMR
(400 MHz, CDCl3): d = 3.86 (3H, s, –OCH3), 6.28 (1H, s,
=CH), 6.62 (1H, d, J = 16.0 Hz, =CH), 6.90–6.96 (3H, m,
Ar), 7.55 (2H, d, J = 8.8 Hz, Ar), 7.75 (1H, d,
J = 15.6 Hz, =CH), 8.36–8.37 (1H, m, Ar), 8.44–8.46 (1H,
m, Ar). 13C NMR (100 MHz, CDCl3): d = 55.4, 86.3,
89.2, 109.4, 114.4, 116.8, 124.7, 125.9, 129.5, 134.9,
138.8, 150.2, 154.3, 161.4, 162.7, 176.3. EI MS: m/z
(rel.abund. %) 405 (M?, 100).
(E)-2-(4-methoxystyryl)-6-bromo-4H-chromen-4-one (4c)
Yield: 66 %; mp 168–170 °C. IR (KBr cm-1): 3076, 3043,
3030, 3003, 2966, 2947, 2935, 2908, 2835, 1700, 1650,
1633, 1600, 1553, 1505, 1458, 1445, 1369, 1284, 1255,
1238, 1166, 1128, 1024, 968, 835, 825, 804, 601. 1H NMR
(400 MHz, CDCl3): d = 3.86 (3H, s, OCH3), 6.29 (1H, s,
=CH), 6.64 (1H, d, J = 16.4 Hz, =CH), 6.94 (2H, d,
J = 8.8 Hz, Ar), 7.41(1H, d, J = 8.8 Hz, Ar), 7.52–7.58
(3H, m, Ar), 7.74 (1H, dd, J = 2.2 Hz, 9.0 Hz, Ar), 8.31
(1H, d, J = 2.0 Hz, Ar). 13C NMR (100 MHz, CDCl3):
d = 55.4, 109.7, 114.4, 117.3, 118.2, 119.7, 125.4, 127.5,
128.2, 129.3, 136.4, 137.1, 154.6, 161.2, 162.4, 176.8. EI
MS: m/z (rel.abund. %) 357 (M?, 100), 359 (M2?, 97).
(E)-7-iodo-2-(2-phenylprop-1-enyl)-4H-chromen-
4-one (4g)
Yield: 61 %, mp 150–152 °C. IR (KBr cm-1): 3052, 2995,
2966, 2952, 2812, 1648, 1598, 1541, 1512, 1436, 1419,
1357, 1253, 1174, 1031, 974, 833, 813. 1H NMR
(400 MHz, CDCl3): d = 2.20 (3H, s, –CH3), 6.51 (1H, s,
=CH), 7.14–7.23 (2H, m, Ar), 7.39–7.46 (2H, m, Ar),
7.59–7.61 (2H, m, Ar), 7.91 (1H, s, =CH), 8.39 (1H, d,
J = 2.0 Hz, Ar), 8.44 (1H, d, J = 1.6 Hz, Ar). 13C NMR
(100 MHz, CDCl3): d = 14.1, 85.5, 107.7, 124.6, 125.5,
127.8, 128.3, 128.4, 129.6, 131.0, 135.8, 136.1, 140.6,
153.4, 164.9, 176.9. EI MS: m/z (rel.abund. %) 389 (M?,
100).
(E)-7-iodo-2-styryl-4H-chromen-4-one (4d)
Yield: 69 %; mp 173–175 °C. IR (KBr cm-1): 3061, 3055,
3020, 2996, 2972, 2941, 2912, 2861, 1625, 1539, 1438,
1361, 1271, 1199, 1091, 977, 860, 750, 650. 1H NMR
(400 MHz, CDCl3): d = 6.33 (1H, s, =CH), 6.76 (1H, d,
J = 16.0 Hz, =CH), 7.15–7.24 (2H, m, Ar), 7.38–7.46 (2H,
m, Ar), 7.60–7.61 (2H, m, Ar), 7.80 (1H, d, J = 16.0 Hz,
=CH), 8.38 (1H, d, J = 2.0 Hz, Ar), 8.45 (1H, d,
J = 1.6 Hz, Ar). 13C NMR (100 MHz, CDCl3): d = 85.3,
107.6, 124.7, 125.3, 127.8, 128.5, 128.1, 129.7, 131.3,
135.6, 136.2, 140.5, 153.4, 165.1, 176.7. EI MS: m/z
(rel.abund. %) 375 (M?, 100).
(E)-2-(4-methoxystyryl)-5-hydroxy-4H-chromen-
4-one (4h)
Yield: 57 %; mp 190–192 °C (191–193 °C (Pinto et al.,
2000)). IR (KBr cm-1): 3620, 3065, 3058, 3000, 2952,
2920, 2900, 1647, 1629, 1602, 1548, 1508, 1442, 1425,
1
1363, 1250, 1195, 1172, 1031, 974, 833, 815. H NMR
(400 MHz, CDCl3): d = 3.85 (3H, s, –OCH3), 6.90–7.06
(5H, m, =CH, Ar), 7.17 (1H, d, J = 14.8 Hz, =CH),
7.45–7.49 (2H, m, Ar), 7.69–7.75 (1H, m, Ar), 7.84
(1H, dd, J = 1.4 Hz, J = 8.0 Hz, Ar), 12.98 (1H, s, OH).
EI MS: m/z (rel.abund. %) 295 (M?, 100).
(E)-6-chloro-7-iodo-2-(2-phenylprop-1-enyl)-4H-chromen-
4-one (4e)
Yield: 64 %; mp 178–180 °C. IR (KBr cm-1): 3076, 3049,
3018, 2974, 1675, 2941, 1622, 1589, 1548, 1448, 1431,
1367, 1332, 1309, 1130, 1068, 987, 933, 881, 862, 736, 696.
1H NMR (400 MHz, CDCl3): d = 2.21 (3H, s, –CH3), 6.52
(1H, s, =CH), 7.35–7.46 (4H, m, Ar), 7.93 (1H, s, =CH),
8.08 (1H, S, Ar), 8.11 (1H, s, Ar), 8.18 (1H, s, Ar). 13C
(E)-2-(2-phenylprop-1-enyl)-4H-chromen-4-one (4i)
Yield: 58 %; mp 151–153 °C. IR (KBr cm-1): 3059, 3022,
2968, 2950, 1650, 1631, 1624, 1548, 1465, 1427, 1388,
1328, 1201, 1172, 1095, 1058, 971, 966, 754, 682. 1H
NMR (400 MHz, CDCl3): d = 2.21 (3H, s, –CH3), 6.50
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757
Acknowledgments The research was supported by school of
chemical sciences, SRTM University, Nanded (MS), India.
(1H, s, =CH), 7.14–7.23 (3H, m, Ar), 7.48–7.61 (4H, m,
Ar), 7.91 (1H, s, =CH), 8.01–8.22 (2H, m, Ar). 13C NMR
(100 MHz, CDCl3): d = 14.2, 85.4, 107.8, 124.5, 125.4,
127.7, 128.4, 128.6, 129.5, 131.2, 135.9, 136.4, 140.5,
148.4, 165.0, 176.7. EI MS: m/z (rel.abund. %) 263 (M?,
100).
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(E)-2-styryl-4H-chromen-4-one (4j)
Yield: 64 %; mp 139–141 °C (140 °C (Pinto et al., 1996)).
IR (KBr cm-1): 3060, 3053, 3022, 2996, 2974, 2939, 2868,
1
1635, 1530, 1441, 1359, 1273, 1188, 1089, 968, 859. H
NMR (400 MHz, CDCl3): d = 6.50 (1H, s, =CH), 6.77
(1H, d, J = 16.0 Hz, =CH), 7.14–7.23 (3H, m, Ar),
7.50–7.61 (4H, m, Ar), 7.81 (1H, d, J = 16.0 Hz, =CH),
8.01–8.22 (2H, m, Ar). 13C NMR (100 MHz, CDCl3):
d = 85.6, 107.7, 124.7, 125.6, 127.5, 128.2, 128.5, 129.7,
131.1, 136.0, 136.3, 140.7, 148.2, 165.0, 175.7. EI MS: m/z
(rel.abund. %) 249 (M?, 100).
(E)-6-chloro-7-iodo-2-styryl-4H-chromen-4-one (4k)
Yield: 64 %; mp 177–180 °C. IR (KBr cm-1): 3069, 3053,
3001, 2981, 1672, 2939, 1629, 1589, 1544, 1436, 1371,
1329, 1322, 1125, 1072, 980, 938, 850, 732, 670. 1H NMR
(400 MHz, CDCl3): d = 6.32 (1H, s, =CH), 6.77 (1H, d,
J = 16.0 Hz, =CH), 7.42–7.44 (3H, m, Ar), 7.61 (2H, d,
J = 6.8 Hz, Ar), 7.81 (1H, d, J = 16.0 Hz, =CH), 8.07
(1H, S, Ar), 8.13 (1H, s, Ar). 13C NMR (100 MHz,
CDCl3): d = 85.6, 109.9, 119.3, 125.0, 125.6, 127.9,
129.0, 130.2, 131.6, 134.7, 139.1, 142.6, 153.3, 162.3,
176.6. EI MS: m/z (rel.abund. %) 408 (M?, 100), 410
(M2?, 33).
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