Synthesis of thiazolidine and thiophene derivatives for evaluation as anticancer agents

Article abstract of DOI:10.1080/10426500802561096

The non-isolated adducts (3a,b) were used as key intermediates to synthesize some novel thiazolidine and thiophene derivatives. Compound (4) exhibited a remarkable antitumor activity against EAC cells compared with the Doxorubicin as a positive control. T

Full text of DOI:10.1080/10426500802561096

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Synthesis of Thiazolidine
and Thiophene Derivatives
for Evaluation as Anticancer
Agents
M. S. A. El-Gaby a , Z. H. Ismail a , S. M. Abdel-
Gawad b , H. M. Aly b & M. M. Ghorab c
a Department of Chemistry, Faculty of Science, Al-
Azhar University at Assiut, Assiut, Egypt
b Department of Chemistry, Faculty of Science
(Girls), Al-Azhar University, Cairo, Egypt
c Department of Drug Radiation Research, National
Center for Radiation Research and Technology, Nasr
City, Cairo, Egypt
Published online: 21 Sep 2009.
To cite this article: M. S. A. El-Gaby , Z. H. Ismail , S. M. Abdel-Gawad , H. M. Aly
& M. M. Ghorab (2009): Synthesis of Thiazolidine and Thiophene Derivatives for
Evaluation as Anticancer Agents, Phosphorus, Sulfur, and Silicon and the Related
Elements, 184:10, 2645-2654
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Phosphorus, Sulfur, and Silicon, 184:2645–2654, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802561096
Synthesis of Thiazolidine and Thiophene Derivatives
for Evaluation as Anticancer Agents
M. S. A. El-Gaby,1 Z. H. Ismail,1 S. M. Abdel-Gawad,2
H. M. Aly,2 and M. M. Ghorab3
1Department of Chemistry, Faculty of Science, Al-Azhar University
at Assiut, Assiut, Egypt
2Department of Chemistry, Faculty of Science (Girls),
Al-Azhar University, Cairo, Egypt
3Department of Drug Radiation Research, National Center for
Radiation Research and Technology, Nasr City, Cairo, Egypt
The non-isolated adducts (3a,b) were used as key intermediates to synthesize some
novel thiazolidine and thiophene derivatives. Compound (4) exhibited a remarkable
antitumor activity against EAC cells compared with the Doxorubicin as a positive
control.
Keywords 1,2,5-Thiadiazole; thiazolidine and thiophene derivatives
INTRODUCTION
1,2,5-Thiadiazole derivatives are known to exhibit a wide spectrum
of biological activity.1,2 In addition to pronounced herbicide activity,
1,2,5-thiadiazole derivatives were found to be efficient muscarine re-
ceptor agonists,3 as well as inhibitors of HIV-1 replication.4 For ex-
ample, 1-(1,1-dimethylethylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-
yloxy)-2-propanol (Timolol) is one of the most important medicines
for the treatment of glaucoma.5,6 Furthermore, antibacterial,7 an-
tifungal,8 insulin releasing,9 carbonic anhydrase inhibitory,10 anti-
inflammatory,11 and antitumor12 properties of the sulfamoyl moiety
have been described. In view of the above observations and as a con-
tinuation of our research program on the synthesis of heterocyclic com-
pounds from readily available starting materials,13–16 we report here
on the synthesis and antitumor activity of some novel thiazolidine and
thiophene derivatives bearing a 1,2,5-thiadiazole moiety.
Received 14 July 2008; accepted 16 October 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
2645

2646
M. S. A. El-Gaby et al.
SCHEME 1
RESULTS AND DISCUSSION
The starting material 4-isothiocyanato-N-(4-methoxy-1,2,5-thiadiazol-
2-yl) benzene sulfonamide (2) was synthesized via the reaction of sul-
fonamide derivative (1) with thiophosgene at room temperature in the
presence of hydrochloric acid (Scheme 1). The mass spectrum of isoth-
iocyanate (2) revealed a molecular ion peak at m/z = 328 (2.27%), and
the base peak was found in the spectrum at m/z = 134, which is char-
acteristic for phenyl isothiocyanate minus hydrogen.
The reactivity of isothiocyanate derivative (2) towards active methy-
lene compounds in the presence of potassium hydroxide followed by
in situ cyclization with halo compounds was studied. Thus, the non-
isolated adducts (3a,b) were prepared by the treatment of isoth-
iocyanate derivative (2) with malononitrile and ethyl cyanoacetate.
Treatment of the non-isolated adduct (3a) with chloroacetonitrile at
room temperature furnished 4-amino-thiazole derivative (4). The other
possible structure (5) was discarded on the basis of spectral data. The
infrared spectrum revealed the following absorption bands: 3487, 3197
(NH2), 3085 (CH-arom.), 2931 (CH-aliph.), 2202 (C≡N), and 1589 cm−1
1
(C=C). The HNMR spectrum (DMSO-d6) exhibited the following sig-
nals: 4.06 (s, 3H, OCH3), 4.21 (hump, 2H, NH2), 6.60 (s, 1H, thiazole-H),
7.25–8.09 (m, 4H, Ar-H), and 9.52 ppm (s, 1H, NH). The formation of
compound (4) is assumed to proceed through the initial alkylation fol-
lowed by in situ heterocyclization17 via a nucleophilic addition of the
secondary amino group to the cyano group and tautomerization, as
shown in Scheme 2.
Cyclization of the non-isolated adduct (3b) at room temperature with
chloroacetonitrile yielded hydroxythiophene derivative (6) rather than
the expected products (7) and (8), on the basis of analytical and spectral
data shown in Scheme 3. Its infrared spectrum showed the following
absorption bands at: 3201 (OH; broad) and 2210 cm−1 (C≡N). Also,
1
its H NMR (DMSO-d6) exhibited the absence of the ethoxycarbonyl
moiety and revealed the presence of the following signals: 3.80 (s, 3H,
OCH3), 7.4–7.9 (m, 6H, Ar-H + 2NH), and 10.8 ppm (s, 1H, OH). The
formation of (6) is assumed to proceed via initial alkylation by loss of
potassium chloride followed by elimination of ethanol.

Thiazolidine and Thiophene Derivatives
2647
SCHEME 2
SCHEME 3

2648
M. S. A. El-Gaby et al.
SCHEME 4
The reaction of the non-isolated adduct (3a) with ethyl chloroacetate
at room temperature produced the novel 4-thiazoli-dinone derivative
(10), and the other possible structure (9) was ruled out on the basis of
analytical and spectral data (Scheme 4).The infrared spectrum of com-
pound (10) showed the following absorption bands: 3197, 3116 (2NH),
2954 (CH-aliph.), 2214 (C≡N), and 1735 cm−1(C=O). Also, its 1H NMR
(DMSO-d6) revealed the following signals: 3.91 (s, 3H, OCH3), 4.6 (s,
2H, CH2), 7.8–8.2 (m, 4H, Ar-H), and 11.60 ppm (s, 1H, NH). The forma-
tion of (10) was assumed to proceed through initial alkylation followed
by elimination of ethanol.
Alternatively, treatment of the non-isolated adduct (3b) with ethyl
chloroacetate gave the thiophene derivative (12), and the other possible
structure (11) was excluded on the basis of analytical and spectral
data (Scheme 5). The infrared spectrum of compound (12) showed the
following absorption bands: 3494, 3105 (OH/NH), 2985 (CH-aliph.),
2210 (C≡N), and 1739 cm−1 (C=O). The 1H NMR spectrum of compound
(12; DMSO-d6) revealed the following signals: 1.30 (t,3H, CH3), 4.10 (s,
3H, OCH3),4.2 (q, 2H, CH2), 7.2–8.1 (m, 6H, Ar-H + 2NH), and 11.8
ppm (br, 1H, OH). The formation of (12) is assumed to proceed via an
initial alkylation followed by the elimination of ethanol.

Thiazolidine and Thiophene Derivatives
2649
SCHEME 5
Treatment of the non-isolated adduct (3a) with phenacyl bromide
at room temperature afforded the corresponding thio-phene derivative
(13) and not thiazolidine derivative (14) on the basis of analytical and
spectral data (Scheme 6). Its infrared spectrum showed the following
absorption bands: 3373, 3277, 3129 (NH, NH2), 2937 (CH-aliph.), 2208
(C≡N), and 1690 cm−1 (C=O). Also, its mass spectrum revealed a molec-
ular ion peak at m/z 512 (35%) together with a base peak at m/z 77.
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 recorded on a Bruker proton NMR-Avance 300
(300MHz), in DMSO-d6 as a solvent, using tetramethylsilane (TMS) as
an internal standard. The mass spectra were performed by HP Model
MS-5988. Elemental analyses were carried out by the Microanalytical
Research Centre, Faculty of Science, Cairo University. Characteristics
of the prepared compounds are given in Table I; analytical results for
C, H, N were within 0.4% of the calculated values.

2650
M. S. A. El-Gaby et al.
SCHEME 6
4-Isothiocyanato-N-(4-methoxy-1,2,5-thiadiazol-3-yl)benzene-
sulfonamide (2)
A mixture of sulfanilamide derivative 1 (0.01 mol), thiophosgene (0.01
mol), and dilute HCl (50 mL) was stirred at room temperature for 1 h.
The solid residue was collected by filtration, washed with cold water,
and recrystallized from acetone to give (2). The IR spectrum of (2)
revealed absorption bands at 3226 (NH), 3099 (CH arom.), 2100 (NCS),
1332, 1162 cm−1 (SO2). The mass spectrum of (2) revealed a molecular
ion peak m/z at 328 (M+, 2.77%), with a base peak at 134 (100%),
and other significant peaks appeared at 264 (43.98%), 231 (4.88%), 198
(61.96%), 167 (7.97%), 97 (37.02%), 57 (41.79%).
4-(4-Amino-2-(dicyanomethylene)thiazol-3-(2H)-yl)-N-(4-
methoxy-1,2,5-thiadiazol-3-yl)benzenesulfonamide (4),
4-(3,5-Dicyano-4-hydroxythiophen-2-ylamino)-N-(4-methoxy-
1,2,5-thiadiazol-3-yl)benzenesulfonamide (6),
4-(2-(Dicyanomethylene)-4-oxothiazolidin-3-yl)-N-(4-methoxy-
1,2,5-thiadiazol-3-yl)benzenesulfonamide (10), Ethyl
4-Cyano-3-hydroxy-5-(4-(N-(4-methoxy-1,2,5-thiadiazol-3-
yl)sulfamoyl)phenylamino)thiophene-2-carboxylate (12), and
4-(4-Amino-5-benzoyl-3-cyanothiophen-2-ylamino)-N-(4-
methoxy-1,2,5-thiadiazol-3-yl)benzenesulfonamide (13):
General Procedure
To a solution of finely powdered potassium hydroxide (0.01 mole) in
dry DMF (10 mL) at room temperature, the malononitrile or ethyl

2651

2652
M. S. A. El-Gaby et al.
cyanoacetate and then the isothiocyanate derivative 2 (0.01 mol) were
added in portions. The reaction mixture was stirred at room temper-
ature for 3 h, then with the appropriate halo compounds (0.01 mol),
and left at room temperature for 24 h. The reaction mixture was cooled
and poured into ice water (60 mL) and acidified with 0.1N HCl. The
resulting precipitate was filtered off, dried, and recrystallized from the
proper solvent.
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 (4, 6, 10, 12, and 13).
Procedure
1. EAC cells were obtained by needle aspiration of the ascetic fluid from
preinoculated mice under aseptic conditions.18
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.19,20
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. The trypan blue exclusion test19,20 was car-
ried out to calculate the percentage of nonviable cells. Compounds
producing more than 70% nonviable cells are considered active.21
ꢀR
5. Doxorubicin (Adriablastina ) is taken as a reference.
No. of non − viable
% of non − −viable cells =
× 100
Total No. of cells
The relationship between surviving fraction and drug concentration
was plotted to obtain the survival curve of EAC cell. The response
parameter calculated was the IC50 value, which corresponds to the

Thiazolidine and Thiophene Derivatives
2653
TABLE II In Vitro Cytotoxic Activity of Some Se-
lected Synthesized Compounds
Non-viable cells (%)
Concentration(µg/ml)
Compd. No.
100
50
25
IC50 (µg/mL)
4
6
10
12
100
50
50
0
0
100
50
40
40
0
0
55
25
20
20
0
0
20
42.8
91
91
>100a
>100a
43.6
13
Doxorubicin
(reference)
aIC50 > 100 (µg/mL) is considered to be inactive.
compound concentration causing 50% mortality in net cells (Table II).
The results obtained from this study showed that 1,2,5-thiadiazole ben-
zenesulfonamide having thiazole moiety (4) is nearly as active as the
positive control (Doxorubicin) with IC50 of 42.8 µg/mL.
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