Synthesis and Antioxidant Activity of Some Derivatives of 2 2 Oxo 4 Phenyl 2h Chromen 7 Yloxy Aceto...
Transcript of Synthesis and Antioxidant Activity of Some Derivatives of 2 2 Oxo 4 Phenyl 2h Chromen 7 Yloxy Aceto...
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Research Article
Journal of Atoms and MoleculesAn International Online JournalAn International Online JournalAn International Online JournalAn International Online Journal
ISSNISSNISSNISSN 2277227722772277 1247124712471247
SYNTHESIS AND ANTIOXIDANT ACTIVITY OF SOME DERIVATIVES OF 2-(2-OXO-4-
PHENYL-2H-CHROMEN-7-YLOXY) ACETO-HYDRAZIDE
Mahmoud Mohamed Abd El-All1,2
, Ahmed Hamdy Halawa1, Ahmed Abd El-Hameed
Hassan1,3
, Mohamed Ahmed El-Nassag1, Gehad Abd El-Raheem Abd El-Jaleel
4, Essam
Mohamed Eliwa1*
, Ahmed Hammam Bedair1
1Chemistry Department, Faculty of Science, AlAzhar University, 11284, Nasr City, Cairo, Egypt2Chemistry Department, Faculty of Science and Art, Al-Baha University, 1988, Al-Baha, Saudi
Arabia3Chemistry Department, Faculty of Medicine, Jazan University, 82621, Jazan, Saudi Arabia
4Pharmacology Department, National Research Center, 12622, Dokki, Cairo, Egypt
Received on: 03-06-2013 Revised on: 18-07-2013 Accepted on: 28072013
ABSTRACT:
A novel series of compounds containing coumarinyl moiety derivatives from 2-(2-oxo-4-phenyl-
2H-chromen-7-yloxy)-acetohydrazide (2) were synthesized. The formed compounds have been
evaluated by correct elemental analysis and spectral data (IR, MS,1H-NMR and
13C-NMR). The
antioxidant evaluation of some selected compounds indicated that tosyl hydrazide derivative 7revealed promising antioxidant activity.
KEY WORDS: Coumarin acetohydrazide, Schiffs bases, oxadiazole, thiazolidinone, pyrazole,antioxidant activity.
INTRODUCTION:
Coumarin and its derivatives are a class of the
most active heteroaromatic compounds that
have drawn much attention due to theirbiological and pharmaceutical activities [1-9].
Many of these com-pounds have proved to be
active as anticancer [10], antifungal [11],
antibacterial [12, 13], antitumor [14], anti-
HIV [15], anti-inflammatory [16],
anticoagulant [17] and antiviral activities
including human immunodeficiency virus
activities are well known [18].
On the other hand, a large number ofhydrazides have been reported to be of
biological interest [19, 20], while oxadiazole
* Corresponding author
Essam Mohamed Eliwa,
Email:[email protected] : +2.0128.5126895
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derivatives have been reported to possess
antibacterial [21, 22], antifungal [23, 24] and
other biological activities. Furthermore, a
number of substituted pyrazoles were found to
exhibit appreciable biological and
chemotherapeutic activities [25-32]. It was
therefore thought worthwhile to incorporate
the hydrazide, oxadiazole and pyrazole
moieties into the coumarin nucleus.
RESULTS AND DISCUSSION
Chemistry
Applying the hydrazinolysis of ethyl 2-(2-
oxo-4-phenyl-2H-chromen-7-yloxy) acetate
(1) [33]with hydrazine hydrate in ethanol at
refluxing temperature, 2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy) acetohydrazide (2) was
obtained in good yield (Scheme 1).
On the other hand, refluxing 2 in formic acid
for 5 hours affo-rded the N-formyl derivative
3 in high yield. Condensation of 3 with 4-
aminobenzoic acid in acetonitrile as a medium
containing a few drops of acetic acid gave 4-
((2-(2-(2-oxo-4-phenyl-2H-chromen-7-
yloxy)acetyl)hydrazinyl)
methyleneamino)benzoic acid (4) as the sole
product. Acetylation of hydrazide compound
2 by refluxing in acetic acid, afforded N'-
acetyl-2-(2-oxo-4-phenyl-2H-chromen-7-
yloxy) acetohydrazide (5). Also, condensation
of hydrazide 2 with 4-nitrobenzoic acid in the
presence of phosphorousoxychloride under
reflux yielded 7-((5-(4-nitrophenyl)-1, 3, 4-
oxadiazol-2-yl) methoxy)-4-phenyl-2H-
chromen-2-one (6) in moderate yield,
(Scheme 1).
Scheme 1
Treatment of acetohydrazide 2 with p-toluene
sulfonyl chlo-ride in dry dioxane in the
presence of a few drops of triethylamine
(TEA) as a catalyst afforded 4-methyl-N -(2-
(2-oxo-4-phenyl-2H-chromen-
7yloxy)acetyl)benzenesulfonohydrazide (7),
while when 2 reacted with proper substituted
benzoyl chlorides namely (4-chloro and 3,5-dinitrobenzoyl chloride) in refluxing dioxane
in the prese-nce of pyridine yielded 4-chloro-
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N'-(2-(2-oxo-4-phenyl-2H-chrom-en-7-
yloxy)acetyl)benzohydrazide (8a) and 3,5-
dinitro-N'-(2-(2-oxo-4-phenyl-2H-chromen-7-
yloxy)acetyl)benzohydrazide (8b), respe-
ctively. Moreover, when 8a was heated with
phosphorousoxychlo-ride at 1200C, gave 1, 3,
4-oxadiazol derivative 9. Condensation of 2
with D-glucose and p-nitroacetophenone in
refluxing ethanol containing a catalytic
amount of acetic acid afforded the correspo-
nding Schiff bases 10 and 11 respectively,
(Scheme 2).
Scheme 2
Condensation of compound 2 with aromatic
aldehydes in boiling ethanol in the presence
of acetic acid afforded the corresponding
benzylidine hydrazide derivatives as N'-(4-
Substitutedbenzylidene)-2-(2-oxo-4-phenyl-
2H-chromen-7-yloxy)acetohydrazide (12a-c),
respectively.Compound 12c underwent cyclocondensation
with thiogly-colic acid to obtain
thiazolidinone derivative 14, the formation of
this compound was assumed to occur via the
addition of thiaol group of thioglycolic acid to
the activated double bond (CH=N) of
hydrazone 12c to yield the corresponding
acyclic non-isolable intermediate 13 which
undergoes intramolecular cyclization by the
elimination of water molecule to afford the
final product 14.
In contrast to the anticipated formation of
pyrazole derivatives 16 a, b, the reaction of 2
with -cyano-4-(substituted)-phenyl
cinnamonitrile (15 a, b) in boiling ethanol
containing a few drops of acetic acid afforded
a products identical in all aspects (m.p., mixedm.p. and spectral data) with compounds 12a
and 12b, respectively. The formation of these
compounds were assumed to proceed via retro
Michael addition through the elimination of
malononitrile from the non-isolable adduct
17a,b. Reaction of 2 with triethyl
orthoformate in ethanol-acetic acid at reflux
temperature furnished the expected product 4-
(2-oxo-4-phenyl-2H-chromen-7-yloxy)-1H-
pyrazol-3(2H)-one (18) (Scheme 3).
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Scheme 3
The reactivity of 2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy) ace-tohydrazide (2)
towards active methylene compounds was
explo-red. Thus, treatment of compound 2
with malononitrile and/or ethyl cyanoacetate
in ethanol-acetic acid under reflux gave a
novel com-pound proved to be identical (m.p.,
mixed m.p. and spectral data) with 7-(2-(5-
amino-3-hydroxy-1H-pyrazol-1-yl)-2-
oxoethoxy)-4-phenyl-2H-chromen-2-one (21).
The formation of this compound could be
interpreted through nucleophilic
transformation into acyc-lic non-isolable
intermediates 19, 20 followed by
intramolecular cyclization, hydrolysis of
imino function to carbonyl group in 19, while
loss of ethanol molecule in 20 andtautomerization for both under the reaction
conditions to afford the final product 21,
(Scheme 4).
Cyclocondensation of compound 2 with
different diketo com-pounds namely
(acetylacetone, benzoylacetone, ethyl
acetoace-tate and ethyl benzoylacetate) in
dioxane-pyridine under reflux temperature
yielded a pyrazole derivative as a single
product (TLC) in each case. On the basis of
elemental and spectral data, the products were
assigned the structures as 7-(2-(3-dimethyl-5-
substitu-ted-1H-pyrazol-1-yl)-2-oxoethoxy)-
4-phenyl-2H-chromen-2-one (23a,b) and 7-
(2-(5-hydroxy-3-substituted-1H-pyrazol-1-
yl)-2-oxoe-thoxy)-4-phenyl-2H-chromen-2-
one (25a,b), respectively. The formation of
these compounds was probably occurring
through the mechanism outline in scheme 4.
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The diazo-coupling of aryl diazonium
chlorides with ethylace-toacetate in alcoholic
sodium acetate solution resulted in the form-
ation of different 2,3-dioxobutyrate-2-aryl
hydrazones (26a,b)[34-37], which on the
reaction with the Coumarin hydrazide 2 in
refluxing dioxane containing pyridine
furnished the products which identified as
ethyl 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4-
phenyl-2H-chromen-7-yloxy)acetyl)-1H-
pyrazol-4(5H)-ylidene)-hydrazinyl)be-nzoate
(28a) and 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-
4-phenyl-2H-chromen-7-ylo-xy)acetyl)-1H-
pyrazol-4(5H)-ylidene) hydrazinyl)-benzoic
acid (28b) respectively. Formation of these
compounds may be explained by
condensation of hydrazide 2 with arylazo
compounds 26a,b afforded acyclic
intermediate 27a,b, which undergoes
intramolecular cyclization and
tautomerization through nucleophilic addition
of the (NH) group to the carbonyl ester site
followed by elimination of ethanol yielded the
expected compounds 28a,b, respectively,
(Scheme 4).
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Scheme 4
Moreover, the reaction of hydrazide 2 with
tetracyanoethyl-ene and ethoxymethylene
ethyl cyanoacetate in dioxane-pyridine under
reflux furnished the products which identifiedas: 5-amino-1-(2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy)acetyl)-1H-pyrazole-3,4-
dicarbonitrile (30) and ethyl 5-amino-1-(2-(2-
oxo-4-phenyl-2H-chro-men-7-yloxy)acetyl)-
1H-pyrazole-4-carboxylate (32) respectively.
The reaction pathway is assumed to proceed
via addition of2 to the activated double bond
to form intermediates 29, 31 followed by
intramolecular cyclization through
nucleophilic addition of (NH) to the cyano
group then hydrogen cyanide and/or ethanol
molecules were eliminated and
tautomerization occurs under the reaction
conditions, (Scheme 5).
On the same manner, attempted for
preparation of 5-amino-3-(methylthio)
pyrazole-4-carbonitrile derivative (34) via the
reaction of hydrazide 2 with [bis (methylthio)
methylene] malononitrile in boiling dioxane
was failed. The first surprising property of the
prod-uct of this reaction is the absence of
sulfur element. Secondly, no evidences for the
presence of an amino (NH2) group in both IR
and1H-NMR spectra. In addition,
1H-NMR
spectrum clearly shows the loss of both
methylthio groups leading to 2-(5-((2-oxo-4-
phenyl-2H-chromen-7-yloxy) methyl)-1, 3, 4-
oxadiazol-2(3H)-ylidene) malon-onitrile (35).
The reaction seems to proceed via formation
of the expected acyclic intermediate 33,
which in turn underwent intramo-lecular
nucleophilic cyclization with elimination of
methylthiol mole-cule, (Scheme 5).
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Scheme 5
Pharmacology
Antioxidant Activity
Antioxidant compounds in food play animportant role as a health-protecting factor.
Scientific evidence suggests that antioxidants
reduce the risk for chronic diseases. The role
of antioxidant is to remove free radicals by
donating hydrogen to free radicals in its
reduction to produce non-reactive species.
The effect of the different synthetic
compounds on DPPH radical scavenging was
compared to ascorbic acid using as positivecontrol and appreciated by the determination
of the IC50 values. The results are listed in
Table 1.
Table 1: Values of IC50 exhibited by test compounds.
Entry Cpd.No. Conc. (g/mL) % inhibition IC50(g/mL)
1 5
250 13.69
52838500 20.98
750 20.61
1000 20.61
2 7
250 24.05
950500 37.27
750 43.88
1000 51.62
3 8a
250 13.91
9647500 15.66
750 19.30
1000 24.54
4 10
250 20.90
4126500 24.54750 31.32
1000 33.21
5 11
250 7.50
15535500 12.02
750 14.06
1000 16.17
6 12a
250 28.40
4649500 31.54
750 34.45
1000 38.82
7 14
250 25.05
1816500 32.12
750 38.46
1000 41.59
8 21
250 13.08
1278500 21.24
750 35.30
1000 42.33
9 23a
250 14.64
16440500 15.51750 16.53
1000 24.62
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10 28a
250 20.98
2101500 29.21
750 35.54
1000 38.09
11 32
250 12.16
5723500 18.43750 18.94
1000 26.22
12 35
250 13.26
12639500 15.95
750 17.70
1000 23.53
Std. Ascorbic acid
250 65.55
91.45500 75.89
750 78.22
1000 83.10
DPPH test is a direct and reliable method for
determining radical scavenging action. The
DPPH radical contains an odd electron, which
is responsible for the absorbance at 515-517
nm and also for a visible deep purple color.
When DPPH accepts an electron donated by
an antioxidant compound, the DPPH is
decolorized that can be quantitativelymeasured from the changes in absorbance.
The ratio of antioxidant/DPPH required to
decrease the concentration of DPPH to 50%
of its initial value, denoted as IC50 or Efficient
Concentration (EC50), is an indicator of
antiradical activity [38]. It is clear from the
tabulated results that compound 7 is the most
active promising compound.
Experimental
General
All melting points and antioxidant activities
are uncorrected. IR spectra (KBr) were
recorded on FT-IR 5300 spectrometer and
Perkin Elmer spectrum RXIFT-IR system (,
cm-1
). The1H NMR spectra were recorded in
(CDCl3 & DMSO-d6) at (300) MHz on a
Varian Mercury VX-300 NMR spectrometer(, ppm) using TMS as an internal standard.13
C NMR spectra were recorded on Varian
Mercury VX 300 NMR using DMSO-d6 as
solvent and TMS as an internal standard.
Mass spectrum was obtained on GC Ms-QP
1000 EX mass spectrometer at 70 eV.
Elemental analyses were carried out by the
Microanalytical Research Center, Faculty of
Science, Cairo University and Al-Azhar
University.
Synthesis
2-(2-oxo-4-phenyl-2H-chromen-7-yloxy)
acetohydrazide (2).
A mixture of (1; 0.03 mol) and hydrazine
hydrate (0.06 mol) in ethanol (30 mL) was
refluxed for 8 h. The reaction mixture was
concentrated and left to cool to give colorless
crystals in 80% yield; mp: 188O
C; IR (vcm-
1): 3340, 3254 (NH2, NH), 1716 (C=O,
lactone) and 1690 (C=O, amide);1H-NMR (
ppm): 4.36 (s, 2H, NH2 exchangeable with
D2O), 4.63 (s, 2H, OCH2), 6.25 (s, 1H, H-3),
6.96-7.58 (m, 8H, Ar-H) and 9.43 (s, 1H, NH
exchangeable with D2O); MS m/z (%): 310
(77); Anal. calcd. for C17H14N2O4: C 65.80, H
4.55, N 9.03. Found: C 65.74, H 4.53, N 9.00.
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N'-formyl-2-(2-oxo-4-phenyl-2H-chromen-7-
yloxy) acetohydrazide (3).
A solution of 2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy)aceto-hydrazide (2; 0.002
mol) in formic acid (20 ml) was refluxed for 1h.The solvent was evaporated and residue was
recrystallized from ethanol to give compound
3 in 82% yield; mp: 160OC; IR (vcm
-1): 3390
(NH), 3076 (CH-aromatic) and 1732, 1664
(C=O);1H-NMR ( ppm): 4.84 (s, 2H,
OCH2), 6.25 (s, 1H, H-3), 6.92-7.56 (m, 8H,
Ar-H) and 7.58, 8.00, 10.06 (3s, 3H, 2NH and
CHO exchangeable with D2O); Anal. calcd.
for C18
H14
N2O
5: C 63.90, H 4.17, N 8.28.
Found: C 63.87, H 4.15, N 8.25.
4-((2-(2-(2-oxo-4-phenyl-2H-chromen-7-
yloxy) acetyl) hydrazinyl) methyleneamino)
benzoic acid (4).
4-aminobenzoic acid (0.004 mole) was added
to a mixture of compound 3 (0.004 mole) in
acetonitrile (15-20 mL) containing a few
drops of acetic acid. The reaction mixture was
vigorously stirred with the refluxing for 5hours. Excess solvent was then removed
under reduced pressure, the precipitate
resulting after cooling was collected by
filtration and recrystallized from
dimethylformamide to give compound 4 in
70% yield; mp: 298OC; IR (vcm
-1): 3366
(OH), 3262 (NH) and 1692 (C=O);1H-NMR
( ppm): 4.84 (s, 2H, OCH2), 6.26 (s, 1H, H-
3), 7.01-8.10 (m, 12H, Ar-H), 9.24 (s, 1H,CH=N) and 10.48, 13.01 (2s, 2H, NH and
OH exchangeable with D2O); Anal. calcd. for
C25H19N3O6: C 65.64, H 4.19, N 9.19. Found:
C 65.63, H 4.16, N 9.18.
N'-acetyl-2-(2-oxo-4-phenyl-2H-chromen-7-
yloxy) acetohydrazide (5).
Compound 2 (0.002 mol) was refluxed in
acetic acid (20 ml) for 5 h. The precipitate
formed after cooling was collected byfiltration and recrystallized from dioxane to
give compound 5 in 77% yield; mp: 210OC;
IR (vcm-1
): 3372, 3234 (2NH) and 1704
(C=O);1H-NMR ( ppm): 1.87 (s, 3H, CH3),
4.79 (s, 2H, OCH2), 6.22 (s, 1H, H-3), 6.25-
7.56 (m, 8H, Ar-H) and 9.84, 10.29 (2s, 2H,
2NH); Anal. calcd. for C19
H16
N2O
5: C 64.77,
H 4.58, N 7.95. Found: C 64.74, H 4.55, N
7.93.
7-((5-(4-nitrophenyl)-1, 3, 4-oxadiazol-2-yl)
methoxy)-4-phenyl-2H-chro-men-2-one (6).
2-(2-oxo-4-phenyl-2H-chromen-7-yloxy)
acetohydrazide (2; 0.002 mol) was refluxed
with p-nitrobenzoic acid (0.002 mol) in
dioxane (20 ml) in the presence of POCl3 (0.6
ml) for 3 h. The reaction mixture was slowlyquenched into crushed ice with stirring and
neutralized it with 5% NaOH. The solid
which separated after standing overnight was
filtered, washed with cold water, dried and
recrystallized from ethanol/benzene, to give
compound 6 in 74% yield; mp: 128OC; IR
(vcm-1
): 1720 (C=O); MS m/z (%): 441 (43);
Anal. calcd. for C24H15N3O6: C 65.31, H 3.43,
N 9.52. Found: C 65.29, H 3.40, N 9.49.
4-methyl-N'-(2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy) acetyl) benzene-sulfonohydrazide (7).
A mixture of 2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy)aceto-hydrazide (2; 0.002 mol) and p-
toluene sulfonyl chloride (0.002 mol) in dry
dioxane (10 ml) and a catalytic amount of
triethyl amine (TEA) was refluxed for 3 h,
then the reaction mixture left to cool. The
white solid was filtered off, washed withethanol several times and recrystallized from
a mixture of ethanol-benzene. Compound 7
was obtained in 70% yield; mp: 224OC; IR
(vcm-1
): 3290 (NH) and 1720 (C=O);1H-
NMR ( ppm): 2.32 (s, 3H, CH3), 4.62 (s, 2H,
OCH2), 6.25 (s, 1H, H-3), 6.82-7.77 (m, 12H,
Ar-H) and 9.90, 10.39 (2s, 2H, 2NH); Anal.
calcd. for C24H20N2O6S: C 62.06, H 4.34, N
6.03. Found: C 62.05, H 4.30, N 6.01.
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General procedure for the preparation of
Substituted-N'-(2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy) acetyl) benzohydrazide (8a,
b).
A mixture of 2-(2-oxo-4-phenyl-2H-chromen-7-yloxy) aceto-hydrazide (2; 0.002
mol) and benzoyl chloride derivatives namely
(p-chlorobenzoyl chloride and 3, 5-
dinitrobenzoyl chloride) (0.002 mol) in dry
dioxane (10 ml) and a catalytic amount of
pyridine was refluxed for 2 h, the resulting
solid on heating was collected by filtration,
washed with ethanol several times and
recrystallized from dimethylformamide to
give compounds 8a, b.
4-chloro-N'-(2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy) acetyl) benzohydr-azide (8a).
Yield: 90%; mp: 225OC; IR (vcm
-1): 3300
(NH), 3074 (CH-aromatic) and 1692 (C=O);1H-NMR ( ppm): 4.83 (s, 2H, OCH2), 6.27
(s, 1H, H-3), 7.02-7.91 (m, 12H, Ar-H) and
10.35, 10.53 (2s, 2H, 2NH); MS m/z (%): 448
(50); Anal. calcd. for C24H17ClN2O5: C 64.22,H 3.82, N 7.90. Found: C 64.18, H 3.80, N
7.87.
3, 5-dinitro-N'-(2-(2-oxo-4-phenyl- 2H-
chromen -7-yloxy) acetyl) benzo-hydrazide
(8b).
Yield: 88%; mp: 210OC; IR (vcm
-1): 3340
(NH) and 1696 (C=O); MS m/z (%): 504 (79);
Anal. calcd. for C24H16N4O9: C 57.15, H 3.20,
N 11.11. Found: C 57.13, H 3.18, N 11.08.
7-((5-(4-chlorophenyl)-1, 3, 4-oxadiazol-2-yl)
methoxy)-4-phenyl-2H-chromen-2-one (9).
4-chloro-N'-(2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy) acetyl)-benzohydrazide (8a; 0.7
mmol) was fused with POCl3 (3 ml) at 120OC
for 1 h. The reaction mixture was slowly
quenched into crushed ice with stirring and
neutralized with 5% NaOH. The solid whichseparated after standing overnight was
filtered, washed with cold water, dried and
recrystallized from ethanol/benzene to give
compound 9 in 80% yield; mp: 132OC; IR
(vcm-1
): 1693 (C=O); MS m/z (%): 430 (100);
Anal. calcd. for C24H15ClN2O4: C 66.91, H
3.51, N 6.50. Found: C 66.88, H 3.50, N 6.48.
2-(2-oxo-4-phenyl-2H-chromen-7-yloxy)-N'-
(2, 3, 4, 5, 6-pentahydroxy-hexylidene)
acetohydrazide (10).
A mixture of 2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy) aceto-hydrazide (2; 0.002
mol) and D-glucose (0.002 mol) in ethanol
(30 ml) and a catalytic amount of acetic acid
was heated at 800C for 1h. The precipitate
formed was filtered off hot, washed with etha-nol several times, dried and recrystallized
from ethanol/benzene, to give compound 10
in 90% yield; mp: 140OC; IR (vcm
-1): 3435
(OH), 3346 (NH) and 1756, 1706 (2C=O);13
C-NMR ( ppm): 171.25, 166.94, 160.58,
160.48, 155.72, 135.50, 135.39, 130.22,
129.40, 128.94, 113.22, 113.14, 112.16,
102.59, 91.18, 78.57, 77.86, 71.57, 71.34,
70.81, 70.64, 66.64 and 61.87; MS m/z (%):
472 (54); Anal. calcd. for C23H24N2O9: C
58.47, H 5.12, N 5.93. Found: C 58.42, H
5.08, N 5.90.
N'-(1-(4-nitrophenyl) ethylidene)-2-(2-oxo-4-
phenyl-2H-chromen-7-yloxy) acetohydrazide
(11).
A mixture of 2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy)aceto-hydrazide (2; 0.002
mol) and p-nitroacetophenone (0.002 mol) inethanol (30 ml) in the presence of acetic acid
(1 ml) was refluxed for 1h, the resulting solid
on heating was collected by filtration and
recrystallized from dioxane to give compound
11 in 95% yield; mp: 222OC; IR (vcm
-1):
3150(NH) and 1720(C=O);1H-NMR ( ppm):
2.34 (s, 3H, CH3), 4.63 (s, 2H, OCH2), 6.24
(s, 1H, H-3), 6.98-8.27 (m, 12H, Ar-H) and
11.15 (s, 1H, NH); Anal. calcd. forC25H19N3O6: C 65.64, H 4.19, N 9.19. Found:
C 65.62, H 4.16, N 9.15.
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General procedure for the preparation of N'-
(4-Substitutedbenzylidene)-2-(2-oxo-4-phenyl-
2H-chromen-7-yloxy) acetohydrazide (12a-c).
A mixture of 2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy)aceto-hydrazide (2; 0.002 mol) andbenzaldehyde derivatives namely (p-
chlorobenzaldehyde, p-methoxybenzaldehyde
and p-nitrobenz-aldehyde) (0.002 mol) in
ethanol (30 ml) in the presence of acetic acid
(1 ml) was refluxed for 1h, the resulting solid
on heating was collected by filtration and
recrystallized from dioxane to give
compounds 12a-c.
N'-(4-chlorobenzylidene)-2-(2-oxo-4-phenyl-2H-chromen-7-yloxy) aceto-hydrazide (12a).
Yield: 95%; mp: 254OC; IR (vcm
-1): 3164
(NH), 1706 (C=O) and 1606 (CH=N);1H-
NMR ( ppm): 5.31 (s, 2H, OCH2), 6.24 (s,
1H, H-3), 7.49-8.01 (m, 12H, Ar-H), 8.38 (s,
1H, CH=N) and 11.62 (s, 1H, NH); Anal.
calcd. for C24H17ClN2O4: C 66.59, H 3.96, N
6.47. Found: C 66.54, H 3.93, N 6.45.
N'-(4-methoxybenzylidene)-2-(2-oxo-4-
phenyl-2H-chromen-7-yloxy)-acetohydrazide
(12b).
Yield: 92%; mp: 218OC; IR (vcm
-1): 3188
(NH), 1720, 1684 (2C=O) and 1608 (CH=N);1H-NMR ( ppm): 3.80 (s, 3H, OCH3), 4.80
(s, 2H, OCH2), 6.24 (s, 1H, H-3), 6.95-7.96
(m, 12H, Ar-H), 8.26 (s, 1H, CH=N) and
11.51 (s, 1H, NH); Anal. calcd. for
C25H20N2O5: C 70.08, H 4.71, N 6.54. Found:
C 70.06, H 4.70, N 6.50.
N'-(4-nitrobenzylidene)-2-(2-oxo-4-phenyl-
2H-chromen-7-yloxy) aceto-hydrazide (12c).
Yield: 97%; mp: 244OC; IR (vcm
-1): 3128
(NH) and 1710 (C=O); MS m/z (%): 443 (46);
Anal. calcd. for C24H17N3O6: C 65.01, H 3.86,
N 9.48. Found: C 65.00, H 3.84, N 9.43.
N-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl)-2-
(2-oxo-4-phenyl-2H-chro-men-7-yloxy)
acetamide (14).
A mixture of N'-(4-nitrobenzylidene)-2-(2-
oxo-4-phenyl-2H-chromen-7-yloxy)acetohydrazide (12c; 0.002) and
thioglycolic acid (0.002 mol) in DMF
containing a few drops of pyridine was
refluxed for 24h, cooled and the reaction
mixture was poured into crushed ice
containing a few drops of dil. HCl. The solid
obtained was filtered off and recrystallized
from a mixture of ethanol-benzene.
Compound 14 was obtained in 85% yield;
mp: 194OC; IR (vcm
-1): 3200(NH) and
1715(C=O);1H-NMR ( ppm): 4.87 (s, 2H,
OCH2), 5.36 (s, 2H, CH2-thiazolidinone),
6.24 (s, 1H, H-3), 6.98-8.43 (m, 13H, Ar-H
and CH- thiazolidinone) and 11.93 (s, 1H,
NH); MS m/z (%): 517 (35); Anal. calcd. for
C26H19N3O7S: C 60.34, H 3.70, N 8.12.
Found: C 60.30, H 3.64, N 8.09.
4-(2-oxo-4-phenyl-2H-chromen-7-yloxy)-1H-
pyrazol-3(2H)-one (18).
A mixture of 2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy)aceto-hydrazide (2; 0.002
mol) and triethylorthoformate (0.002 mol) in
ethanol (20 ml) in the presence of acetic acid
(2 ml) was refluxed for 8h, then the reaction
mixture left to cool. The white solid was
filtered off, and crystallized from ethanol to
give compound18
in 82% yield; mp: 98
O
C;IR (vcm-1
): 3300 (NH) and 1716 (C=O); MS
m/z (%): 319 (14); Anal. calcd. for
C18H12N2O4: C 67.50, H 3.78, N 8.75. Found:
C 67.49, H 3.76, N 8.72.
7-(2-(5-amino-3-hydroxy-1H-pyrazol-1-yl)-2-
oxoethoxy)-4-phenyl-2H-chromen-2-one (21).
A mixture of 2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy)aceto-hydrazide (2; 0.002 mol) and
malononitrile and/or ethyl cyano-acetate(0.002 mol) in ethanol (30 ml) in the presence
of acetic acid (1 ml) was refluxed for 8h, the
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resulting solid on heating was collected by
filtration and recrystallized from dioxane to
give com-pound 21 in 85% yield; mp: 245OC; IR (vcm
-1): 3415 (OH), 3320, 3258
(NH2) and 1714, 1672 (2C=O);
1H-NMR (
ppm): 4.79(s, 2H, OCH2), 6.27 (s, 1H, H-3),
6.99-7.56 (m, 11H, Ar-H, CH-pyrazole and
NH2 exchangeable with D2O) and 10.31 (s,
1H, OH exchan-geable with D2O);13
C-NMR
( ppm): 166.67, 161.26, 160.45, 155.75,
155.58, 135.43, 130.24, 129.42, 128.97,
128.36, 113.53, 112.87, 112.26, 102.60 and
66.77; Anal. calcd. for C20H15N3O5: C 63.66,
H 4.01, N 11.14. Found: C 63.62, H 4.00, N
11.10.
General procedure for the preparation of 7-
(2-(3-methyl-5-substituted-1H-pyrazol-1-yl)-
2-oxoethoxy)-4-phenyl-2H-chromen-2-one
(23a, b).
A mixture of 2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy)aceto-hydrazide (2; 0.002 mol) and
acetylacetone or benzoylacetone (0.002 mol)
in 1,4-dioxane (10 ml) and a catalytic amount
of pyridine was refluxed for 6 h, then the
reaction mixture left to cool. The solid
product was filtered off, washed with ethanol
and recrystallized from ethanol/benzene, to
give compounds 23a, b.
7-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-
oxoethoxy)-4-phenyl-2H-chromen-2-one
(23a).
Yield: 80%; mp: 156O
C; IR (vcm-1
): 1756,1706 (2C=O);
1H-NMR ( ppm): 2.22 (s, 3H,
CH3), 2.23 (s, 3H, CH3), 5.64 (s, 2H, OCH2),
6.26 (s, 1H, H-3), 6.99-7.58 (m, 9H, Ar-H and
CH-pyrazole); Anal. calcd. for C22H18N2O4: C
70.58, H 4.85, N 7.48. Found: C 70.52, H
4.80, N 7.45.
7-(2-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-2-
oxoethoxy)-4-phenyl-2H-chromen-2-one
(23b).
Yield: 75%; mp: 244OC; IR (vcm
-1): 1754,
1708 (2C=O); MS m/z (%): 436 (64); Anal.calcd. for C27H20N2O4: C 74.30, H 4.62, N
6.42. Found: C 74.28, H 4.59, N 6.40.
General procedure for the preparation of 7-
(2-(5-hydroxy-3-substituted-1H-pyrazol-1-yl)-
2-oxoethoxy)-4-phenyl-2H-chromen-2-one
(25a,b).
A mixture of 2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy)aceto-hydrazide (2; 0.002
mol) and ethyl acetoacetate or ethyl benzo-
ylacetate(0.002 mol) in 1,4-dioxane (10 ml)
and a catalytic amount of pyridine was
refluxed for 6 h, then the reaction mixture left
to cool. The white solid was filtered off and
recrystallized from DMF to give compounds
25a, b.
7-(2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)-2-
oxoethoxy)-4-phenyl-2H-chromen-2-one
(25a).
Yield: 80%; mp: 248OC; IR (vcm
-1): 3188
(OH) and 1716 (C=O);1H-NMR ( ppm):
1.99 (s, 3H, CH3), 4.79 (s, 2H, OCH2), 6.26
(s, 1H, H-3), 6.99-7.56 (m, 9H, Ar-H and CH-
pyrazole) and 10.29 (s, 1H, OH); MS m/z (%):
376 (12); Anal. calcd. for C21H16N2O5: C
67.02, H 4.28, N 7.44. Found: C 67.00, H
4.25, N 7.40.
7-(2-(5-hydroxy-3-phenyl-1H-pyrazol-1-yl)-2-
oxoethoxy)-4-phenyl-2H-chromen-2-one
(25b).
Yield: 82%; mp: 254OC; IR (vcm
-1): 3410
(OH) and 1704 (C=O); MS m/z (%): 438 (58);
Anal. calcd. for C26H18N2O5: C 71.23, H 4.14,
N 6.39. Found: C 71.19, H 4.11, N 6.35.
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General procedure for the preparation of
ethyl 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4-
phenyl-2H-chromen-7-yloxy)acetyl)-1H-
pyrazol-4(5H)-ylidene)hydrazinyl)benzoate
(28a) and 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-
4-phenyl-2H-chromen-7-yloxy)-acetyl)-1H-
pyrazol-4(5H)-ylidene)hydra-zinyl)benzoic
acid (28b).
A mixture of 2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy)aceto-hydrazide (2; 0.002 mol) and
ethyl 4-((1-ethoxy-1,3-dioxobutan-2-
yl)diazenyl)benzoate or 4-((1-ethoxy-1,3-
dioxobutan-2-yl)diazenyl)-benzoic acid
(0.002 mol) in dioxane (10 ml) and a catalytic
amount of pyridine was refluxed for 6 h, then
the reaction mixture left to cool for 28a, while
28b, the solid obtained on heating. The solid
product was filtered off, washed with ethanol
several times and recrystallized from the
proper solvent to give compounds 28a,b.
Ethyl 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4-
phenyl-2H-chromen-7-yloxy)-acetyl)-1H-
pyrazol-4(5H)-ylidene) hydrazinyl) benzoate
(28a)
Yield: 92%; mp: 150OC; IR (vcm
-1):
3248(NH) and1706 (C=O);1H-NMR ( ppm):
1.32 (t, 3H, CH3), 2.16 (s, 3H, CH3), 4.26 (q,
2H, CH2), 4.63 (s, 2H, OCH2), 6.26 (s, 1H, H-
3), 6.97-8.00 (m, 12H, Ar-H) and 10.29 (s,
1H, NH); Anal. calcd. for C30H24N4O7: C
65.21, H 4.38, N 10.14. Found: C 65.19, H
4.35, N 10.13.4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4-phenyl-
2H-chromen-7-yloxy)-acetyl)-1H-pyrazol-
4(5H)-ylidene) hydrazinyl) benzoic acid
(28b).
Yield: 82%; mp: 290OC; IR (vcm
-1): 3250
(NH) and 1728, 1702, 1690 (3C=O);1H-
NMR ( ppm): 2.10 (s, 3H, CH3), 4.88 (s, 2H,
OCH2), 6.23 (s, 1H, H-3), 7.05-7.80 (m, 12H,
Ar-H), 10.70 (s, 1H, NH) and 12.38 (s, 1H,OH); Anal. calcd. for C28H20N4O7: C 64.12, H
3.84, N 10.68. Found: C 64.11, H 3.82, N
10.65.
5-amino-1-(2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy) acetyl)-1H-pyra-zole-3, 4-
dicarbonitrile (30).
A mixture of 2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy) aceto-hydrazide (2; 0.002
mol) and tetracyanoethelyene (0.002 mol) in
1,4-dioxane (10 ml) and a catalytic amount of
pyridine was refluxed for 2 h. The precipitate
formed was filtered off hot, washed with
ethanol several times, dried and recrystallized
from DMF to give compound 30 in 80%
yield; mp: 330O
C; IR (vcm-1
): 3327 (NH2),2214 (CN) and 1700 (C=O); MS m/z (%): 411
(23); Anal. calcd. for C22H13N5O4: C 64.23, H
3.19, N 17.02. Found: C 64.19, H 3.15, N
17.00.
Ethyl 5-amino-1-(2-(2-oxo-4-phenyl-2H-
chromen-7-yloxy) acetyl)-
1H-pyrazole-4-carboxylate (32).
A mixture of 2-(2-oxo-4-phenyl-2H-chromen-7-yloxy)aceto-hydrazide (2; 0.002 mol) and
ethoxymethylene ethyl cyanoacetate (0.002
mol) in 1,4-dioxane (10 ml) and a catalytic
amount of pyridine was refluxed for 7 h, then
the reaction mixture left to cool. The white
solid was filtered off, washed with ethanol
and recrystallized from a mixture of ethanol-
benzene. Compound 32 was obtained in 79%
yield; mp: 154OC; IR (vcm
-1): 3378 (NH2)
and 1700 (C=O); 1H-NMR ( ppm): 1.27 (t,
3H, CH3), 4.21 (q, 2H, CH2), 5.29 (s, 2H,
OCH2), 5.58 (s, 2H, NH2), 6.25 (s, 1H, H-3),
7.01-7.65 (m, 8H, Ar-H) and 7.85 (s, 1H, CH-
pyrazole); Anal. calcd. for C23H19N3O6: C
63.74, H 4.42, N 9.70. Found: C 63.71, H
4.40, N 9.67.
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2-(5-((2-oxo-4-phenyl-2H-chromen-7-yloxy)
methyl)-1, 3, 4-oxadiazol-2(3H)-ylidene)
malononitrile (35).
A mixture of 2-(2-oxo-4-phenyl-2H-chromen-
7-yloxy)aceto-hydrazide (2; 0.002 mol) and 2-(bis(methylthio)methylene)-malononitrile
(0.002 mol) in 1,4-dioxane (10 ml) and a
catalytic amount of pyridine was refluxed for
2 h, the resulting solid on heating was
collected by filtration, washed with ethanol
several times and recrystallized from DMF to
give compound 35 in 75% yield; mp: 252OC;
IR (vcm-1
): 3248(NH), 2210 (CN) and
1702(C=O);1H-NMR ( ppm): 4.79 (s, 2H,
OCH2), 6.26 (s, 1H, H-3), 6.99-7.57 (m, 8H,
Ar-H) and 10.28 (s, 1H, NH); Anal. calcd. for
C21H12N4O4: C 65.62, H 3.15, N 14.58.
Found: C 65.59, H 3.13, N 14.54.
Pharmacology
(2,2-diphenyl-1-picrylhydrazyl) (DPPH)
Radical Scavenging Activity
In the DPPH assay, antioxidants reduce the
free radical 2, 2-diphenyl-1- picrylhydrazyl.
In the presence of an antioxidant, the purple
color of DPPH
fades and the change of
absorbance can be followed
spectrophotometrically at 515 nm [39].
Test compounds are dissolved in N, N-
dimethylformamide (DMF) solution to
specific concentrations and each sample was
mixed with DPPH in DMF solution, the blank
sample contains the same amount of DMF
and DPPH. The mixtures were left for 15 min
at 25 C then the absorbance measured at 517
nm using the UV-VIS spectrophotometer.
Generally, the results are reported as the
percent of inhibition, mean that, the amount
of antioxidant necessary to decrease the initial
DPPH
concentration by 50 %. The
percentage of DPPH radical scavenger was
calculated using this equation: [(A0At)/A0]x100, where A0 is the absorbance value of
blank sample, at a particular time and At is the
absorbance value of the tested sample. The
IC50 (concentration causing 50% inhibition of
DPPH) values of each test compound are
determined. Ascorbic acid can be used as
positive controls.
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How to cite this article:
Mahmoud Mohamed Abd El-All , Ahmed Hamdy Halawa , Ahmed Abd El-Hameed Hassan ,
Mohamed Ahmed El-Nassag , Gehad Abd El-Raheem Abd El-Jaleel , Essam Mohamed Eliwa,
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