Synthesis and antioxidant evaluation of some new 3-substituted coumarins

Article abstract of DOI:10.1002/ardp.201000263

3-Acetylcoumarin (1) was utilized as a key intermediate for the synthesis of 2-aminothiazole derivative 3 via bromination of 1 to afford acetylbromide 2 followed by treatment with thiourea or via Biginelli reaction of 1. Treatment of 3 with 5-chloro-3-met

Full text of DOI:10.1002/ardp.201000263

710
Arch. Pharm. Chem. Life Sci. 2011, 344, 710–718
Full Paper
Synthesis and Antioxidant Evaluation of Some New
3-Substituted Coumarins
Wafaa S. Hamama, Moged A. Berghot, Eman A. Baz, and Moustafa A. Gouda
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
3-Acetylcoumarin (1) was utilized as a key intermediate for the synthesis of 2-aminothiazole derivative
3 via bromination of 1 to afford acetylbromide 2 followed by treatment with thiourea or via
Biginelli reaction of 1. Treatment of 3 with 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde,
2-methyl-4H-benzo[d][1,3]oxazin-4-one, furo[3,4-b]pyrazine-5,7-dione or 2-methyl-5,6,7,8-tetrahydro-4H-
benzothieno[2,3-d][1,3]oxazin-4-one afforded diazine derivatives 4–7. Also, pyridopyrimidine 8 was
obtained via a one pot reaction of 6-aminothiouracil, p-chlorobenzaldehyde and 3-acetylcoumarin.
Moreover, refluxing of 6-aminothiouracil with one equivalent amount of 2 afforded the
thiazolopyrimidine 9, while the pyrrolothiazolopyrimidine 10 was revealed when two equivalent
amounts of 2 was used. Furthermore, treatment of enamine 11 with 2-aminobenzothiazole or
6-aminothiouracil afforded the pyrimidine derivatives 12 and 13, respectively. Transamination of
enamine 11 with m-anisidine followed by cyclization of the resulting enaminone 14 gave the desired
quinoline 15. Also, treatment of 11 with thiophenol in dioxane gave the mercapto derivative 16.
Moreover, coupling of 11 with 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl-diazonium chloride,
followed by complete cyclization of the resulting product afforded the pyridopyrazolothiazine 19
via the intermediate 18. Furthermore, the pyrazolopyrimidine 20 was revealed via a one pot
condensation of 11, 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one and ammonium acetate. The thiadiazine
derivatives 21–23 were obtained via treatment of 2 with the corresponding o-aminothiols.
Desulphonation of 23 afforded the pyrazolotriazine 24. Finally, reaction of
2
with
2-hydroxybenzaldehyde gave benzofuran derivative 25. Representative compounds of the
synthesized products were evaluated as antioxidant agents.
Keywords: Antioxidant activity / Coumarin / Pyridopyrimidine / Thiadiazine / Thienopyrimidine
Received: September 10, 2010; Revised: October 25, 2010; Accepted: October 29, 2011
DOI 10.1002/ardp.201000263
Introduction
pounds inhibited cell proliferation of a gastric carcinoma cell
line, a colon-carcinoma cell line, a hepatoma-derived cell line
and a lymphoblastic cell line [7]. In view of the above men-
tioned findings and as continuation of our effort [8, 9], to
identify new candidates that may be valuable designing new,
potent, selective and less toxic antioxidant agents, we report
in the present work the synthesis of some new 3-substituted
coumarin starting from 3-acetyl-2H-chromen-2-one (1) [10].
Coumarin derivatives constitute an important class of
heterocyclic compounds with anticoagulant (e.g., warfarin,
acenocoumarol) [1, 2], anticoagulant rodenticide (e.g.,
brodifacoum, bromadiolone) [3], insecticide (e.g., coumaphos)
[4], antibacterial (e.g., novobiocin, clorobiocin) [5, 6], and
pharmacological properties. The cytotoxic activities of the
coumarin and its known metabolite 7-hydroxycoumarin
were tested in several human tumor cell lines. Both com-
Results and discussion
Chemistry
Correspondence: Moustafa A. Gouda, Faculty of Science, Mansoura
University, Mansoura, 35516, Egypt.
E-mail: dr_mostafa_chem@yahoo.com
Fax: þ2050 2246781
The synthetic procedure adopted to obtain the target com-
pounds are depicted in Schemes 1–6. The starting compound
3-(2-bromoacetyl)-2H-chromen-2-one (2) [11] was prepared
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Arch. Pharm. Chem. Life Sci. 2011, 344, 710–718
Bioactive 3-substituted coumarin derivatives
711
CHO
Cl
O
O
H3C
Br
Br2/ CHCl3
S
N
N
N
N
O
2
Ph
OH
O
O
O
4
N
S
C
CH3
Ph
CH3
O
N
H2N
NH2
/ TEA
O
1
O
O
S
S
S
C
NH2
O
N
N
I2/
H2N
NH2
N
H3C
N
H3C
N
O
3
O
O
5
O
O
O
Scheme 1. Synthesis of 2-amino-4-(3-coumarinyl)thiazole (3).
O
N
N
3
N
S
N
O
N
N
O
according to the reported method via bromination of 3-acetyl-
2H-chromen-2-one (1) [10]. Reaction of 2 with thiourea in
refluxing ethanol gave the corresponding 2-amino-4-(3-cou-
marinyl)thiazole (3) [12] (see Scheme 1).
O
O
6
O
O
N
In another route, compound 3 was obtained in a good yield
via Biginelli reaction of 3-acetylcoumarin with thiourea and
iodine. It is evident from the literature that quinazolines
and condensed quinazolines exhibited potent central ner-
vous system (CNS) activities, e.g. analgesic, anti-inflammatory
[13], also, azolopyrimido-quinolines, pyrimidoquinazolines
exhibited good antioxidant, anti-inflammatory and analgesic
activities [14]. Furthermore, thienopyrimidines (bioisostere
of quinazoline and condensed quinazoline) possess potent
CNS and antibacterial activities [15, 16].
S
N
O
N
S
H3C
N
S
H3C
O
7
O
Scheme 2. Synthesis of diazine derivatives 4–7.
Thus, compound 3 was condensed with 5-chloro-3-methyl-
1-phenyl-1H-pyrazole-4-carbaldehyde [17] in dimethylform-
amide catalyzed by triethylamine to give thiazolopyrimidine
derivative 4 (bioisostere of quinazoline). Furthermore, com-
pound 3 reacted with 2-methyl-4H-benzo[d][1,3]oxazin-4-one
[18], furo[3,4-b]pyrazine-5,7-dione or 2-methyl-5,6,7,8-tetrahy-
dro-4H-benzothieno[2,3-d][1,3]oxazin-4-one [19] to give the
quinazoline 5, pyrrolopyrazine 6 (bioisostere of quinazoline),
and thienopyrimidine 7 (bioisostere of quinazoline) deriva-
tives, respectively (see Scheme 2).
Cl
N
OH
1,
CHO
Cl
N
DMF/ TEA
HS
Ar
N
8
Ar
O
O
Also, pyridopyrimidine 8 was obtained via a one pot reac-
tion of 6-aminothiouracil, p-chlorobenzaldehyde, and 3-
acetyl coumarin in dimethylformamide catalyzed by
triethylamine. Moreover, the reaction of 6-aminothiouracil
with one equivalent amount of 2 in dimethylformamide
catalyzed by triethylamine afforded the thiazolopyrimidine
9 (bioisostere of quinazoline), while the pyrrolothiazolo-pyr-
imidine 10 was afforded when two equivalent amounts of 2
were used. The latter was obtained in another route via the
reaction of 9 with another one equivalent amount of 2
in dimethylformamide catalyzed by triethylamine (see
Scheme 3).
2, 1 mol
HN
N
DMF/ TEA
S
S
N
H
NH2
N
9
NH2
2, 1 mol
DMF/ TEA
O
Ar
2, 2 mol
N
Ar
DMF/ TEA
S
N
H
N
10
Ar=
O
O
Furthermore, treatment of enamine 11 [20] (obtained
through refluxing of 1 with dimethylformamide-dimethyl-
Scheme 3. Synthesis of pyrimidine derivatives.
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W. S. Hamama et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 710–718
acetal (DMF-DMA) in dioxane) with 2-aminobenzothiazole in
dioxane and acetic acid mixture or 6-aminothiouracil in
dimethylformamide catalyzed by triethylamine afforded
the desired thiazolopyrimidine 12 and pyridopyrimidine
13 (bioisostere of quinazoline), respectively. Transami-
nation of enamine 11 with m-anisidine, followed by cycliza-
tion of the resulting enaminone 14 under acidic condition
gave the desired quinoline 15. Also, treatment of 11 with
thiophenol in dioxane gave the mercapto derivative 16.
Attempting for the preparation of thiane 17 through
cyclization of 16 under influence of conc. H2SO4 failed (see
Scheme 4).
Moreover, coupling of 11 with 4,6-dimethyl-1H-pyrazolo[3,4-
b]pyridin-3-yl-diazonium chloride [21] in pyridine, followed
by complete cyclization of the resulting product afforded the
pyridopyrazolothiazine 19 via the intermediate 18.
Furthermore, the pyrazolopyrimidine 20 was revealed via a
one pot condensation of 11, 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one [22] and ammonium acetate (see Scheme 5).
The thiadiazines 21–23 were obtained via treatment of 2
with 4-amino-5-phenyl-4H-1,2,4-triazolo-3-thiol [23], 4-(pyri-
din-2-yl)thiosemicarbazide [24] or 4-amino-6-benzyl-3-mer-
capto-1,2,4-triazin-5(4H)-one [25] in dimethylformamide
catalyzed by triethylamine. Desulphonation of 23 under
N
N
S
HO
NH2
N
S
O
O
O
O
Dioxane/ AcOH
O
CH3
12
O
1
HN
OH
DMF-DMA
Dioxane
S
N
H
NH2
N
DMF/ TEA
NH2
HS
N
13
N
Ar
O
CH3
OCH3
N
O
CH3
O
O
NH
11
PCl5
N
S
OCH3
Dioxane
O
14
O
Dioxane
OCH3
O
15
O
SH
O
O
Ar=
S
O
O
OH
O
Dioxane
O
16
O
17
Scheme 4. Synthesis of thiazolopyrimidine 12, pyridopyrimidine 13, quinoline 15, and mercapto 16 derivatives.
O
CH3
N
N2Cl
N
CHO
Ar
CH3
O
O
N
HN
CH3
N
N
N
H3C
N
H
N
N
Pyridine
O
19
N
N
H
H3C
N
18
CH3
11
H3C
O
CH3
N
N
Ph
Ar=
N
Amm. acetate
Ar
N
O
O
Ph
20
Scheme 5. Synthesis of pyrazolopyridine derivatives 19 and 20.
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Arch. Pharm. Chem. Life Sci. 2011, 344, 710–718
Bioactive 3-substituted coumarin derivatives
713
Table 1. ABTS Antioxidant activity assay.
the influence of acetic anhydride gave the pyrazolotriazine
24. The biological activities of benzofuran ring system [26]
promoted us to synthesize the benzofuran incorporated
coumarin moiety. Thus, compound 2 was reacted with
2-hydroxybenzaldehyde in dimethylformamide in the
presence of potassium carbonate to afford benzofuran
derivative 25 (see Scheme 6).
Compound No.
Compound No.
%Inhibition
Absorbance of samples
Control of ABTS
Ascorbic acid
7-Hydroxycoumarin
1
2
3
4
5
6
7
0.498
0.057
0.153
0.180
0.248
0.128
0.163
0.260
0.352
0.328
0.089
0.100
0.224
0.331
0.298
0.082
0.169
0.327
0.332
0.276
0.200
0.068
0.123
0.129
0.322
0.225
0.0
88.55
68.58
63.58
50.20
74.29
67.26
47.79
29.31
34.13
82.12
79.91
55.02
33.53
40.16
83.53
66.06
34.33
33.33
46.38
59.83
86.34
75.30
61.44
35.34
54.81
Assignment of the new synthesized compounds was based
on elemental analyses, IR, 1H-NMR, mass spectral data (C.f.
Exp. Part).
Biological activity
ABTS Antioxidant assay
8
9
The antioxidant activity of the synthesized compounds was
evaluated by the ABTS antioxidant activity method described
by Lissi et al. [27]. Some of the 3-substituted coumarin deriva-
tives exhibited an antioxidant effect as shown in Table 1.
Compared with the control (L-ascorbic acid), the antioxidant
potency of compounds 8, 13, and 21 was found to be highest,
while compounds 1, 2, 3, 4, 9, 10, 14, 22, 23, and 25 showed a
moderate antioxidant activity and the rest tested compounds
showed a weak activity. On the other hand, compounds 7-
hydroxycoumarin, 3, 4, 8, 9, 13, 14, 21, and 22 exhibited a
high antioxidant activity compared to the starting material
1. From the structure–activity relationship (SAR) point of
view, the presence of thienopyrimidine, pyridopyrimidine,
enaminone, triazole or thiadiazine moieties at the 3-position
10
11
12
13
14
15
16
19
20
21
22
23
24
25
N
N
SH
N N
N
Ph
Ph
Ar
N
N
S
NH2
S
N
Ar
21
NH2
HN
N
H
N
N
O
S
N
N
H
O
22
2
NH2
SH
Ph
N
O
N
N
S
Ar
N
N
Ac2O
N
Ph
Ph
N
Ar
N
N
N
Dioxane/TEA
N
23
O
CH3
OH
O
24
CHO
Scheme 6. Synthesis of thiadiazole 21–23,
pyrazolotriazine 24, and benzofuran 25
derivatives.
DMF/ K2CO3
O
O
25
O
Ar=
O
O
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W. S. Hamama et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 710–718
of the coumarin enhanced the antioxidant activity, also, the
presence of thiolopyrimidine group increases the antioxi-
dant activity as in the case of compounds 8 and 1 (Table 1).
The compounds 7-hydroxycoumarin, 1, 3, 4, 8, 9, 13, 14, 21,
and 22 were selected to test for Bleomycin-dependent DNA
damage (Table 2). Damage to DNA in the presence of a
Bleomycin–Fe complex has been adopted as a sensitive and
specific method to examine potential pro-oxidant agents [28].
If the samples to be tested are able to reduce the Bleomycin–
Fe3þ to Bleomycin–Fe2þ, DNA degradation in this system will
be stimulated, resulting in a positive test for pro-oxidant
activity. DNA degradation is accompanied by the formation
of a product similar to malondialdehyde (MDA). L-Ascorbic
From the structure activity relationship (SAR), it is note-
worthy that compounds 3, 8, 9, and 13 have SH, OH, and NH2
groups attached to aromatic ring (thiazole, tiazolopyrimi-
dine, and pyridopyrimidine) which is effective in inhibiting
Bleomycin from DNA damage.
Conclusion
The newly prepared ring systems seem to be interesting for
biological studies. Furthermore, the present investigation
offers rapid and effective new procedures for the synthesis
of a new class of 3-substituted coumarin. The new compounds
were investigated for antioxidant activity. Compounds 8, 13,
and 21 exhibited a high antioxidant activity when compared
to the ascorbic acid; these compounds manifested the best
protective effect against DNA damage induced by Bleomycin.
acid as a reducing agent can reduce Fe3þ to Fe2þ
.
Table 2 shows that compounds 3, 8, 9, 13, and 21 have an
ability to protect DNA from the induced damage by
Bleomycin. Also, compounds 3, 4, 8, 9, 13, and 21 exhibited
a high antioxidant activity compared to the starting
materials. On the other hand, compounds 3, 8, 9, and 13
exhibited more potent antioxidant activity compared with 7-
hydroxycoumarin. Elstner et al. [29], reported that coumarin
and 7-hydroxycoumarin have been used for the scavenging of
free radicals. It is noteworthy that 7-hydroxycoumarin
examined in the present investigation also possesses a
hydroxyl group attached to an aromatic ring, and it is effec-
tive in inhibiting lipid peroxidation. Similarly, the presence
of a hydroxyl group attached to an aromatic ring in the
molecule of erianin accounts for its antioxidative activity.
The tertiary amine structure present in the alkaloid tetrahy-
dropalmatine contributes to its antioxidative activity.
Experimental
All melting points are in degree centigrade (uncorrected) and
were determined on Gallenkamp electric melting point appa-
ratus. IR spectra were recorded (KBr) on a Mattson 5000 FTIR
spectrophotometer in The Microanalytical Center (Faculty of
Science; Mansoura University). 1H-NMR spectra of compounds
were determined on a Varian XL 200 MHz (Faculty of Science,
Cairo University), while, for compounds 8 and 12 13C-NMR spec-
tra were acquired on a JEOL ECX-400 spectrometer Chemistry
Department, School of Engineering and Science University of
Jacobs, Bremen, Germany, operating at 400 MHz. The mass spec-
tra were recorded on (Kratos, 70 eV) MS equipment and/or a
Varian MAT 311 A spectrometer, in the Microanalytical Center
(Faculty of Science; Cairo University). High resolution mass spec-
tra (HRMS) were recorded using both a Bruker HCT ultra and a
high resolution (Bruker Daltonics micrOTOF) instruments from
methanol or dichloromethane solutions using the positive elec-
trospray ionization mode (ESI). Elemental analyses (C, H, and N)
were carried out at the Microanalytical Center of Cairo Univ.,
Giza, Egypt. Biological activities were carried in the
Pharmacognosy Department, Faculty of Pharmacy, Mansoura
University, Mansoura, Egypt.
Table 2. Pro-oxidant effects of 3-substituted coumarins on ferric
Bleomycin-induced DNA damage.
Compound No.
Bleomycin-dependent DNA damage
Absorbance of samples
Synthesis of 3-(4-hydroxy-3-methyl-1-phenyl-1,4-
dihydropyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-8-yl)-2H-
chromen-2-one (4)
A mixture of 3 (0.5 g, 2 mmol), 5-chloro-3-methyl-1-phenyl-1H-
pyrazole-4-carbaldehyde (0.44 g, 2 mmol), and triethylamine
(0.42 mL, 3 mmol) in dimethylformamide (20 mL) was refluxed
for 48 h. The reaction mixture was left to cool and poured into ice
cold water (50 mL). The formed precipitate was filtered off, dried
and recrystallized from benzene/ethanol mixture to furnish 4.
Reddish brown powder, yield, 75%, mp: 202–2048C; IR (KBr):
Control
Ascorbic acid
7-Hydroxycoumarin
1
3
4
8
9
13
14
21
22
0
0.098 ꢁ 0.001
0.104 ꢁ 0.002
0.126 ꢁ 0.001
0.094 ꢁ 0.002
0.115 ꢁ 0.002
0.098 ꢁ 0.001
0.099 ꢁ 0.003
0.101 ꢁ 0.002
0.216 ꢁ 0.003
0.108 ꢁ 0.004
0.127 ꢁ 0.001
nmax, cmꢀ1: 3384 (OH), 1698 (C O), 1639 (C N), 1604 (C C).
–
–
–
–
–
–
1H-NMR (DMSO-d6): d 2.43 (s, 3H, CH3), 4.50 (s, 1H, C8-H), 5.85
(s, 1H, C2-H), 7.36–8.21 (m, 9H, Ar-H), 8.58 (s, 1H, C4-H of coumarin),
9.70 (br, s, OH). MS: m/z (%) ¼ 413 (Mþ þ 1, 3.7), 412 (14.4), 411
(Mþ – OH, 4.88), 402 (0.94), 359 (3.82), 343 (7.37), 341 (30.45), 327
(4.63), 299 (1.13), 272 (9.44), 266 (1.44), 244 (100.00), 242 (2.38), 216
(18.08), 211 (29.53), 201 (4.69), 186 (3.40), 174 (10.07), 172 (27.26), 146
All compounds were dissolved in DMSO/MeOH (1:1) and tested at
the final concentration of (0.1 mL of 1 mg/mL). The extent of
DNA damage is expressed by increase in absorbance at 520 nm.
The values are mean ꢁ SD (n ¼ 3).
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Arch. Pharm. Chem. Life Sci. 2011, 344, 710–718
Bioactive 3-substituted coumarin derivatives
715
(8.77), 145 (43.99), 128 (16.90), 113 (11.98), 110 (1.36), 109 (1.31), 101
(64.13), 99 (5.61), 97 (1.80), 77 (78.14), 74 (31.00), 50 (54.61). Anal.
calcd. for C23H16N4O3S (428.46): C, 64.47; H, 3.76; N, 13.08%. Found:
C, 64.03; H, 3.82; N, 13.81%.
Anal. calcd. for C22H14ClN3O3S (435.88): C, 60.62; H, 3.24;
N, 9.64%. Found: C, 60.58; H, 3.21; N, 9.61%.
Synthesis of 7-amino-3-(2-oxo-2H-chromen-3-yl)-5H-
thiazolo[3,2-a]pyrimidin-5-one (9) and 3,3’-(5-oxo-5,8-
dihydropyrrolo[2,3-d]thiazolo[3,2-a]pyrimidine-3,7-diyl)-
bis(2H-chromen-2-one) (10)
Synthesis of 2-methyl-3-(4-(2-oxo-2H-chromen-3-yl)-
thiazol-2-yl)quinazolin-4(3H)-one (5), 6-(4-(2-oxo-2H-
chromen-3-yl)thiazol-2-yl)-5H-pyrrolo[3,4-b]pyrazine-
5,7(6H)-dione (6), and 2-methyl-3-(4-(2-oxo-2H-
chromen-3-yl)thiazol-2-yl-5,6,7,8-tetrahydro-4H-
General Procedure
A mixture of 6-aminothiouracil (0.14 g, 1 mmol), triethylamine
(0.42 mL, 3 mmol), and compound 2 (0.27 g, 1 mmol) or (0.53 g,
2 mmol) in dimethylformamide (20 mL) was refluxed for 12 h.
The resulting solution was cooled at room temperature and
poured into crushed ice. The solid obtained was filtered off,
washed with water, dried and crystallized from benzene/ethanol
to give 9 and 10, respectively.
In another route, compound 10 was obtained via the reaction
of 9 (0.31 g, 1 mmol) with 2 (0.27 g, 1 mmol) under the same
previous conditions.
benzothieno[2,3-d] [1,3]quinazolin-4(3H)-one (7)
A mixture of 3 (1.22 g, 5 mmol), 2-methyl-4H-benzo[d][1,3]oxazin-
4-one (0.64 g, 4 mmol), furo[3,4-b]pyrazine-5,7-dione (0.3 g,
2 mmol) or 2-methyl-5,6,7,8-tetrahydro-4H-benzothieno[2,3-d]
[1,3]oxazin-4-one (0.44 g, 2 mmol), and freshly fused sodium
acetate (1.0 g, 12 mmol) was fused in a sand bath at 200–
2108C for 5 h, then acetic acid (20 mL) was added. The reaction
mixture was refluxed for another 3 h, poured into ice cold water,
the resulting precipitate was filtered off, dried and recrystallized
from dimethylformamide/methanol mixture to afford 5–7,
respectively.
Compound 9; brown crystals, yield: 88%, mp: 276–2808C,
IR (KBr): nmax, cmꢀ1: 3403, 3388 (NH2), 1718, 1635 (2 CO), 1625
Compound 5; grey crystals, yield: 82%, mp: 3218C, IR (KBr):
nmax, cmꢀ1: 1714 (brs, 2 CO). 1H-NMR (DMSO-d6): d 2.42 (s, 3H,
CH3), 7.32–8.19 (m, 9H, Ar-H), 8.50 (s, 1H, C4-H, coumarin). MS: m/z
(%) ¼ 372 (Mþ – CH3, 1.4), 356 (24.3), 328 (4.9), 300 (2.5), 286
(15.5), 255 (2.6), 244 (100.0), 216 (18.3), 211 (31.6), 186 (3.5), 183
(24.0), 160 (31.0), 145 (21.2), 137 (43.5), 119 (85.1), 102 (27.3), 92
(38.1), 76 (23.7). Anal. calcd. for MS: m/z (%) ¼ 373 (Mþ, 1.1):
C, 65.11; H, 3.38; N, 10.85%. Found: C, 65.13; H, 3.36; N, 10.92%.
Compound 6; black powder, Yield, 71%, mp: 3208C, IR (KBr):
nmax, cmꢀ1: 1706, 1645 (3 CO). MS: m/z (%) ¼ 374 (Mþ – 2, 11.1),
327 (11.6), 269 (13.1), 244 (21.1), 241 (13.8), 226 (11.1), 210 (10.6),
201 (10.2), 178 (18.2), 165 (15.95), 150 (15.1), 145 (11.6), 143 (27.8),
127 (32.8), 104 (30.6), 96 (36.5), 82 (95.9), 69 (47.3), 57 (100.0). Anal.
calcd. for C18H8N4O4S (376.35): C, 57.45; H, 2.14; N, 14.89%.
Found: C, 57.49; H, 2.23; N, 14.96%.
–
(C N). HRMS (micrOTOF): m/z for C15H8N3O3S, Calcd.: 311.3200
–
(Mþ). Found: 310.0300 (Mþ – H). Anal. calcd. for C15H9N3O3S
(311.32): C, 57.87; H, 2.91; N, 13.50%. Found: C, 57.93; H, 2.97;
N, 13.58%.
Compound 10; brown powder, yield: 89, 78%, mp: 3208C, IR
(KBr): nmax, cmꢀ1: 3386 (NH), 1716, 1646 (3 C O). H-NMR (DMSO-
1
–
–
d6): d 6.85–8.55 (m, Ar-H, C4-H, coumarin, NH). MS: m/z (%) ¼ 479
(Mþ, 0.5), 454 (0.5), 386 (9.4), 356 (15.8), 329 (7.99), 300 (3.99), 271
(4.8), 227 (5.4), 200 (11.3), 173 (4.96), 150 (7.4), 126 (13.1), 115
(18.8), 91 (21.5), 76 (53.2), 62 (72.4), 55 (100.0). Anal. calcd.
for C26H13N3O5S (479.46): C, 65.13; H, 2.73; N, 8.76%. Found: C,
65.21; H, 2.75; N, 8.80%.
Synthesis of 3-(4a,9-dihydro-4H-fluoren-4-ol-9-thia-1,4a-
diaza)-chromen-2-one (13), 3-(4-hydroxy-2-
Compound 7; brown powder, yield: 85%, mp: 3208C, IR (KBr):
nmax, cmꢀ1: 1716, 1644 (2 CO). MS: m/z (%) ¼ 446 (Mþ – 1, 21.1), 212
(18.1), 171 (37.8), 91 (59.5). Anal. calcd. for C23H17N3O3S2 (447.53):
C, 61.73; H, 3.83; N, 9.39%. Found: C, 61.77; H, 3.87; N, 9.43%.
mercaptopyrido[2,3-d]pyrimidin-7-yl)-2H-chromen-2-
one(13), (E)-3-(3-(3-methoxyphenylamino)acryloyl)-2H-
chromen-2-one (14), and (E)-3-(3-(phenylthio)acryloyl)-
2H-chromen-2-one (16)
Synthesis of 3-(5-(4-chlorophenyl)-4-hydroxy-2-mercapto-
5,6-dihydropyrido[2,3-d]pyrimidin-7-yl)-2H-chromen-2-one
(8)
To a solution of enaminone 11 (0.24 g, 1 mmol) in a mixture of
dioxane and acetic acid mixture (20 mL) 2-aminobenzothiazole
(0.15 g, 1 mmol) was added. The reaction mixture was refluxed
for 12 h and the resulting solution was cooled at room tempera-
ture and poured into crushed ice. The solid obtained was filtered
off, washed with water, dried and crystallized from benzene/
ethanol mixture to afford 12.
A solution of 1 (0.56 g, 3 mmol) in dimethylformamide (50 mL),
p-chlorobenzaldehyde (0.42 g, 3 mmol), and catalytic amounts of
triethylamine (0.5 mL, 3 mmol) were added. The reaction mix-
ture was refluxed for 1 h and then 6-aminothiouracil (0.43 g,
3 mmol) was added. Further, whole reaction mixture was
allowed to reflux for another 10 h. The resulting solution was
cooled at room temperature and poured into crushed ice. The
solid obtained was filtered off, washed with water, dried and
crystallized from benzene/ethanol to afford 8.
Similarly, a solution of enaminone 11 (0.24 g, 1 mmol), 6-
aminothiouracil (0.29 g, 2 mmol), and triethylamine (0.42 mL,
3 mmol) in dimethylformamide (20 mL) was refluxed for 15 h
and crystallized from benzene/ethanol mixture to afford 13.
Also, a solution of enaminone 11 (0.24 g, 1 mmol) and m-anisi-
dine (0.49 mL, 4 mmol) or thiophenol (0.11 mL, 1 mmol) in
dioxane (20 mL) was refluxed for 8 h and 6 h and crystallized
from benzene/ethanol mixture to furnish 14 and 16, respectively.
Compound 12, yellow powder, yield: 75%, mp: 300–3038C, IR
Yellowish brown crystals, yield: 73%, mp: 264–2668C, IR (KBr):
nmax, cmꢀ1: 3384 (OH), 2923, 2865 (C–H, aliphatic), 2510 (SH),
1677 (C O), 1606 (C N). 1H-NMR (DMSO-d6): d 2.95–3.0 (m, 2H,
–
–
–
–
CH2), 5.25–5.27 (m, 1H, CH), 7.0–7.66 (m, 8H, Ar), 8.45 (s, 1H, C4-H,
coumarin), 11.8 (s, 1H, OH), 12.0 (s, 1H, SH). MS: m/z (%); the (–) ESI
mass spectrum showed one quasi-molecular ion peak at 434
(M–H), pointing 435 as the molecular mass of the compound.
(KBr): nmax, cmꢀ1: 3335 (OH), 1715 (C O), 1614 (C N). 1H-NMR
–
–
–
–
(DMSO-d6): d 5.32 (br, d, 1H, pyrimidine), 5.79 (br, d, 1H, pyrimi-
dine), 7.1–8.16 (m, 8H, Ar-H), 8.52 (s, 1H, C4-H, coumarin), 8.70
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716
W. S. Hamama et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 710–718
(s, 1H, OH). MS: m/z (%) ¼ 331 (Mþ – OH, 4.36), 316 (2.1), 300 (1.95),
288 (1.9), 271 (2.8), 259 (2.2), 243 (3.5), 214 (3.6), 203 (14.6), 189
(4.9), 173 (100.0), 161 (5.9), 145 (13.5), 131 (12.98), 127 (7.3), 102
(11.96), 89 (2.8), 74 (10.3), 62 (28.99). Anal. calcd. for C19H12N2O3S
(348.38): C, 65.51; H, 3.47; N, 8.04%. Found: C, 68.71; H, 3.69;
N, 8.51%.
solution of 11 (0.48 g, 2 mmol) in pyridine (10 mL). The reaction
mixture was stirred for another 2 h. The crude product was
filtered off, dried well, and heated in dioxane (20 mL) containing
acetic acid (20 mL) for 7 h. The resulting solution was cooled at
room temperature and poured into crushed ice and treated with
conc. ammonia. The solid obtained was filtered off, washed with
water, dried, and crystallized from benzene/ethanol mixture to
furnish 19.
Compound 13, green powder, yield: 71%, mp: 2448C, IR (KBr):
nmax, cmꢀ1: 3378 (OH), 2525 (SH), 1713 (C O), 1606 (C N). 1H-
–
–
–
–
NMR (DMSO-d6): d 6.53–8.32 (m, 6H, Ar-H), 8.45 (s, 1H, C4-H,
coumarin), 11.95 (brs, 1H, OH), 12.40 (brs, 1H, SH). MS: m/z
(%) ¼ 323 (Mþ, 60.8), 311 (100), 280 (15.9), 242 (9.4), 193 (47.3),
173 (37.3), 142 (53.4), 115 (50.1), 94 (61.96), 88 (68.2). Anal. calcd.
for C16H9N3O3S (323.33): C, 59.44; H, 2.81; N, 13.0%. Found: C,
59.39; H, 2.78; N, 12.97%.
Brown powder, yield: 76%, mp: 3208C, IR (KBr): nmaþx, cmꢀ1
:
–
1724, 1644 (2 CO), 1608 (C N). MS: m/z (%) ¼ 356 (M – CH3,
–
100.0), 328 (15.6), 224 (15.6), 147 (26.7), 85 (28.9), 52 (66.7). Anal.
calcd. for C20H13N5O3 (371.35): C, 64.69; H, 3.53; N, 18.86%.
Found: C, 64.74; H, 3.58; N, 18.93%.
Compound 14, brown crystals, yield: 72%, mp: 286–2888C, IR
Synthesis of 3-(3-methyl-1-phenyl-1H-pyrazolo-
[3,4-b]pyridin-6-yl)-2H-chromen-2-one (20)
1
(KBr): nmax, cmꢀ1: 3274 (NH), 1722, 1643 (2 C O), 1606 (C N). H-
–
–
–
–
NMR (DMSO-d6): d 3.8 (s, 3H, OCH3), 5.90 (br, 1H, a-olefinic-H),
6.58–7.90 (m, 9H, Ar-H, b-olefinic-H), 8.45 (s, 1H, C4-H, coumarin),
10.15 (brs, 1H, NH). MS: m/z (%) ¼ 322 (Mþ þ 1, 9.8), 321 (100),
173 (63.1), 148 (61.0), 132 (47.8), 116 (14.6), 88 (15.5), 76 (18.2).
Anal. calcd. for C19H15NO4 (321.33): C, 71.02; H, 4.71; N, 4.36%.
Found: C, 71.14; H, 4.76; N, 4.44%.
A mixture of 11 (0.48 g, 2 mmol), 4-methyl-1-phenyl-1H-pyrrol-
2(3H)-one (0.35 g, 2 mmol), and ammonium acetate (1 g,
12 mmol) was fused for 5 h in a sand bath at 1708C. Further,
whole reaction mixture was allowed to reflux for another 3 h in
glacial acetic acid (20 mL), cooled, and then poured into crushed
ice. The solid obtained was filtered off, washed with water, dried
and crystallized from dimethylformamide/ethanol mixture to
afford 20.
Compound 16, yellow crystals, yield: 73%, mp: 209–2108C,
IR (KBr): nmax, cmꢀ1: 1718, 1641 (2 CO), 1606 (C C). 1H-NMR
–
–
(DMSO-d6): d 5.90 (br, 1H, a-olefinic-H), 7.41–8.05 (m, 10H, Ar-H,
b-olefinic-H), 8.47 (br, s, 1H, C4-H, coumarin). Anal. calcd.
for C18H12O3S (308.35): C, 70.11; H, 3.92%. Found: C, 70.21; H,
3.95%.
Brown crystals, yield: 73%, mp: 2008C, IR (KBr): nmax, cmꢀ1
:
1724 (CO), 1644 (C N). H-NMR (DMSO-d ): d 2.37 (s, 3H, CH ), 7.4–
1
–
–
6
3
8.2 (m, 11H, Ar-H), 8.42 (brs, 1H, C4-H, coumarin). MS: m/z
(%) ¼ 355 (Mþþ 2, 13.90), 341 (Mþ – CH3, 26.26), 328 (4.85), 315
(4.85), 304 (10.98), 287 (2.57), 267 (5.54), 252 (8.68), 238 (3.64), 224
(12.18), 197 (3.95), 183 (11.88), 170 (576), 149 (7.33), 131 (8.79), 128
(24.21), 106 (13.21), 91 (41.38), 77 (100.0), 64 (31.53). Anal. calcd.
for C22H15N3O2 (353.37): C, 74.78; H, 4.28; N, 11.89%. Found: C,
74.75; H, 4.24; N, 11.92%.
Synthesis of 3-(7-methoxyquinolin-4-yl)-2H-chromen-2-
one (15)
To compound 14 (0.32 g, 1 mmol) in dioxane (20 mL), phos-
phorus pentachloride (1 g, 0.21 mmol) was added and the reac-
tion mixture was refluxed for 6 h. The resulting solution was
cooled at room temperature and poured into crushed ice and
treated with conc. ammonia. The solid obtained was filtered off,
washed with water, dried and crystallized from benzene/ethanol
mixture to give 15.
Synthesis of 3-(3-phenyl-7H-[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazin-6-yl)-2H-chromen-2-one (21), 3-(2-
(pyridin-2-ylamino)-6H-1,3,4-thiadiazin-5-yl)-2H-chromen-
2-one (22), and 3-benzyl-7-(2-oxo-2H-chromen-3-yl)-
[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4(8H)-one (23)
Black powder, yield: 70%, mp: 3208C, IR (KBr): nmax, cmꢀ1: 1722
1
(C O), 1606 (C N). H-NMR (DMSO-d ): d 3.94 (s, 3H, OCH ), 7.24–
–
–
–
–
6
3
8.31 (m, 9H, Ar-H), 8.48 (brs, 1H, C4-H, coumarin). Anal. calcd.
for C19H13NO3 (303.31): C, 75.24; H, 4.32; N, 4.62%. Found: C,
75.18; H, 4.30; N, 4.57%.
General Procedure
A
mixture of 3-(2-bromoacetyl)-2H-chromen-2-one (2) (0.8 g,
3 mmol), triethylamine (0.42 mL, 3 mmol), and 4-amino-5-phe-
nyl-4H-1,2,4-triazole-3-thiol (0.58 g, 3 mmol), N-(pyridin-2-yl)hy-
drazinecarbothioamide (0.34 g, 2 mmol) or 4-amino-6-benzyl-3-
mercapto-1,2,4-triazin-5(4H)-one (0.94 g, 4 mmol) in dimethylform-
amide (20 mL) was refluxed for 12, 8, and 9 h, respectively. The
resulting solution was cooled, poured into ice-cold water, filtered
off, dried, and crystallized from dimethylformamide/ethanol
mixture to furnish 21–23, respectively.
Attempting for preparation of 3-(4-hydroxy-4H-
thiochromen-4-yl)-2H-chromen-2-one (17)
A suspension of compound 16 (0.5 g, 2 mmol) in H2SO4 (5 mL)
was heated on water bath at 808C for 5 h. The resulting solution
was cooled at room temperature and poured into crushed ice and
treated with conc. ammonia. The solid obtained was filtered off,
washed with water, dried and crystallized from benzene/ethanol
mixture.
Compound 21; brown powder, yield: 69%, mp: 1828C, IR (KBr):
1
nmax, cmꢀ1: 1720 (CO), 1606 (C N). H-NMR (DMSO-d ): d 2.9 (s, 2H,
–
–
6
CH2), 6.9–7.9 (m, 9H, Ar-H), 8.45 (s, 1H, C4-H, coumarin). Anal.
calcd. for C19H12N4O2S (360.39): C, 63.32; H, 3.36; N, 15.55%.
Found: C, 63.38; H, 3.41; N, 15.59%.
Synthesis of 2,4-dimethyl-1,5,6,8a,9-pentaaza-fluorene-7-
yl(2H-chromen-2-on-3-yl)ketone (19)
A well stirred solution of 4,6-dimethyl-1H-pyrazolo[3,4-b]pyri-
dine-3-diazonium chloride (0.42 g, 2 mmol) in conc. HCl
(2 mL) and water (2 mL) was cooled in an ice bath and diazotized
with the solution of NaNO2 (0.14 g, 2 mmol) in water (2 mL). The
cold diazonium solution was added slowly to a well stirred
Compound 22, dark brown crystals, yield: 66%, mp: 2808C, IR
(KBr): nmax, cmꢀ1: 3343 (NH), 1714 (CO), 1604 (C N). 1H-NMR
–
–
(DMSO-d6): d 3.33 (s, 2H, CH2), 6.71–8.14 (m, 8H, Ar-H), 8.47
(s, 1H, C4-H, coumarin), 9.47 (brs, 1H, NH). 13C-NMR (DMSO-d6):
d 159.0, 155.4, 153.1, 147.8, 138.0, 137.8, 132.3, 129.2, 128.8,
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Arch. Pharm. Chem. Life Sci. 2011, 344, 710–718
Bioactive 3-substituted coumarin derivatives
717
125.4, 121.4, 121.3, 119.6, 116.5, 116.4, 114.7, 110.2, 24.4. Anal.
calcd. for C17H12N4O2S (336.37): C, 60.70; H, 3.60; N, 16.66%.
Found: C, 60.76; H, 3.64; N, 16.68%.
Ascorbic acid (20 mL, 2 mM) solution was used as a standard
antioxidant (positive control). Blank sample was run using
solvent without ABTS (Table 2).
Compound 23, green crystals, yield: 89%, mp: 217–2208C, IR
(KBr): nmax, cmꢀ1: 1712 (br, 2 CO), 1608 (C N). MS: m/z (%) ¼ 402
–
–
Bleomycin-dependent DNA damage
(Mþ, 7.8), 370 (Mþ – S, 8.6), 268 (7.7), 253 (8.1), 226 (8.8), 198 (13.6),
176 (8.5), 165 (13.2), 145 (12.7), 144 (22.5), 142 (32.9), 116 (100.0),
115 (90.5), 88 (82.8), 76 (71.4), 63 (39.1). Anal. calcd. for
C21H14N4O3S (402.43): C, 62.68; H, 3.51; N, 13.92%. Found: C,
62.72; H, 3.54; N, 13.99%.
The assay was done according to Aeschlach et al. [30] and Chan &
Tang [31], with minor modifications. The reaction mixture
(0.5 mL) contained DNA (0.5 mg/mL), Bleomycin sulfate
(0.05 mg/mL), and MgCl2 (5 mM), FeCl3 (50 mM) and the samples
were dissolved in DMSO to be tested at concentration (20 mL of
1 mg/mL). L-Ascorbic acid was used as a positive control. The
mixture was incubated at 378C for 1 h. The reaction was termi-
nated by addition of 0.05 mL EDTA (0.1 M). The color was devel-
oped by adding thiobarbituric acid (TBA) (0.5 mL) (1%, w/v) and
HCl (0.5 mL) (25%, v/v) followed by heating at 808C for 10 min.
After centrifugation, the extent of DNA damage was measured by
the increase in absorbance at 532 nm (Table 2).
Synthesis of 1-acetyl-3-benzyl-7-(2-oxo-2H-chromen-3-
yl)pyrazolo[5,1-c][1,2,4] triazin-4(1H)-one (24)
Compound 23 (0.8 g, 2 mmol) in acetic anhydride (10 mL) was
refluxed for 3 h at 1008C. The resulting solution was cooled,
poured into ice-cold water, filtered off, dried, and crystallized
from dimethylformamide/ethanol mixture to give 24.
Black crystals, yield: 84–88%, mp: 3208C, IR (KBr): nmax, cmꢀ1
:
1727 (br, 2 CO), 1604 (C N). H-NMR (DMSO-d ): d 1.95 (s, 3H, CH ),
1
The authors have declared no conflict of interest.
–
–
6
3
2.73 (s, 2H, CH2), 6.80–8.45 (m, 11H, Ar-H, C4-H, coumarin). MS: m/z
(%) ¼ 412 (Mþ, 0.7), 369 (0.7), 336 (11.6), 320 (5.3), 244 (12.6), 217
(11.5), 188 (9.2), 174 (19.2), 156 (2.4), 144 (20.5), 119 (11.9), 115 (19.7),
97 (42.4), 76 (33.6), 73 (38.4). Anal. calcd. for C23H16N4O4 (412.4): C,
66.99; H, 3.91; N, 13.59%. Found: C, 67.04; H, 3.96; N, 13.67%.
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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com