SYNTHESIS OF NEW BENZOFURAN-1,3-THIAZOLIDIN-4-ONE DERIVATIVES FROM NATURAL SOURCES AND STUDY OF THEIR
ANTIOXIDANT ACTIVITY © 2013 N. A. Abdel Latifa, b, #, Sh. H. Abdel Hafeza, c, L. M. Breaka
aChemistry Department, Faculty of Science, Taif University, Taif, KSA bNatural Compounds Chemistry Department, Pharmaceutical Industries Division, National Research Center, Dokki, Egypt cChemistry Department, Faculty of Science, Assuit University, Assuit, Egypt Received November 12, 2012; in final form, January 14, 2013
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.
Keywords:1,3-thiazolidin-4-one, benzofuran, Schiff bases, anti-oxidant activity, khellinone, khellin.
DOI: 10.7868/S0132342313040027
INTRODUCTION
A natural furochromone khellin (1) (4,9-dimethoxy-7-methyl-5H-furo[3,2-g] 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. Similar to psoralen, visnadin, khellin, and coumarin bind with DNA through cross-links to produce monoad-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 derivatives, namely «-acetokhellinone (2') and khellinone (2) (Scheme 1). These two products are important molecules for synthesis of new khellin derivatives [6]. The ring-opening reaction (ROR) of chromone was investigated ab initio and using density functional theory methods by Kona et al. [7, 8].
Khellin exhibits high anti-atherosclerotic and lip-id-altering 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 combined with sun exposure, it helps to treat the skin disease known as vitiligo, in which pigment-carrying melanocytes of skin are lost. Khellin may also be ben-
#Corresponding author (phone: 00966 530203556; e-mail: nehad_km@yahoo.com).
eficial in treating inflammation, psoriasis, minor burns and wounds, and certain dermatological problems [13].
OCH
O
KOH M H2O "
O CH3
OCH3 (1)
KOH C2H5OH
OCH
CH3
OH
OCH 3 (2)
OO
O v "OH OCH3 (2')
CH3
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
100
90
80
70
c 60
.g 50
'jo 40
In 30
20
10
0
10 ppm 20 ppm 30 ppm
Trolox 1 2 3a 3b 3c 3d 3e 3f 4a 4b 4c 4d 4e 4f
Compound name
Fig. 1. Inhibition (%) of DPPH radical by tested compounds.
[17], antithyroid [18], antituberculer, and antidiabetic [19]. For this reason, synthetic connection of thiazoli-dinone moiety with a natural product khellin may increase biological activities of both and yield an antioxidant. Considering the foregoing benefits, we aimed to link biologically active thiazolidinones with the natural khellin to access new classes of biologically active compounds.
O OCH
ft f" CH3 Ar-NH2
och3oh
O ^ "OH OCH3 (2)
C^ /Ar N
O T "OH OCH3 (3a—f)
HSCH2COOH
OCH3 s-
N
ch3
OH Ar
O
OCH3 (4a—f)
Entry Ar Entry Ar
a Ethyl d 4-Methylphenyl
b Phenyl e 4-Chlorophenyl
c 2-Nitrophenyl f 4-Methoxyphenyl
Scheme 2.
RESULTS AND DISCUSSION Chemistry
In frames of our ongoing research to synthesize potentially biologically active thiazolidinone derivates we describe a series of 5-((£)-1-(substituted imi-no)ethyl)-4,7-dimethoxy benzofuran-6-ol (3a—3f) and 2 - (4, 7 - dimethoxy- 6 - hydroxybenzofuran- 5 -yl) -2-methyl-^- (substituted) 1, 3 -thiazolidin-4-one (4a— 4f) (Scheme 2). The series of Shiff s bases (3a—3f) were prepared according to [24] by refluxing different aromatic and/or aliphatic amines and khellinone (2) in 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 NMR spectra in CDCl3 or DMSO-d6 showed the most important signals at 5 1.99-2.1 for CH3 and 3.8-4.02, for the two methoxy groups. Our target compounds 2-melhyl-3-aryl-2-(4,6- dimethoxy- 6 - hydroxy- 5 -yl benzofuran) -1,3-thiazolidin-4-one (4a—4f) were obtained by reactions described in [20], performed by refluxing the solutions of Schiffs bases (3a—3f) and thioglycolic acid in dry benzene in the presence of anhydrous ZnCl2 for 1012 h.
Formation of 2,3-disubtituded 4-thiazolidinone (4a—4f) was confirmed by IR spectroscopy, which showed the characteristic bands in the range of 16901730 cm-1 due to (C=O) group. The NMR spectra in CDCl3 or DMSO-d6 showed the most important signals at 5 3.34-3.38 ppm corresponding to the methylene group (COCH2S).
Antioxidant activity
Antioxidant capacities of khellin (1), khellinone (2), and all the prepared compounds were assessed using two methods, that is DPPH and hydroxyl radical scavenging assay, in comparison with standard compounds. 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 monitored by the decrease in absorbance of the colored free radical [21].
In the hydroxyl radical assay OH, radicals were generated to attack the substrate, deoxyribose. When heated with TBA in acid solution, the resulting products of radical attack form a pink chromogen. Since these two methods are based on different mechanisms for radical inhibition, they can provide complementary insight into the expected antioxidant capacities of compounds under study.
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)—exhibited close inhibition effects against DPPH exceeding that of khellin and other tested substituted compounds. 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, 9.72, 8.27, and 10.59 |M for (3f), (3d), (4d), and (3c) respectively compared with 5.42 ^M for Trolox.
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.
DPPH radical scavenging activities indicate that the most effective substituted compounds (3f), (3d), (4d), and (3c) have more hydrogen atoms or electron donation capacity which converts DPPH to a stable DPPH radical. Also, inhibition of OH radical generation increased when the effective substituted compounds were applied. EC50 values indicate that the effective substituted compounds have moderate antioxidant activity.
CONCLUSIONS
In this study, a series of Schiffbases, 5-((E)-1-((sub-stituted imino)ethyl)-4,7-dimethoxybenzofuran-6-ol (3a—3f) and 2-(4,7-dimethoxy-6-hydroxybenzofuran-5-yl)-2-methyl-N-(substituted)-1,3-thiazolidin-4-one (4a—4f) were synthesized and evaluated for their anti-oxidant 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.
EXPERIMENTAL General
The melting points were recorded in an electrothermal capillary melting point apparatus and were not corrected. Thin layer chromatography was performed using F254 fluorescent silica gel plates (Merck), which were examined under UV 254 and 365 nm light.
Fig. 2. Inhibition (%) of hydroxyl radical by tested compounds.
Silica gel (230-400 mesh) was used for flash chroma-tography separations. Elemental analysis for C, H, N, and S was performed on a Vario EL III equipment (Micro analytical center, Cairo University, Cairo, Egypt). Infrared spectra (v, cm-1) were recorded on a Jasco FT-IR 4100 instrument using KBr disks (Micro analytical center). 1HNMR spectra were recorded on a Varion Mercury VX-300 NMR spectrometer. 1HNMR were run at 300 MHz in deuterated chloroform (CDCl3) or dimethyl sulphoxide (DMSO-d6). Chemical shifts are reported as 5 (ppm) and were related to those of the solvents. Spectra were internally referenced to TMS. Mass spectra were recorded on a Shimadzu GCMS-QP-1000 EX mass spectrometer at 70 eV (Micro analytical center). Chemicals used for antioxidant activity assays were deoxyribose, Trolox, thiobarbituric acid (TBA), 1,1-diphenyl-2-picrylhy
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