J.

Atoms and Molecules/ 3(4); 2013 / 537552 Research Article

Eliwa ME et al

Journal of Atoms and Molecules

An International Online Journal
ISSN 2277 1247

SYNTHESIS AND ANTIOXIDANT ACTIVITY OF SOME DERIVATIVES OF 2-(2-OXO-4PHENYL-2H-CHROMEN-7-YLOXY) ACETO-HYDRAZIDE Mahmoud Mohamed Abd El-All 1,2, Ahmed Hamdy Halawa 1, Ahmed Abd El-Hameed Hassan 1,3, Mohamed Ahmed El-Nassag 1, Gehad Abd El-Raheem Abd El-Jaleel 4, Essam Mohamed Eliwa1* , Ahmed Hammam Bedair 1
1

Chemistry Department, Faculty of Science, AlAzhar University, 11284, Nasr City, Cairo, Egypt 2 Chemistry Department, Faculty of Science and Art, Al-Baha University, 1988, Al-Baha, Saudi Arabia 3 Chemistry Department, Faculty of Medicine, Jazan University, 82621, Jazan, Saudi Arabia 4 Pharmacology Department, National Research Center, 12622, Dokki, Cairo, Egypt Revised on: 18-07-2013 Accepted on: 28072013

Received on: 03-06-2013 ABSTRACT:

A novel series of compounds containing coumarinyl moiety derivatives from 2-(2-oxo-4-phenyl2H-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 7 revealed 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 their biological 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], antiHIV [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 of hydrazides have been reported to be of biological interest [19, 20], while oxadiazole All rights reserved 2011 www.jamonline.in 537

* Corresponding author Essam Mohamed Eliwa, Email: esam_mohamed453@yahoo.com Tel : +2.0128.5126895

J. Atoms and Molecules/ 3(4); 2013 / 537552 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-(2oxo-4-phenyl-2H-chromen-7-yloxy) acetate (1) [33] with hydrazine hydrate in ethanol at refluxing temperature, 2-(2-oxo-4-phenyl-2Hchromen-7-yloxy) acetohydrazide (2) was obtained in good yield (Scheme 1).

Eliwa ME et al 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 4aminobenzoic acid in acetonitrile as a medium containing a few drops of acetic acid gave 4((2-(2-(2-oxo-4-phenyl-2H-chromen-7yloxy)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-7yloxy) 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, 4oxadiazol-2-yl) methoxy)-4-phenyl-2Hchromen-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-(2All rights reserved 2011

(2-oxo-4-phenyl-2H-chromen7yloxy)acetyl)benzenesulfonohydrazide (7), while when 2 reacted with proper substituted benzoyl chlorides namely (4-chloro and 3,5dinitrobenzoyl chloride) in refluxing dioxane in the prese-nce of pyridine yielded 4-chlorowww.jamonline.in 538

J. Atoms and Molecules/ 3(4); 2013 / 537552 N'-(2-(2-oxo-4-phenyl-2H-chrom-en-7yloxy)acetyl)benzohydrazide (8a) and 3,5dinitro-N'-(2-(2-oxo-4-phenyl-2H-chromen-7yloxy)acetyl)benzohydrazide (8b), respectively. Moreover, when 8a was heated with phosphorousoxychlo-ride at 120 0C, gave 1, 3,

Eliwa ME et al 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 corresponding 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'-(4Substitutedbenzylidene)-2-(2-oxo-4-phenyl2H-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., mixed m.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)-1Hpyrazol-3(2H)-one (18) (Scheme 3).

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J. Atoms and Molecules/ 3(4); 2013 / 537552

Eliwa ME et al

Scheme 3 The reactivity of 2-(2-oxo-4-phenyl-2Hchromen-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-(5amino-3-hydroxy-1H-pyrazol-1-yl)-2oxoethoxy)-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 and tautomerization 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-5substitu-ted-1H-pyrazol-1-yl)-2-oxoethoxy)4-phenyl-2H-chromen-2-one (23a,b) and 7(2-(5-hydroxy-3-substituted-1H-pyrazol-1yl)-2-oxoe-thoxy)-4-phenyl-2H-chromen-2one (25a,b), respectively. The formation of these compounds was probably occurring through the mechanism outline in scheme 4.

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J. Atoms and Molecules/ 3(4); 2013 / 537552 The diazo-coupling of aryl diazonium chlorides with ethylace-toacetate in alcoholic sodium acetate solution resulted in the formation 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-4phenyl-2H-chromen-7-yloxy)acetyl)-1Hpyrazol-4(5H)-ylidene)-hydrazinyl)be-nzoate (28a) and 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo4-phenyl-2H-chromen-7-ylo-xy)acetyl)-1H-

Eliwa ME et al 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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J. Atoms and Molecules/ 3(4); 2013 / 537552 Scheme 4 Moreover, the reaction of hydrazide 2 with tetracyanoethyl-ene and ethoxymethylene ethyl cyanoacetate in dioxane-pyridine under reflux furnished the products which identified as: 5-amino-1-(2-(2-oxo-4-phenyl-2Hchromen-7-yloxy)acetyl)-1H-pyrazole-3,4dicarbonitrile (30) and ethyl 5-amino-1-(2-(2oxo-4-phenyl-2H-chro-men-7-yloxy)acetyl)1H-pyrazole-4-carboxylate (32) respectively. The reaction pathway is assumed to proceed via addition of 2 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).

Eliwa ME et al 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 and 1H-NMR spectra. In addition, 1H-NMR spectrum clearly shows the loss of both methylthio groups leading to 2-(5-((2-oxo-4phenyl-2H-chromen-7-yloxy) methyl)-1, 3, 4oxadiazol-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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J. Atoms and Molecules/ 3(4); 2013 / 537552 Scheme 5 Pharmacology Antioxidant Activity

Eliwa ME et al 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 positive control and appreciated by the determination of the IC50 values. The results are listed in Table 1.

Antioxidant compounds in food play an important 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 Table 1: Values of IC50 exhibited by test compounds. Entry 1 Cpd.No. 5 Conc. (g/mL) 250 500 750 1000 250 500 750 1000 250 500 750 1000 250 500 750 1000 250 500 750 1000 250 500 750 1000 250 500 750 1000 250 500 750 1000 250 500 750 1000 % inhibition 13.69 20.98 20.61 20.61 24.05 37.27 43.88 51.62 13.91 15.66 19.30 24.54 20.90 24.54 31.32 33.21 7.50 12.02 14.06 16.17 28.40 31.54 34.45 38.82 25.05 32.12 38.46 41.59 13.08 21.24 35.30 42.33 14.64 15.51 16.53 24.62

IC50(g/mL) 52838

950

8a

9647

10

4126

11

15535

12a

4649

14

1816

21

1278

23a

16440

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J. Atoms and Molecules/ 3(4); 2013 / 537552 250 500 750 1000 250 500 750 1000 250 500 750 1000 250 500 750 1000 20.98 29.21 35.54 38.09 12.16 18.43 18.94 26.22 13.26 15.95 17.70 23.53 65.55 75.89 78.22 83.10

Eliwa ME et al

10

28a

2101

11

32

5723

12

35

12639

Std.

Ascorbic acid

91.45

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 quantitatively measured 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). The 1H 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 All rights reserved 2011

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: 188 OC; IR (vcm1 ): 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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J. Atoms and Molecules/ 3(4); 2013 / 537552 N'-formyl-2-(2-oxo-4-phenyl-2H-chromen-7yloxy) acetohydrazide (3). A solution of 2-(2-oxo-4-phenyl-2Hchromen-7-yloxy)aceto-hydrazide (2; 0.002 mol) in formic acid (20 ml) was refluxed for 1 h.The solvent was evaporated and residue was recrystallized from ethanol to give compound 3 in 82% yield; mp: 160 OC; 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 C18H14N2O5: 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-7yloxy) 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 5 hours. 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: 298 OC; IR (vcm-1): 3366 (OH), 3262 (NH) and 1692 (C=O); 1H-NMR ( ppm): 4.84 (s, 2H, OCH2), 6.26 (s, 1H, H3), 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-7yloxy) acetohydrazide (5). Compound 2 (0.002 mol) was refluxed in acetic acid (20 ml) for 5 h. The precipitate formed after cooling was collected by filtration and recrystallized from dioxane to give compound 5 in 77% yield; mp: 210 OC; All rights reserved 2011

Eliwa ME et al 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), 6.257.56 (m, 8H, Ar-H) and 9.84, 10.29 (2s, 2H, 2NH); Anal. calcd. for C19H16N2O5: 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 slowly quenched 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: 128 OC; 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-chromen7-yloxy) acetyl) benzene-sulfonohydrazide (7). A mixture of 2-(2-oxo-4-phenyl-2H-chromen7-yloxy)aceto-hydrazide (2; 0.002 mol) and ptoluene 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 with ethanol several times and recrystallized from a mixture of ethanol-benzene. Compound 7 was obtained in 70% yield; mp: 224 OC; IR (vcm-1): 3290 (NH) and 1720 (C=O); 1HNMR ( 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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J. Atoms and Molecules/ 3(4); 2013 / 537552 General procedure for the preparation of Substituted-N'-(2-(2-oxo-4-phenyl-2Hchromen-7-yloxy) acetyl) benzohydrazide (8a, b). A mixture of 2-(2-oxo-4-phenyl-2Hchromen-7-yloxy) aceto-hydrazide (2; 0.002 mol) and benzoyl chloride derivatives namely (p-chlorobenzoyl chloride and 3, 5dinitrobenzoyl 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-chromen7-yloxy) acetyl) benzohydr-azide (8a). Yield: 90%; mp: 225 OC; IR (vcm-1): 3300 (NH), 3074 (CH-aromatic) and 1692 (C=O); 1 H-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-phenyl2Hchromen -7-yloxy) acetyl) benzo-hydrazide (8b). Yield: 88%; mp: 210 OC; 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-chromen7-yloxy) acetyl)-benzohydrazide (8a; 0.7 mmol) was fused with POCl3 (3 ml) at 120 OC for 1 h. The reaction mixture was slowly quenched into crushed ice with stirring and neutralized with 5% NaOH. The solid which separated after standing overnight was filtered, washed with cold water, dried and All rights reserved 2011

Eliwa ME et al recrystallized from ethanol/benzene to give compound 9 in 80% yield; mp: 132 OC; 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-2Hchromen-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 80 0C for 1h. The precipitate formed was filtered off hot, washed with ethanol several times, dried and recrystallized from ethanol/benzene, to give compound 10 in 90% yield; mp: 140 OC; 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-4phenyl-2H-chromen-7-yloxy) acetohydrazide (11). A mixture of 2-(2-oxo-4-phenyl-2Hchromen-7-yloxy)aceto-hydrazide (2; 0.002 mol) and p-nitroacetophenone (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 compound 11 in 95% yield; mp: 222 OC; 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. for C25H19N3O6: C 65.64, H 4.19, N 9.19. Found: C 65.62, H 4.16, N 9.15. www.jamonline.in 546

J. Atoms and Molecules/ 3(4); 2013 / 537552 General procedure for the preparation of N'(4-Substitutedbenzylidene)-2-(2-oxo-4-phenyl2H-chromen-7-yloxy) acetohydrazide (12a-c). A mixture of 2-(2-oxo-4-phenyl-2H-chromen7-yloxy)aceto-hydrazide (2; 0.002 mol) and benzaldehyde derivatives namely (pchlorobenzaldehyde, 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-phenyl2H-chromen-7-yloxy) aceto-hydrazide (12a). Yield: 95%; mp: 254 OC; IR (vcm-1): 3164 (NH), 1706 (C=O) and 1606 (CH=N); 1HNMR ( 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-4phenyl-2H-chromen-7-yloxy)-acetohydrazide (12b). Yield: 92%; mp: 218 OC; IR (vcm-1): 3188 (NH), 1720, 1684 (2C=O) and 1608 (CH=N); 1 H-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-phenyl2H-chromen-7-yloxy) aceto-hydrazide (12c). Yield: 97%; mp: 244 OC; 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.

Eliwa ME et al 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-(2oxo-4-phenyl-2H-chromen-7yloxy)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: 194 OC; 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)-1Hpyrazol-3(2H)-one (18). A mixture of 2-(2-oxo-4-phenyl-2Hchromen-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 compound 18 in 82% yield; mp: 98 OC; 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)-2oxoethoxy)-4-phenyl-2H-chromen-2-one (21). A mixture of 2-(2-oxo-4-phenyl-2H-chromen7-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 www.jamonline.in 547

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J. Atoms and Molecules/ 3(4); 2013 / 537552 resulting solid on heating was collected by filtration and recrystallized from dioxane to give com-pound 21 in 85% yield; mp: 245 O C; 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); 13C-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-chromen7-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)-2oxoethoxy)-4-phenyl-2H-chromen-2-one (23a). Yield: 80%; mp: 156 OC; 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.

Eliwa ME et al 7-(2-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-2oxoethoxy)-4-phenyl-2H-chromen-2-one (23b). Yield: 75%; mp: 244 OC; 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-2Hchromen-7-yloxy)aceto-hydrazide (2; 0.002 mol) and ethyl acetoacetate or ethyl benzoylacetate(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)-2oxoethoxy)-4-phenyl-2H-chromen-2-one (25a). Yield: 80%; mp: 248 OC; 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 CHpyrazole) 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)-2oxoethoxy)-4-phenyl-2H-chromen-2-one (25b). Yield: 82%; mp: 254 OC; 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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J. Atoms and Molecules/ 3(4); 2013 / 537552 General procedure for the preparation of ethyl 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo-4phenyl-2H-chromen-7-yloxy)acetyl)-1Hpyrazol-4(5H)-ylidene)hydrazinyl)benzoate (28a) and 4-(2-(3-methyl-5-oxo-1-(2-(2-oxo4-phenyl-2H-chromen-7-yloxy)-acetyl)-1Hpyrazol-4(5H)-ylidene)hydra-zinyl)benzoic acid (28b). A mixture of 2-(2-oxo-4-phenyl-2H-chromen7-yloxy)aceto-hydrazide (2; 0.002 mol) and ethyl 4-((1-ethoxy-1,3-dioxobutan-2yl)diazenyl)benzoate or 4-((1-ethoxy-1,3dioxobutan-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-4phenyl-2H-chromen-7-yloxy)-acetyl)-1Hpyrazol-4(5H)-ylidene) hydrazinyl) benzoate (28a) Yield: 92%; mp: 150 OC; 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, H3), 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-phenyl2H-chromen-7-yloxy)-acetyl)-1H-pyrazol4(5H)-ylidene) hydrazinyl) benzoic acid (28b). Yield: 82%; mp: 290 OC; IR (vcm-1): 3250 (NH) and 1728, 1702, 1690 (3C=O); 1HNMR ( 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

Eliwa ME et al 3.84, N 10.68. Found: C 64.11, H 3.82, N 10.65. 5-amino-1-(2-(2-oxo-4-phenyl-2H-chromen7-yloxy) acetyl)-1H-pyra-zole-3, 4dicarbonitrile (30). A mixture of 2-(2-oxo-4-phenyl-2Hchromen-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: 330 OC; 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-2Hchromen-7-yloxy) acetyl)1H-pyrazole-4-carboxylate (32). A mixture of 2-(2-oxo-4-phenyl-2H-chromen7-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 ethanolbenzene. Compound 32 was obtained in 79% yield; mp: 154 OC; 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, CHpyrazole); 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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J. Atoms and Molecules/ 3(4); 2013 / 537552 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-chromen7-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: 252 OC; 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) Radical Scavenging Activity (DPPH)

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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, Ndimethylformamide (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 All rights reserved 2011

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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 , Ahmed Hammam Bedair Synthesis and antioxidant activity of some derivatives of 2-(2-oxo-4phenyl-2H-chromen-7-yloxy) aceto-hydrazide J. Atoms and Molecules, 3(4), 2013 : 537 552. All rights reserved 2011 www.jamonline.in 552