Design, synthesis, antioxidant and anticancer activity of new coumarin derivatives linked with thiazole, isoxazole or pyrazole moiety

Article abstract of DOI:10.2174/1570180813666161026153743

Background: Three new series of coumarin derivatives 4a-e, 6a-d and 7a-d were synthesized and characterized by elemental analyses and spectral data including 2D NMR. All compounds 4a-e, 6a-d and 7a-d were evaluated for their in vitro antioxidant and antic

Full text of DOI:10.2174/1570180813666161026153743

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Letters in Drug Design & Discovery, 2017, 14, 773-781
RESEARCH ARTICLE
eISSN: 1 58 7 05 - 16 82 08 8X
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Design, Synthesis, Antioxidant and Anticancer Activity of New Coumarin
Derivatives Linked with Thiazole, Isoxazole or Pyrazole Moiety
SB EC N
I
ET NH AC ME
a,b,*
a,c
a
a
Khaled R. A. Abdellatif
, Mohamed A. Abdelgawad , Heba A. H. Elshemy , Nesma M. Kahk
d
and Dalia M. El Amir
a
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt;
b
Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah 21418, Kingdom of
c
Saudi Arabia; Pharmaceutical Chemistry Department, College of Pharmacy, Al Jouf University, Sakaka Al Jouf 2014,
Saudi Arabia; Pharmacognosy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
d
Abstract: Background: Three new series of coumarin derivatives 4a-e, 6a-d and 7a-d were
synthesized and characterized by elemental analyses and spectral data including 2D NMR. All
compounds 4a-e, 6a-d and 7a-d were evaluated for their in vitro antioxidant and anticancer activity
against Hep-G2 hepatic cancer and MCF-7 breast cancer cell lines.
A R T I C L E H I S T O R Yꢀ
Method: Compounds 4c, 4e, 6d and 7c showed higher antioxidant activity (IC50 = 78, 20, 90 and 46
µM, respectively) than the reference drug silymarin (IC50 = 76 µM).
Received: September 04, 2016
Revised: October 11, 2016
Accepted: October 21, 2016
Results and Conclusion: However, the anticancer screening for the three series showed promising
DOI:
1
0.2174/1570180813666161026153743
anticancer activity against hepatic Hep-G2 cancer cell line and compounds 4d, 4e, 6a and 6c (IC50 =
1
890, 5327, 5715 and 10339 µM, respectively) have more potent cytotoxic activity than cisplatin
IC50 = 11898 µM). On the other hand, all compounds showed no anticancer activity against MCF-7
cell line except compound 6a with IC50 = 32441 µM in comparison with cisplatin (IC50 = 15030 µM).
(
Keywords: Coumarin, pyrazole, isoxazole, thiazole, antioxidant, anticancer.
1
. INTRODUCTION
generation and antioxidant defense as a force in cancer
prevention [5]. Because of evidences from bench and clinical
studies indicate that elevated intracellular reactive oxygen
species early contribute in cancer initiation and progression,
an opposite approach to mediate an increase in cellular
reactive oxygen species levels is to use antioxidants to
deplete tumor cells from reactive oxygen species induced
survival signaling pathways [6].
Free radicals are a group of unstable substances that are
constantly generated for specific metabolic requirement and
quenched by an efficient antioxidant network in the body [1].
When the generation of these species exceeds the levels of
antioxidant mechanism, it leads to oxidative stress which
results in the damage of tissues and biomolecules, eventually
lead to disease leading conditions such as inflammation,
carcinogenesis and atherogenesis [2].
Coumarin and its derivatives form a unique class of
compounds that have recently drawn much attention due to
its broad pharmacological activities such as anticancer [7]
Moreover, cancer is a serious clinical problem that poses
significant socioeconomical effects on the human healthcare
and is the second leading cause of death in most countries
after cardiovascular diseases [3]. Apart from the use of
surgery and radiotherapy, chemotherapy is an important
treatment modality for cancers. However, owing to toxicity
and drug-resistance problems with chemotherapeutic agents,
it remains a great challenge to discover and develop more
effective and specific anticancer drugs [4]. In vitro studies
and experimental studies in animals have suggested that the
reactive oxygen species (ROS) are essential factor in carcino-
genesis and there is a crucial balance between free-radical
(
(
[
compound I, Fig. 1), anti-inflammatory [8], antioxidant [9]
compound II, Fig. 1), anticonvulsant [10], anticoagulant
11] antimicrobial [12] and antituberculosis [13]. Along with
coumarin ring, thiazole analogs are used as antitumor [14]
and antioxidant agents [15]. Moreover, isoxazoles are an
important class of heterocycles which are largely employed
in the area of pharmaceuticals and therapeutics as anticancer
[
16] and antioxidant compounds [17]. On the other hand,
pyrazole derivatives are well known for their potent
anticancer [18, 19] activities. Based on these findings and in
continuation of our previous work [20-22] for synthesis of
new derivatives of good anti-cancer activity, we describe the
synthesis of some compounds featuring different hetero-
cyclic rings attached to the coumarin moiety with the aim of
obtaining more potent pharmacologically active antioxidant
& anticancer agents (Fig. 1).
*
Address correspondence to this author at the Pharmaceutical Organic
Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-
Suef, Egypt; Tel: 00201002535444; Fax: 0020822317958;
E-mail: khaled.ahmed@pharm.bsu.edu.eg
1
875-628X/17 $58.00+.00
©2017 Bentham Science Publishers

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74 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 7
Abdellatif et al.
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2
2
. RESULTS AND DISCUSSION
.1. Chemistry
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chloroacetyl chloride in DMF containing few drops of
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thiazolylcoumarin derivative was not obtained.
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Scheme 1. Synthetic protocol for compounds 4a-e.

Design, Synthesis, Antioxidant and Anticancer Activity of New Coumarin Derivatives
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 7 775
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Scheme 2. Synthetic protocol for compounds 6a-d and 7a-d.
(
form A) or 1,3 diarylpyrazole derivatives (form B). The
compounds (4a-e, 6a-d and 7a-d) had broad range of
activities (IC50 = 20 – 15034 µM) in comparison with
silymarin (IC50 = 76 µM). Within the isoxazole derivatives
(4a-e), the ethoxy derivative (4e, IC50 = 20 µM) > the other
ethoxy derivative (4c, IC50 = 78 µM) > tolyl derivative (4d,
IC50 = 158 µM) > phenyl derivative (4a, IC50 = 373 µM) >
methoxy derivative (4b, IC50 = 427 µM). While for isoxazole
derivatives (6a-d), the methoxy derivative (6d) showed the
highest potency (IC50 = 90 µM), the bromo derivative (7c)
was the most potent one (IC50 = 46 µM) within the pyrazole
derivatives (7a-d) and both were more potent than the
reference drug silymarin (IC50 = 76 µM).
structure of the obtained pyrazole derivative 7a-d was
proved by all spectral data including 2D NMR to clarify its
structure. Taking compound 7c as an example (Fig. 2), to
ensure which form (A or B) was produced we have to study
the long range heteronuclear coupling by studying the
HMBC spectrum (Fig. 3) of the product. In form B the key
correlation that can solve this challenge is the correlation
between H-5 in pyrazole ring at δ
H
7.82 ppm with the
quaternary carbon of the phenyl substitution at N-1 pyrazole
at δ
C
136.36 ppm. In form A no correlation can be seen
between the two protons of the pyrazole ring and that
quaternary carbon. Since the HMBC spectrum of the
obtained product did not show any correlation with between
2.3. Anticancer Screening
H
pyrazole protons at δ (7.82, 6.76) ppm and the C-1 of the
Cytotoxic evaluation of the target compounds (4a-e, 6a-d
and 7a-d) against human hepatic carcinoma cell line (Hep-
G2) and human breast carcinoma cell line (MCF-7) using
Sulforhodamine-B (SRB) stain assay [25] demonstrated that
thiazolylcoumarin derivatives 4a-e showed variable
anticancer activity where the tolyl derivative (4d) and the
ethoxy derivative (4e) showed potent activity against Hep-
G2 cell line with IC50 = 1890 and 5327 µM., respectively in
comparison with reference drug cisplatin (IC50 = 11898 µM)
but they showed no activity against MCF-7 cell line.
Moreover, all isoxazolyl-coumarin derivatives 6a-d showed
C
phenyl substitution at δ 136.36 ppm, we can make sure that
the obtained product is A. This product is also confirmed by
the downfield shift of the C-3 in pyrazole ring which
appeared at δ 140.56 ppm. If form B was produced, the
C
pyrazole C-3 could be detected at about δ
C
128 ppm.
2
.2. Antioxidant Activity
The antioxidant studies using DPPH free radical
scavenging method [24] (Table 1) showed that the target
good anticancer activity against Hep-G2 cell line with IC50
715 – 20458 µM. However, only the methoxy derivative
(6a) showed moderate activity against MCF-7 cell line with
IC50 value of 32441 µM in comparison with cisplatin (IC50
5030 µM). On the other hand, among pyrazolyl-coumarin
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derivatives 7a-d, both ethoxy and bromo derivatives 7b and
7c showed moderate anticancer activity against Hep-G2 cell
line with IC50 = 14442 and 17892 µM, respectively with no
anticancer activity against MCF-7 cell line.
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7
76 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 7
Abdellatif et al.
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3
. CONCLUSION
derivatives ethoxy substituent showed the highest
antioxidant activity as in compounds 4c and 4e (IC50 = 78
and 20, respectively), while 6-bromo-8-methoxy derivative
Three new series of coumarin scaffold linked to thiazole
derivatives (4a-e), isoxazole moiety (6a-d) and pyrazole
derivatives (7a-d) were synthesized for evaluation as
antioxidant and as anticancer agents against human liver
cancer cell line (HEPG-2) and human breast cancer cell line
6
d showed the highest antioxidant activity in the series of
coumarin linked to isoxazole moiety (IC50 = 90 µM). On the
other hand, 6-bromo substituent showed the best antioxidant
activity among coumarin linked pyrazole derivatives as in
compound 7c (IC50 = 46 µM) compared to the reference drug
(
MCF-7). Structure activity relationship (SAR) study for the
synthesized compounds revealed that for thiazolyl coumarin

Design, Synthesis, Antioxidant and Anticancer Activity of New Coumarin Derivatives
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 7 777
Table 1. IC50 (concentration required for 50 % scavenging of
DPPH free radical) for target compounds 4a-e, 6a-d
and 7a-d.
substituent in compounds 4d and 4e (IC50 = 1890, 5327 µM)
have more potent cytotoxic activity than cisplatin as
reference drug (IC50 = 11898 µM). Moreover, in isoxazole
derivatives both 8-methoxy and 6-bromo substituents in
compounds 6a and 6c, respectively showed more potent
anticancer activity with (IC50 = 5715 and 10339 µM
respectively) than the reference cisplatin drug.
Compound No.
IC50 (µM)
4
4
4
4
4
6
6
6
6
7
7
7
7
a
b
c
373
427
78
4. EXPERIMENTAL
d
e
158
20
4
.1. Chemistry
General
a
b
c
542
367
147
90
Melting points were determined on a Griffin apparatus
and were uncorrected. Infrared (IR) spectra were recorded on
a Shimadzu 435 Spectrometer, using KBr discs and values
-
1
1
13
were represented in cm . H-NMR and C-NMR spectra
were carried out on a Bruker 400 MHz spectrometer in
Faculty of pharmacy Beni Suef University, Egypt. Samples
d
a
b
c
15034
499
46
3 6
were dissolved in CDCl or DMSO-d with TMS as the
internal standard, where J (coupling constant) values were
estimated in hertz (Hz) and chemical shifts were recorded in
ppm on δ scales. Mass spectra were run on a Hewlett
Packard 5988 spectrometer at the regional center for
mycology & biotechnology, Al-Azhar University, Egypt.
Element analysis was carried out for C, H, N at the regional
center for mycology & biotechnology, Al-Azhar University,
Egypt. Progress of the reactions was monitored using thin
layer chromatography (TLC) sheets that precoated with UV
fluorescent silica gel MERCK 60 F 254 that was visualized
by UV lamp. Solvent system was chloroform: methanol (in
different ratio). All chemicals purchased from the Aldrich
Chemical Company (Milwaukee, WI), were used without
further purification. Compound 3a was prepared according
to a reported procedure [25].
d
372
76
Silymarin
Table 2. IC50 of in vitro cytotoxic activity of cisplatin and the
test compounds on human liver tumor cell line (HEPG-
2
) and human breast tumor cell line (MCF-7).
IC50 (µM)
Compound No.
Hep-G2
MCF-7
4
4
a
>50000
>50000
>50000
1890
>50000
>50000
>50000
>50000
>50000
32441
2
-Chloro-N-[4-(2-oxo-2H-chromen-3-yl)-thiazol-2-yl]-
b
acetamide derivatives (3a-c)
4
c
Chloroacetyl chloride (1.35ml, 0.012 mol) was added to a
solution of 3-(2-amino-thiazol-4-yl)-chromen-2-one derivative
4
d
2
a-c (0.01 mol) in DMF (15 mL) containing few drops of
4
6
e
5327
triethyl amine. The reaction mixture was stirred at room
temperature for 24h. The separated solid product was
filtered, and crystallized from toluene to afford compounds
a
5715
6
b
14293
10339
20458
>50000
14442
17892
>50000
11898
>50000
>50000
>50000
>50000
>50000
>50000
>50000
15030
3
a-c. Physical and spectral data for 3b-c are listed below:
6
c
2
-Chloro-N-[4-(8-methoxy-2-oxo-2H-chromen-3-yl)-
6
7
7
d
a
b
thiazol-2-yl]-acetamide (3b)
White powder; yield, 68%; mp 240-242 °C; IR 3433
(
NH), 3073 (CH aromatic), 3002 (CH aliphatic), 1647 (broad,
-1 1
3
two CO) cm ; H NMR (DMSO): δ 3.94 (s, 3H, OCH ),
7
c
4
2
.44 (s, 2H, CH ), 7.34 (d, J = 7.6 Hz, 2H, coumarin H-5 and
7
d
H-7), 7.39 (t, J = 7.6 Hz, 1H, coumarin H-6), 8.07 (s, 1H,
thiazole H-5), 8.56 (s, 1H, coumarin H-4), 12.70 (s, 1H, NH,
Cisplatin
D O exchangeable); EIMS, M/z: 352.01 (M+2, 19.23),
2
+.
3
51.03 (M+1, 8.94), 350.02 (M , 54.84), 349.11 (M-1,
silymarin (IC50 = 76 µM). Also, the anticancer screening of
the prepared compounds showed higher and promising
anticancer activity against hepatic Hep-G2 cancer cell line
where compounds containing thiazole scaffold p-tolyl
15 11 2 4
0.91), 274.05 (100%); Anal. Calcd. For C H ClN O S
(350.78): C, 51.36; H, 3.16; N,7.99. Found: C, 51.52; H,
3.20; N, 8.21.

7
78 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 7
Abdellatif et al.
2
2
-Chloro-N-[4-(8-ethoxy-2-oxo-2H-chromen-3-yl)-thiazol-
-yl]-acetamide (3c)
1H, NH-Ph, D
2
O exchangeable); 6.60 (m, 3H, phenyl H-2,
H-4 & H-6); 7.10 (t, J = 7.2 Hz, 2H, phenyl H-3 & H-5);
7
.34 (m, 3H, coumarin H-5, H-6 & H-7); 8.02 (s, 1H,
White powder; yield 60%; mp 250-252 °C; IR (KBr)
446 (NH), 3080 (CH aromatic), 2932 (CH aliphatic), 1684
thiazole H-5); 8.58 (s, 1H, coumarin H-4); 12.33 (s, 1H, NH-
3
13
-
1
1
CO, D
2
O exchangeable).; C NMR (DMSO-d
), 56.54 (CH ), 114.10 (phenyl C-2, C-6), 114.55
thiazole C-5), 114.86 (phenyl C-4), 117.02 (coumarin C-7),
20.01 (coumarin C-4a), 120.42 (coumarin C-5), 120.84
coumarin C-3), 125.28 (coumarin C-6), 129.11 (phenyl C-3,
C-5), 139.31 (coumarin C-4), 142.13 (thiazole C-4), 142.44
coumarin C-8a), 146.72 (coumarin C-8), 147.44 (phenyl C-
), 157.80 (thiazole C-2), 158.99 (C=O coumarin), 170.35
6
): δ 46.46
(
(
CO coumarine), 1609 (C=O amide) cm ; H NMR
(
(
CH
2
3
DMSO): δ 1.44 (t, J = 6.8 Hz, 3H, CH
CH ), 4.44 (s, 2H, COCH
2
3
), 4.20 (q, J = 6.8
), 7.35 (m, 3H,
Hz, 2H, CH
2
3
1
coumarin H-5, H-6, H-7), 8.07 (s,1H, thiazole H-5), 8.56 (s,
(
1
H, coumarin H-4), 12.71 (s, 1H, NH, D
2
O exchangeable);
), 64.90 (CH CH ),
15.28 (thiazole C-5), 115.48 (coumarin C-7), 120.08
1
3
C NMR: δ 15.05 (CH
3
), 42.72 (COCH
2
2
3
(
1
1
(
coumarin C-4a), 120.43 (coumarin C-5), 120.76 (coumarin
+.
(
C=O amide); EIMS, M/z: 408.07 (M+1, 4.57), 407.07 (M ,
17 3 4
2.93), 106.07 (100 %).; Anal. Calcd. For C21H N O S
C-3), 125.28 (coumarin C-6), 139.47 (coumarin C-4), 142.27
coumarin C-8a), 142.67 (thiazole C-4), 145.97 (coumarin
1
(
(
407.44): C,61.90; H,4.21; N,10.31. Found: C,62.13; H,4.25;
C-8), 157.68 (thiazole C-2), 159.07 (C=O coumarin), 165.89
N,10.48.
(
(
COCH
M+1, 10.34), 364.05 (M , 54.43), 260.03 (100%); Anal.
S (364.80): C, 52.68; H, 3.59; N,
.68. Found: C, 52.91; H, 3.62; N, 7.83.
2
Cl); EIMS, M/z: 366.04 (M+2, 19.41), 365.06
+.
N-[4-(8-ethoxy-2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-2-
phenylamino-acetamide (4c)
Calcd. For C16
H
13ClN
2
O
4
7
Yield 83%; mp 226-228 °C; IR (KBr) 3388 (2 NH), 2929
(CH aliphatic), 1689 (C=O coumarin), 1605 (C=O amide)
N-[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-2-arylamino-
acetamide derivatives (4a-e)
-
1 1
cm ; H NMR (DMSO-d
.94 (s, 2H, COCH
2
s, 1H, NH-Ph, D O exchangeable); 6.59-6.61 (m, 3H,
6
): δ 1.43 (t, J = 6.4 Hz, 3H, CH
3
);
3
(
2
), 4.21 (q, J = 6.4 Hz, 2H, OCH ); 6.08
2
2
-Chloroacetamide derivative (0.005 mol), potassium
iodide (0.69gm, 0.005 mol) and the respective amine (0.005
mol) in DMF (25 mL) were heated under reflux for 2-6 h
then poured into ice cold water. The formed solid was
collected by filtration, washed with ethanol and crystallized
from absolute ethanol to afford white powder of compounds
phenyl H-2, H-4 & H-6); 7.11 (t, J = 7.2 Hz, 2H, phenyl H-3,
H-5); 7.32-7.37 (m, 3H, coumarin H-5, H-6 & H-7); 8.02 (s,
1
H, thiazole H-5); 8.57 (s, 1H, coumarin H-4); 12.31 (s, 1H,
13
NH-CO, D
CH ), 46.61 (COCH
C-6), 114.86 (thiazole C-5), 115.43 (phenyl C-4), 117.02
coumarin C-7), 120.16 (coumarin C-4a), 120.43 (coumarin
C-5), 120.89 (coumarin C-3), 125.19 (coumarin C-6), 129.42
2
O exchangeable); C NMR (DMSO-d
6
): δ 15.08
(
3
2
), 64.88 (CH CH3), 112.69 (phenyl C-2,
2
4
a-e. Physical and spectral data are listed below:
(
N-[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-2-phenylamino-
acetamide (4a)
(
phenyl C-3, C-5), 139.28 (coumarin C-4), 142.47 (thiazole
Yield 85%; mp 220-222 °C; IR (KBr) 3310, 3141 (2
NH), 3053 (CH aromatic), 2922 (CH aliphatic), 1689 (C=O
C-4, coumarin C-8a), 146.00 (coumarin C-8), 148.45 (phenyl
C-1), 157.87 (thiazole C-2), 159.03 (C=O coumarin), 170.71
-
1
1
+.
coumarin), 1605 (C=O amide) cm ; H NMR (DMSO-d
6
): δ
); 6.08 (t, J = 5.6 Hz, 1H, NH-
O exchangeable); 6.57-6.62 (m, 3H, phenyl H-2, H-4,
(C=O amide); EIMS, M/z: 421.67 (M , 6.98), 40.13 (100
4
.06 (d, J = 5.6 Hz, 2H, CH
2
19 3 4
%); Anal. Calcd. For C22H N O S (421.47): C,62.69;
Ph, D
2
H,4.54; N,9.97. Found: C,62.85; H,4.61; N,10.06.
H-6); 7.10 (t, J = 7.6 Hz, 2H, phenyl H-3 & H-5); 7.40 (t, J =
7
.2 Hz, 1H, coumarin H-6); 7.46 (d, J = 8.4 Hz, 1H,
N-[4-(2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-2-(4-
methylphenyl)amino-acetamide (4d)
coumarin H-8); 7.64 (t, J = 7.2, 1H, coumarin H-7); 7.84 (d,
J = 8.4 Hz, 1H, coumarin H-5); 8.00 (s, 1H, thiazole H-5);
Yield 74%; mp 258-260 °C; IR (KBr) 3438, 3317 (2
NH), 3081 (CH aromatic), 2944 (CH aliphatic), 1692 (C=O
coumarin, C=O amide) cm ; H NMR (DMSO-d
8
.59 (s, 1H, coumarin H-4); 12.29 (s, 1H, NH-CO, D O
2
13
exchangeable); C NMR (DMSO-d
6
): δ 46.61 (CH
2
), 112.70
-1 1
6
): δ 3.94 (s,
(
phenyl C-2, C-6), 114.75 (thiazole C-5), 116.40 (phenyl C-
3
1
H, CH
3
),4.07 (d, J = 6 Hz, 2H, CH
2
); 6.30 (t, J = 5.6 Hz,
4
), 117.08 (coumarin C-8), 119.48 (coumarin C-4a), 120.76
H, NH-Ph, D
2
O exchangeable); 6.61 (m, 2H, phenyl H-2,
(
coumarin C-3), 125.26 (coumarin C-6), 129.32 (coumarin
H-6); 7.11-7.14 (m, 2H, phenyl H-4, H-5); 7.32-7.39 (m, 3H,
coumarin H-5, H-6, H-7); 8.01 (s, 1H, thiazole H-5); 8.56 (s,
H, coumarin H-4); 12.38 (s, 1H, NHCO,
C-5), 129.44 (phenyl C-3, C-5), 132.40 (coumarin C-7),
39.07 (coumarin C-4), 142.51 (thiazole C-4), 148.45 (phenyl
1
1
2
D O
3
-ph),
C-1), 152.98 (coumarin C-8a), 157.82 (thiazole C-2), 159.24
13
exchangeable); C NMR (DMSO-d
46.46 (CH ), 109.88 (phenyl C-6), 114.10 (phenyl C-2),
14.58 (phenyl C-4), 114.87 (thiazole C-5), 117.35
coumarin C-8), 120.02 (coumarin C-4a), 120.44 (phenyl C-
), 120.86 (coumarin C-3), 125.29 (coumarin-6), 129.11
coumarin C-5), 129.18 (coumarin C-7), 139.33 (coumarin
C-4), 142.15 (phenyl C-3), 142.44 (thiazole C-4), 146.73
coumarin C-8a), 147.45 (phenyl C-1), 157.82 (thiazole C-
2), 159.00 (C=O coumarin), 170.36 (C=O amide); EIMS,
6
): δ 22.96 (CH
(
(
C=O coumarin), 170.71 (C=O amide); EIMS, M/z: 378.17
M+1, 1.59), 377.02 (M+ , 8.12), 55.11 (100%); Anal. Calcd.
.
2
1
For C20
H
15
N
3
O
3
S (377.42): C,63.65; H,4.01; N,11.13.
(
Found: C,63.94; H,4.08; N,11.28.
5
(
N-[4-(8-methoxy-2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-2-
phenylamino-acetamide (4b)
(
Yield 79%; mp 313-315 °C; IR (KBr) 3380, 3180 (2
NH), 2938 (CH aliphatic), 1671 (C=O coumarin), 1606
+.
M/z: 391.16 (M , 0.80), 111.05 (100%); Anal. Calcd. For
S (391.44): C,64.43; H,4.38; N,10.73. Found:
C,64.56; H,4.45; N,10.91.
-
1
1
(
C=O amide) cm ; H NMR (DMSO-d
6
): δ 3.94 (s, 3H,
21 17 3 3
C H N O
OCH
3
); 4.06 (d, J = 6.8 Hz, 2H, CH
2
); 6.08 (t, J = 6.8 Hz,

Design, Synthesis, Antioxidant and Anticancer Activity of New Coumarin Derivatives
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 7 779
N-[4-(8-ethoxy-2-Oxo-2H-chromen-3-yl)-thiazol-2-yl]-2-(4-
methylphenyl)amino-acetamide (4e)
CH
3
); 3.21 (s,3H, N-CH
3
2
); 4.21 (q, J = 6.8 Hz, 2H, CH );
6.36 (d, J = 10.8 Hz, 1H, CH-N); 7.13-7.28 (m, 3H,
coumarin H-5, H-6, H-7); 8.02 (d, J = 10.8 Hz, 1H, CO-CH);
Yield 72%; mp 208-210 °C; IR (KBr) 3370, 3219 (2
NH), 2983 (CH aromatic), 2925 (CH aliphatic), 1678 (C=O
+.
8
.58 (s,1H, coumarin H-4); EIMS, M/z: 287.04 (M , 9.50),
-
1
1
97.99 (100%); Anal. Calcd. For C16
H
17NO
4
(287.31): C,
coumarin), 1605 (C=O amide) cm ; H NMR (DMSO-d
6
): δ
); 4.04 (s,
3
); 5.99 (s, 1H,
6
6.89; H, 5.96; N, 4.88. Found: C, 67.04; H, 6.03; N, 4.97.
1
2
.44 (t, J = 6.8 Hz, 3H, CH
2
CH
3
); 2.18 (s, 3H, CH
CH
3
H, COCH ), 4.13 (q, J = 6.8 Hz, 2H, CH
2
2
6
-Bromo-8-methoxy-3-(3-Dimethylaminoacryloyl)-
NH-Ph,, D
2
O exchangeable); 6.39-6.43 (m, 3H, phenyl H-2,
chromen-2-one (5d)
H-4, H-6); 6.98 (t, J = 7.6 Hz, 1H, phenyl H-6); 7.35 (m, 3H,
coumarin H-5, H-6, H-7); 8.01 (s, 1H, thiazole H-5); 8.56 (s,
Orange crystals; yield 73%; mp 219-221 °C; IR (KBr)
3048 (CH aromatic), 2928 (CH aliphatic), 1730 (C=O
1
H, coumarin H-4); 12.27 (s, 1H, NH-CO,
2
D O
1
3
-1 1
exchangeable); C NMR (DMSO-d
1.78 (CH -ph), 46.65 (COCH ), 64.87 (CH
phenyl C-6), 113.49 (phenyl C-2), 114.82 (thiazole C-5),
15.38 (phenyl C-4), 118.09 (coumarin C-7), 120.11
coumarin C-4a), 120.37 (coumarin C-5), 120.80 (coumarin
C-3), 125.22 (coumarin C-6), 129.43 (phenyl C-5), 138.46
phenyl C-3), 139.32 (coumarin C-4), 142.23 (thiazole C-4),
42.45 (coumarin C-8a), 145.96 (coumarin C-8), 148.41
phenyl C-1), 157.82 (thiazole C-2), 159.04 (C=O coumarin),
6
): δ 15.05 (CH
2
CH
3
),
coumarin), 1636 (C=O enaminone) cm ; H NMR (CDCl
3
):
), 3.98 (s,3H,
), 6.29 (d, J = 11.2 Hz, 1H, CH-N), 7.20 (s, 1H,
coumarin H-7), 7.34 (s, IH, coumarin H-5), 7.93 (d, J = 11.2
2
3
2
2
CH3), 109.88
δ 2.99 (s, 3H, N-CH
OCH
3 3
), 3.20 (s, 3H, N-CH
(
3
1
1
3
(
Hz, 1H, COCH), 8.47 (s,1H, coumarin H-4); C NMR
(CDCl ): δ 37.77 (NCH ), 45.47 (NCH ), 56.38 (OCH ),
3
3
3
3
(
1
95.36 (=CH-N), 116.67 (coumarin C-6), 117.67 (coumarin
C-7), 120.67 (coumarin C-3, C-4a), 122.71 (coumarin C-5),
143.40 (coumarin C-8a), 144.53 (coumarin C-4), 147.55
(coumarin C-8), 155.72 (COCH), 158.65 (C=O coumarin),
175.63 (C=O enaminone); EIMS, M/z: 352.99 (M+2, 7.43),
(
1
2
+.
70.79 (C=O amide); EIMS, M/z: 435.14 (M , 18.36),
98.11 (100 %); Anal. Calcd. For C23 S (435.50):
C,63.43; H,4.86; N,9.65. Found: C,64.56; H,4.90; N,9.87.
21 3 4
H N O
+.
351.92 ( M+1, 1.74), 350.97 (M , 6.98), 98.00 (100%).
Anal. Calcd. For C15 (352.15): C, 51.16; H, 4.01;
N, 3.98. Found: C, 51.38; H, 4.09; N, 4.02.
H
14Br NO
4
3
5
-(3-Dimethylamino-acryloyl)-chromen-2-one derivatives
a-d
3
-Isoxazol-5-yl-chromen-2-one derivatives 6a-d
DMFDMA (2.26 gm, 0.02 mol) was added to a hot
solution of 3-acetylchromene-2-one derivatives 1b-e (0.01
mol) in toluene (25 mL) and the reaction mixture was heated
under reflux for 4-12 h. The progress of the reaction was
monitored by TLC. After cooling, the separated solid
product was filtered and crystallized from absolute ethanol to
afford compounds 5a-d. Physical and spectral data are listed
below:
A mixture of of 5a-d derivative (0.01mol) and hydroxyl
amine HCl (1.42 g, 0.01 mol) in absolute ethanol (30 mL)
was heated under reflux for 4 h. The formed solid was
collected by filtration and crystallized from absolute ethanol
to give compounds 6a-d. Physical and spectral data are listed
below:
3
-Isoxazol-5-yl-8-methoxy-chromen-2-one (6a)
8
-Methoxy-3-(3-Dimethylaminoacryloyl)-chromen-2-one
White crystals; yield 85%; mp 217-219 °C; IR (KBr)
039 (CH aromatic), 2930 (CH aliphatic), 1721 (C=O
(
5a)
3
-
1
1
Orange crystals; yield 65%; mp 170-172 °C; IR (KBr)
128 (CH aromatic), 2938 (CH aliphatic), 1718 (C=O
coumarine) cm ; H NMR (DMSO): δ 3.94 (s,3H, OCH
3
);
3
7.08 (S, 1H, isoxazole H-4); 7.30-7.40 (m, 2H, coumarin H-
6, H-7); 7.48 (d, J = 6.8 Hz, IH, Coumarin H-5); 8.73 (s, 2H,
-
1 1
coumarin), 1641 (C=O enaminone) cm ; H NMR (CDCl
δ 2.99 (s, 3H, N-CH ), 3.19 (s, 3H, N-CH ), 3.99 (s, 3H,
OCH ), 6.33 (d, J = 12 Hz, 1H, CH-N), 7.12-7.28 (m, 3H,
coumarin H-5, H-6, H-7), 7.93 (d, J = 12 Hz, 1H, CO-CH),
3
):
1
3
coumarin H-4, isoxazole H-3); C NMR (DMSO): δ 56.63
3
3
3
(OCH ), 104.76 (isoxazole C-4), 114.76 (coumarin C-4a),
3
115.89 (coumarin C-7), 119.45 (coumarin C-3), 121.21
(coumarin C-5), 125.45 (coumarin C-6), 141.44 (coumarin
C-4), 142.98 (isoxazole C-3), 146.78 (coumarin C-8a),
152.38 (isoxazole C-5), 157.24 (coumarin C-8), 162.53
(C=O); EIMS, M/z: 244.07 (M+1, 15.64), 243.03 (M , 100);
Anal. Calcd. For C13 NO (243.21): C, 64.20; H, 3.73; N,
5.76. Found: C, 64.43; H, 3.75; N, 5.84.
1
3
8
.58 (s,1H, coumarin H-4). C NMR (CDCl
NCH ), 45.37 (NCH ), 56.38 (OCH ), 95.36 (=CH-N),
14.64 (coumarin C-7), 119.71 (coumarin C-4a), 120.55
3
): δ 37.72
(
3
3
3
1
+.
(
coumarin C-5), 124.35 (coumarin C-6), 126.59 (coumarin
C-3), 144.35 (coumarin C-8a), 145.96 (coumarin C-4), 146.87
H
9
4
(
coumarin C-8), 155.48 (COCH), 159.28 (C=O coumarin),
+.
1
9
6
75.63 (C=O enaminone); EIMS, M/z: 273.10 (M , 39.26),
8
-Ethoxy-3-isoxazol-5-yl-chromen-2-one (6b)
4
7.99 (100%); Anal. Calcd. For C15H15NO (273.28): C,
5.92; H, 5.53; N, 5.13. Found: C, 66.17; H, 5.65; N, 5.26.
White crystals; yield 80%; mp 152-154 °C; IR (KBr)
041 (CH aromatic), 2924 (CH aliphatic), 1743 (C=O
3
8
-Ethoxy-3-(3-Dimethylaminoacryloyl)-chromen-2-one
-1
1
coumarine) cm ; H NMR (DMSO): δ 1.42 (t, J = 6.8 Hz,
(
5b)
3
H, CH
3
2
); 4.19 (q, J = 6.8 Hz, 2H, CH ); 7.07 (s, 1H,
Orange crystals; yield 55%; mp 160-162 °C; IR (KBr)
046 (CH aromatic), 2921 (CH aliphatic), 1723 (C=O
coumarin), 1641 (C=O enaminone), 1604 (C=C), 1267 (O-
isoxazole H-4); 7.31-7.38 (m, 2H, coumarin H-6, H-7); 7.46
3
(d, J = 7.2 Hz, IH, coumarin H-5); 8.72 (s, 2H, coumarin H-
1
3
3
4, isoxazole H-3); C NMR (DMSO): δ 15.04 (CH ), 64.95
-
1
1
CH
2
ether linkage), 1105 (C-N bond) cm ; H NMR
): δ 1.52 (t, J = 6.8 Hz, 3H, CH CH ); 3.00 (s,3H, N-
(CH
2
), 104.74 (isoxazole C-4), 114.68 (coumarin C-4a),
(
CDCl
3
2
3
116.71 (coumarin C-7), 119.53 (coumarin C-3), 121.15

7
80 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 7
Abdellatif et al.
(
coumarin C-5), 125.43 (coumarin C-6), 141.47 (coumarin
C-4), 143.05 (isoxazole C-3), 146.02 (coumarin C-8a),
52.35 (isoxazole C-5), 157.29 (coumarin C-8), 162.54
(coumarin C-5), 124.01 (phenyl C-2, C-6), 125.32 (coumarin
C-6), 127.94 (phenyl C-4), 129.65 (phenyl C-3, C-5), 136.69
(pyrazole C-5), 140.49 (phenyl C-1), 140.68 (pyrazole C-3),
143.07 (coumarin C-8a), 144.60 (coumarin C-4), 146.79
1
+.
(
C=O); EIMS, M/z: 258.04 (M+1, 9.49), 257.01 (M ,
7.94), 255.95 (M-1, 0.77) 145.99 (100%); Anal. Calcd. For
+.
5
(coumarin C-8), 156.15 (C=O); EIMS, M/z: 318.28 (M ,
14 2 3
10.81), 76.99 (100%); Anal. Calcd. For C19H N O
C
14
H
11NO
4
(318.33): C, 65.37; H, 4.31; N, 5.44. Found: C,
6
5.64; H, 4.37; N, 5.62.
(318.33): C, 71.69; H, 4.43; N, 8.80. Found: C, 71.87; H,
4
.47; N, 8.94.
6
-Bromo-3-isoxazol-5-yl-chromen-2-one (6c)
8
-Ethoxy-3-(1-Phenyl-1H-pyrazol-5-yl)-chromen-2-one
White crystals; yield 82%; mp 189-191 °C; IR (KBr)
-
1
1
(7b)
3
057 (CH aromatic), 1733 (C=O coumarine) cm ; H NMR
(
DMSO): δ 7.01 (s, 1H, isoxazole H-4), 7.47 (d, J = 8.8 Hz,
Buff crystals; yield 65%; mp 160-162 °C; IR (KBr) 3036
(CH aromatic), 2931 (CH aliphatic), 1721 (C=O coumarine)
1
8
H, coumarin H-8), 7.86 (d, J = 8.8 Hz, 1H, coumarin H-7),
-
1 1
.20 (s, IH, coumarin H-5), 8.73 (s,1H, coumarin H-4), 8.76
cm ; H NMR (DMSO): δ 1.390 (t, J = 6.8 Hz, 3H, CH
4.17 (q, J = 6.8 Hz, 2H, CH ), 6.76 (s, 1H, pyrazole H-4),
7.23-7.43 (m, 8H, Ar-H), 7.81 (s, 1H, pyrazole H-3), 8.17 (s,
3
),
1
3
(
(
s, 1H, isoxazole H-3); C NMR (DMSO): δ 105.19
2
isoxazole C-4), 115.65 (coumarin C-6), 117.02 (coumarin
1
3
C-4a), 119.01 (coumarin C-8), 120.85 (coumarin C-3),
1H, comarine H-4); C NMR (DMSO): δ 14.98 (CH
64.85 (CH ), 110.74 (pyrazole C-4), 115.97 (coumarin C-7),
3
),
1
31.99 (coumarin C-5), 135.97 (coumarin C-7), 139.78
coumarin C-4), 152.47 (isoxazole C5), 152.74 (isoxaxole C-
), 157.21 (coumarin C-8a), 162.25 (C=O coumarin); EIMS,
M/z: 292.92 (M+2, 98.30), 291.95 (M+1, 16.06), 290.91
2
(
118.77 (coumarin C-4a), 119.65 (coumarin C-3), 120.41
(coumarin C-5), 123.96 (phenyl C-2, C-6), 125.63 (coumarin
C-6), 127.97 (phenyl C-4), 129.67 (phenyl C-3, C-5), 136.72
(pyrazole C-5), 140.50 (phenyl C-1), 140.68 (pyrazole C-3),
143.09 (coumarin C-8a), 144.79 (coumarin C-4), 146.02
3
+
.
(
M , 100.00); Anal. Calcd. For C12
H
6
BrNO
3
(292.08): C,
4
9.34; H, 2.07; N, 4.80. Found: C, 49.51; H, 2.04; N, 4.91.
+
.
(
coumarin C-8), 158.15 (C=O); EIMS, M/z: 332.11 (M ,
6
-Bromo-3-isoxazol-5-yl-8-methoxy-chromen-2-one (6d)
6.07), 83.17 (100%); Anal. Calcd. For C H N O (332.35):
C, 72.28; H, 4.85; N, 8.43. Found: C, 72.39; H, 4.89; N,
2
0
16
2
3
White crystals; yield 86%; mp 219-221 °C; IR (KBr)
081 (CH aromatic), 2947 (CH aliphatic), 1731 (C=O
8
.57.
3
-
1
1
coumarine) cm ; H NMR (DMSO): δ 3.96 (s, 3H, CH
3
);
6
-Bromo-3-(1-Phenyl-1H-pyrazol-5-yl)-chromen-2-one
7
.10 (d, J = 1.6 Hz, 1H, isoxazole H-4); 7.55 (s, 1H,
(
7c)
coumarin H-7); 7.74 (s, IH, coumarin H-5); 8.69 (s,1H,
1
3
coumarin H-4); 8.75 (d, J = 1.6 Hz, 1H, isoxazole H-3);
NMR (DMSO): δ 57.20 (OCH ), 105.20 (isoxazole C-4),
15.82 (coumarin C-6), 116.89 (coumarin C-4a), 118.37
coumarin C-7), 120.74 (coumarin C-3), 122.97 (coumarin
C-5), 140.05 (coumarin C-4), 142.36 (isoxazole C-3), 147.70
coumarin C-8a), 152.46 (isoxazole C-5), 156.79 (coumarin
C-8), 162.20 (C=O); EIMS, M/z: 322.94 (M+2, 93.58),
C
Brown crystals; yield 68%; mp 168-170 °C; IR (KBr)
-1 1
3090 (CH aromatic), 1729 (C=O) cm ; H NMR (DMSO): δ
.76 (d, J = 1.6 Hz, 1H, pyrazole H-4), 7.35 (m, 1H,
coumarin H-8), 7.32-7.43 (m, 5H, phenyl-H), 7.80 (d, J =
.4 Hz, 1H, coumarin H-7), 7.82 (d, J = 1.6 Hz, 1H, pyrazole
H-3), 7.98 (d, J = 2.4 Hz, 1H, coumarin H-5), 8.14 (s, 1H,
3
6
1
(
2
(
1
3
comarin H-4); C NMR (DMSO): δ 110.93 (pyrazole C-4),
16.85 (coumarin C-6), 118.98 (coumarin C-8), 119.73
+.
1
3
21.95 (M+1, 16.17), 320.93 (M , 100); Anal. Calcd. For
(
coumarin C-4a), 120.97 (coumarin C-3), 123.96 (phenyl C-
C
13
H
8
BrN O
4
(322.11): C, 48.47; H, 2.50; N, 4.35. Found: C,
2
1
, C-6), 127.98 (phenyl C-4), 129.70 (phenyl C-3, C-5),
31.35 (coumarin C-5), 135.30 (coumarin C-7), 136.36
4
8.62; H, 2.53; N, 4.38.
(
pyrazole C-5), 140.56 (phenyl C-1), 140.56 (pyrazole C-3),
3
7
-(1-Phenyl-1H-pyrazol-5-yl)-chromen-2-one derivatives
a-d
1
43.12 (coumarin C-4),152.83 (coumarin C-8a), 157.99
C=O); EIMS, M/z: 368.37 (M+2, 5.68), 367.57 (M+1,
0.95), 178.07 (100%); Anal. Calcd. For C18
367.20): C, 58.88; H, 3.02; N, 7.63. Found: C, 59.12; H,
.98; N, 7.78.
(
A mixture of compounds 5a-d derivatives (0.01 mol) and
2
2 2
H11BrN O
phenyl hydrazine HCl (1.42 g, 0.01 mol) in absolute ethanol
(
(
30 mL) was heated under reflux for 8 h. The solvent was
2
evaporated and the formed solid was collected and
crystallized from absolute ethanol to give compounds 7a-d.
Physical and spectral data are listed below:
6-Bromo-8-methoxy-3-(1-Phenyl-1H-pyrazol-5-yl)-
chromen-2-one (7d)
White crystals; yield 70%; mp 189-191 °C; IR (KBr)
8
-Methoxy-3-(1-Phenyl-1H-pyrazol-5-yl)-chromen-2-one
-
1
3
050 (CH aromatic), 2936 (CH aliphatic), 1734 (C=O) cm ;
(
7a)
1
H NMR (DMSO): δ 3.92 (s, 3H, CH ), 6.76 (d, J = 1.6 Hz,
3
Buff crystals; yield 73%; mp 129-131 °C; IR (KBr) 3061
1H, pyrazole H-4), 7.32-7.38 (m, 1H, phenyl H-4), 7.40-7.43
(m, 4H, phenyl H-3, H-5, coumarin H-5, H-7), 7.50-7.52 (m,
2H, phenyl H-2, H-6), 7.82 (d, J = 1.6 Hz, 1H, pyrazole H-
-
1
1
(
CH aromatic), 2935 (CH aliphatic), 1723 (C=O) cm ; H
), 6.76 (s, 1H, pyrazole
NMR (DMSO): δ 3.90 (s, 3H, OCH
3
1
3
H-4), 7.24-7.43 (m, 8H, Ar-H), 7.81 (s, 1H, pyrazole H-3),
8
(
3), 8.11 (s, 1H, coumarin H-4); C NMR (DMSO): δ 57.15
1
3
.15 (s, 1H, comarin H-4); C NMR (DMSO): δ 56.57
), 110.74 (pyrazole C-4), 115.21 (coumarin C-7),
18.85 (coumarin C-4a), 119.58 (coumarin C-3), 120.47
(CH ), 110.91 (pyrazole C-4), 116.76 (coumarin C-6),
3
CH
3
117.80 (coumarin C-7), 119.94 (coumarin C-4a), 120.86
(coumarin C-3), 122.35 (coumarin C-5), 123.95 (phenyl C-2,
1

Design, Synthesis, Antioxidant and Anticancer Activity of New Coumarin Derivatives
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 7 781
C-6), 127.97 (phenyl C-4), 129.69 (phenyl C-3, C-5), 136.32
pyrazole C-5), 140.55 (phenyl C-1), 140.57 (pyrazole C-3),
42.44 (coumarin C-8a), 143.39 (coumarin C-4), 147.72
coumarin C-8), 157.68 (C=O); EIMS, M/z: 397.99 (M+2,
[9]
Osman, H.; Arshad, A.; Lam, C.K.; Bagley, M.C. Microwave-
assisted synthesis and antioxidant properties of hydrazinyl thiazolyl
coumarin derivatives. Chem. Cent. J., 2012, 6, 1-10.
Indulatha, V.N.; Gopal, N.; Jayakar, B. Anticonvulsant activity of
some novel N-(4’oxo-2’-(aryl/ heteryl substituted) thiazolidin-3’-
yl)-3-carboxamido-2H-chromen-2-ones. Res. J. Pharm. Biol.
Chem. Sci., 2012, 3(1), 315-322.
(
1
[
[
[
[
10]
(
1
+.
1.40), 396.00 (M , 13.42), 76.97 (100%); Anal. Calcd. For
(397.22): C, 57.45; H, 3.30; N, 7.05. Found:
C
19
H
13BrN
2
O
3
11]
12]
13]
Abdelhafez, O.M.; Amin, K.M.; Batran, R.Z.; Maher, T.J.; Nada,
S.A.; Sethumadhavan, S. Synthesis, anticoagulant and PIVKA-II
induced by new 4-hydroxycoumarin derivatives. Bioorg. Med.
Chem., 2010, 18(10), 3371-3378.
C, 57.64; H, 3.34; N, 7.17.
4
.2. Measurement of Potential Antioxidant Activity using
Cacic, M.; Trkovnik M.; Cacic, F.; Has-Schon, E., Synthesis and
antimicrobial activity of some derivatives of (7- Hydroxy-2-oxo-
2H-chromen-4-yl)-acetic acid hydrazide. Molecules, 2006, 11, 134-
DPPH Free Radical Scavenging Method
The ability of the test compounds listed in Table 1 to
scavenge DPPH free radical was determined by measuring
the absorbance at 517 nm using the UV-VIS spectro-
photometer according to the previously reported method
1
47.
Cardoso, S.H.; Barreto, M.B.; Lourenço, M.C.S.; Graças, M. D.;
Henriques, M.O.; Candéa, A.L.P.; Kaiser, C.R.; De Souza, M.V.N.
Antitubercular activity of new coumarins. Chem. Biol. Drug Des.,
2011, 77, 489-493.
[
26].
[
14]
15]
Amit, C.; Sheelmani; Singh, A.; Payal, C.; Dhawan, R.K.
Chemistry of anticancer thiazole compounds. Adv. J. Pharm. Life
Sci. Res., 2014, 2(1), 1-7.
Jaishree, V.; Ramdas, N.; Sachin, J.; Ramesh, B. In vitro
antioxidant properties of new thiazole derivatives. J. Saudi Chem.
Soc., 2012, 16(4), 371-376.
4
.3. In Vitro Anticancer Activity
[
The test compounds and the reference drug cisplatin
were evaluated as anticancer agents against Hep-G2
hepatic cancer and MCF-7 breast cancer cell lines using
Sulforhodamine-B (SRB) stain assay method as reported
previously [27].
[16]
Kalirajan, R.; Rafick, M.H.M.; Sankar, S.; Jubie, S. Docking
studies, synthesis, characterization and evaluation of their
antioxidant and cytotoxic activities of some novel isoxazole-
substituted 9-anilinoacridine derivatives. Sci. World J., 2012, 2012,
1
-6.
[
17]
18]
Patil, S.L.; Bhalgat, C.M.; Burli, S.; Chithale, S.K. Synthesis,
antibacterial and antioxidant properties of newer 3-(1-benzofuran-
2-yl)-5-substituted aryl-1, 2-oxazole. Int. J. Chem. Sci. Appl., 2010,
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
1
(1), 42-49.
[
Nitulescu, G.M.; Draghici, C.; Olaru, O.T. New potential antitumor
pyrazole derivatives: Synthesis and cytotoxic evaluation: Int. J.
Mol. Sci., 2013, 14(11), 21805-21818.
ACKNOWLEDGEMENTS
[
19]
20]
Kaur, A.; Arora, R.; Gill, N.S. Pyrazole as an anticancer agent. Int.
J. Nat. Prod. Sci., 2012, 1, 247.
Declared none.
[
Abdellatif, K.R.A.; Belal, A.; Omar, H.A. Design, synthesis and
biological evaluation of novel triaryl (Z)-olefins as tamoxifen
analogues. Bioorg. Med. Chem. Lett., 2013, 23, 4960-4963.
Abdellatif, K.R.A.; Abdelall, E.K.A.; Abdelgawad, M.A.; Ahmed,
R.R.; Bakr, R.B. Synthesis and Anticancer Activity of Some New
Pyrazolo[3,4-d]pyrimidin-4-one Derivatives. Molecules, 2014, 19,
REFERENCES
[21]
[22]
[23]
[24]
[25]
[
1]
Sena, L.A.; Chandel, N.S. Physiological roles of mitochondrial
reactive oxygen species. Mol. Cell, 2012, 48(2), 158-167.
[
2]
De Zwart, L.L.; Meerman, J.H.; Commandeur, J.N.; Vermeulen,
N.P. Biomarkers of free radical damage application in experimental
animals and in humans. Free Radic. Biol. Med., 1999, 26(1-2),
3
297-3309.
Gouda, A.M.; Abdelazeem, A.H.; Arafa, E.A.; Abdellatif, K.R.A.
Design, synthesis and pharmacological evaluation of novel
pyrrolizine derivatives as potential anticancer agents. Bioorg.
Chem., 2014, 53, 1-7
2
02-226.
[
3]
Thakor, T.; Savjani, J. Synthesis and cell line study of pyrazole
substituted coumarin derivatives. Int. J. Pharm. Tech Res., 2014,
Secci, D.; Carradori, S.; Bolasco, A.; Chimenti, P.; Yáñez, M.;
Ortuso, F.; Alcaro, S. Synthesis and selective human monoamine
oxidase inhibition of 3-carbonyl, 3-acyl, and 3-carboxyhydrazido
coumarin derivatives. Eur. J. Med. Chem., 2011, 46(10), 4846-4852.
Rajasekaran, S.; Rao, G.K.; Nu, S.P.P.; Ranjan, A. Design,
synthesis, antibacterial and in vitro antioxidant activity of
substituted 2H- benzopyran-2-one derivatives. Int. J. Chem. Tech.
Res., 2011, 3(2), 555-559.
6
(4), 1397-1406.
[
[
[
[
4]
5]
6]
7]
Hotta, K.; Ueoka, H. New cytotoxic agents: A review of the
literature. Crit. Rev. Oncol. Hematol., 2005, 55, 45-65.
Sardas, S. The role of antioxidants in cancer prevention and
treatment. Indoor Built Environ., 2003, 12, 401-404.
Fuchs-Tarlevesky, V.ꢀ Role of antioxidants in cancer therapy.
Nutrition, 2013, 29, 15-21.
Amin, K.M.; Abou-Seri, S.M.; Awadallah, F.M.; Eissa, A.A.M.M.;
Hassan, G.S.; Abdulla, M.M. Synthesis and anticancer activity of
some 8-substituted-7-methoxy-2H-chromen-2-one derivatives
toward hepatocellular carcinoma HepG2 cells. Eur. J. Med. Chem.,
Veerabhadraiah, U.; Rao, V.R. and Rao, T.V.P. Reaction of
mercaptoacetic acid and chloroacetyl chloride with benzalamino
thiazolylcoumarins. Collect. Czech. Chem. Commun., 1990, 55,
5
35-539.
2
015, 90, 221-231.
[
[
26]
27]
Anthony, K.P.; Saleh, M.A. Free radical scavenging and
[
8]
Khode, S.; Maddi, V.; Aragade, P.; Palkar, M.; Ronad, P.K.;
Mamledesai, S.; Thippeswamy, A.H.M.; Satyanarayana, D.
Synthesis and pharmacological evaluation of a novel series of 5-
antioxidant activities of silymarin components. Antioxidants, 2013,
2
(4), 398-407.
Fu, L.; Feng, X.; Wang, J.; Xun, Z.; Hu, J.; Zhang, J.-J.; Zhao, Y.;
Huang, Z.; Shi, D. Efficient synthesis and evaluation of antitumor
activities of novel functionalized 1,8-naphthyridine derivatives.
Am. Chem. Soc., 2014, 5, 1-18.
(
substituted)aryl-3- (3-coumarinyl) -1-phenyl-2-pyrazolines as
novel anti-inflammatory and analgesic agents. Eur. J. Med. Chem.,
009, 44(4), 1682-1688.
2