Synthesis of new benzofuran-1,3-thiazolidin-4-one derivatives from natural sources and study of their antioxidant activity

Article abstract of DOI:10.1134/S106816201304002X

Synthesis of benzofuran-1,3-thiazolidinone derivatives is described herein. These compounds were prepared via a concise and short route by condensation reaction of khellinone with aromatic/aliphatic amines followed by cyclization using thioglycolic acid. The newly synthesized compounds were characterized using the well known spectroscopic tools (IR, ¹H NMR, and mass spectroscopy), as well as microanalysis. In frames of biological screening of the compounds, antioxidant activity was assessed in vitro.

Full text of DOI:10.1134/S106816201304002X

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2013, Vol. 39, No. 4, pp. 438–443. © Pleiades Publishing, Ltd., 2013.
Synthesis of New Benzofuranꢀ1,3ꢀThiazolidinꢀ4ꢀOne Derivatives
from Natural Sources and Study of Their Antioxidant Activity1
N. A. Abdel Latifa, b, 2, Sh. H. Abdel Hafeza, c, and L. M. Breaka
a Chemistry Department, Faculty of Science, Taif University, Taif, KSA
b Natural Compounds Chemistry Department, Pharmaceutical Industries Division, National Research Center, Dokki, Egypt
c Chemistry Department, Faculty of Science, Assuit University, Assuit, Egypt
Received November 12, 2012; in final form, January 14, 2013
Abstract—Synthesis of benzofuranꢀ1,3ꢀthiazolidinone derivatives is described herein. These compounds
were prepared via a concise and short route by condensation reaction of khellinone with aromatic/aliphatic
amines followed by cyclization using thioglycolic acid. The newly synthesized compounds were characterized
using the well known spectroscopic tools (IR, 1H NMR, and mass spectroscopy), as well as microanalysis. In
frames of biological screening of the compounds, antioxidant activity was assessed in vitro.
Keywords: 1,3ꢀthiazolidinꢀ4ꢀone, benzofuran, Schiff bases, antiꢀoxidant activity, khellinone, khellin
DOI: 10.1134/S106816201304002X
2
1
INTRODUCTION
burns and wounds, and certain dermatological probꢀ
lems [13].
A natural furochromone khellin (1) (4,9ꢀ
dimethoxyꢀ7ꢀmethylꢀ5Hꢀfuro[3,2ꢀg] chromen–5–
one), obtained from fruits and seeds of Ammi visnaga L.
is a natural source of several furochromones, namely,
visnagin, khellin, khellolglucoside, and ammiol. Simꢀ
ilar to psoralen, visnadin, khellin, and coumarin bind
with DNA through crossꢀlinks to produce monoadꢀ
ducts. Thus, khellin is used in photochemotherapy of
dermatoses, such as vitiligo and psoriasis [1–5]. It is
known that hydrolysis of khellin yields very interesting
O
O
OCH3
OCH 3
KOH
H O
2
CH 3
O
O
O
CH3
OH
OCH 3
(2)
OCH3
(1)
KOH
C H OH
derivatives, namely
ω
ꢀacetokhellinone (2') and khellꢀ
2
5
inone ( ) (Scheme 1). These two products are imporꢀ
2
tant molecules for synthesis of new khellin derivatives
[6]. The ringꢀopening reaction (ROR) of chromone
was investigated ab initio and using density functional
theory methods by Kona et al. [7, 8].
O
O
OCH3
CH3
Khellin exhibits high antiꢀatherosclerotic and
lipidꢀaltering activity [9] and is an active constituent of
many modern medicines [10]. Khellin helps to relieve
bladder and urinary tract constriction and spasms,
may relieve urinary colic [11] and is beneficial for the
health of the gallbladder and bile duct; it also promotes
the discharge of gallstones and gallbladder colic [12].
The benefits of khellin extend to the skin: when comꢀ
bined with sun exposure, it helps to treat the skin disꢀ
ease known as vitiligo, in which pigmentꢀcarrying
melanocytes of skin are lost. Khellin may also be benꢀ
eficial in treating inflammation, psoriasis, minor
O
OH
OCH3
(2')
Scheme 1. The experimental chemical pathway
for khellin hydrolysis.
On the other hand, in recent years, the interest in
thiazolidinone chemistry increased remarkably due to
biologically activity of its derivatives and important
therapeutic products ranging from antibacterial [14]
and antifungal [15] to anticonvulsant [16], antifungal
[17], antithyroid [18], antituberculer, and antidiabetic
[19]. For this reason, synthetic connection of thiazoliꢀ
1
The article is published in the original.
Corresponding author: phone: 00966 530203556; eꢀmail:
2
ehad_km@yahoo.com).
438

SYNTHESIS OF NEW BENZOFURANꢀ1,3ꢀTHIAZOLIDINꢀ4ꢀONE DERIVATIVES
O
439
Ar
100
90
80
70
60
50
40
30
20
10
0
OH
C
10 ppm
20 ppm
30 ppm
OCH3
OCH3
CH3
N
ArꢀNH2
O
OH
OCH3
(3a–f)
O
OH
OCH3
(2)
HSCH2COOH
OCH
3 S
Trolox 1 2 3a 3b 3c 3d 3e 3f 4a 4b 4c 4d 4e 4f
Compound name
O
N
CH3
OH
Ar
O
Fig. 1. Inhibition (%) of DPPH radical by tested comꢀ
OCH3
(4a–f)
pounds.
dinone moiety with a natural product khellin may
increase biological activities of both and yield an antiꢀ
oxidant. Considering the foregoing benefits, we aimed
to link biologically active thiazolidinones with the natꢀ
ural khellin to access new classes of biologically active
compounds.
Entry
Ar
Entry
Ar
a
b
c
Ethyl
Phenyl
2ꢀNitrophenyl
d
e
f
4ꢀMethylphenyl
4ꢀChlorophenyl
4ꢀMethoxyphenyl
Scheme 2.
Formation of 2,3ꢀdisubtituded 4ꢀthiazolidinone
4a 4f) was confirmed by IR spectroscopy, which
showed the characteristic bands in the range of 1690–
1730 cm–1 due to (C=O) group. The 1H NMR spectra
in CDCl3 or DMSOꢀd6 showed the most important
RESULTS AND DISCUSSION
(
–
Chemistry
In frames of our ongoing research to synthesize
potentially biologically active thiazolidinone derivates
signals at
δ
3.34–3.38 ppm corresponding to the
we describe a series of 5ꢀ((
imino)ethyl)ꢀ4,7–dimethoxy benzofuranꢀ6ꢀol (3a
3f) and 2ꢀ(4,7ꢀdimethoxyꢀ6ꢀhydroxybenzofuranꢀ5ꢀyl)ꢀ
2ꢀmethylꢀ ꢀ(substituted)1,3ꢀthiazolidinꢀ4ꢀone (4a 4f
(Scheme 2). The series of Shiff’s bases (3a 3f) were
prepared according to [24] by refluxing different aroꢀ
matic and/or aliphatic amines and khellinone ( ) in
E)ꢀ1ꢀ(substituted
methylene group (COCH2S).
–
Antioxidant Activity
Antioxidant capacities of khellin (
N
– )
–
1), khellinone (2),
and all the prepared compounds were assessed using
two methods, that is DPPH and hydroxyl radical scavꢀ
enging assay, in comparison with standard comꢀ
pounds. The DPPH free radical assay incorporates a
metastable free radical that is capable of accepting
hydrogen radicals from antioxidants in solution. The
reaction between DPPH and antioxidant can be monꢀ
itored by the decrease in absorbance of the colored
2
absolute ethanol in the presence of catalytic amount of
glacial acetic acid. Structures of the newly synthesized
products (3a–3f) were inferred from their analytical
and spectral data. The IR spectra of compounds (3a
3f) showed characteristic bands at 3440–3300 cm–1 for
OH group and at 1620 cm–1, for C=N; band of C=O
–
group disappeared. The 1H NMR spectra in CDCl3 or free radical [21].
DMSOꢀd6 showed the most important signals at
In the hydroxyl radical assay OH, radicals were
generated to attack the substrate, deoxyribose. When
heated with TBA in acid solution, the resulting prodꢀ
ucts of radical attack form a pink chromogen. Since
these two methods are based on different mechanisms
for radical inhibition, they can provide complemenꢀ
tary insight into the expected antioxidant capacities of
compounds under study.
δ
1
.99–2.1 for CH3 and 3.8–4.02, for the two methoxy
groups. Our target compounds 2ꢀmelhylꢀ3ꢀarylꢀ2ꢀ
(4,6ꢀdimethoxyꢀ6ꢀhydroxyꢀ5ꢀyl benzofuran)ꢀ1,3ꢀ
thiazolidinꢀ4ꢀone (4a 4f) were obtained by reactions
described in [20], performed by refluxing the solutions of
Schiff’s bases (3a 3f) and thioglycolic acid in dry benꢀ
zene in the presence of anhydrous ZnCl2 for 10–12 h.
–
–
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
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440
100
ABDEL LATIF et al.
azolidinꢀ4ꢀone (4a–4f) were synthesized and evaluꢀ
10 ppm
20 ppm
30 ppm
ated for their antioxidant activity by DPPH radical
scavenging activity and hydroxyl radical scavenging
activity according to Fenton’s method. All synthesized
structures were elucidated by means of various spectral
methods. Compounds (3f), (3d), (4d), and (3c) proved
to have better antioxidant activity if compared ti
khellin or standard compounds used in the present
study. Compound (3f) influences greatly antioxidant
activity.
90
80
70
60
50
40
30
20
10
0
EXPERIMENTAL
Ascorbic 1 2 3a 3b 3c 3d 3e 3f 4a 4b 4c 4d 4e 4f
General
The melting points were recorded in an electroꢀ
thermal capillary melting point apparatus and were
not corrected. Thin layer chromatography was perꢀ
formed using F254 fluorescent silica gel plates (Merck),
which were examined under UV 254 and 365 nm light.
Silica gel (230–400 mesh) was used for flash chromaꢀ
tography separations. Elemental analysis for C, H, N,
and S was performed on a Vario EL III equipment
(Micro analytical center, Cairo University, Cairo,
Fig. 2. Inhibition (%) of hydroxyl radical by tested comꢀ
pounds.
DPPH Radical Scavenging Activities
The resulting values of DPPH radical inhibition by
individual tested compounds are plotted in Fig. 1.
Four compounds—(3f), (4a), (3d), and (4d)—exhibꢀ
ited close inhibition effects against DPPH exceeding
that of khellin and other tested substituted comꢀ
pounds. The relative activities of (3f), (3d), (4d), and
3c) were 67.1, 63.3, 61.9, and 57.5% respectively
compared to Trolox and 125.6; 118.0; 115.0, and
107.0%, compared to khellin. EC50 values were 8.57,
Egypt). Infrared spectra (
, cm–1) were recorded on a
ν
Jasco FTꢀIR 4100 instrument using KBr disks (Micro
analytical center). 1HNMR spectra were recorded on
a Varion Mercury VXꢀ300 NMR spectrometer.
1H NMR were run at 300 MHz in deuterated chloroꢀ
form (CDCl3) or dimethyl sulphoxide (DMSOꢀd6).
(
9.72, 8.27, and 10.59
respectively compared with 5.42
µ
M
for (3f), (3d), (4d), and (3c
)
Chemical shifts are reported as
δ
(ppm) and were
μM
for Trolox.
related to those of the solvents. Spectra were internally
referenced to TMS. Mass spectra were recorded on a
Shimadzu GCMSꢀQPꢀ1000 EX mass spectrometer at
70 eV (Micro analytical center). Chemicals used for
antioxidant activity assays were deoxyribose, Trolox,
thiobarbituric acid (TBA), 1,1ꢀdiphenylꢀ2ꢀpicrylhyꢀ
drazyl (DPPH), ascorbic acid, methanol, and dimethꢀ
ylsulfoxide (DMSO) obtained from Sigma Chemical
Co. (St. Louis, MO, USA). All other chemicals and
reagents used were analytical grade.
Hydroxyl Radical Scavenging Activities
The resulting values of hydroxyl radical inhibition
by individual tested compounds are plotted in Fig. 2.
The results indicate that four compounds—(3f), (4a),
3d, and (4d) exhibited highest and close inhibition
effects against hydroxyl radical if compared to other
tested compounds. The relative activities of (3f), (3d),
4d), and (3c) compared with ascorbic acid were
(
(
60.36, 56.22, 58.34, and 48.26% and compared with
khellin, 142.2, 132.5, 137. 5, and 113.7%, respectively.
General Procedure of 5ꢀ((E)ꢀ1ꢀ(Substituted
imino)ethyl)ꢀ4,7ꢀdimethoxybenzofuranꢀ6ꢀol
DPPH radical scavenging activities indicate that
the most effective substituted compounds (3f), (3d),
(3a–3f) Synthesis
(4d), and (3c) have more hydrogen atoms or electron
A mixture of 0.01 mol compound (
2) and 0.01 mol
donation capacity which converts DPPH to a stable
DPPH radical. Also, inhibition of OH radical generaꢀ
tion increased when the effective substituted comꢀ
pounds were applied. EC50 values indicate that the
effective substituted compounds have moderate antiꢀ
oxidant activity.
of an appropriate amine was refluxed in absolute ethaꢀ
nol (30 mL) in the presence of a catalytic amount of
glacial acetic acid for 5–7 h. The reaction mixture was
cooled and the precipitate was filtered and recrystalꢀ
lized from ethanol to give compounds (3a
5ꢀ((E)ꢀ1ꢀ(Ethylimino)ethyl)ꢀ4,7ꢀdimethoxybenzoꢀ
furanꢀ6ꢀol (3a). Yield (87%); mp 132–134 ; FTꢀIR:
(cm–1)3437 (OH), 3135 (C–H aromatic), 2930 (C–
–3f).
°
C
ν
CONCLUSIONS
1
H aliphatic), and 1622 (C=N). H NMR ( , ppm):
δ
In this study, a series of Schiff bases, 5ꢀ((E)ꢀ1ꢀ 2.103 (s, 3H, CH3), 2.1 (t, 3H, CH3), 2.7 (q, 2H,
((substituted imino)ethyl)ꢀ4,7ꢀdimethoxybenzofuꢀ CH2), 4.05 (s, 3H, OCH3), 4.15 (s, 3H, OCH3), 7.5
ranꢀ6ꢀol (3a
–3f) and 2ꢀ(4,7ꢀdimethoxyꢀ6ꢀhydroxyꢀ (d, 1H, H2 furan), 6.9 (d, 1H, H3 furan), and 13.09 (s,
benzofuranꢀ5ꢀyl)ꢀ2ꢀmethylꢀNꢀ(substituted)ꢀ1,3ꢀthiꢀ 1H, OH) exchangeable with D2O. Mass spectra
m/z
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
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SYNTHESIS OF NEW BENZOFURANꢀ1,3ꢀTHIAZOLIDINꢀ4ꢀONE DERIVATIVES
441
(%): 263 (15) [M M
+.], 220 (51.3), 205 (36.6), 179 (32.5), (45.2) [ +.], 310 (11.5), 234 (27.3), 222 (100), 193
123 (57.5), and 108 (100). Anal. Found: C,71.15; H, (63.7), 176 (23.7). Anal. Found: C, 66.83; H, 5.55; N,
7.19; N, 5.90. Calcd. C14H17NO4 (263): C, 71.19; H, 4.09. Calcd. C19H19NO5 (341): C, 66.86; H, 5.57; N,
7.20; N, 5.93.
4.11.
5ꢀ((E)ꢀ1ꢀ(Phenylimino)ethyl)benzofuranꢀ4,7ꢀdimeꢀ
thoxybenzofuranꢀ6ꢀol (3b). Yield (89%); mp 140–
General Procedure for 2ꢀ(4,7ꢀDimethoxyꢀ6ꢀ
hydroxybenzofuranꢀ5ꢀyl)ꢀ2ꢀmethylꢀNꢀ(substituted)ꢀ
1,3ꢀthiazolidinꢀ4ꢀone
142°
C
; FTꢀIR:
(cm–1) 3293 (OH), 3136 (C–H aroꢀ
ν
1
matic), 3067 (C–H aliphatic), and 1661 (C=N). H
NMR ( , ppm): 2.03 (s, 3H, CH3), 3.8 (s, 6H,
δ
( –4f) Synthesis
4a
solution of 5ꢀ((
imino)ethyl)ꢀ4,7ꢀdimethoxybenzofuranꢀ6ꢀol (3a
2OCH3), 7.57 (d, 1H, H2 furan), 7.01 (d, 1H, H3
furan), 7.27(m, 5H, ArꢀH), and 9.89 (s, 1H, OH)
To
a
E)ꢀ1ꢀ(substitutedꢀ
–3f
)
exchangeable with D2O. Mass spectra
(11) [
+.], 283 (11.9), 268 (11.5), 215 (23.2), 173
(100), 108 (68.5).
m/z (%): 311
(0.001 mol) in dry benzene (15 mL), freshly distilled
mercaptoacetic acid (0.001 mol) and anhydrous ZnCl2
(0.1 g) were added and the mixture was heated under
reflux for 10–12 h. The solvent was evaporated under
reduced pressure, the residue was washed with 5%
M
Anal. Found: C, 69.43; H, 5.46; N, 4.49. Calcd.
C18H17NO4 (311): C, 69.45; H, 5.47; N, 4.50.
5ꢀ((E)ꢀ1ꢀ(2ꢀNitrophenylimino)ethyl)ꢀ4,7ꢀdimethoꢀ
sodium carbonate solution (3 × 20 mL) and water (2 ×
xybenzofuranꢀ6ꢀol (3c). Yield (84%); mp 133–135
°
C
;
20 mL), dried, and recrystallized from ethanol.
FTꢀIR:
ν
(cm–1) 3439 (OH), 3139 (C–H aromatic),
2ꢀ(4,7ꢀDimethoxyꢀ6ꢀhydroxybenzofuranꢀ5ꢀyl)ꢀ2ꢀ
2934 (C–H aliphatic), and 1621(C=N). 1H NMR (
δ
,
methylꢀNꢀethylꢀ1,3ꢀthiazolidinꢀ4ꢀone (4a). Yield
ppm): 2.01 (s, 3H, CH3), 4.1 (s, 6H, 2OCH3), 7.97 (d,
1H, H2 furan), 7.03 (d, 1H, H3 furan), 7.53(m, 5H,
(75%); mp 155–157
°
C; FTꢀIR:
(cm–1) 3290 (OH),
ν
3120 (C–H aromatic), 2912 (C–H aliphatic), and
ArꢀH), and 11.3 (s, 1H, OH) exchangeable with D2O
.
1
1770 (C=O). H NMR
(δ, ppm): 1.93(s, 3H, CH3),
Mass spectra m/z (%): 370 (33.1) [
M
+.], 260 (63.1),
2.3 (s, 2H, SCH2CO), 3.83 (s, 6H, 2OCH3), 7.89 (d,
1H, H2 furan), 7.08 (d, 1H, H3 furan), 7.48 (m, 5H,
207 (47.5), 190 (100), 176 (39.1). Anal. Found: C,
58.25; H, 4.30; N, 11.32. Calcd. C18H16N3O6 (370): C,
58.38; H, 4.32; N, 11.35.
ArꢀH), and 9.8 (s, 1H, OH) exchangeable with D2O
.
Mass spectra (%): 325 (8.1) [
m
/
z
M
+.], 310 (70.1), 295
5ꢀ((E)ꢀ1ꢀ(4ꢀMethylphenylimino)ethyl)ꢀ4,7ꢀdimethoꢀ
(63.1), 220 (100), 193 (71.3). Anal. Found: C, 55.35;
H, 5.83; N, 4.30. Calcd. C15H19NO5S (325): C, 55.38;
H, 5.85; N, 4.31.
xybenzofuranꢀ6ꢀol (3d). Yield (87%); mp 145–147 C;
°
FTꢀIR:
matic), 2953 (C–H aliphatic), and 1611 (C=N). H
NMR ( , ppm): 1.93 (s, 6H, 2CH3), 4.09 (s, 6H,
ν
(cm–1) 3345 3345(OH), 3120 (C–H aroꢀ
1
2ꢀ(4,7ꢀDimethoxyꢀ6ꢀhydroxy benzofuranꢀ5ꢀyl)ꢀ2ꢀ
δ
methylꢀNꢀphenylꢀ1,3ꢀthiazolidinꢀ4ꢀone (4b). Yield
2OCH3), 7.99 (d, 1H, H2 furan), 7.2 (d, 1H, H3
furan), 7.65 (dd, 4H, ArꢀH), and 9.9 (s, 1H, OH)
(79%); mp 166–168
°
C; FTꢀIR:
ν
(cm–1) 3295 (OH),
3105 (C–H aromatic), 2980 (C–H aliphatic), and
exchangeable with D2O. Mass spectra
m/z (%): 325
1
+.], 310 (33.1), 249 (11.3), 208 (100),
1760 (C=O). H NMR (δ, ppm): 1.93 (s, 3H, CH3),
(25.3) [M
2.29 (s, 2H, SCH2CO), 3.99 (s, 6H, 2OCH3), 7.97 (d,
1H, H2 furan), 7.2 (d, 1H, H3 furan), 7.53 (m, 5H,
ArꢀH), and 10.8 (s, 1H, OH) exchangeable with D2O.
177(31.2). Anal. Found: C, 70.12; H, 5.81; N, 4.29.
Calcd. C19H19NO4 (325): C, 70.15; H, 5.85; N, 4.31.
5ꢀ((E)ꢀ1ꢀ(4ꢀChlorophenylimino)ethyl)ꢀ4,7ꢀdimethoꢀ
Mass spectra m/z (%): 373 (8.2) [M
+.], 220 (100), 205
xybenzofuranꢀ6ꢀol (3e). Yield (88%); mp 148–150 C;
°
FTꢀIR:
ν
(cm–1) 3310 (OH), (C–H aromatic), 3965 (58.6), 193 (77.2), 145 (28.5 ). Anal. Found: C, 61.11;
1
(C–H aliphatic), and 1655 (C=N). H NMR (
δ
,
H, 5.05; N, 3.74. Calcd. C19H19NO5S (373): C, 61.13;
H, 5.09; N, 3.75.
ppm): 1.82 (s, 3H, CH3), 3.97 (s, 6H, 2OCH3), 8.01
(d, 1H, H2 furan), 7.30 (d, 1H, H3 furan), 7.51 (dd,
4H, ArꢀH), and 11.3 (s, 1H, OH) exchangeable with
2ꢀ(4,7ꢀDimethoxyꢀ6ꢀhydroxybenzofuranꢀ5ꢀyl)ꢀ2ꢀ
methylꢀNꢀ(2ꢀnitrophenyl)ethylꢀ1,3ꢀthiazolidinꢀ4ꢀone
D2O. Mass spectra
m/z (%): 435/347 (35,11.5)
(4c). Yield (81%); mp 170–172
3305 (OH), 3112 (C–H aromatic), 2990 (C–H aliꢀ
phatic), and 1759 (C=O). 1H NMR (
, ppm): 1.95 (s,
°C; FTꢀIR:
ν
(cm–1)
[
M+ +2], 310 (22.4), 193 (61.1), 176 (100), 145
/M
(25.1), 114 (33.1). Anal. Found: C, 62.49; H, 4.60; N,
4.02. Calcd. C18H16NO4Cl (345.5): C, 62.52; H, 4.63;
N, 4.05.
δ
3H, CH3), 2.35 (s, 2H, SCH2CO), 4.02 (s, 6H,
2OCH3), 7.85 (d, 1H, H2 furan), 7.09 (d, 1H, H3 fuꢀ
ran), 7.49 (m, 4H, ArꢀH), and 9.83 (s, 1H, OH) exꢀ
5ꢀ((E)ꢀ1ꢀ(4ꢀMethoxyphenylimino)ethyl)ꢀ4,7ꢀdimeꢀ
thoxybenzofuranꢀ6ꢀol (3f). Yield (89%); mp 155–
changeable with D2O. Mass spectra
m/z (%): 418 (32.1)
157°C; FT–IR:
ν
(cm–1) 3310 (–OH), 3125 (C–H
[M
+.], 372 (11.2), 344 (39.3), 205 (100), 176 (75.3).
aromatic), 2982 (C–H aliphatic), and 1676 (C=N).
Anal. Found: C, 54.52; H, 4.28; N, 6.67. Calcd.
C19H18N2O7S (418): C, 54.55; H, 4.31; N, 6.70.
1H NMR (
δ
, ppm): 1.83 (s, 3H, CH3), 3.83 (s, 9H,
3OCH3), 8.03 (d, 1H, H2 furan), 7.21 (d, 1H, H3
furan), 7.43 (dd, 4H, Ar–H), and 10.3 (s, 1H, OH)
2ꢀ(4,7ꢀDimethoxyꢀ6ꢀhydroxybenzofuranꢀ5ꢀyl)ꢀ2ꢀ
exchangeable with D2O. Mass spectra m/z (%): 341 methylꢀNꢀ(4ꢀmethylphenyl)ꢀ1,3ꢀthiazolidinꢀ4ꢀone (4d).
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
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ABDEL LATIF et al.
Yield (78%); mp 181–183
°
C; FTꢀIR:
ν
(cm–1) 3298
(OH), 3125 (C–H aromatic), 2975 (C–H aliphatic),
was prepared by dissolving 24 mg of DPPH in 100 mL
MeOH, and then stored at 20 in the dark until
needed. The working solution was obtained by diluting
10 mL of stock solution with 45 mL MeOH, to obtain
an absorbance of 1.1 0.1 units at 517 nm controlled
on a Shimadzu UVꢀ1063 spectrophotometer. Briefly, a
°C
1
and 1775 (C=O). H NMR ( , ppm): 1.88 (s, 3H,
δ
CH3), 2.4 (s, 2H, SCH2CO), 3.92(s, 6H, 2OCH3),
8.01 (d, 1H, H2 furan), 7.15 (d, 1H, H3 furan), 7.49
(dd, 4H, ArꢀH), and 10.2 (s, 1H, OH) exchangeable
with D2O. Mass spectra m/z (%): 387 (43.3) [M
+], 372
(12.3), 297 (54.1), 206 (55.1), 219 (100), 204 (63.3).
Anal. Found: C, 62.01; H, 5.41; N, 3.60. Calcd.
C20H21NO5S (387): C, 62.02; H, 5.43; N, 3.62.
volume of 10
and 30 g/mL) of tested compounds dissolved in
DMSO was added to 990 of 0.094 mM DPPH in
MeOH, to reach 1 mL. Solutions were continuously
monitored at 517 nm over a 2 h period at 25 . After
μL of different concentrations (10, 20,
μ
μL
°
C
2ꢀ(4,7ꢀDimethoxyꢀ6ꢀhydroxybenzofuranꢀ5ꢀyl)ꢀ2ꢀ
methylꢀNꢀ(4ꢀchlorophenyl)ꢀ1,3ꢀthiazolidinꢀ4ꢀone (4e).
45 min, changes in absorbance were minimal for all
samples. The antioxidant abilities were expressed as
Yield (80%); mp 188–190
°
C; FTꢀIR:
ν
(cm–1) 3310
(OH), 3110 (C–H aromatic), 2960 (C–H aliphatic),
μ
M Trolox equivalents. Each sample was analyzed in
triplicate. The percentage inhibition of the DPPH
radical by the samples was calculated according to the
following equation:
1
and 1768 (C=O). H NMR ( , ppm): 2,02 (s, 3H,
δ
CH3), 2.34 (s, 2H, SCH2CO), 3,92 (s, 6H, 2OCH3),
7.95 (d, 1H, H2 furan), 7.13 (d, 1H, H3 furan), 7.52
(dd, 4H, ArꢀH), and 11.3 (s, 1H, OH) exchangeable
Inhibition % = (AB
– AA)/AB × 100,
with D2O. Mass spectra
m/z (%): 407/409 (66/21.3)
where AB is the absorption of the blank sample (
t
= 0
[
M+ +2], 372 (15.1), 297 (73.1), 281 (44.5), 220
/M
min) and AA is the absorption of a tested compound or
standard substance solution ( = 45 min).
t
(100). Anal. Found: C, 55.91; H, 4.40; N, 3.41. Calcd.
C19H18NO5SCl (407.5): C, 55.95; H, 4.42; N, 3.44.
The EC50 value defined as the concentration of
antioxidant in the reactive system necessary to
decrease the initial DPPH concentration by 50% was
calculated from the results.
2ꢀ(4,7ꢀDimethoxyꢀ6ꢀhydroxybenzofuranꢀ5ꢀyl)ꢀ
2ꢀmethylꢀNꢀ(4ꢀmethoxyphenyl)ꢀ1,3ꢀthiazolidinꢀ4ꢀ
one (4f). Yield (77%); mp 178–180
3288 (OH), 3119 (C–H aromatic), 2939 (C–H aliꢀ
phatic), and 1770 (C=O). 1H NMR (
, ppm): 1.88 (s,
3H, CH3), 2.23 (s, 2H, SCH2CO), 3.95 (s, 9H,
3OCH3), 7.95 (d, 1H, H2 furan), 7.08 (d, 1H, H3 fuꢀ
ran), 7.53 (dd, 4H, ArꢀH), and 9.9 (s, 1H, OH) exꢀ
°
C; FTꢀIR:
(cm–1)
ν
δ
Hydroxyl Radical Scavenging Assay
Hydroxyl radical scavenging activity was measured
according to Fenton method [24]. Samples (10
khellin ( ), khellinone ( ), all the prepared comꢀ
pounds, and a standard compound (ascorbic acid) at
different concentrations (10, 20, and 30 g/mL) were
µL) of
1
2
changeable with D2O. Mass spectra
m/z (%): 341
(63.2) [
M
+.], 311 (33.4), 235 (100), 176 (55.6). Anal.
Found: C, 66.83; H, 5.55; N, 4.09. Calcd. C19H19NO5
(341): C, 66.86; H, 5.57; N, 4.11.
µ
dissolved in DMSO, then incubated with 9.0 mM
FeSO4 (1.0 mL), 0.3% H2O2 (1.0 mL) in 0.5 mL saliꢀ
cylic acid–ethanol solution (9.0 mM) for 30 min at
37°C. Hydroxyl radical was detected by monitoring
Evaluation of Antioxidant Activity DPPH (1,1ꢀ
Diphenylꢀ2ꢀpicrylꢀhydrazyl) Radical
Scavenging Activity Assay
absorbance at 510 nm. The total volume of the mixture
in each tube was made up to 3 mL by adding the
required amount of distilled water. Inhibition (I) of
deoxyribose degradation in percent was calculated
according to the following equation:
Method of DPPH scavenging has been chosen to
evaluate the in vitro antioxidant activity of target comꢀ
pounds due to the simple, rapid, sensitive, and reproꢀ
ducible procedures [22].
I (%) = 100
× (A0 – A1/A0),
Scavenging activities of khellin (1) khellinone (2),
where A0 is the absorbance of the control reaction mixꢀ
ture and A1 is the absorbance of the test compound.
all the prepared compounds, and a standard comꢀ
pound (Trolox) were measured using the technique
reported [23]. Bleaching of a purpleꢀcolored methanol
solution of DPPH depended on hydrogen atom or
electron donation abilities of tested compounds. The
bleaching rate of the stable free radical, DPPH, is
monitored at a characteristic wavelength in the presꢀ
ence of the sample. DPPH absorbs at 517 nm but,
upon reduction by an antioxidant, its absorption
decreases. When a hydrogen atom or electron is transꢀ
ferred to the odd electron in DPPH, the absorbance at
517 nm decreases proportionally to the increases of
Statistical Analysis
Each of the measurements described was carried
out in three replicate experiments and the results were
plotted by Excel 2011 software.
ACKNOWLEDGMENTS
This work was financial supported by Taif Univerꢀ
nonꢀradical forms of DPPH. Stock solution of DPPH sity, project number 1/433/1748. Also, we would like
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 39
No. 4
2013

SYNTHESIS OF NEW BENZOFURANꢀ1,3ꢀTHIAZOLIDINꢀ4ꢀONE DERIVATIVES
443
12. Saad, B. and Said O., GrecoꢀArab and Islamic Herbal
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