Synthesis and antiproliferative activity of 2-arylidene 6-(2-aryl-2-oxoethoxy)benzofuran-3-one derivatives

Article abstract of DOI:10.2174/1570180813999160429113316

The synthesis of 2-arylidene 6-(2-aryl-2-oxoethoxy)benzofuran-3-one derivatives was reported and selected compounds were determined for their anticancer activity evaluation in National Cancer Institute NCI, USA according to the drug screening protocol of the institute against approximately 60 tumor cell lines derived from nine cancer diseases. Compound 3r, namely 2-(4-chlorobenzylidene)-6-[2-(4-methoxyphenyl)-2-oxoethoxy]benzofuran-3-one exhibited the highest antitumor activity against non-small lung cancer cell lines.

Full text of DOI:10.2174/1570180813999160429113316

Send Orders for Reprints to reprints@benthamscience.ae
563
Letters in Drug Design & Discovery, 2016, 13, 563-569
ISSN: 1570-1808
eISSN: 1875-628X
Volume 13, Number 6
Impact
Factor:
0.77
Synthesis and Antiproliferative Activity of 2-arylidene
6-(2-aryl-2-oxoethoxy)Benzofuran-3-one Derivatives
BENTHAM
S
CIENCE
Seref Demirayaka, Leyla Yurttasb,*, Ahmet Cagri Karaburunb, Nalan Gundogdu-Karaburunb and
Ismail Kayagilc
aDepartment of Pharmaceutical Chemistry, School of Pharmacy, Medipol University, 34083 Istanbul,
b
Turkey; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470
Eskisehir, Turkey; cDepartment of Chemistry, Faculty of Arts & Science, Mehmet Akif Ersoy
University, 15030 Burdur, Turkey
Abstract: The synthesis of 2-arylidene 6-(2-aryl-2-oxoethoxy)benzofuran-3-one derivatives was re-
ported and selected compounds were determined for their anticancer activity evaluation in National
Cancer Institute NCI, USA according to the drug screening protocol of the institute against
approximately 60 tumor cell lines derived from nine cancer diseases. Compound 3r, namely 2-(4-
chlorobenzylidene)-6-[2-(4-methoxyphenyl)-2-oxoethoxy]benzofuran-3-one exhibited the highest
antitumor activity against non-small lung cancer cell lines.
Leyla Yurttas
Keywords: Antitumor activity, aurone, benzofuranone, chalcone, cytotoxic activity.
Received: August 03, 2015
Revised: September 22, 2015
Accepted: October 29, 2015
INTRODUCTION
strand scission activity [15, 16]. Additionally, the inhibitory
activity of aurones was attributed to the structural mimicry
between the benzofuranone ring of the aurone and the ade-
nine of ATP (Adenosine triphosphate) [17]. In recent studies,
especially hydroxylated aurones have come into prominence
with higher anticancer activity [18-20].
Chalcones are molecular structures which consist of two
benzene ring connected with ꢀ,ꢁ-unsaturated carbonyl group
(Fig. 1). Natural sourced flavonoids and isoflavonoids are
chalcone including molecules which have known with broad
spectrum of pharmacological activities such as anticancer,
antileishmanial, anti-inflammatory, anti-HIV, antifungal,
antiparasitic and antiprotozoal. Among them, cytotoxic ac-
tivity profile of these compounds have attracted attention due
to increasing number of encouraging research findings [1-4].
One of the most important finding is anticancer activity po-
tential of naturally occurring bioactive chalcones xanthohu-
mol and cardamonin (Fig. 1) [5-7]. Another natural molecule
sulfuretin (Fig. 1) has been reported with promising antican-
cer activity alongside high antiinflammatory activity which
is in aurone frame, a chalconic structure [8]. Aurones (Fig.
1) are molecules which have 2-benzylidene benzofuran-3-
(2H)-one scaffold in its molecular framework and they
commonly found in flavonoids. During past decade numer-
ous biological activities of aurones and their derivatives have
been published such as the inhibition of platelet aggregation,
analgesic, antiasthmatic, anti-inflammatory, antiallergic,
antihyperlipidemic and coronary dilation effects [9-11].
Among these pharmacological diversity, cytotoxic activity of
newly synthesized compounds were mostly studied [12-14].
The antiproliferative properties of these compouns against
cancer cells were ascribed to binding P-glycoprotein inhibit-
ing cyclin-dependent kinases (CDKs), blocking sphingosine
kinase, interfering microtubule assembly, modulating
ABCG2 (breast cancer resistance protein)-mediated multi-
drug resistance, exhibiting antioxidative activity and DNA
In the view of above observations and as an extending
study of our previous studies [21, 22], we have synthesized
2-arylidene 6-(2-aryl-2-oxoethoxy)benzofuran-3-one deriva-
tives (3a-3t) using 6-hydroxyaurone as intermediate product
and investigated their antiproliferative activity against vary-
ing tumour cell lines.
MATERIALS AND METHODS
Chemistry
The chemicals were purchased from Sigma-Aldrich
Chemical Co (Sigma-Aldrich Corp., St. Louis, MO, USA)
and Merck KGaA (Darmstadt, Germany). Melting points
were determined using a Electrothermal 9100 digital melting
point apparatus (Essex, UK). Spectroscopic analyses were
recorded with the following instruments : IR spectra were IR
1
Shimadzu 8400S FT-IR spectrometer (Tokyo, Japan), H-
NMR spectra on a Bruker 500 MHz spectrometer (Billerica,
MA, USA) in DMSO-d6 with TMS as internal standard and
mass spectra using a Agilent 110 MSD spectrometer (Santa
Clara, CA, USA) instruments and elemental analyses were
performed on a Perkin Elmer EAL 240 elemental analyser
(Perkin Elmer, Norwalk, CT, USA).
General Procedure for the Synthesis of 2-arylidene 6-(2-
aryl-2-oxoethoxy)benzofuran-3-one Derivatives (3a-3t)
*Address correspondence to this author at the Anadolu University, Faculty
of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskisehir,
Turkey; Tel: +90-222-3350580/3783; Fax: +90-222-3350750;
E-mail: lyurttas@anadolu.edu.tr
The synthesized 2-arylidene-6-hydroxybenzofuranone
derivatives (2a-2d) were reacted with appropriate 2’-
1875-628X/16 $58.00+.00
©2016 Bentham Science Publishers

564 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6
Demirayak et al.
O
OCH3
O
OCH3
O
HO
OH
HO
OH
OH
CH=CH(CH3)2
a
b
c
O
O
OH
OH
O
O
HO
d
e
Fig. (1). The chemical structures of a) chalcone, b) xanthohumol, c) cardamomin, d) aurone e) sulfuretin.
bromoacetophenone derivatives in acetone at reflux
conditions and in presence of potassium carbonate as a basic
medium. At the end of the reaction, excess acetone was
evaporated and the residue was washed with water. Then, it
was filtered off to obtain crude product and the dried crude
product was crystallized from ethanol.
Ar-H), 7.96-8.01 (3H, m, Ar-H). For C24H18O5 calculated
(%) C 74.60, H 4.70, O 20.70; found (%) C 74.71, H 4.74, O
20.75. MS [M+1]+: m/z 387.3.
2-Benzylidene-6-[2-(4-chlorophenyl)-2-oxoethoxy]benzo-
furan-3-one (3d)
IR (KBr) ꢀmax (cm-1): 3087, 3045 (Ar-H and =CH-),
2978, 2841 (Aliphatic-H), 1705, 1687 (C=O), 1638-1480
(C=C), 1276, 1222 (C-O). 1H-NMR ꢁ (ppm): 5.86 (2H, s, O-
CH2-), 6.86 (1H, s, =CH-), 6.95 (1H, dd, J: 1.97 Hz, J: 8.57
Hz, Ar-H), 7.11 (2H, d, J: 8.87 Hz, Ar-H), 7.26 (2H, brs, Ar-
H), 7.40-7.49 (2H, m, Ar-H), 7.79-7.91 (3H, m, Ar-H), 8.06
(2H, d, J: 7.45 Hz, Ar-H). For C23H15ClO4 calculated (%) C
70.69, H 3.87, O 16.37; found (%) C 70.75, H 3.92, O 16.34.
MS [M+1]+: m/z 391.4.
2-Benzylidene-6-(2-phenyl-2-oxoethoxy)benzofuran-3-
one (3a)
IR (KBr) ꢀmax (cm-1): 3076, 3065 (Ar-H and =CH-),
2966, 2851 (Aliphatic-H), 1708, 1687 (C=O), 1638-1480
(C=C), 1276, 1222 (C-O). 1H-NMR ꢁ (ppm): 5.85 (2H, s, O-
CH2-), 6.85 (1H, s, =CH-), 6.95 (1H, dd, J: 2.06 Hz, J: 8.57
Hz, Ar-H), 7.27 (1H, d, J: 1.87 Hz, Ar-H), 7.41-7.49 (3H, m,
Ar-H), 7.60 (2H, t, J: 7.61 Hz, Ar-H), 7.72 (2H, d, J: 8.62
Hz, Ar-H), 7.96 (2H, d, J: 7.60 Hz, Ar-H), 8.06 (2H, d, J:
7.45 Hz, Ar-H). For C23H16O4 calculated (%) C 77.52, H
4.53, O 17.96; found (%) C 77.46, H 4.58, O 17.93. MS
[M+1]+: m/z 357.2.
2-Benzylidene-6-[2-(4-nitrophenyl)-2-oxoethoxy]benzofu-
ran-3-one (3e)
IR (KBr) ꢀmax (cm-1): 3100, 3064 (Ar-H and =CH-),
2964, 2915, 2856 (Aliphatic-H), 1708, 1694 (C=O), 1651-
1490 (C=C), 1274, 1220 (C-O). 1H-NMR ꢁ (ppm): 5.91 (2H,
s, O-CH2-), 6.85 (1H, s, =CH-), 6.98 (1H, dd, J: 2.01 Hz, J:
8.56 Hz, Ar-H), 7.28 (1H, d, J: 2.02 Hz, Ar-H), 7.53 (2H, d,
J: 8.44 Hz, Ar-H), 7.74-7.85 (4H, m, Ar-H), 8.30 (2H, d, J:
8.81 Hz, Ar-H), 8.40 (2H, d, J: 8.83 Hz, Ar-H). For
C23H15NO6 calculated (%) C 68.83, H 3.77, O 23.92; found
(%) C 68.78, H 3.82, O 23.96. MS [M+1]+: m/z 402.2.
2-Benzylidene-6-[2-(4-methylphenyl)-2-oxoethoxy]benzo-
furan-3-one (3b)
IR (KBr) ꢀmax (cm-1): 3081, 3034 (Ar-H and =CH-),
2978, 2841 (Aliphatic-H), 1705, 1687 (C=O), 1638-1480
1
(C=C), 1276, 1223 (C-O). H-NMR ꢁ (ppm): 2.42 (3H, s,
Ar-CH3), 5.81 (2H, s, O-CH2-), 6.86 (1H, s, =CH-), 6.94
(1H, dd, J: 1.25 Hz, J: 8.75 Hz, Ar-H), 7.25 (1H, brs, Ar-H),
7.40 (2H, d, J: 7.88 Hz, Ar-H), 7.44-7.50 (2H, m, Ar-H),
7.72 (2H, d, J: 8.55 Hz, Ar-H), 7.96-7.99 (4H, m, Ar-H). For
C24H18O4 calculated (%) C 77.82, H 4.90, O 17.28; found
(%) C 77.76, H 4.71, O 17.25. MS [M+1]+: m/z 371.4.
2-(4-Methylbenzylidene)-6-(2-phenyl-2-oxoethoxy)benzo-
furan-3-one (3f)
IR (KBr) ꢀmax (cm-1): 3078, 3033 (Ar-H and =CH-),
2-Benzylidene-6-[2-(4-methoxylphenyl)-2-oxoethoxy]ben-
zofuran-3-one (3c)
2975, 2840 (Aliphatic-H), 1704, 1688 (C=O), 1639-1484
1
(C=C), 1273, 1221 (C-O). H-NMR ꢁ (ppm): 2.34 (3H, s,
IR (KBr) ꢀmax (cm-1): 3078, 3036 (Ar-H and =CH-),
Ar-CH3), 5.82 (2H, s, O-CH2-), 6.88 (1H, s, =CH-), 6.98
(1H, dd, J: 1.27 Hz, J: 8.76 Hz, Ar-H), 7.29 (1H, brs, Ar-H),
7.45 (2H, d, J: 7.86 Hz, Ar-H), 7.63-7.74 (4H, m, Ar-H),
7.85-7.92 (4H, m, Ar-H). For C24H18O4 calculated (%) C
77.82, H 4.90, O 17.28; found (%) C 77.79, H 4.82, O 17.24.
MS [M+1]+: m/z 371.3.
2981, 2854 (Aliphatic-H), 1703, 1688 (C=O), 1635-1476
1
(C=C), 1271, 1220 (C-O). H-NMR ꢁ (ppm): 3.93 (3H, s,
Ar-O-CH3), 5.83 (2H, s, O-CH2-), 6.87 (1H, s, =CH-), 6.88
(1H, d, J: 8.70 Hz, Ar-H), 7.22 (1H, s, Ar-H), 7.28 (2H, d, J:
7.94 Hz, Ar-H), 7.50-7.56 (2H, m, Ar-H), 7.72-7.75 (3H, m,

New 2-arylidene 6-(2-aryl-2-oxoethoxy)benzofuran-3-one Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6 565
1
2-(4-Methylbenzylidene)-6-[2-(4-methylphenyl)-2-oxoe-
thoxy]benzofuran-3-one (3g)
(C=C), 1259, 1226 (C-O). H-NMR ꢁ (ppm): 3.87 (3H, s,
Ar-O-CH3), 5.82 (2H, s, O-CH2-), 6.87 (1H, s, =CH-), 6.96
(1H, dd, J: 1.32 Hz, J: 8.70 Hz, Ar-H), 7.33 (1H, brs, Ar-H),
7.40 (2H, d, J: 7.64 Hz, Ar-H), 7.48-7.52 (2H, m, Ar-H),
7.79 (2H, d, J: 8.48 Hz, Ar-H), 7.95-7.97 (4H, d, Ar-H). For
C24H18O5 calculated (%) C 74.60, H 4.70, O 20.70; found
(%) C 74.68, H 4.72, O 20.73. MS [M+1]+: m/z 387.3.
IR (KBr) ꢀmax (cm-1): 3095, 3068 (Ar-H and =CH-),
2966, 2838 (Aliphatic-H), 1708, 1693 (C=O), 1649-1487
1
(C=C), 1278, 1222 (C-O). H-NMR ꢁ (ppm): 2.34 (3H, s,
Ar-CH3), 2.41 (3H, s, Ar-CH3), 5.79 (2H, s, O-CH2-), 6.81
(1H, s, =CH-), 6.93 (1H, dd, J: 1.86 Hz, J: 8.55 Hz, Ar-H),
7.24 (1H, d, J: 1.72 Hz, Ar-H), 7.29 (2H, d, J: 7.99 Hz, Ar-
H), 7.40 (2H, d, J: 8.02 Hz, Ar-H), 7.70 (1H, d, J: 8.54 Hz,
Ar-H), 7.85 (2H, d, J: 8.0 Hz, Ar-H), 7.96 (2H, d, J: 7.99 Hz,
Ar-H). For C25H20O4 calculated (%) C 78.11, H 5.24, O
16.65; found (%) C 78.16, H 5.28, O 16.70. MS [M+1]+: m/z
385.1.
2-(4-Methoxybenzylidene)-6-[2-(4-methylphenyl)-2-oxoe-
thoxy]benzofuran-3-one (3l)
IR (KBr) ꢀmax (cm-1): 3060, 3025 (Ar-H and =CH-),
2960, 2850 (Aliphatic-H), 1704, 1684 (C=O), 1630-1467
1
(C=C), 1270, 1227 (C-O). H-NMR ꢁ (ppm): 2.35 (3H, s,
Ar-CH3), 3.91 (3H, s, Ar-O-CH3), 5.82 (2H, s, O-CH2-), 6.80
(1H, s, =CH-), 6.94 (1H, dd, J: 2.01 Hz, J: 8.60 Hz, Ar-H),
7.12 (2H, d, J: 8.56 Hz, Ar-H), 7.23 (1H, d, J: 1.56 Hz, Ar-
H), 7.29 (2H, d, J: 7.83 Hz, Ar-H), 7.70 (1H, d, J: 8.53 Hz,
Ar-H), 7.80 (2H, d, J: 8.21 Hz, Ar-H), 8.05 (2H, d, J: 7.84
Hz, Ar-H). For C25H20O5 calculated (%) C 74.99, H 5.03, O
19.98; found (%) C 75.02, H 5.04, O 19.93. MS [M+1]+: m/z
401.1.
2-(4-Methylbenzylidene)-6-[2-(4-methoxyphenyl)-2-oxoe-
thoxy]benzofuran-3-one (3h)
IR (KBr) ꢀmax (cm-1): 3066, 3023 (Ar-H ve =CH-), 2966,
2851 (Aliphatic-H), 1708, 1687 (C=O), 1638-1480 (C=C),
1
1276, 1222 (C-O). H-NMR ꢁ (ppm): 2.34 (3H, s, Ar-CH3),
3.92 (3H, s, Ar-O-CH3), 5.81 (2H, s, O-CH2-), 6.80 (1H, s,
=CH-), 6.92 (1H, dd, J: 2.05 Hz, J: 8.65 Hz, Ar-H), 7.11
(2H, d, J: 8.82 Hz, Ar-H), 7.23 (1H, d, J: 1.68 Hz, Ar-H),
7.29 (2H, d, J: 7.99 Hz, Ar-H), 7.71 (1H, d, J: 8.54 Hz, Ar-
H), 7.85 (2H, d, J: 8.0 Hz, Ar-H), 8.06 (2H, d, J: 7.99 Hz,
Ar-H). For C25H20O5 calculated (%) C 74.99, H 5.03, O
19.98; found (%) C 75.06, H 5.08, O 19.92. MS [M+1]+: m/z
401.1.
2-(4-Methoxybenzylidene)-6-[2-(4-methoxyphenyl)-2-
oxoethoxy]benzofuran-3-one (3m)
IR (KBr) ꢀmax (cm-1): 3087, 3042 (Ar-H and =CH-),
2956, 2921, 2863 (Aliphatic-H), 1703, 1687 (C=O), 1600-
1489 (C=C), 1276, 1220 (C-O). 1H-NMR ꢁ (ppm): 3.87 (3H,
s, Ar-O-CH3), 3.98 (3H, s, Ar-O-CH3), 5.78 (2H, s, O-CH2-),
6.84 (1H, s, =CH-), 6.90 (1H, dd, J: 2.07 Hz, J: 8.65 Hz, Ar-
H), 7.06 (2H, d, J: 8.12 Hz, Ar-H), 7.11 (2H, d, J: 7.79 Hz,
Ar-H), 7.23 (1H, d, J: 1.68 Hz, Ar-H), 7.29 (2H, d, J: 7.99
Hz, Ar-H), 7.71 (1H, d, J: 8.54 Hz, Ar-H), 7.98 (2H, d, J:
7.97 Hz, Ar-H). For C25H20O6 calculated (%) C 72.11, H
4.84, O 23.05; found (%) C 72.15, H 4.75, O 23.09. MS
[M+1]+: m/z 417.2.
2-(4-Methylbenzylidene)-6-[2-(4-chlorophenyl)-2-oxoeth-
oxy]benzofuran-3-one (3i)
IR (KBr) ꢀmax (cm-1): 3071, 3042 (Ar-H and =CH-),
2978, 2841 (Aliphatic-H), 1705, 1687 (C=O), 1638-1480
1
(C=C), 1276, 1222 (C-O). H-NMR ꢁ (ppm): 2.41 (3H, s,
Ar-CH3), 5.80 (2H, s, O-CH2-), 6.78 (1H, s, =CH-), 6.91
(1H, dd, J: 1.77 Hz, J: 8.68 Hz, Ar-H), 7.23 (1H, d, J: 1.55
Hz, Ar-H), 7.29 (2H, d, J: 7.99 Hz, Ar-H), 7.71 (1H, d, J:
8.54 Hz, Ar-H), 7.85 (2H, d, J: 8.0 Hz, Ar-H), 8.29 (2H, d, J:
8.79 Hz, Ar-H), 8.41 (2H, d, J: 8.78 Hz, Ar-H). For
C24H17ClO4 calculated (%) C 71.20, H 4.23, O 15.81; found
(%) C 71.24, H 4.29, O 15.90. MS [M+1]+: m/z 405.5.
2-(4-Methoxybenzylidene)-6-[2-(4-chlorophenyl)-2-oxoe-
thoxy]benzofuran-3-one (3n)
IR (KBr) ꢀmax (cm-1): 3083, 3040 (Ar-H and =CH-),
2950, 2928, 2869 (Aliphatic-H), 1706, 1690 (C=O), 1612-
1494 (C=C), 1278, 1223 (C-O). 1H-NMR ꢁ (ppm): 3.88 (3H,
s, Ar-O-CH3), 5.79 (2H, s, O-CH2-), 6.86 (1H, s, =CH-), 6.92
(1H, dd, J: 2.05 Hz, J: 8.61 Hz, Ar-H), 7.08 (2H, d, J: 8.06
Hz, Ar-H), 7.12 (2H, d, J: 7.64 Hz, Ar-H), 7.27 (1H, d, J:
1.74 Hz, Ar-H), 7.30 (2H, d, J: 7.80 Hz, Ar-H), 7.80 (1H, d,
J: 8.52 Hz, Ar-H), 7.95 (2H, d, J: 7.98 Hz, Ar-H). For
C24H17ClO5 calculated (%) C 68.50, H 4.07, O 19.01; found
(%) C 68.45, H 4.10, O 19.08. MS [M+1]+: m/z 421.4.
2-(4-Methylbenzylidene)-6-[2-(4-nitrophenyl)-2-oxoe-
thoxy]benzofuran-3-one (3j)
IR (KBr) ꢀmax (cm-1): 3101, 3073 (Ar-H and =CH-),
2962, 2912, 2863 (Aliphatic-H), 1704, 1695 (C=O), 1644-
1483 (C=C), 1273, 1221 (C-O). 1H-NMR ꢁ (ppm): 2.40 (3H,
s, Ar-CH3), 5.92 (2H, s, O-CH2-), 6.89 (1H, s, =CH-), 6.97
(1H, dd, J: 2.02 Hz, J: 8.46 Hz, Ar-H), 7.30 (1H, d, J: 2.05
Hz, Ar-H), 7.53 (2H, d, J: 8.57 Hz, Ar-H), 7.72 (1H, d, J:
8.54 Hz, Ar-H), 7.99 (2H, d, J: 8.82 Hz, Ar-H), 8.32 (2H, d,
J: 8.81 Hz, Ar-H), 8.54 (2H, d, J: 8.72 Hz, Ar-H). For
C24H17NO6 calculated (%) C 69.39, H 4.13, O 23.11; found
(%) C 69.43, H 4.16, O 23.15. MS [M+1]+: m/z 416.1.
2-(4-Methoxybenzylidene)-6-[2-(4-nitrophenyl)-2-oxoe-
thoxy]benzofuran-3-one (3o)
IR (KBr) ꢀmax (cm-1): 3102, 3062 (Ar-H and =CH-),
2956, 2913, 2846 (Aliphatic-H), 1708, 1687 (C=O), 1646-
1484 (C=C), 1270, 1224 (C-O). 1H-NMR ꢁ (ppm): 3.88 (3H,
s, Ar-O-CH3), 5.84 (2H, s, O-CH2-), 6.88 (1H, s, =CH-), 6.95
(1H, dd, J: 2.03 Hz, J: 8.60 Hz, Ar-H), 7.31 (1H, d, J: 2.11
Hz, Ar-H), 7.63 (2H, d, J: 8.54 Hz, Ar-H), 7.76 (2H, d, J:
8.64 Hz, Ar-H), 7.91 (2H, d, J: 8.92 Hz, Ar-H), 8.25-8.29
2-(4-Methoxybenzylidene)-6-(2-phenyl-2-oxoethoxy)ben-
zofuran-3-one (3k)
IR (KBr) ꢀmax (cm-1): 3075, 3028 (Ar-H and =CH-),
2974, 2840 (Aliphatic-H), 1705, 1682 (C=O), 1636-1478

566 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6
Demirayak et al.
(1H, m, Ar-H), 8.40 (2H, d, J: 8.73 Hz, Ar-H). For
C24H17NO7 calculated (%) C 66.82, H 3.97, O 25.96; found
(%) C 66.78, H 3.95, O 25.94. MS [M+1]+: m/z 432.2.
2-(4-Chlorobenzylidene)-6-[2-(4-nitrophenyl)-2-
oxoethoxy]benzofuran-3-one (3t)
IR (KBr) ꢀmax (cm-1): 3105, 3068 (Ar-H and =CH-),
2960, 2918, 2851 (Aliphatic-H), 1708, 1693 (C=O), 1649-
1487 (C=C), 1278, 1222 (C-O). 1H-NMR ꢁ (ppm): 5.90 (2H,
s, O-CH2-), 6.87 (1H, s, =CH-), 6.97 (1H, dd, J: 2.05 Hz, J:
8.57 Hz, Ar-H), 7.32 (1H, d, J: 2.03 Hz, Ar-H), 7.54 (2H, d,
J: 8.56 Hz, Ar-H), 7.72 (1H, d, J: 8.56 Hz, Ar-H), 7.96 (2H,
d, J: 8.85 Hz, Ar-H), 8.29 (2H, d, J: 8.79 Hz, Ar-H), 8.41
(2H, d, J: 8.78 Hz, Ar-H). For C23H14ClNO6 calculated (%)
C 63.39, H 3.24, O 22.03; found (%) C 63.45, H 3.31, O
22.12. MS [M+1]+: m/z 436.3.
2-(4-Chlorobenzylidene)-6-(2-phenyl-2-oxoethoxy)benzo-
furan-3-one (3p)
IR (KBr) ꢀmax (cm-1): 3077, 3045 (Ar-H and =CH-),
2978, 2841 (Aliphatic-H), 1705, 1687 (C=O), 1638-1480
(C=C), 1276, 1222 (C-O). 1H-NMR ꢁ (ppm): 5.87 (2H, s, O-
CH2-), 6.88 (1H, s, =CH-), 6.96 (1H, dd, J: 1.67 Hz, J: 8.60
Hz, Ar-H), 7.25 (1H, brs, Ar-H), 7.55 (2H, d, J: 8.44 Hz, Ar-
H), 7.61 (2H, t, J: 7.50 Hz, Ar-H), 7.73 (2H, d, J: 8.49 Hz,
Ar-H), 7.97 (2H, d, J: 8.41 Hz, Ar-H), 8.06 (2H, d, J: 8.15
Hz, Ar-H). For C23H15ClO4 calculated (%) C 70.69, H 3.87,
O 16.37; found (%) C 70.75, H 3.92, O 16.34. MS [M+1]+:
m/z 391.4.
Table 1. Some characteristics of 2-arylidene 6-(2-aryl-2-
oxoethoxy)benzofuran-3-one derivatives.
Compound
-R
-R’
M.P. (°C)
Molecular Formula
3a
3b
3c
3d
3e
3f
-H
-H
-H
-CH3
-OCH3
-Cl
191
193
194
201
232
184
188
181
223
208
186
201
171
217
215
202
203
178
212
237
C23H16O4
C24H18O4
2-(4-Chlorobenzylidene)-6-[2-(4-methylphenyl)-2-oxoe-
thoxy]benzofuran-3-one (3q)
IR (KBr) ꢀmax (cm-1): 3077, 3045 (Ar-H and =CH-),
-H
C24H18O5
2978, 2841 (Aliphatic-H), 1705, 1687 (C=O), 1638-1480
1
(C=C), 1276, 1222 (C-O). H-NMR ꢁ (ppm): 2.34 (3H, s,
-H
C23H15ClO4
C23H15NO6
C24H18O4
Ar-CH3), 5.88 (2H, s, O-CH2-), 6.89 (1H, s, =CH-), 6.97
(1H, dd, J: 1.72 Hz, J: 8.59 Hz, Ar-H), 7.23 (1H, brs, Ar-H),
7.56 (2H, d, J: 8.40 Hz, Ar-H), 7.62 (2H, t, J: 7.62 Hz, Ar-
H), 7.70 (2H, d, J: 8.41 Hz, Ar-H), 7.94 (2H, d, J: 8.40 Hz,
Ar-H), 8.11 (1H, d, J: 8.08 Hz, Ar-H). For C24H17ClO4
calculated (%) C 71.20, H 4.23, O 15.81; found (%) C 71.24,
H 4.27, O 15.72. MS [M+1]+: m/z 405.4.
-H
-NO2
-H
-CH3
-CH3
-CH3
-CH3
-CH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-Cl
3g
3h
3i
-CH3
-OCH3
-Cl
C25H20O4
C25H20O5
C24H17ClO4
C24H17NO6
C24H18O5
2-(4-Chlorobenzylidene)-6-[2-(4-methoxyphenyl)-2-oxoe-
thoxy]benzofuran-3-one (3r)
3j
-NO2
-H
IR (KBr) ꢀmax (cm-1): 3074, 3040 (Ar-H and =CH-),
3k
3l
2972, 2840 (Aliphatic-H), 1702, 1683 (C=O), 1635-1475
-CH3
-OCH3
-Cl
C25H20O5
1
(C=C), 1272, 1220 (C-O). H-NMR ꢁ (ppm): 3.88 (3H, s,
3m
3n
3o
3p
3q
3r
C25H20O6
Ar-O-CH3), 5.88 (2H, s, O-CH2-), 6.89 (1H, s, =CH-), 6.97
(1H, dd, J: 1.58 Hz, J: 8.56 Hz, Ar-H), 7.32 (1H, brs, Ar-H),
7.61 (2H, d, J: 8.55 Hz, Ar-H), 7.71 (2H, t, J: 7.62 Hz, Ar-
H), 7.77 (2H, d, J: 8.42 Hz, Ar-H), 7.99 (2H, d, J: 8.38 Hz,
Ar-H), 8.07 (1H, d, J: 8.18 Hz, Ar-H). For C24H17ClO5
calculated (%) C 68.50, H 4.07, O 19.01; found (%) C 68.47,
H 4.12, O 19.09. MS [M+1]+: m/z 421.4.
C24H17ClO5
C24H17NO7
C23H15ClO4
C24H17ClO4
C24H17ClO5
C23H14Cl2O4
C23H14ClNO4
-NO2
-H
-Cl
-CH3
-OCH3
-Cl
-Cl
2-(4-Chlorobenzylidene)-6-[2-(4-chlorophenyl)-2-oxoeth-
oxy]benzofuran-3-one (3s)
3s
3t
-Cl
IR (KBr) ꢀmax (cm-1): 3112, 3065 (Ar-H and =CH-),
2978, 2841 (Aliphatic-H), 1704, 1687 (C=O), 1638-1480
(C=C), 1276, 1227 (C-O). 1H-NMR ꢁ (ppm): 5.85 (2H, s, O-
CH2-), 6.89 (1H, s, =CH-), 6.96 (1H, dd, J: 1.96 Hz, J: 8.65
Hz, Ar-H), 7.27 (1H, d, J: 1.85 Hz, Ar-H), 7.56 (2H, d, J:
8.49 Hz, Ar-H), 7.69 (2H, d, J: 8.51 Hz, Ar-H), 7.73 (1H, d,
J: 8.6 Hz, Ar-H), 7.98 (2H, d, J: 8.51 Hz, Ar-H), 8.07 (2H, d,
J: 8.49 Hz, Ar-H). For C23H14Cl2O4 calculated (%) C 64.96,
H 3.32, O 15.05; found (%) C 64.91, H 3.42, O 15.12. MS
[M+1]+: m/z 426.2.
-Cl
-NO2
Anticancer Activity
The effects of the benzofuranone compounds on the per-
centage growth were investigated in sixty human tumour cell
lines comprising nine neoplastic diseases namely; leukemia
(L, 4 or 6 cell lines), non-small cell lung cancer (NSCLC, 9
cell lines), colon cancer (CC, 7 cell lines), central nervous
system cancer (CNSC, 6 cell lines), melanoma (M, 8 or 9

New 2-arylidene 6-(2-aryl-2-oxoethoxy)benzofuran-3-one Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6 567
O
O
i
Cl
+
Cl
O
HO
OH
H
HO
1
O
O
ii
1
+
O
HO
R
2a-2d
R
O
O
R'
Br
iii
2a-2d
+
O
O
R'
O
R
R : H, CH3, OCH3, Cl, NO2
R :H, CH3, OCH3, Cl
3a-3t
Scheme (1). The synthesis of the compounds (3a-3t). Reactants and reaction conditions; i AlCl3, Nitrotoluene, 2h, 50-60 oC ; ii : n-
butanol/isobutanol, HCl, reflux, 1h ; iii : K2CO3, Acetone, reflux, 3h.
cell lines), ovarian cancer (OC, 6 or 7 cell lines), renal can-
cer (RC, 8 cell lines), prostate cancer (PC, 2 cell lines),
breast cancer (BC, 6 or 8 cell lines). The evaluation of anti-
cancer activity was performed at the National Cancer Insti-
tute (NCI) of Bethesda, USA, according to in vitro screening
program at 10–5 mol/l [25, 26].
protons were seen at 8.54-6.88 ppm. Due to E and Z
isomerism of the arylidene structure, it is possible to see
peaks at two different places of the spectrum. The presence
of isomeric forms was confirmed by thin layer
chromatography, but in the NMR spectra this situation was
not observed that one of the isomers may have been lost in
the synthesis steps or during purification. All compounds
gave satisfactory elemental analyses results within +0.4 %.
In the MS spectra, the electron spraying technique with
positive polarity mode was applied and M+1 peaks were
detected as base peak in agreement with the molecular
weights.
RESULTS AND DISCUSSION
Chemistry
The synthesis of the target compounds 3a-3t were pre-
pared in three steps as shown in Scheme (1). Initially, resor-
cinol (1,3-dihydroxybenzene) was reacted with aluminium
chloride and chloro acetylchloride in nitrotoluene. First,
chloro acetyl residue was bonded to aromatic ring (ortho
position) according to Friedel-Crafts reaction, then ring clo-
sure reaction was occurred with phenolic hydroxyl group and
chloro acetyl group. The obtained product, 6-
hydroxybenzofuran-3-one (1), was reacted with four differ-
ent benzaldehyde derivatives according to Claisen-Schmidt
condensation. The synthesized 2-arylidene-6-hydroxybenzo-
furanone derivatives (2a-2d) and 2’-bromoacetophenone
derivatives were reacted to achieve 2-arylidene 6-(2-aryl-2-
oxoethoxy)benzofuran-3-one (3a-3t). The structures of the
final compounds were elucidated by using IR, 1H-NMR, MS
spectral data and elemental analyses results. In the IR spectra
of the compounds, characteristic stretching bands were
observed at 1708-1682, 1651-1467 and 1278-1220 cm-1 due
to C=O, C=C and C-O bonds. In double bond region, two
carbonyl function was detected that belongs to C=O bonds
which are on third position of benzofuranone ring and on
Anticancer Activity
All final compounds (3a-3t) were offered to National
Cancer Institute, USA (NCI) for testing their anticancer ac-
tivity. The cytotoxic activities of selected compounds were
evaluated according to Developmental Therapeutics Program
(DTP) drug screening protocols of the institute. In vitro
single dose (105 M) anticancer assay was performed in full
NCI 60 cell panel representing leukemia (L), non-small cell
lung cancer (NSCLC), colon cancer (CC), central nervous
system cancer (CNSC), melanoma (M), ovarian cancer (OC),
renal cancer (RC), prostate cancer (PC), and breast cancer
(BC). Results were given as percentage growth of the cancer
diseases which were treated with tested compounds (Table
2). According to mean values, only compound 3r exhibited
antitumor activity with a percentage growth under 100 %.
The other percentage growth values belongs to the other se-
lected compounds (3c, 3i, 3o) were found over this number.
The percentage growth values represent growth percentage
of tumor cells treated with test compounds. Therefore smal-
ler values means higher activity. When we evaluate antitu-
mor activity according to subpanels, compound 3r showed
the highest activity to non-small cell lung cancer and breast
cancer with growth percentages 64.52 and 79.82 %, respecti-
vely. Compound 3o affected renal cancer cell lines with a
1
benzoyl moiety. In the H-NMR spectra, protons of acetyl
residue were observed at about 5.92-5.78 ppm. The
methylene protons, –C=CH-, were resonated as singlets at
about 6.89-6.78 ppm. All other aliphatic and aromatic
protons were observed at expected regions. The aromatic

568 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6
Demirayak et al.
Table 2. 60 human tumor cell lines’ anticancer screening data at single dose assay as percent cell growth promotion of selected com-
pounds.
Com
NSCLC
CC
BC
OC
L
RC
M
PC
CNSC
Mean
3c
3i
104.05
101.49
98.02
107.2
98.73
107.71
94.93
97.18
105.07
102.03
79.82
108.12
96.89
100.66
127.70
141.30
132.28
95.44
104.50
79.26
92.76
93.41
86.88
92.76
105.03
247.18
269.91
113.45
100.68
105.31
107.34
113.57
92.09
109.62
108.54
107.13
97.38
3o
3r
108.74
95.73
64.52
NSCLC Non-small cell lung cancer, CC Colon cancer, BC breast cancer, OC ovarian cancer, L leukemia, RC renal cancer, M melanoma, PC prostate cancer, CNSC central nervous
system cancer.
mean percentage growth of 79.26 %. Prostate cancer cell
lines were determined as the most resistant cell lines against
to compounds 3c and 3i which they had percentage growth
values over 200 %. If we examine results at cellular level, it
is not possible to interpret, clearly that it varies. Compound
3c exhibited significantly cytotoxic activty with a percentage
growth of 5.59 % against UO-31 which is a renal cancer cell
line. Compound 3i showed noticeble activity to SK-MEL-28
cell line with a percentage growth of 48.37 % (melanoma).
As stated above, PC-3 cell line (prostate cancer) was found
as the most resistant cell against to compound 3c and 3i
(percentage growth : ꢀ389.44 %). Compound 3o and 3r e-
xhibited observable antitumor activity against SK-MEL-2
(41.43%) and RXF 393 ( 49.98 %) which are melanoma and
renal cancer cell lines, respectively. Compound 3r also sho-
wed respectable activity against ovarian cancer cell lines
IGROV1 and OVCAR-8 with the values of 52.16 and 61.25
%. A clear inference could not be made based on these re-
sults. But we can comment that methoxy and chloro substi-
tuents contributed to antitumor activity referring to com-
pound 3r which possesses both of the substituents [23,24].
This study is thought to be develop with new anticancer acti-
vity tests and newly synthesized compounds in further stu-
dies.
their thanks to NCI (USA) and Anadolu University BIBAM
(Türkiye) for anticancer test results and NMR spectra,
respectively.
REFERENCES
[1]
Narsinghani, T.; Sharma, M.C.; Bhargav, S. Synthesis, docking
studies and antioxidant activity of some chalcone and aurone de-
rivatives. Med. Chem. Res., 2013, 22, 4059-4068.
Saxena, H.O.; Faridi, U.; Kumar, J.K.; Luqman, S.; Darokar, M.P.;
Shanker, K.; Chanotiya, C.S.; Gupta, M.M.; Negi, A.S. Synthesis
of chalcone derivatives on steroidal framework and their anticancer
activities. Steroids, 2007, 72, 892-900.
[2]
[3]
[4]
Kumar, S.K.; Hager, E.; Pettit, C.; Gurulingappa, H.; Davidson,
N.E.; Khan, S.R. Design, synthesis, and evaluation of novel bo-
ronic-chalcone derivatives as antitumor agents. J. Med. Chem.,
2003, 46, 2813-2815.
Manjulatha, K.; Srinivas, S.; Mulakayala, N.; Rambabu, D.; Prab-
hakar, M.; Arunasree, K.M.; Alvala, M.; Rao, M.V.B.; Pal, M.
Ethylenediamine diacetate (EDDA) mediated synthesis of aurones
under ultrasound: Their evaluation as inhibitors of SIRT1. Bioorg.
Med. Chem. Lett., 2012, 22, 6160-6165.
Detsi, A.; Majdalani, M.; Kontogiorgis, C.A.; Hadjipavlou-Litina,
D.; Kefalas, P. Natural and synthetic 2’-hydroxy-chalcones and
aurones: Synthesis, characterization and evaluation of the antioxi-
dant and soybean lipoxygenase inhibitory activity. Bioorg. Med.
Chem., 2009, 17, 8073-8085.
[5]
[6]
[7]
Tronina, T.; Bartmanska, A.; Filip-Psurska, B.; Wietrzyk, J.;
Popꢁonski, J.; Huszcza, E. Fungal metabolites of xanthohumol with
potent antiproliferative activity on human cancer cell lines in vitro.
Bioorg. Med. Chem., 2013, 21, 2001-2006.
Morales-Camilo, N.; Salas, C.O.; Sanhueza, C.; Espinosa-Bustos,
C.; Sepulveda-Boza, S.; Reyes-Parada, M.; Gonzalez-Nilo, F.;
Caroli-Rezende, M.; Fierro, A. Synthesis, biological evaluation,
and molecular simulation of chalcones and aurones as selective
MAO-B inhibitors. Chem. Biol. Drug Des., 2015, 85, 685-695.
Poudel, S.; Song, J.; Jin, E.J.; Song, K. Sulfuretin-induced miR-
30C selectively downregulates cyclin D1 and D2 and triggers cell
death in human cancer cell lines. Biochem. Biophys. Res. Commun.,
2013, 431, 572-578.
Zheng, X.; Wang, H.; Liu, Y.M.; Yao, X.; Tong, M.; Wang, Y.H.;
Liao, D.F. Synthesis, characterization, and anticancer effect of
trifluoromethylated aurone derivatives. J. Heterocyclic Chem.,
2015, 52, 296.
Harkat, H.; Blanc, A.; Weibel, J.M.; Pale, P. Versatile and expedi-
tious synthesis of aurones via AuI-catalyzed cyclization. J. Org.
Chem., 2008, 73, 1620-1623.
CONCLUSION
In this work, twenty new 2-arylidene 6-(2-aryl-2-
oxoethoxy)benzofuran-3-one derivatives (3a-3t) were syn-
thesized by Friedel-Crafts and Claisen-Schmidt condensation
reactions in good yields. The structures of the compounds
[8]
[9]
1
were elucidated with IR, H-NMR, MS spectroscopic data
and elemental analysis results. Their anticancer activity were
evaluated against 60 tumor cell lines derived from nine can-
cer disease. Compound 3r possessing 4-chloro and 4-
methoxy substituents showed the highest antitumor activity
among tested four compounds (3c, 3i, 3o).
[10]
[11]
CONFLICT OF INTEREST
Hallgas, B.; Patonay, T.; Kiss-Szikszai, A.; Dobosa, Z.; Hollósy,
F.; Eros, D.; Gy, L.O.; Idei, K.M. Comparison of measured and
calculated lipophilicity of substituted aurones and related com-
pounds. J. Chromatogr. B, 2004, 801, 229-235.
The authors confirm that this article content has no con-
flict of interest.
[12]
[13]
Sim, H.M.; Loh, K.Y.; Yeo, W.K.; Lee, C.Y.; Go, M.L. Aurones as
modulators of ABCG2 and ABCB1: Synthesis and structure–
activity relationships. Chem. Med. Chem., 2011, 6, 713-724.
Lewin, G.; Aubert, G.; Thoret, S.; Dubois, J.; Cresteil, T. Influence
of the skeleton on the cytotoxicity of flavonoids. Bioorg. Med.
Chem., 2012, 20, 1231-1239.
ACKNOWLEDGEMENTS
The study was financially supported by Anadolu Univer-
sity, Turkey (BAP Project No: 050301). The authors present

New 2-arylidene 6-(2-aryl-2-oxoethoxy)benzofuran-3-one Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 6 569
[14]
[15]
Deepthi, M.; Harinadha Babu V.; Madhava Reddy, B. Synthesis of
some modified aurones as antileukemic and antibacterial agents.
Indian J. Chem., 2013, 52B, 1455-1461.
Zwergel, C.; Valente, S.; Salvato, A.; Xu, Z.; Talhi, Q.; Mai, A.;
Silva, A.; Altuccice, L.; Kirsch, G. Novel benzofuran–chromone
and –coumarin derivatives: synthesis and biological activity in
K562 human leukemia cells. Med. Chem. Commun., 2013, 4, 1571-
1579.
Cheng, H.; Zhang, L.; Liu, Y.; Chen, S.; Cheng, H.; Lu, X.; Zheng,
Z.; Zhou, G.C. Design, synthesis and discovery of 5-
hydroxyaurone derivatives as growth inhibitors against HUVEC
and some cancer cell lines. Eur. J. Med. Chem., 2010, 45, 5950-
5957.
Sim, H.; Lee, C.; Rachel, P.L.; Go, M.L. Dimethoxyaurones:
Potent inhibitors of ABCG2 (breast cancer resistance protein). Eur.
J. Pharm. Sci., 2008, 35, 293-306.
Parate, A.; Sharma, R.; Maheshwari, I. Structural indents for 5-
hydroxyaurone derivatives as potent anticancer agents against
HUVEC cancer cell lines-kNN MFA approach. Der Pharmacia
Sinica, 2013, 4, 121-129.
French, K.J.; Schrecengost, R.S.; Lee, B.D.; Zhuang, Y.; Smith,
S.N.; Eberly, J.L.; Yun, J.K.; Smith, C.D. Discovery and evaluation
of inhibitors of human sphingosine kinase1. Canc. Res., 2003, 63,
5962-5969.
Okombi, S.; Rival, D.; Bonnet, S.; Mariotte, A.M.; Perrier, E.;
Boumendjel, A. Discovery of benzylidenebenzofuran-3(2H)-one
(aurones) as inhibitors of tyrosinase derived from human melano-
cytes. J. Med. Chem., 2006, 49, 329-333.
Gundogdu-Karaburun, N.; Karaburun, A.C.; Demirayak, S.; Kay-
agil, ꢀ.; Yurttas, L. Synthesis and anticancer activity of some 2-
[3/4-(2-substituted phenyl-2-oxoethoxy)benzylidene]-6-substituted-
2,3-dihydro-1H-inden-1-one derivatives. Lett. Drug Des. Discov.,
2014, 11, 578-85.
Demirayak, S., Yurttas, L Gundogdu-Karaburun, N.; Karaburun,
A.C.; Kayagil, I. Synthesis and anticancer activity evaluation of
new aurone derivatives. J. Enzyme Inhib. Med. Chem., 2014, 30,
816-825.
Yurttas, L.; Demirayak, S.; Akalın Ciftci, G.; Ulusoylar Yıldırım,
S.; Kaplancıklı, Z.A. Synthesis and biological evaluation of some
1,2- disubstituted benzimidazole derivatives as new potential anti-
cancer agents. Arch. Pharm. Chem. Life Sci., 2013, 346, 403-414.
Demirayak, S.; Yurttaꢁ, L. Synthesis and anticancer activity of
some 1,2,3-trisubstituted pyrazinobenzimidazole derivatives. J. En-
zyme Inhib. Med. Chem., 2014, 29, 811-822.
[21]
[22]
[23]
[16]
[17]
[18]
[24]
[25]
Higginbotham, L.; Stephen, H. Coumaraone Series. I. The prepara-
tion of 4-, 5- and 6-methylcoumaran-2-ones and some derivates of
o-, m- and p-tolyloxyacetic acids. J. Am. Chem. Soc., 1920, 117,
1534-1542.
Balakrishna, K.J.; Rao, N.P.; Seshadri, T.R. A method of distin-
guishing between flavones and flavonols. Proc. Indian Natl. Sci.
Acad. A., 1949, 29, 394-403.
[19]
[20]
[26]