Synthesis and anti-oxidant evaluation of some novel sulfa drugs

Article abstract of DOI:10.2174/1570180814666170607144811

Background: Curcumins were reported to possess anti-inflammatory and antiangiogenic. Furthermore, Curcumin is a very potent free radical scavenger than vitamin E. Moreover, cyanoacetamides were reported to possess, antimicrobial antifungal, insulin releasing, antiinflammatory and antitumor. Thus the present study focuses on the synthesis of some novel structure hybrids incorporating either curcumin or cyanoacetamide with sulphonamide, aiming to reach a more potent antioxidant agent. Methods: 4-arylazoenol derivatives 12-16 and E-hydrazo derivatives 19-23 were prepared and their structure was confirmed by variable spectra analysis. The newly synthesized compounds were screened for their antioxidant activity using ABTS and Bleomycin-dependent DNA damage methods. Results: Coupling of the diazonium salts 7-11 of different sulpha drugs with curcumin 1 or with cyanoacetamide 18 afforded the corresponding 4-arylazoenol derivatives 12-16 and E-hydrazo derivatives 19-23. Among all the synthesized compounds, 12-16, 18, 20 and 22 were the most potent antioxidant compounds. Conclusion: The objective of the present study was to synthesize and evaluate the antioxidant activity of some novel sulfonamides structure hybrids incorporating either curcumin or N-[4- (aminosulfonyl) phenyl]-2-cyanoacetamide moiety with the hope of discovering new structure serving as antioxidant agent. The data showed clearly that most of compounds displayed good in vitro antioxidant activities.

Full text of DOI:10.2174/1570180814666170607144811

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1425
Letters in Drug Design & Discovery, 2017, 14, 1425-1432
RESEARCH ARTICLE
ISSN: 1570-1808
eISSN: 1875-628X
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Synthesis and Anti-Oxidant Evaluation of Some Novel Sulfa Drugs
BENTHAM
S
CIENCE
Moustafa A. Gouda1,2,* and Belal H.M. Hussein1,3
2
1Department of Chemistry, Faculty of Science and Arts, Taibah University, Ulla, KSA; Department of Chemistry,
3
Faculty of Science, Mansoura University, El-Gomhoria Street, 35516, Mansoura, Egypt; Department of Chemistry,
Faculty of Science, Suez Canal University, Ismailia, Egypt
Abstract: Background: Curcumins were reported to possess anti-inflammatory and antiangiogenic.
Furthermore, Curcumin is a very potent free radical scavenger than vitamin E. Moreover,
cyanoacetamides were reported to possess, antimicrobial antifungal, insulin releasing, anti-
inflammatory and antitumor. Thus the present study focuses on the synthesis of some novel struc-
ture hybrids incorporating either curcumin or cyanoacetamide with sulphonamide, aiming to reach a
more potent antioxidant agent.
Methods: 4-arylazoenol derivatives 12-16 and E-hydrazo derivatives 19-23 were prepared and their
A R T I C L E H I S T O R Yꢀ
structure was confirmed by variable spectra analysis. The newly synthesized compounds were screened
Received: January 17, 2017
Revised: May 18, 2017
Accepted: May 22, 2017
for their antioxidant activity using ABTS and Bleomycin-dependent DNA damage methods.
Results: Coupling of the diazonium salts 7-11 of different sulpha drugs with curcumin 1 or with
cyanoacetamide 18 afforded the corresponding 4-arylazoenol derivatives 12-16 and E-hydrazo de-
rivatives 19-23. Among all the synthesized compounds, 12-16, 18, 20 and 22 were the most
potent antioxidant compounds.
DOI:
10.2174/1570180814666170607144811
Conclusion: The objective of the present study was to synthesize and evaluate the antioxidant
activity of some novel sulfonamides structure hybrids incorporating either curcumin or N-[4-
(aminosulfonyl) phenyl]-2-cyanoacetamide moiety with the hope of discovering new structure serv-
ing as antioxidant agent. The data showed clearly that most of compounds displayed good in vitro
antioxidant activities.
Keywords: N-[4-(aminosulfonyl)phenyl]-2-cyanoacetamide, sulphonamides, diazonium salt, anti-oxidant, curcumin, antifungal.
1. INTRODUCTION
antitumor properties [14]. Furtheremore, some sulfonamides
are reported as antibacterial [15], antifungal [16] and anti-
cancer agent [17]. They also have valuable application in
medicine for the treatment of Alzheimer’s disease [18].
Curcumin was reported to possess many biological prop-
erties such as anti-inflammatory and antiangiogenic activities
[1-3]. Furthermore, different types of antioxidants (vitamins
C and E, glutathione, lipoic acid, etc.) have chain oxidation
processes, causing thus a high scientific interest [4, 5]. Cur-
cumin is a more potent free radical scavenger when com-
pared with vitamin E [6]. Studies have shown that Curcumin
is a powerful scavenger of the superoxide anion, the hy-
droxyl radical, nitrogen dioxide and protects DNA against
singlet-oxygen-induced strand [7, 8].
In view of the above-mentioned facts and in continuation
of our interest in the synthesis of biologically active hetero-
cycles [19-23], the present study focuses on the synthesis of
some novel structure hybrids incorporating either curcumin
or cyanoacetamide with sulphonamide. This combination
was suggested to investigate the influence of such hybridiza-
tion and structure variation on the anticipated biological
activities, aiming to reach a more potent antioxidant agent.
Moreover, cyanoacetamides were used as a key interme-
diate to design different heterocyclic moiety with different
ring sizes [9]. In addition, many cyanoacetamide derivatives
have been reported to possess, antimicrobial [10], antifungal
[11], insulin releasing [12], anti-inflammatory [13], and
2. MATERIALS AND METHODS
2.1. General
Melting points were obtained on capillary melting point
apparatus and were uncorrected. Infrared (IR) spectra υ (cm-1)
were performed on a nicolet i55 FTIR Spectrophotometer
in Faculty of Science and Arts, Ulla, Taibah University,
*Address correspondence to this author at the Department of Chemistry,
Faculty of Science and Arts, Taibah University, Ulla, KSA; Tel: +2050
6432235; Fax: 05021876422; E-mail: dr_mostafa_chem@yahoo.com
1875-628X/17 $58.00+.00
©2017 Bentham Science Publishers

1426 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 12
Gouda and Hussein
1
KSA. The H-NMR and 13C-NMR spectra were determined
DMSO-d6) (δ/ppm): 184.1(C5), 183.7 (C3), 149.5 (C1), 148.3
(C5" ),147.9 (C5'), 146.7 (C4'), 146.4 (C4"), 143.5 (C4'"), 139.7
(C1'''), 136.2 (C7), 127.3 (C2"',C6'"), 126.3 (C1'), 125.6 (C1"),
122.8 (C2'", C6'"), 120.9 (C2), 119.9 (C2"), 117.7 (C2'), 116.8
(C6), 115.8 (C3'", 5"'), 115.7(C3'), 115.6 (C3"), 111.5 (C6"),
110.7 (C6'), 109.5 (C4), 55.7 (OCH3), 55.68 (OCH3); MS m/z
(rel. int.%) = 549 (M+-2, 13.3) 548 (33.3), 403 (40.0),
313(40.0), 253 (33.3), 66 (60.6),150 (13.3), 117 (100) 82
(66.7), 80(60.0 ), 58(46.7); Anal. Calc. For C27H25N3O8S: C,
58.79; H, 4.57; N, 7.62. Found: C, 58.75; H, 4.50; N, 7.55.
on a Bruker Spectrophotometer at 600 and 150 MHz respec-
tively, using TMS as an internal reference and DMSO-d6 as
solvent and were carried out in the king Abdulaziz Univer-
sity, KSA. Mass spectra (MS) were measured on 70 eV with
a Varian MAT 311 A Spectrometer. Elemental analyses (C,
H and N) were carried out at the Microanalytical Center of
Cairo University, Giza, Egypt. Biological activities were
carried out in Pharmacognosy Department, Faculty of Phar-
macy, Mansoura University, Mansoura, Egypt.
2.2.1.3. 4-((E)-((1E, 3E, 6E)-3-hydroxy-1-(4-hydroxy-3-
methoxyphenyl)-7-(3-hydroxy-4-methoxyph-enyl)-5-oxohepta-
1, 3, 6-trien-4-yl) diazenyl) N-acetyl-benzenesulfonamide 14
2.2. Experimental
2.2.1. General Procedure for the Synthesis of 4-arylazo
Curcumin 12-16
o
Yield: 73 %; reddish brown powder; m.p.: 247 C; IR
(νmax, cm−1): 1160, 1085 (SO2), 1508 (N=N), 1629 (C=C),
1634 (br, 2C=O), 3110, 3239 (NH, OH), 3422 (br, 2OH); 1H-
NMR (600 MHz, CDCl3/DMSO-d6) (δ/ppm): 2.00 (s, 3H,
CH3 ) 2.97 (br, 2H, 2OH phenolic), 3.94 (s, 3H, OCH3) ,
3.87(s, 3H, OCH3), 6.78-8.18 (m, 14H, Ar–H, 2CH=CH),
9.25 (br, 1H, NH) , 13.64 (br, 1H, OH enolic); 13C- NMR
(150 MHz, CDCl3/DMSO-d6) (δ/ppm): 184.1 (C5), 183.7
(C3), 169.3 (C7'"), 149.6 (C1), 149.5(C5"), 148.4(C5'), 147.8
(C4'), 146.8 (C4"), 144.2 (C4'"), 130.4 (C1'''), 129.8 (C7), 129.3
(C2"',C6'"), 129.0 (C1'), 128.9 (C1") 126.9 (C2'", C6'"), 122.5
(C2) 121.0 (C2'"), 119.6 (C2'),118.0 (C6), 116.7(C3'",5"'), 116.0
(C3'), 115.6 (C3"), 111.4 (C6"), 111.0 (C6'), 108.9 (C4), 55.9
(OCH3), 55.8 (OCH3), 23.4 (CH3). MS m/z (rel. int.%): 611
(M++H2O, 13.3), 150 (29.7), 135(62.2), 106 (46.0), 69
(54.0), 52 (100); Anal. Calcd. For C30H31N3O9S: C, 59.10; H,
5.13; N, 6.89. Found: C, 59.16; H, 5.08; N, 6.82.
A solution of NaNO2 (0.4 g, 5.8 mole in 5 mL H2O) was
added drop wise to a well cooled stirred solution of 4-
aminobenzenesulfonic acid 2 (0.87 g, 0.005 mol), p-
aminobenzenesulphonamide 3 (0.86 g, 0.00 5 mol), N-(4-
aminophenylsulfonyl) acetamide 4 (1.07 g, 0.005mol), 1-(4-
aminophenylsulfonyl) guanidine 5 (1.07 g,0 .005 mol) and 4-
amino-N-(4,6-dimethylpyrimidin-2-yl) benzenesulfonamide
6 (1.4 g, 0.005 mol) in a mixture of concentrated HCl (3 mL)
and H2O (3 mL ). The above cooled diazonium solution was
added slowly to a well stirred solution of curcumin 1 (1.84 g,
0.005 mol) in pyridine (25 mL). The reaction was stirred for
2 h. The formed precipitate was filtered off, dried and crys-
tallized from EtOH /benzene to give the sulpha derivatives
12, 13, 14, 15 and 16, respectively.
2.2.1.1. 4-((E)-((1E, 3E, 6E)-3-hydroxy-1-(4-hydroxy-3-
methoxyphenyl)-7-(3-hydroxy-4-methoxyphenyl)-5-oxohepta-
1, 3, 6-trien-4-yl) diazenyl) benzenesulfonic acid 12
2.2.1.4. 4-((E)-((1E, 3E, 6E)-3-hydroxy-1-(4-hydroxy-3-methoxy-
phenyl) -7-(3-hydroxy-4-methoxyphenyl) -5-oxohepta-1, 3,
6-trien-4-yl) diazenyl)1-(phenylsulfonyl) guanidine 15
o
Yield: 65%, reddish brown powder. m.p.: above 315 C;
IR (νmax, cm−1): 1097, 1177 (SO2), 1511 (N=N), 1592
(C=C), 1692 (C=O), 3373, 3424, 3504 (4OH); 1H NMR
(600MHz, CDCl3/DMSO-d6) (δ/ppm): 3.12 (br, 2H, 2 OH
phenolic), 3.77 (s, 3H, OCH3), 3.93(s, 3H, OCH3), 6.48-7.89
(m, 14H, Ar–H, 2CH=CH), 8.68 (br, 1H, OH acid ) 12.50
(br, 1H, OH enolic); 13C-NMR (150 MHz, CDCl3/DMSO-
d6) (δ/ppm): 184.2 (C5), 183.6 (C3), 147.9 (C1), 147.8 (C5"),
147.7(C5'), 143.7 (C4'), 143.4(C4"), 138.9 (C4'"),130.5 (C1'''),
139.2 (C7), 126.8 (C2"',C6'"), 125.1 (C1'), 124.6 (C1"), 122.9
(C2'", 6'"), 121.2(C2), 119.8 (C2"), 118.3(C2'), 116.1 (C6), 115.9
(C3'",5"'), 115.8 (C3'),115.7 (C3"), 111.4(C6"), 111.0 (C6'),
110.3 (C4) , 55.87 (2C, OCH3); MS m/z (rel. int.%): 552
(14.6, M+), 344 (14.6), 272 (12.2), 228 (17.1), 195 (22.0),
150 (46.3), 98 (58.5), 77 (56.1), 55 (100), 52 (58.8); Anal.
Calc. for C27H24N2O9S: C, 58.69; H, 4.38; N, 5.07; Found: C,
58.62; H, 4.33; N, 5.01.
o
Yield: 68 %; reddish brown powder; m.p.: 190 C; IR
(νmax, cm−1): 1090, 1210 (SO2), 1510 (N=N), 1634 (br,
1
2C=O), 3226, 3347 (NH2, NH, OH), 3442 (br, 2OH); H-
NMR (600 MHz, CDCl3/DMSO-d6) (δ/ppm): 3.37(br, 2H,
2OH, phenolic), 3.73 (s, 3H, OCH3), 3.84(s, 3H, OCH3),
6.44-7.99 (m, 14H, Ar–H, 2CH=CH), 8.65(br, 2H, NH2),
9.50 (br, 1H, NHSO2), 9.85 (br, 1H, =NH), 13.54 (br, 1H,
OH enolic); 13C-NMR (CDCl3/DMSOd6) (δ/ppm): 183.8
(C5), 183.0 (C3), 158.3 (C7'"), 149.5(C1), 149.2 (C5"),147.9
(C5'), 146.7 (C4'), 140.5 (C4"), 138.2, (C4'"), 135.9 (C1'''), 129.9
(C7), 127.1(C2"', C6'"), 126.4 (C1'), 125.7 (C1"), 124.9
(C2'",C6'"), 122.9 (C2) 121.0 (C2'"), 119.8 (C2'), 116.8 (C6),
115.8 (C3'",5"'), 115.7 (C3'), 111.5 (C3"), 110.7(C6"), 111.0
(C6'), 109.5 (C4), 55.7 (OCH3), 55.6 (OCH3). Anal. Calc. for
C29H31N5O8S: C, 57.13; H, 5.13; N, 11.49. Found: C, 57.13;
H, 5.13; N, 11.49. MS m/z (rel. int.%): 609.19 (31.6, M-
CH4), 520 (31.6), 356 (100), 313(31.6), 284(100), 166
(94.7), 149 (57.9), 128 (94.7)111 (52.6), 91 (63.2), 57 (63.2).
2.2.1.2. 4-((E)-((1E, 3E, 6E)-3-hydroxy-1-(4-hydroxy-3-
methoxyphenyl)-7-(3-hydroxy-4-methoxyphenyl)-5-oxohepta-
1, 3, 6-trien-4-yl) diazenyl)benzenesulfonamide 13
o
2.2.1.5. 4-((E)-((1E, 3E, 6E)-3-hydroxy-1-(4-hydroxy-3-
methoxyphenyl)-7-(3-hydroxy-4-methoxyphe-nyl)-5-oxohepta-
1,3,6-trien-4-yl)diazenyl)-N-(4,6-dimethylpyrimidin-2-yl) ben-
zene sulfonamide 16
Yield: 81 %; reddish brown powder; m.p.: above 320 oC;
IR (νmax, cm−1): 1096, 1154, (SO2), 1508 (N=N), 1629
(C=C), 1634 (br, 2C=O), 3240, 3259 (NH2, OH), 3443 (br,
Yield: 70 % ; reddish brown powder; m.p.: 177 C; IR
(νmax, cm−1): 1090, 1180, (SO2), 1508 (N=N) 1629 (C=C),
1634 (br, 2C=O), 3240, 3259, (NH2, OH), 3443 (br, 2OH);
1H-NMR (600 MHz, CDCl3/DMSO-d6 (δ/ppm): 3.40 (br,
2H, 2 OH phenolic), 3.89 (s, 3H, OCH3), 3.93 (s, 3H, OCH3),
6.43-7.870 (m, 14H, Ar-H, 2CH=CH), 9.51 (br, 2H, NH2),
13.55 (br, 1H, OH enolic); 13C-NMR (150 MHz, CDCl3/

Synthesis and Anti-Oxidant Evaluation of Some Novel Sulfa Drugs
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 12 1427
2OH); 1H- NMR (600 MHz, CDCl3/DMSO-d6) (δ/ppm):
2.26 (s, 3H, CH3), 2.30 (s, 3H, CH3), 3. 16 (br, 2H, 2 OH
phenolic), 3.78 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 6.46-8.10
(m, 14H, Ar–H, 2CH=CH), 9.25 (br, 1H, NH), 12.29 (br,
1H, OH enolic); 13C-NMR (CDCl3/DMSO-d6) (δ/ppm):
183.9 (C5), 183.0 (C3) 167.3 (C7'"), 156.3 (C8'",10''') , 149.6
(C1), 148.4 (C5"), 147.9 (C5'), 147.0 (C4'), 146.8 (C4"), 143.8,
(C4'"), 140.5 (C1'''), 136.4 (C7), 130.2 (C2"', C6'"), 129.9 (C1'),
126.5 (C1"), 125.3 (C2'", 6'"), 122.8 (C2), 119.7 (C2'"), 117.9
(C2'), 116.3 (C6), 116.1(C3'",5"'), 115.9 (C3'), 115.8 (C3"),
113.4 (C6"),111.3 (C6'), 111.2 (C9'"), 109.0 (C4), 55.8 (2C,
OCH3), 23.2 (2C, CH3). MS (m/z) (rel. int.%): 657 (13.0,
M+), 498 (21.7), 214 (13.0), 145(8.7), 122.6 (34.8),105
(39.1), 77 (34.8), 80 (60), 64 (100), 55(65); Anal. Calc. for
C33H31N5O8S: C, 60.26; H, 4.75; N, 10.65. Found: C, 60.20;
H, 4.71; N, 10.98.
144.2(C1'), 140.7(C4), 139.0 (C1), 138.8 (C4'), 127.0 (2C, C3'),
126.9 (2C, C2), 126.4 (2C, C3), 120.0 (2C, C2'), 115.9
(CN),109.5 (NH-N=C); MS m/z (rel. int. %): 406 ([M+-NH2],
0.6), 234 (2.5), 2224 (86.0), 198 (13.0), 173 (18.2), 172
(100), 156 (62.6), 108 (53.1), 92 (88.6), 77 (23.2), 57 (18.9),
52 (21.4); Anal. Calc. for C15H13N5O6S2: C, 42.65; H, 3.34;
N, 19.89. Found: C, 42.60; H, 3.28; N, 19.82.
2.2.2.3. (E)-2-cyano-N-(4-aminosulfonylphenyl)-2-(2-(4-N-
acetylaminosulfonylphenyl) hydrazono) acetamide 21
Yield, 82%; orange dye; mp: 305-307 oC; IR (KBr): νmax
,
cm-1: 1368, 1159 (SO2), 1534 (N=N), 2235(CN), 1671, 1711
1
(2C=O), 3187, 3224, 3367 (NH2, 3NH); H-NMR (DMSO-
d6) (δ/ppm): 1.92 (s, 3H, CH3), 6.95-8.01 (m, 8H, Ar–H),
9.88 (br, 2H, NH2), 11.77 (br,s, 1H, NHCO), 12.01 (br, 1H,
NH=N), 12.67 (br, 1H , NHSO2); 13C-NMR (DMSO-d6): δ
168.5(COacetyl), 159.0 (CO), 145.7 (C1'), 140.6 (C4), 138.7 (C1),
133.8 (C4'), 129.0 (2C, C3'), 126.4 (2C, C2), 119.9 (2C, C3),
115.8 (2C, C2'), 110.3 (CN), 110.2 (NH-N=C), 23.0(CH3).
Anal. For C17H16N6O6S2: C, 43.96; H, 3.47; N, 18.09. Found:
C, 43.96; H, 3.47; N, 18.09.
2.2.2. General procedure for the synthesis of 4((Z)-2-(2-(4-
arylhydrazono)-(2-cyanoacetamido) benzenesulfonamide
19-23
A well stirred solution of 4-aminobenzenesulfonic acid 2
(0.87 g, 0.005 mol ), p-aminobenzenesulphonamide 3 (0.86
g, 0.005 mol), N-(4-aminophenylsulfonyl) acetamide 4 (1.07
g, 0.005 mol), 1-(4-aminophenylsulfonyl) guanidine 5 (1.07
g, 0.005 mol) and 4-amino-N-(4,6-dimethylpyrimidin-2-yl)
benzene sulfonamide 6 (1.4 g, 0.005 mol) in a mixture of
concentrated HCl (3 mL) and H2O (3 mL ) was cooled in an
ice bath and then a solution of NaNO2 (0.4 g, 0.0058 mol in 5
mL H2O) was added drop wise. The above cooled diazonium
solution was added slowly to a well stirred solution of 4-(2-
cyanoacetamido) benzene sulfonamide 18 (1.2 g, 0.005 mol)
in pyridine (25 mL). The reaction mixture was stirred for 2
h. The crude product was filtered off, dried well and crystal-
lized from EtOH/benzene to give compounds respectively
19-23.
2.2.2.4.
(E)-2-cyano-N-(4-aminosulfonylphenyl)-2-(2-(4-
guanidinosulfonylphenyl) hydrazono) acetamide 22
o
Yield, 82%; Scarlet red dye; mp: 273-275 C; IR (KBr):
νmax, cm-1: 1391, 1136 (SO2), 1531 (N=N), 1630 (C=N),
1671 (C=O), 2222 (CN), 3189, 3231, 3336, 3381, 3425,
1
(2NH2, 4NH); H-NMR (DMSO-d6) (δ/ppm): 3.72 (br, 1H,
NH=C), 7.02 (br, 2H, C-NH2), 7.61-8.34 (m, 8H, Ar–H),
8.80 (br, 1H, NH-SO2), 8.81 (br, 2H, SO2NH2), 9.88 (br, 1H,
NH=N) 11.83 (br, 1H , NHCO); 13C-NMR (DMSO-d6)
(δ/ppm): 159.6 (CO) , 143.5 (C=NH), 142.0 (C1'), 140.9 (C4),
138.6 (C1), 126.7 (C4'), 126.3 (2C, C3'), 126.2 (2C, C2), 119.9
(2C, C3), 115.4 (2C, C2'), 110.7. (CN), 108.0 (NH-N=C);
MS: m/z (rel. int.%): 438 ([M+-CN], 14.6), 373 (1.3), 272
(12.2), 320 (2.6), 268 (4.8), 249 (2.3), 223 (10.4), 172 (65.9),
156 (42.1), 108 (24.4), 92 (42.5), 85 (48.4), (58.5), 71 (51.5),
57 (100), 52 (3.2); Anal. for C16H16N8O5S2: Calc. C, 41.37;
H, 3.47; N, 24.12. Found: C, 41.30; H, 3.41; N, 24.20.
2.2.2.1. (E)-4-(2-(2-N-(4-aminosulfonylphenyl)-amino-1-cyano-
2-oxoethylidene) hydra zinyl) benzene sulfonic acid 19
o
Yield, 67%; Yellow sheet; mp: 304-305 C; IR (KBr):
νmax, cm-1: 1155, 1329 (SO2), 1532 (N=N), 1674 (C=O),
1
2.2.2.5. (E)-2-cyano-N-(4-aminosulfonylphenyl)-2-(2-(4-N-
2222 (CN), 3181, 3233, 3325, 3397 (OH, NH2, 2NH); H-
(4,6-dimethylpyrimidin-2-yl)
hydrazono) acetamide 23
aminosulfonylphenyl)-
NMR (DMSO-d6) (δ/ppm): 6.50-8.53 (m, 8H, Ar–H), 9.76
(br, 2H, NH2), 11.92 (br, 1H, NH=N), 12.72 (br, 1H,
NHCO), 13.85 (br, 1H, HO); 13C-NMR (DMSO-d6) (δ/ppm):
158.1(CO), 148.3(C1'), 143.8(C4'), 140.8(C4), 128.5(2C, C3'),
127.3(2C, C2), 123.8 (2C, C3)119.9(2C, C2'), 115.7(CN),
109.1(NH-N=C) ; MS m/z (rel. int.%): 342 (M+-SO3H, 0.1),
223 (1.2), 197 (0.5), 97 (0.7), 79 (100), 71 (2.5), 51 (22.6),
50 (18.9. Anal. Calcd. for C15H13N5O6S2: C, 42.55; H, 3.09;
N, 16.54. Found: C, 42.50; H, 3.01; N, 16.64.
o
Yield, 82%; orange dye; mp: above 315 C; IR (KBr):
νmax, cm-1: 1157, 1337, (SO2), 1523 (N=N), 1625 (C=N),
1677 (C=O), 2217(CN), 3185, 3237, 3364 (2NH2, 4NH),).
1H-NMR (DMSO-d6) (δ/ppm): 2.24 (br, s, 6H, 2CH3),
6.55(s, 1H, CHpyrimidine), 7.01-7.87 (m, 10H, Ar–H, NH2), 8.87
(br, 1H, NH), 9.92 (br, 1H, NHCO), 12.00 (s,1H, NH-N=C);
13C-NMR (DMSO-d6) (δ/ppm): 167.1(C2 pyrimiidine), 159.2
(2C, C4,6 pyrimiidine), 156.1 (CO), 145.8 (C1'), 141.3 (C4), 138.7
(C1), 129.4 (C4'), 127.0 (2C, C3'), 126.2 (2C, C2), 120.0 (2C,
C3), 115.4 (2C, C2'), 113.3 (CN), 110.4 (C5 pyrimiidine), 109.7
(NH-N=C), 22.9(2C, 2CH3). MS: m/z (rel. int.%): 328 (0.1,
M+- 4-N-carbonylaminobenzenesulfon-amide), 260 (0.5), 221
(0.6), 199 (0.5, 4-N-carbonylaminobenzenesulfonamide),
191 (0.8), 172 (4.5), 126(19.8), 98 (11.6), 82(13.9), 77 (100),
71 (20.5), 52 (41.3); Anal. for C21H20N8O5S2: C, 47.72; H,
3.81; N, 21.20. Found: C, 47.66; H, 3.75; N, 21.14.
2.2.2.2.
(E)-2-cyano-N-(4-aminosulfonylphenyl)-2-(2-(4-
aminosulfonylphenyl) hydrazono)-acetamide 20
Yield, 82%; scarlet red dye; mp: above 315 oC; IR (KBr):
νmax, cm-1: 1156, 1340 (SO2), 1530 (N=N), 1672 (C=O),
2229 (CN), 3190, 3247, 3345, (2NH2, 2NH); 1H-NMR
(DMSO-d6o(δ/ppm): 6.90-7.94 (m, 8H, Ar–H), 9.89 (br, 2H,
NH2), 11.99 (br, 1H, NH2), 12.27 (br, 1H, NH=N), 12.67 (br,
1H, NHCO); 13C-NMR (DMSO-d6) (δ/ppm): 159.1(CO),

1428 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 12
Gouda and Hussein
2.3. Pharmacological Studies
methyl and methoxy protons respectively, three broad sig-
nals at δ 3.16, 9.25, 12.29 ppm due to 2phenolic OH, NH
and enolic OH protons respectively and the aromatic protons
at δ = 6.46-8.10. Furthermore, 13C-NMR spectrum showed
three signals at δ 109.0, 55.8 and 23.2 ppm due to (C4), (2C,
OCH3) and (2C, CH3). Its mass spectrum displayed the mo-
lecular ion peak at m/z 657 corresponding to a molecular
formula C33H31N5O8S.
More details about the ABTS Screening Assay [24] and
the Bleomycin-dependent DNA damage assay [25, 26] are
presented in literature [19-22].
3. RESULTS AND DISCUSSION
3.1. Chemistry
Furthermore, coupling reaction of 18, which was pre-
pared in a high yield and purity via cyanoacetylation of 3
with 3, 5-dimetyl-1-cyanoacetyl Pyrazole 17 [27] through
the modification of the reported procedure [28] with of dia-
zonium salts 7-11 to afford the corresponding E-hydrazo
derivatives 19-23 (Scheme 2).
The synthetic strategies adopted to obtain the correspond-
ing sulpha derivatives are depicted in Schemes 1 and 2.
Fadda et al. [23], synthesized a new azodisperse dyes via
coupling of curcumin 1 different aromatic diazonium chlo-
rides. These dyes are capable of dyeing different types of
fibers, also they showed a wide spectrum of biological activ-
ity [23]. Consequently, the authors decided to couple the
diazonium salts of different sulpha drugs with curcumin 1,
aiming to reach a more potent antioxidant agent. Thus, cur-
cumin 1 coupled with the diazonium salts 7-11 to afford the
corresponding 4-arylazo derivatives 12-16 (Scheme 1).
The analytical and spectral data of Sulfonamide deriva-
tives 19-23 showed clearly that compounds 19-23 were
found in the E-hydrazo forms. Compound 25 was taken as a
typical example of the series prepared, revealed absorption
bands in the IR spectrum at (3425, 3381, 3336, 3231, 3189)
2222, 1671, 1630 1531 and (1391, 1136) cm−1 corresponding
to (2NH2, 4NH), (CN), (C=O), (C=N), (N=N) and (SO2)
The structure of curcumin derivatives 12-16 was eluci-
dated based on its analytical and spectral data. The analytical
and spectral data of curcumin derivatives 12-16 showed
clearly that compounds 12-16 were found in the enolazo-
forms. IR spectrum of compound 16 taken as a typical ex-
ample of series prepared, revealed absorption bands at (1096,
1154), 1508, 1629, 1634 (br) and (3240, 3259, 3443) cm−1
corresponding to SO2, N=N, C=C and 2C=O, (3OH, NH)
1
functions, respectively. Its H-NMR spectrum showed six
broad singlet signals at δ 3.72, 7.02, 8.80, 8.81, 9.88 and
11.83 ppm due to NH=C, C-NH2, NH=N, NH-SO2, SO2NH2
and NHCO protons in addition to aromatic protons at δ 7.61-
8.34 ppm. Furthermore, its 13C-NMR signals at 110.7 at
108.0 due to (CN), (NH-N=C) carbons respectively. Moreo-
ver, its mass spectrum showed the molecular ion peak at m/z
438 (M+-CN) which in agreement with the molecular for-
mula C16H16N8O5S2.
1
groups, respectively. Its H-NMR spectrum displayed four
singlet signals at δ= (2.26, 2.30) and (3.78, 3.92) ppm due to
O
OH
NH2
N2Cl
NaNO2/HCl
OH
1
HO
OMe
OMe
pyridine
SO2NHR
SO2NHR
2-6
7-11
2, 7, 12: NHR=OH
H
4
O
O
1
7
2"
2'
1'
3, 8, 13 : R=H
1"
3"
5
3'
4'
3
2
6
4, 9, 14: R= COCH3
N
5"
OMe
6"
4"
HO
5'
OMe
6'
N
1"'
OH
NH
2'"
5, 10, 15: R=
6"'
NH2
4'"
3"'
5'"
7"'
SO2NHR
N
N
6, 11, 16: R=
10'"
9"'
8"'
CH3
12-16
H3C
Scheme 1. Synthesis of curcumin derivatives 12-16.

Synthesis and Anti-Oxidant Evaluation of Some Novel Sulfa Drugs
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 12 1429
CH3
H
N
7-11
N
SO2NH2
dioxane
H2N
SO2NH2
+
H3C
N
NC
pyridine
O
CN
O
18
3
17
7, 19: NHR=OH
8, 20: R=H
N
3'
H
2'
1'
O
N
4'
9, 21: R= COCH3
10, 22: R=
N
NH
3
O
NH
2
S
4
NH2
NHR
O
1
O
S
7"
H2N
(E- hydrazo)
O
11, 23: R=
N
N
8"
CH3
10''
9''
19-23
H3C
Scheme 2. Synthesis of sulfonamide derivatives 19-23.
3.2. Pharmacology
The results, Table 1, Showed that most of compounds
anchored to curcumin moiety 12-16 displayed good antioxi-
dant compared with ascorbic acid as shown in Table 1.
3.2.1. ABTS Antioxidant Assay
The newly synthesized compounds were screened for
their antioxidant activity using ABTS method which was
reported by Lissi et al. [24].
On the other hand, curcumin 1 exhibited higher activity
than the ascorbic acid. Furthermore, compounds 18, 20 and
22 have good antioxidant activity. Whereas, compound 21
Table 1. Assay for ABTS Antioxidant activity and Bleomycin-dependent DNA damage.
Compound No.
Absorbance
ABTS
%Inhibition
Bleomycin-dependent DNA damage
Absorbance
Control
0.500
0.061
0.011
0.418
0.129
0.120
0.131
0.066
0.091
0.089
0.398
0.058
0.162
0.079
0.320
0.00
-----
Ascorbic Acid
87.80
97.78
16.40
75.42
77.14
75.04
87.42
82.66
82.20
20.40
88.40
67.60
84.20
36.00
0.062
0.052
0.086
0.094
0.052
0.088
0.105
0.077
0.750
-------
0.055
------
1
3
12
13
14
15
16
18
19
20
21
22
23
0.083
-------
% Inhibition= [A (control) - A (test)/ A (control)] X 100 Eqn. (1)
A (control): Absorbance for ascorbic acid
A (test): Absorbance for the tested samples
Control: Ascorbic acid.

1430 Letters in Drug Design & Discovery, 2017, Vol. 14, No. 12
Gouda and Hussein
O
OH
HO
OH
OH
OH
O
O
HO
OMe
OH
OMe
ascorbic acid
presence of phenolic OH and,
unsaturated ketone enhance
the anti-oxidant activity
OH
O
OH
O
N
N
OH
HO
N
OM e decrease the electron
OMe
N
OH
HO
availability on SO2NH2
decrease the anti-oxidant activity
OMe
OM e
SO2N H2
SO2NHCOCH3
OH
OH
presence of sulphonamide moiety
O
O
enhance the antioxidant activity
HO
N
N
OH
H O
N
N
OH
OM e
OMe
OMe
OM e
SO2NHR
SO2OH
Fig. (1). Structure activity relationship of the more potent antioxidant compounds.
copound 20 more potent than
O
OHHO
N
ascorbic acid due to presence
N
SO2NH2
HO
H
HN
HN
of 2SO2NH2 moiety
CN
20
O
OH
O
H2NO2S
O
N
N
SO2NH2
H
H
N
SO2NH2
NC
CN
20-23
O
18
RHNO2S
cyanoacetylation of NH2
group enhance the anti-oxidant
activity of compound 3
presence of sulphonamide moiety
enhance the antioxidant activity
O
H2N
SO2NH2
N
N
SO2NH2
H
HN
3
CN
19
HO3S
Fig. (2). Structure activity relationship of the more potent antioxidant compounds.
has moderate antioxidant activity and the rest of compounds
have weak activities.
more potent anti-oxidant compounds 1, 12, 13, 14, 15, 16, 18,
20 and 22. The results in Table 1 showed that compounds 1
(0.052) and 20 (0.055) exhibited high protection against
DNA damage induced by the bleomycin iron complex than
Ascorbic acid, thus, diminishing chromogen formation be-
tween the damaged DNA and TBA molecules [27, 28].
3.3. Bleomycin-dependent DNA Damage Assay
Furthermore, the protective activity against DNA damage
induced by bleomycin iron complex was examined for the

Synthesis and Anti-Oxidant Evaluation of Some Novel Sulfa Drugs
Letters in Drug Design & Discovery, 2017, Vol. 14, No. 12 1431
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CONCLUSION
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The objective of the present study was to synthesize and
evaluate the antioxidant activity of some novel sulfonamides
structure hybrids incorporating either curcumin or N-[4-
(aminosulfonyl) phenyl]-2-cyanoacetamide moiety with the
hope of discovering new structure serving as antioxidant
agent. The data showed clearly that most of the compounds
displayed good in vitro antioxidant activities.
[16]
CONSENT FOR PUBLICATION
Not applicable.
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Chem. Soc., 1998, 120, 10994-10995.
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Gouda, M.A.; Berghot, M.A.; Baz, E.A.; Hamama, W.S. Synthesis,
antitumor and antioxidant evaluation of some new thiazole and
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Res., 2012, 21, 1062-1070.
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antioxidant and antitumor evaluation of some new thiazolidine and
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Hamama, W.S.; Berghot, M.A.; Baz, E.A.; Gouda, M.A. Synthesis
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CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
[19]
[20]
We deeply appreciate the assistance of Dr. Ahmed
Abass, Pharmacognosy Department, Faculty of Pharmacy,
Mansoura University, Mansoura, Egypt for screening of the
biological activities of the tested compounds. This work
was supported by the Taibah University, Kingdom of Saudi
Arabia (Project no: 1435/6148, Year: 2014).
[21]
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