Antitumor activity of some novel 1,2,5-thiadiazole derivatives

Article abstract of DOI:10.1080/10426500801967815

Some novel thiourea,1,2,4-triazole, quinazoline, thieno[2,3-d]pyrimi-dine, and thiazolidine derivatives were synthesized to evaluate their antitumor activity. Compound (3f) is nearly as active as reference drug, (Doxorubicin) as positive control.

Full text of DOI:10.1080/10426500801967815

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Phosphorus, Sulfur, and Silicon
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Antitumor Activity of Some
Novel 1,2,5-Thiadiazole
Derivatives
Z. H. Ismail a , M. M. Ghorab b , E. M. A. Mohamed a
, H. M. Aly a & M. S. A. El-Gaby c
a Department of Chemistry, Faculty of
Science(Girls), Al-Azhar University, Cairo, Egypt
b Department of Drug Radiation Research, National
Center for Radiation Research and Technology, Nasr
City, Cairo, Egypt
c Department of Chemistry, Faculty of Science, Al-
Azhar University at Assiut, Assiut, Egypt
Published online: 26 Sep 2008.
To cite this article: Z. H. Ismail , M. M. Ghorab , E. M. A. Mohamed , H. M. Aly & M.
S. A. El-Gaby (2008) Antitumor Activity of Some Novel 1,2,5-Thiadiazole Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:10, 2541-2554, DOI:
10.1080/10426500801967815
To link to this article: http://dx.doi.org/10.1080/10426500801967815
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Phosphorus, Sulfur, and Silicon, 183:2541–2554, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801967815
Antitumor Activity of Some Novel 1,2,5-Thiadiazole
Derivatives
Z. H. Ismail,1 M. M. Ghorab,2 E. M. A. Mohamed,1
H. M. Aly,1and M. S. A. El-Gaby3
1Department of Chemistry, Faculty of Science(Girls), Al-Azhar
University, Cairo, Egypt
2Department of Drug Radiation Research, National Center for
Radiation Research and Technology, Nasr City, Cairo, Egypt
3Department of Chemistry, Faculty of Science, Al-Azhar University at
Assiut, Assiut, Egypt
Some novel thiourea,1,2,4-triazole, quinazoline, thieno[2,3-d]pyrimi-dine, and thi-
azolidine derivatives were synthesized to evaluate their antitumor activity. Com-
pound (3f) is nearly as active as reference drug, (Doxorubicin) as positive control.
Keywords 1,2,5-Thiadiazole; antitumor activity; pyrazole; quinazoline derivatives;
thiourea
INTRODUCTION
Pyrazole1 and 1,2,5-thiadiazole2,3 derivatives are biological impor-
tant compounds. Substituted 1,2,5-thiadiazoles were found to be
efficient muscarine4 receptor agonists as well as inhibitors of
HIV-1 replication.5 For example, 1-(1,1-dimethylethylamino)-3-(4-
morpholino-1,2,5-thiadiazol-3-ylo-xy)-2-propanol (Timolol) is one of the
most important medicines for treatment of glaucoma.6,7 Furthermore,
antibacterial,8 antifungal,9 insulin releasing,10 carbonic anhydrase
inhibitory,11 anti-inflammatory,12 and antitumor13properties of sul-
famoyl moiety were described. Having the above facts in mind, and in
continuation of our efforts to synthesize biologically active heterocyclic
compounds from readily available starting materials,14−17 we report
here on the synthesis and antitumor activity of some novel pyrazole
and 1,2,5-thiadiazole derivatives containing sulfamoyl moiety.
Received 11 December 2007; accepted 17 January 2008.
Address correspondence to M. S. A. El-Gaby, Department of Chemistry, Faculty of Sci-
ence, Al-Azhar University at Assiut, Assiut 71524, Egypt. E-mail: m elgaby@hotmail.com
2541

2542
Z. H. Ismail et al.
RESULTS AND DISCUSSION
Isothiocyanate derivatives are useful and widely used building blocks
in the synthesis of nitrogen, sulfur and oxygen heterocyclic compounds
and organometallic compounds of academic, pharmaceutical, and in-
dustrial interest.18,19 Isothio-cyanatosulfonamides (2a,b) were synthe-
sized by treatment of sulfonamide derivatives (1a,b) with thiophosgene
in the presence of dilute hydrochloric acid at room temperature in quan-
titative yields, Scheme 1.
SCHEME 1
The reactivity of isothiocyanates (2a,b) towards some nucleophilic
reagents was studied. Condensation of isothiocyanate derivative (2a)
with sulfonamide derivatives in refluxing dioxane in the presence of tri-
ethylamine furnished the 1,3-disubstituted thiourea derivatives (3a–i),
Scheme 2. The structures of compounds (3a–i) were supported by an-
alytical and spectral data. The infrared spectra of compounds (3a–i)
SCHEME 2

Antitumor Activity of Some Novel 1,2,5-Thiadiazole Derivatives
2543
showed the absence of N C S functional group in addition to the
presence of NH and SO2 functional groups. Mass spectrum of com-
pound (3a) revealed a molecular ion peak corresponding to the formula
C22H20N6O4S3 (M+ = 528; 28.21%) with a base peak at m/z 80 (100%),
Table I. Also, mass spectrum of compound (3e) showed a molecular ion
peak at m/z 609(31.7%) and the base peak was observed in the spectrum
at m/z 71(100%). Mass spectrum of compound (3f) revealed a molecular
ion peak at m/z 634(0.73%) with a base peak at m/z 52(100%), Chart
1
1. The H NMR spectrum of compound (3b; DMSO-d6) exhibited the
following signals: 1.87 (s, 3H, COCH3), 5.8, 6.56 (2s, 2H, pyrazole-H),
7.3 –7.58 (m, 14H, Ar-H+NH) and 9.8, 10.4, 11.6 ppm (3s, 3H, 3NH; ex-
1
changeable). Also, the H NMR spectrum of compound (3g; DMSO-d6)
showed the following signals: 2.3 (s, 3H, CH3), 5.9, 6.8 (2s, 2H, pyrazole-
H),7.3 –7.72 (m, 16H, Ar-H + NH) and 7.9,8.4,10.4 ppm (3s, 3H, 3NH;
exchangeable).
CHART 1 Mass fragmentation pattern of compound (3f).

2544
Z. H. Ismail et al.
TABLE I Spectral Data of the Newly Synthesized Compounds
(2a–13)
Compd. no.
IR / ν
(cm−1
)
m/z (%)
max
2a
3445 (NH), 3000 (CH-arom.),
2030 (NCS), 1586
(C N), 1345, 1163
(SO2).
356 (M+; 17.49%), 292 (11.10%),
256 (3.36%), 198 (9.31%),
158 (100%; base peak), 131
(33.46%), 97 (18.30%), 77
(38.60%), 55 (17.49%) .
328 (M+; 17.40%), 264 (43.98%),
231 (4.88%), 198 (61.96%),
167(7.97%), 134 (100%;
base peak), 111 (24.14%),
97 (37.02%), 71 (40.15%),
57 (41.79%).
2b
3226 (NH), 3099 (CH arom.),
2100 (NCS), 1555
(C N), 1332, 1162
(SO2).
3a
3b
3342, 3250 (NH2), 1592
(C N), 1326, 1156
(SO2).
528 (M+; 28.21%), 397 (46%),
321 (28%), 281 (56%), 199
(43%), 131 (41%), 80 (100%;
base peak).
3476, 3430 (2NH), 1708
(C O), 1592
—
(C N),1330, 1160
(SO2).
3c
3d
3e
3414, 3360 (NH2), 1630,
1590 (C N), 1328, 1162
(SO2).
3476, 3350, 3102 (3NH),
1620 (C N), 1398, 1148
(SO2).
3422, 3100 (2NH), 1592
(C N), 1392, 1160
(SO2).
—
—
609 (M+; 31.7%),213
(34%),130(31%), 86 (53%),
71 (100%; base peak), 64
(58%), 57 (58%).
3f
3450, 3394 (2NH), 3094
(CH-arom.), 1626
(C N), 1384, 1162
(SO2).
632 (M-2; 0.7%), 476 (0.8%), 356
(5.03%), 314 (4.1%), 255
(51%), 156 (40%), 134
(5.6%), 65 (88%), 52 (100%;
base peak).
3g
3h
3482, 3300 (2NH), 1564
(C N), 1328, 1158
(SO2).
3460, 3230 (2NH), 3076
(CH-arom.), 1592
(C N), 1390, 1158
(SO2).
—
670 (M+;0.51%), 551(4.51%),437
(1.54%), 367 (4.47%), 356
(8%), 250 (5.93%), 159
(100%; base peak).
3i
3464, 3380 (2NH), 1598
(C N), 1326, 1154
(SO2).
656 (M+; 0.7%), 592 (1.43%),
523 (6.4%), 495 (5.3%), 356
(27%), 277 (100%; base
peak), 236 (2%), 158 (98%),
77 (56%)

Antitumor Activity of Some Novel 1,2,5-Thiadiazole Derivatives
2545
TABLE I Spectral Data of the Newly Synthesized Compounds (2a–13)
(continued)
Compd. no.
IR / ν
(cm−1
)
m/z (%)
max
5
3398, 3350 (NH2), 2923 (CH-aliph.), 290 [M-(NHSO2+ NH2); 30%], 261
1627 (C N), 1334, 1141 (SO2).
(15%), 217 (19.6%), 213 (100%;
base peak), 185 (29%), 73
(0.5%).
—
7
9
3267 (NH), 3082 (CH- arom.), 2923
(CH- aliph.), 1651 (C N),
1323, 1157 (SO2).
3406, 3271, 3116 (3NH), 3062
(CH-arom.), 2931 (CH-aliph.),
1647 (C O), 1610 (C N),
1330, 1161 (SO2).
—
11
12
3429, 3332, 3224 (3NH), 2943
(CH-aliph.), 2198 (C≡N), 1620
(C N), 1330, 1134 (SO2).
506 (M+; 0.54%), 467 (0.7%),
411(2.5%), 395 (1.05%), 313
(2.8%), 266 (4.3%), 170 (0.3%),
150 (100%; base peak), 69(8%)
506 (M+; 10.54%), 465 (19%), 402
(23%), 348 (18%), 321 (100%;
base peak), 276 (58%), 174
(69%), 113 (93%), 69 (64%),
231 (56%).
3436, 3186 (2NH), 2935
(CH-aliph.),1596 (C N),1342,
1161 (SO2).
13
3222 (NH), 2983 (CH- aliph.), 1740
(C O), 1591 (C N), 1324,
1157 (SO2).
—
Refluxing of isothiocyanate derivative (2b) with thiosemicarb-azide
in ethanol in the presence of triethylamine afforded 3-amino-5-thioxo-
1H-1,2,4-triazole derivative (5) on the basis of analytical and spectral
data, Scheme 3. Its infrared spectrum showed the following absorption
bands: 3398, 3350 (NH, NH2), 2923 (CH-aliph.), and 1627cm−1(C =
N). Also, its mass spectrum revealed a molecular ion peak at m/z 290
[30%; M+-(NHSO2+ NH2)] and the base peak was found in the spec-
trum at m/z 213 (100%). The formation of triazole derivative (5) is as-
sumed to proceed via initial formation of the intermediate (4) followed
by elimination of hydrogen sulfide. Cyclocondensation of 3,5-dichloro-
anthranilic acid with isothiocyanate derivative (2b) under reflux in
dioxane in the presence of triethylamine yielded the corresponding
6,8-dichloro-4-oxo-2-thioxo-1,2-dihydroquinazoline derivative (7). The
molecular structure of (7) was identified by analytical and spectral
1
data. Its H NMR spectrum (DMSO-d6) showed the following signals:
4.01 (s, 3H, OCH3), 7.6 –8.2 (m, 7H, Ar-H + NH), and 11.1 ppm (s,
1H, NH; exchangeable). The formation of quinazoline derivative (7)

2546
Z. H. Ismail et al.
SCHEME 3
is assumed to proceed via the formation of thiourea inter-mediate (6)
followed by intramolecular cyclization through elimination of water,20
Scheme 3.
The novel thiourea derivative (9) was obtained when isothiocyanate
derivative (2b) was allowed to react with ethyl-2-amino-4,5,6,7-tetra-
hydrobenzo[b]thiophene-3-carbo-xylate (8a) in refluxing ethanol in the
presence of triethylamine. Trials to cyclize thiourea derivative (9) into
the corresponding thieno[2,3-d]pyrimidine derivative (10) under differ-
ent conditions failed. The molecular structure of thiourea derivative (9)
was readily established based on analytical and spectral data, Scheme
4. 1HNMR spectrum of ( 9; in DMSO-d6) showed the following signals:
1.3 (t, 3H, CH3), 1.6 (m, 8H, cyclohexyl), 4.0 (s, 3H, OCH3), 4.1 (q,
2H, CH2), 7.8 –8.0 (m, 4H, Ar-H), and 11.3, 11.8, 11.9 ppm (3s, 3H,
3NH; exchangeable). On the other hand, when isothiocyanate deriva-
tive (2b) was allowed to react with 2-amino-3-cyano-4,5,6,7-tetrahydro-
benzo[b]thiophene (8b) in ethanol in the presence of triethylamine
under reflux, the thiourea derivative (11) was obtained after cooling

Antitumor Activity of Some Novel 1,2,5-Thiadiazole Derivatives
2547
SCHEME 4
of the filtrate, while thieno[2,3-d]pyrimidine derivative (12) was sep-
arated while hot. The structures of compounds (11) and (12) are sup-
ported by their elemental analysis and spectral data. Infrared spec-
trum of compound(11) showed the presence of absorption band at 2198
cm−1 that is characteristic for C≡N functional group in addition to ab-
sorption bands due to NH group. Also, its mass spectrum afforded a
molecular ion peak at m/z 506 (M+; 0.54%) in addition to the base peak
at m/z 150(100%), Chart 2. The infrared spectrum of compound(12)
displayed the absence of C≡N functional group. Its mass spectrum fur-
nished a molecular ion peak at m/z 506 (10.64%) and the base peak
was found in the spectrum at m/z 321(100%), Chart 3. The formation
of thieno[2,3-d]pyrimidine derivative (12) is assumed to proceed via
the formation of thiourea derivative (11) followed by intramolecular
cyclization through nucleophilic addition of amino group to the cyano
group.
Isothiocyanate derivative (2b) was cyclized with sulfanyl-acetic acid
in refluxing acetic acid to furnish 2-thioxothiazolidine derivative (13),
Scheme 5. The structure of (13) was established via analytical and
spectral data. Its spectrum showed the following absorption bands:
3222 (NH), 2983, 2937(CH-aliph.), and 1740 cm−1(C O; thiazolidin-
one). Also, its 1H NMR spectrum (DMSO-d6) revealed the following
signals: 3.7(s, 3H, OCH3), 4.2 (s, 2H, CH2), and 7.2–8.1 ppm (m, 5H,
Ar-H + NH). The formation of thiazolidinone (13) is assumed to proceed
through initial nucleophilic attack of mercapto group to thiocarbanyl

2548
Z. H. Ismail et al.
CHART 2 Mass fragmentation pattern of compound (11).
CHART 3 Mass fragmentation pattern of compound (12).

Antitumor Activity of Some Novel 1,2,5-Thiadiazole Derivatives
2549
SCHEME 5
moiety of isothiocyanate followed by intramolecular cyclization via
dehydration.21
EXPERIMENTAL
All melting points are uncorrected and were determined on a Stuart
melting point apparatus. IR spectra were recorded on a Shimadzu-440
IR spectrophotometer using the KBr technique (Shimadzu, Japan). 1H
NMR spectra were measured on a BRUKER proton NMR-Avance 300
(300 MHz, spectrometer), in DMSO-d6 as a solvent, using tetramethyl-
silane (TMS) as an internal standard. The mass spectra were performed
by Hewlett Packard Model MS-5988 spectrometer. Elemental analyses
were carried out at the Microanalytical Unit, Faculty of Science, Cairo
University.
4-Isothiocyanato-N-(1-phenyl-1H-pyrazol-5-
yl)benzenesulfonam-ide (2a) and
4-isothiocyanato-N-(4-methoxy-1,2,5-thiadiazol-3-
yl)benzenesulfonamide (2b) General Procedure
Sulfonamide derivatives (0.01 mol) were dissolved in H2O (200 mL)
containing concentrated HCl (50 mL). To this of CSCl2 (0.012 mol was
added in one portion. Stirring began immediately and continued un-
til all of the red color of CSCl2 had disappeared 1h and the product
was precipitate as a white crystals. The resulting solid was filtered
off, dried, and recrystallized from acetone to give 2a,b, respectively,
(Table II).

2550
Z. H. Ismail et al.
TABLE II Characterization Data for Newly Synthesized Compounds
(2a–13)
Elemental analyses Calcd. (Found)
Compd.
no.
M.p.
(◦C)
Yield
(%)
Mol. formula
(mol.wt.)
C %
H %
N %
2a
2b
3a
3b
3c
3d
3e
3f
3g
3h
3i
118–120
148–150
152–154
132–134
180–182
230–232
110–112
142–144
125–126
134–136
128–130
230–232
220–222
148–150
224–226
118–120
213–215
85
90
85
81
83
85
80
84
85
83
85
69
81
76
40
48
79
C16H12N4O2S2
(356)
53.92
(53.60) (3.00)
36.57
(36.30)
49.99
3.39
15.72
(15.90)
17.06
(17.40)
15.90
(15.60)
14.73
(14.50)
19.64
(19.50)
16.03
(16.30)
16.08
(16.30)
17.65
(17.90)
18.05
(18.30)
16.70
(16.40)
17.06
(17.30)
25.44
(25.20)
13.56
(13.20)
12.65
(12.40)
16.59
(16.30)
16.59
(16.80)
13.92
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
10H8N4O3S3
2.46
(2.70)
3.81
(328)
22H20N6O4 S3
(528)
24H22N6O5 S3
(570)
23H22N8O4S3
(570)
25H21N7O4 S4
(611)
26H23N7O5 S3
(609)
28H26N8O4 S3
(634)
27H24N8O4 S3
(620)
31H26N8O4S3
(670)
30H24N8O4S3
(656)
11H11N7 O3S3
(385)
17H11Cl2N5O4S3
(516)
21H23N5O5S4
(553)
19H18N6O3S4
(506)
19H18N6O3S4
(506)
12H10N4O4S4
(402)
(49.80) (3.60)
50.51 3.89
(50.31) (3.70)
48.41 3.89
(48.30) (3.60)
49.08 3.46
(49.30) (3.20)
51.22 3.80
(51.40) (3.50)
52.98 4.13
(52.70) (4.40)
52.24 3.90
(52.60) (3.60)
55.51 3.91
(55.80) (3.60)
54.86 3.68
(54.60) (3.30)
34.28 2.88
(34.50) (2.50)
39.54 2.15
(39.30) (2.40)
45.55 4.19
(45.20) (4.50)
45.04 3.58
(45.40) (3.20)
45.04 3.58
(45.20) (3.40)
35.81 2.50
(35.51) (2.80)
5
7
9
11
12
13
(13.70)

Antitumor Activity of Some Novel 1,2,5-Thiadiazole Derivatives
2551
N-(1-phenyl-1H-pyrazol-5-yl)-4-(3-(4-
sulfamoylphenyl)thioureido)-benzenesulfonamide (3a),
N-(diaminomethylene)-4-(3-(4-(N-(1-phenyl-1H-pyrazol-5-yl)-
sulfamoyl)-phenyl)thioureido)benzene-sulfonamide(3b),
N-(4,6-dimethylpyrimidin-2-yl)-4-(3-(4-(N-(1-phe-nyl
1H-pyrazol-5-yl)sulfamoyl)phenyl)thioureido)benzenesulfon-
amide (3c),
N-(5-methylisoxazol-3-yl)-4-(3-(4-(N-(1-phenyl-1H-pyr-azol-5-
yl)sulfamoyl)phenyl)thioureido)benzenesulfonamide (3d),
N-(1-phenyl-1H-pyrazol-5-yl)-4-(3-(4-(N-thiazol-2-yl-
sulfamoyl)phe-nyl)-thioureido)benzenesulfonamide (3e),
N-(4-(3-(4-(N-(1-phenyl-1H-pyrazol-5-
yl)sulfamoyl)phenyl)thioureido)phenylsulfonyl)-acetamide (3f),
N-(4-methyl-pyrimidin-2-yl)-4-(3-(4-(N-(1-phenyl-1H-pyrazol-5-
yl)sulfamoyl)-phenyl)-thioureido)-benzenesulfon-amide (3g),
4,4’-thiocarbonyl-bis(azanediyl)-bis(N-(1-phenyl-1H-pyrazol-5-
yl)benzenesulfonamide) (3h) and
N-(1-phenyl-1H-pyra-zol-5-yl)-4-(3-(4-(N-quinoxalin-2-yl-
sulfamoyl)-phenyl)thioureido)-benzenesulfonamide (3i)
A mixture of isothiocyanate derivative 2a (0.01 mol) and sulfonamide
derivatives in dioxane (20 mL) containing triethyl-amine (0.5 mL) was
heated under reflux for 2 h. The reaction mixture then cooled and
poured into cold water and acidified with HCl. The solid product was
collected and recrystallized from dioxane to give 3a–i, (Table II).
4-(3-Amino-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)-N-(4-methoxy-
1,2,5-thiadiazol-3-yl) benzenesulfonamide (5)
A mixture of 2b (0.01 mol) and thiosemicarbazide (0.01 mol) in dioxane
(30 mL) containing a few drops of triethylamine was refluxed for 48 h.
The reaction mixture then cooled and poured into cold water and acidi-
fied with dilute HCl. The solid product was collected and recrystallized
from ethanol to give 5, (Table II).
4-(6,8-Dichloro-4-oxo-2-thioxo-1,2-dihydroquinazolin-3(4H)-yl)-
N-(4-methoxy-1,2,5-thiadiazol-3-yl)benzenesulfonamide (7)
A mixture of 2b (0.01 mol) and 3,5-dichloroanthranilic acid (0.01 mol) in
dioxane (20 mL) containing 3 drops of triethylamine was heated under
reflux for 1 h, filtered while hot and the solid obtained was recrystallized
from dioxane to gave 7, (Table II).

2552
Z. H. Ismail et al.
Ethyl-2-(3-(4-(N-(4-methoxy-1,2,5-thiadiazol-3-
yl)sulfamoyl)phen-yl)thioureido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxy-late (9)
A mixture of 2b (0.01 mole) and ethyl-2-amino-4,5,6,7-tetra-hydrobenzo
[b]thiophene-3-carboxylate 8a (0.01 mol) in ethanol (50 mL) containing
3 drops of triethylamine was heated under reflux for 3 h. The solid
obtained was recrystallized from dioxane to give 9, (Table II).
4-(3-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-
yl)thiourei-do)-N-(4-methoxy-1,2,5-thiadiazol-3-
yl)benzenesulfonamide (11) and
4-(2-Thioxo-1,2,5,6,7-hexahydrobenzo[4,5]thieno[2,3-d]pyr-
imidin-4-yl)-1-benzenesulfon amides (12)
A mixture of 2b (0.01 mol) and 2-amino-3-cyano-4,5,6,7-tetrahydro-
benzo[b]thiophene 8b (0.01 mol), in ethanol (50 mL) containing 3 drops
of triethyl-amine was refluxed for 3 h. The reaction mixture was fil-
tered while hot to give compound 12. The reaction mixture was diluted
with water. The solid product so formed was collected by filtration and
recrystallized to give 11, Table II.
N-(4-methoxy-1,2,5-thiadiazol-3-yl)-4-(4-oxo-2-thioxo-
thiazolid-in-3-yl)benzenesulfonamide (13)
A mixture of 2b (0.01 mol) and thioglycolic acid (0.01 mol) in dioxane (30
mL) containing a few drops of triethylamine was heated under reflux
for 3 h. The reaction mixture then cooled and poured into cold water
and acidified with dilute HCl. The solid product was recrystallized from
ethanol to give 13, (Table II).
Antitumor Activity (In-Vitro Study)
Reagents
1. RPMI 1640 medium (sigma).
2. Ehrlich Ascites Carcinoma cells (EAC) suspension (2.5 × 106/ml).
3. Trypan blue dye; A stock solution was prepared by dissolving one
gram of the dye in distilled water (100 ml). The working solution
was then prepared by diluting (1 ml) of the stock solution with (9
ml) of distilled water. The stain was used then for staining the dead
EAC cells.
4. The compounds tested were (3e,f), (9), (11), and (13).

Antitumor Activity of Some Novel 1,2,5-Thiadiazole Derivatives
2553
TABLE III In-Vitro Cytotoxic Activity of Some New Synthesized
Compounds
Non-viable cells (%)
Concentration (µg/ml)
Compd. no.
100
50
25
IC50 (µg/ml)
3e
3f
9
11
0
100
20
30
0
0
50
10
10
0
0
20
5
5
0
>100a
50
>100a
>100a
>100a
43
13
Doxorubicin (reference)
100
55
20
*IC50 > 100 (ꢀ g/ml) is considered to be inactive
Procedure
1. EAC cells were obtained by needle aspiration of the ascetic fluid
from pre-inoculated mice under aseptic conditions.22
2. The cells were tested for viability and contamination by staining
certain cell volume of this fluid by an equal volume of the working
solution of trypan blue dye.23−25
3. The ascetic fluid was diluted with saline (1:10) to contain 2.5 × 106
cells on a hemocytometer.
4. In a set of sterile test tubes 0.1 ml of tumor cells suspension, 0.8
ml RPMI 1640 media, and 0.1 ml of each tested compound (corre-
sponding to 100, 50, and 25 µg/ml) were mixed. The test tubes were
incubated at 37◦C for 2 h. Trypan blue exclusion test22−23 was car-
ried out to calculate the percentage of non-viable cells. Compounds
producing more than 70% non viable cells are considered active.24
5. Doxorubicin (Adriablastina)is taken as a reference.
No. of non viable
Total No. of cells
% of non-viable cells =
× 100
The relationship between surviving fraction and drug concentration
was plotted to obtain the survival curve of EAC cell. The response pa-
rameter calculated was IC50 value which corresponds to the compound
concentration causing 50% mortality in net cells (Table III). The re-
sults obtained from this study showed that pyrazole having thiourea,
pyrimidine, and sulfonamide moieties (3f) is nearly as active as the
positive control Doxorubicin with IC50 of 50 µg/ml.Au: Insert asterisk
into table. Is Box in parentheses supposed to be there.

2554
Z. H. Ismail et al.
REFERENCES
[1] M. S. A. El-Gaby, N. M. Taha, J. A. Micky, and M. A. M. Sh. El-Sharief, Acta Chim.
Slov., 49, 159 (2002).
[2] S.Yoon, J. Cho, and K. Kim, J. Chem. Soc. Perkin Trans 1, 109 (1998).
[3] E. I. Strunskaya, Z. A. Bredikhina, N. M. Azancheev, and A. A. Bredikhina, Russ.
J. Org. Chem., 37,(9) 1330 (2001).
[4] Y. Cao, M. Zhang, C. Wu, S. Lee, M. E. Worblewsk, T. Whipple, P. I. Nagy, K. Takacs-
Novak, A. Balazs, S. Toros, and W. S. Messer, J. Med. Chem., 46, 4273 (2003).
[5] Y. Hanasaki, H. Watanabe K. Katsuura, H. Takayama S. Shirakawa, K. Yamaguchi,
S. Sakai, K. Ijichi, M. Fujiwara, K. Konno, T. Yokota, S. Shigeta, and M. Baba,
J. Med. Chem., 38 (12), 2038 (1995).
[6] S. J. Sorensen and S. R. Abel, Ann. Pharmacother., 30, 43 (1996); Chem. Abstr., 124,
219106 b (1996).
[7] L. M. Weinstock, D. M. Mulvey, and R. Tull, J. Org. Chem., 41 (19), 3121 (1976).
[8] M. S. A. El-Gaby, A. A. Atalla, A. M. Gaber, and K. A. Abd Al-Wahab, IL Farmaco,
55, 596 (2000).
[9] M. S. A. El-Gaby, A. M. Gaber, A. A. Atalla, and K. A. Abd Al-Wahab, IL Farmaco,
57, 613 (2002).
[10] T. H. Maren, Ann. Rev. Pharmacol. Toxicol.,16, 309 (1976).
[11] C. T. Supuran, A. Scozzafava, B. C. Jurca, and M. A. Iies, Eur J. Med. Chem., 33, 83
(1998).
[12] J. J. Li, D. Anderson, E. G. Burton, J. N. Cogburn, J. T. Collins, D. J. Garland, S. A.
H. Huang, P. C. Isokson, C. M. Koboldt, E. W. Logusch, M. B. Morton, W. Perkins, E.
J. Reinhard K. Seibert, A. W. Veenhuizen, Y. Zhang, and D. B. Reitz, J. Med. Chem.,
38, 4570 (1995).
[13] S. M. Sondhi, M. Johar, N. Singhal, S. G. Dastidar, R. Shukla, and R. Raghubir,
Monat. Fu¨r Chem., 131, 511 (2000).
[14] S. M. Abdel-Gawad, M. S. A. El-Gaby, H. I. Heiba, H. M. Aly, and M. M. Ghorab, J.
Chin. Chem. Soc., 52, 1227 (2005).
[15] S. M. Abdel-Gawad, M. S. A. El-Gaby, and M. M. Ghorab, IL Farmaco, 55, 287
(2000).
[16] M. M. Ghorab, S. M. Abdel-Gawad, and M. S. A. El-Gaby, IL Farmaco, 55, 249
(2000).
[17] M. S. A. El-Gaby, S. M. Abdel-Gawad, M. M. Ghorab, H. I. Heiba, and H. M. Aly,
Phosphorus, Sulfur, and Silicon, 181, 279 (2006).
[18] A. K. Mukerjee and R. Share, Chem. Rev., 91 (1), 1 (1991).
[19] S. Sharma, Sulfur Report, 8 (5), 327 (1989).
[20] M. S. A. El-Gaby, J. A. Micky, N. M. Taha, and M. A. M. Sh. El- Sharief, J. Chin.
Chem. Soc., 49, 407 (2002).
[21] S. P. Singh, S. S. Parmar, K. Rhman, and V. I. Stenberg, Chem. Rev., 81 (2), 175
(1981).
[22] M. M. El-Merzabani, A. A. El-Aaser, A. K. El-Dueini, and A. M. EL-Masry, Planta
Medica., 36, 87 (1979).
[23] D. Raffa, G. Daidone, B. Maggio, S. Cascioferro, F. Plescig, and D. Schillaci, IL
Farmaco, 59, 215 (2004).
[24] D. J. Takemoto, C. Dunford, and M. M. McMurray, Toxicon., 20, 593 (1982).
[25] M. M. El-Merzabani, A. A. El-Aaser, M. A. Attia, A. K. El-Dueini, and A. M. Ghazal,
Planta Medica, 36, 150 (1979).