Synthesis, characterization and in vitro antimicrobial activity of novel 2-thioxo-4-thiazolidinones and 4,4′-bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfones

Article abstract of DOI:10.1016/j.ejmech.2009.05.005

2-Thioxo-4-thiazolidinones (3a,b) were achieved by cyclocondensation of isothiocyanatosulfonamides (1a,b) with sulfanylacetic acid at reflux temperature in dioxane in the presence of triethylamine. Compound (3a) was exploited to synthesize the versatile hitherto unknown 2-thioxo-4-thiazolidinones (5-10) via its reaction with some electrophiles. Cyclization of 4,4′-diisothiocyanate diphenylsulfone (11) with sulfanylacetic acid furnished 4,4′-bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfone (12) which on treatment with excess 4-methoxybenzaldehyde in refluxing dioxane in the presence of piperidine yielded the bisbenzylidene derivative (13). The novel synthesized compounds were characterized by IR, ¹H NMR and mass spectral studies. All the synthesized compounds were screened in vitro for their antibacterial and antifungal activities.

Full text of DOI:10.1016/j.ejmech.2009.05.005

European Journal of Medicinal Chemistry 44 (2009) 4148–4152
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, characterization and in vitro antimicrobial activity
of novel 2-thioxo-4-thiazolidinones and 4,40-bis
(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfones
,
b
b
Mohamed S.A. El-Gaby a , Gameel A.M. El-Hag Ali , Ahmed A. El-Maghraby ,
*
Mohamed T. Abd El-Rahman b, Mohamed H.M. Helal b
a Department of Chemistry, Faculty of Science, Al-Azhar University in Assiut, Assiut 71524, Egypt
b Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Thioxo-4-thiazolidinones (3a,b) were achieved by cyclocondensation of isothiocyanatosulfonamides
(1a,b) with sulfanylacetic acid at reflux temperature in dioxane in the presence of triethylamine.
Compound (3a) was exploited to synthesize the versatile hitherto unknown 2-thioxo-4-thiazolidinones
(5–10) via its reaction with some electrophiles. Cyclization of 4,40-diisothiocyanate diphenylsulfone (11)
with sulfanylacetic acid furnished 4,40-bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfone (12) which on
treatment with excess 4-methoxybenzaldehyde in refluxing dioxane in the presence of piperidine
yielded the bisbenzylidene derivative (13). The novel synthesized compounds were characterized by IR,
1H NMR and mass spectral studies. All the synthesized compounds were screened in vitro for their
antibacterial and antifungal activities.
Received 4 February 2009
Received in revised form
4 May 2009
Accepted 7 May 2009
Available online 19 May 2009
Keywords:
Isothiocyanates
4-Thiazolidinones
Bisthiazolidinones
Antimicrobial activity
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
[13–16], we report herein a simple and one-pot route to the
synthesis of hitherto unknown 2-thioxo-4-thiazolidinone and 4,40-
Derivatives of 4-thiazolidinone have been demonstrated to
possess antibacterial [1], antifungal [2], anticonvulsant [3], anti-
cancer [4], antituberculosis [5] and anti-human immunodeficiency
virus type 1 (HIV-1) [6] activities. Peptidoglycan is an essential
component of the cell wall of both Gram-positive and Gram-
negative bacteria. 4-Thiazolidinones have been reported as novel
inhibitors of the bacterial enzyme Mur B which was a precursor
acting during the biosynthesis of peptidoglycan [7]. In addition,
antibacterial [8], antifungal [9], insulin releasing [10] and carbonic
anhydrase inhibitory [11] activities of sulfonamides were reported.
A literature survey revealed that many different protocols have
been developed in a way that allows the synthesis of 4-thiazolidi-
none skeletons [12]. The method more used employs a two-step
preparation: reaction of substituted isothiocyanates with sulfanyl-
acetic acid or its ester followed by acid cyclization of the resulting
(thiocarbamoyl)sulfanylacetic acids and acetate [12]. Based on
these facts and in continuation of our studies on the synthesis and
biological activity of heterocycles including 4-thiazolidinones
bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfone derivatives via
the reaction of isothiocyanates with sulfanylacetic acid in order to
evaluate their antimicrobial activity.
2. Results and discussion
2.1. Chemistry
Isothiocyanates are useful, widely-used building blocks in the
synthesis of nitrogen, sulfur and oxygen heterocycles and organo-
metallic compounds of academic, pharmaceutical and industrial
interests [17,18]. Isothiocyanatosulfonamides 1a,b were synthe-
sized by thiophosgenation of sulfonamides in the presence of dilute
HCl at room temperature [19], Scheme 1.
Cyclocondensation of isothiocyanates 1a,b with sulfanylacetic
acid in dioxane in the presence of triethylamine at reflux temper-
ature yielded the 2-thioxo-4-thiazolidinones 3a,b, Scheme 2. The
molecular structure of compounds 3a,b was confirmed on the basis
of their elemental analyses and spectral data. The infrared spec-
trum of 3a showed NH2 stretching bands at 3348, 3258 cmꢀ1, in
addition to stretching band at 1738 cmꢀ1 attributed to the C]O
functional group (4-thiazolidinone). The 1H NMR spectrum of
* Corresponding author. Tel.: þ966 557395238; fax: þ208 82181436.
E-mail address: m_elgaby@hotmail.com (M.S.A. El-Gaby).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.05.005

M.S.A. El-Gaby et al. / European Journal of Medicinal Chemistry 44 (2009) 4148–4152
4149
Scheme 1.
compound 3a revealed the presence of
a singlet signal at
d
4.21 ppm corresponding to methylene moiety of thiazolidinone,
in addition to the presence of aromatic and NH2 protons. Mass
spectrum of 3a exhibited a molecular ion peak at m/z 288 (98.8%)
corresponding to the molecular formula C9H8N2O3S3. The base peak
was found in the spectrum at m/z 64 which is characteristic for SO2
moiety. The formation of 3 is assumed to proceed through nucle-
ophilic attack of mercapto functional group of sulfanylacetic acid to
the thiocarbonyl moiety of isothiocyanate followed by intra-
molecular cyclization through dehydration of the non-isolable
intermediate 2 [20] as depicted in Scheme 2.
The methylene moiety in compound 3a was exploited to
synthesize hitherto unknown thiazolidinone derivatives through
its reaction with some electrophiles. Treatment of compound 3a
with tetracyanoethylene led to the formation of 5-dicyano-
methylene-2-thioxo-4-thiazolidinone derivative 5 and the other
possible structure pyranothiazole 6 was eliminated on the basis of
analytical and spectral data. Its infrared spectrum showed the
strong and sharp absorption band at 2200 cmꢀ1 corresponding to
the C^N functional group. The 1H NMR spectrum of compound 5 in
DMSO-d6 revealed the absence of methylene moiety. In addition,
the structure of 5 was supported by its mass spectrum which
revealed a molecular ion peak at m/z 350 (2.06%). Compound 5 was
assumed to be formed via Michael addition of the active methylene
group in 3a to the activated double bond in tetracyanoethylene to
form 4 followed by the elimination of malononitrile [21] to furnish
5, Scheme 3. Condensation of compound 3a with dimethylforma-
mide–dimethylacetal (DMF–DMA) in refluxing m-xylene yielded
the 5-dimethylaminomethylene-3-[4-(N-dimethylaminomethyle-
nesulfamoyl)phenyl]-2-thioxo-4-thiazolidinone 7. The infrared
spectrum of compound 7 indicated the absence of the NH2
absorption band and contains characteristic absorption band at
1690 cmꢀ1 for the C]O functional group. The molecular structure
of compound 7 was established by 1H NMR spectrum which
Scheme 3.
reaction of compound 3a with triethyl orthoformate at 200 ꢁC
under solvent free condition, Scheme 3.
A Knoevenagel condensation of compound 3a with aromatic
aldehydes in refluxing dioxane in the presence of triethylamine
furnished benzylidene derivatives 9a,b. Mass spectrum of compound
9a revealed a molecular ion peak at m/z 390 (4.85%) together with
base peak at m/z 148. The reaction of compound 3a with tereph-
thalaldehyde in dioxane in the presence of a catalytic amount of
triethylamine at reflux temperature led to the formation of bisben-
zylidene derivative 10, Scheme 4. 1H NMR spectrum of compound 10
exhibited the presence of two signals at
d 2.98 and 3.18 corre-
sponding to dimethyleneaminomethylene and N-dimethylamino-
methylenesulfamoyl fragments, respectively. The molecular ion
peak of compound 7 was found in the mass spectrum at m/z 398
(9.5%) corresponding to the molecular formula C15H18N4O4S3. Also,
in the mass spectrum the base peak was found at m/z ¼ 101. 5-
Ethoxymethylene derivative 8 was obtained in 87% yield by the
Scheme 2.
Scheme 4.

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M.S.A. El-Gaby et al. / European Journal of Medicinal Chemistry 44 (2009) 4148–4152
indicated the absence of methylene moiety which was present in the
parent compound and showed absorption at 7.78–8.05 ppm
isothiocyanates and sulfanylacetic acid in order to investigate their
antimicrobial activity.
d
attributed to two amino, methylene-H, aromatic protons.
4,40-Bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfone 12 was
achieved by cyclization of 4,40-diisothiocyanate diphenylsulfone 11
[22] with sulfanylacetic acid in refluxing dioxane in the presence of
triethylamine, Scheme 5. The mass spectrum of compound 12
showed a molecular ion peak at m/z 480 (45.7%) and the base peak
was observed at m/z 64 (SO2 moiety). Reaction of compound 12
with excess 4-methoxybenzaldehyde by refluxing in dioxane in the
presence of a catalytic amount of piperidine afforded the 4,40-bis[5-
(4-methoxybenzylidene)-2-thioxo-4-thiazolidinone-3-yl]dipheny-
lsulfone. Mass spectrum of compound 13 showed a molecular ion
peak at m/z 390 (5.95%) with base peak at m/z 108 which is char-
acteristic for anisole moiety.
3. Experimental
All melting points are uncorrected and were determined on
a digital Gallen-Kamp MFB-595 instrument. IR spectra (KBr) were
measured on a Shimadzu 440 spectrometer. 1H NMR spectra were
recorded in dimethyl-sulfoxide (DMSO-d6) on a Varian Gemini 200
(200 MHz) spectrometer using TMS as an internal standard; chem-
ical shifts are reported as
GSMS-QP 1000 Ex mass spectrometer at 70 eV. Elemental analyses
were carried out at the Microanalytical Center of Cairo University.
d units. Mass spectra were measured on
3.1. General procedure for the reaction of isothiocyanate derivatives
with sulfanylacetic acid
2.2. In vitro evaluation antimicrobial activity
A mixture of sulfanylacetic acid (0.92 g, 100 mmol) and either of
each 1 (100 mmol) or 11 (2.32 g, 100 mmol) and triethylamine
(1.01 g, 100 mmol) in dioxane (20 mL) was refluxed for 3 h. The
reaction mixture was left to cool at room temperature. The solid
product, so formed, was collected by filtration and recrystallized
from an appropriate solvent.
All the synthesized compounds were evaluated in vitro for their
antibacterial activity against Staphylococcus aureus (NCTC-7447),
Bacillus cereus (ATCC-14579), Serratia marcescens (IMRU-70) and
Proteus mirabilis (NCT-289). Also, the antifungal activity against
Aspergillus ochraceus Wilhelm (AUCC-230) and Penicillium chrys-
ogenum Thom (AUCC-530) was evaluated using the agar-diffusion
technique [23]. A 1 mg mLꢀ1 solution in dimethylformamide (DMF)
was used. The bacteria and fungi were grown on nutrient agar and
Czapek’s–Dox agar media, respectively. DMF as a negative control
did not show inhibition zones. The agar media were inoculated
with different microorganism cultures tested. After 25 h of incu-
bation at 30 ꢁC for bacteria and 48 h for fungi, the diameter of
3.1.1. 3-(4-Sulfamoylphenyl)-2-thioxo-4-thiazolidinone (3a)
White crystals (dioxane), Yield: 80%, m.p. 265–267 ꢁC; IR (KBr,
cmꢀ1): (NH2) 3348, 3258, (CO) 1738; 1H NMR(DMSO-d6, ppm):
d 4.21
(s, 2H, CH2), 7.52–7.91 ppm (m, 6H, Ar and NH2 protons); MS: m/z 288
(Mþ), 246, 214, 202, 198, 156, 150, 135, 118, 90, 76. Anal. Calcd. for
C9H8N2O3S3:C,37.50;H,2.77;N,9.72.Found:C,37.40;H,2.70;N,9.50.
inhibition zone (mm) was measured. Ampicillin (25
m
g mLꢀ1) and
Mycostatine (30
m
g mLꢀ1) were used as reference drugs for anti-
3.1.2. 3-[4-(N-Pyrimidin-2-yl)sulfamoyl]phenyl-2-thioxo-4-
thiazolidinone (3b)
bacterial and antifungal activities, respectively.
Most of the synthesized compounds were found to possess
various antimicrobial activities towards all the microorganisms
used (Table 1). Thiazolidinones 5, 9a and 10 having biologically
active sulfamoyl and thioxo moieties were found to possess highest
antibacterial towards B. cereus with minimal inhibitory concen-
White crystals (dioxane), Yield: 63%, m.p. 284–285 ꢁC; IR (KBr,
cmꢀ1): (NH) 3100, (CO) 1742; 1H NMR (DMSO-d6, ppm):
d 4.14 (s,
2H, CH2), 7.34–7.61 ppm (m, 4H, Ar-protons), 6.65 (t, J ¼ 4.7 Hz, 1H,
CH-pyrimidine), 8.62 (d, J ¼ 4.8 Hz, 2H, two CH-pyrimidine), 11.01
(br, 1H, NH); MS: m/z 367 (M þ 1). Anal. Calcd. for C13H10N4O3S3: C,
42.62; H, 2.73; N, 15.30. Found: C, 42.50; H, 2.60; N, 15.40.
tration (MIC) values <50 m . In addition thiazolidinone
g mLꢀ1
derivative 3b bearing pyrimidine nucleus, sulfamoylphenyl and
thioxo moieties revealed high activity against P. chrysogenum Thom
3.1.3. 4,40-Bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfone (12)
MIC values <50
m
g mLꢀ1. These compounds are nearly as active as
Yellow crystals (dioxane), Yield: 70%, m.p. 250–251 ꢁC; IR (KBr,
reference drugs. However none of the test compounds show
superior activity than the reference drugs.
In conclusion, we report herein a convenient route for the
synthesis of some novel 2-thioxo-4-thiazolidinones starting from
cmꢀ1): (CO) 1748 cmꢀ1 1H NMR (DMSO-d6, ppm):
; d 4.41 (s, 4H,
2CH2), 7.59–8.20 ppm (m, 8H, Ar-protons); MS: m/z 480 (Mþ), 406,
332, 198, 140, 134, 118, 90, 77, 76. Anal. Calcd. for C18H12N2O4S5: C,
45.00; H, 2.50; N, 5.83. Found: C, 44.90; H, 2.40; N, 5.70.
Scheme 5.

M.S.A. El-Gaby et al. / European Journal of Medicinal Chemistry 44 (2009) 4148–4152
4151
Table 1
Antimicrobial activity of the synthesized compounds (diameter zones in mm).
Compound no.
Gram-positive bacteria
Gram-negative bacteria
Fungi
Staphylococcus aureus
Bacillus cereus
Serratia marcescens
Proteus mirabilis
Aspergillus ochraceus Wilhelm
Penicillium chrysogenum Thom
(NCTC-7447)
(ATCC-14579)
(IMRU-70)
(NTC-289)
(AUCE-230)
(AUCC-530)
3a
3b
5
7
8
9a
9b
10
28
18
15
16
25
14
27
13
15
17
40
–
13
16
32
15
12
34
10
33
13
16
43
–
20
22
24
12
23
18
15
19
10
13
40
–
24
19
18
20
23
17
19
22
24
25
40
–
18
15
14
16
12
14
19
16
26
11
10
40
16
35
14
16
18
10
17
15
12
11
16
43
12
13
Ampicillin
Mycostatine
Less active 1–1.5 cm; moderately active: 1.5–2 cm; highly active 2–3 cm; very highly active 3–4.5 cmꢀ1
.
3.1.4. 5-Dicyanomethylene-3-(4-sulfamoylphenyl)-2-thioxo-4-
thiazolidinone (5)
poured into ice water. The solid product was collected by filtration,
washed with water and recrystallized from an appropriate solvent.
A mixture of 3a (2.88 g, 100 mmol), tetracyanoethylene (1.28 g,
100 mmol) and triethylamine (1.01 g, 100 mmol) in ethanol (10 mL)
was refluxed for 30 min. After cooling, the resulting solid product
was collected by filtration, washed with water, and the crude
product recrystallized. Brown crystals (dioxane), m.p. >300 ꢁC; IR
(KBr, cmꢀ1): (NH2) 3353, 3261, (CH-arom.) 3066, (C^N) 2200,
3.2.1. 5-(4-Methylbenzylidene)-3-(4-sulfamoylphenyl)-2-thioxo-4-
thiazolidinone (9a)
Yellow crystals (acetic acid), Yield: 67%, m.p. >300 ꢁC; IR (KBr,
cmꢀ1): (NH2) 3340, 3250, (CH-arom). 3012, (CH-aliph). 2924, (CO)
1712; MS: m/z 390 (Mþ), 391 (M þ 1), 392 (M þ 2), 148. Anal. Calcd.
for C17H14N2O3S3: C, 52.30; H, 3.58; N, 7.17. Found: C, 52.20; H, 3.50;
N, 7.20.
(C]O) 1690; 1H NMR (DMSO-d6, ppm):
d 7.54 (s, 2H, NH2), 7.7–
8.01 ppm (m, 4H, Ar-protons); MS: m/z 350 (Mþ), 274, 222, 214,136,
135, 134, 76. Anal. Calcd. for C12H6N4O3S3: C, 41.14; H, 1.71; N, 16.00.
Found: C, 41.10; H, 1.60; N, 16.20.
3.2.2. 5-(4-Methoxybenzylidene)-3-(4-sulfamoylphenyl)-2-thioxo-
4-thiazolidinone (9b)
3.1.5. 5-Dimethylaminomethylene-3-[4-(N-
dimethylaminomethylensulfamoyl)phenyl]-2-thioxo-4-
thiazolidinone (7)
Orange crystals (acetic acid), Yield: 74%, m.p. 296–298 ꢁC; IR
(KBr, cmꢀ1): (NH2) 3350, 3266, (CH-aliph). 2930, (CO) 1712 cmꢀ1
;
1H NMR (DMSO-d6, ppm):
d 3.88 (s, 3H, OCH3), 7.15–7.80 (m, 8H, Ar-
A mixture of 3a (2.88 g, 100 mmol) and dimethylformamide–
dimethylacetal (DMF–DMA) (2.38 g, 200 mmol) was refluxed in dry
m-xylene (10 mL) for 1 h. The solvent was removed by evaporation
under reduce pressure and the remainder was left to cool. The solid
product so formed was collected by filtration, washed with petro-
leum ether (b.p. 40–60 ꢁC) and the crude product recrystallized.
Brown crystals (ethanol), Yield: 60%, m.p. 230–232 ꢁC; IR (KBr,
cmꢀ1): (CH-aliphatic) 2921, (CO) 1690; 1H NMR (DMSO-d6, ppm):
protons), 7.91 (s, 1H, benzylidene-H), 8.10 (s, 2H, NH2). Anal. Calcd.
for C17H14N2O4S3: C, 50.24; H, 3.44; N, 6.89. Found: C, 50.10; H, 3.30;
N, 6.80.
3.3. Preparation of 4,40-bis[3-(4-sulfamoylphenyl)-5-methylene-2-
thioxo-4-thiazolidinone-5-yl]benzene (10)
This compound was synthesized from 3a (5.76 g, 200 mmol)
and terephthalaldehyde (2.10 g, 100 mmol) in a manner similar to
that described for the preparation of 9. Orange crystals (acetic acid),
yield: 80%, m.p. >300 ꢁC; IR (KBr, cmꢀ1): (NH2) 3360, 3268, (CO)
d
2.98, 3.18 (2s, 12H, 2N(CH3)2), 7.45–8.01 (m, 4H, Ar-protons), 8.10,
8.39 (2s, 2H, two methine-H); MS: m/z 398 (Mþ), 399 (M þ 1), 269,
263,135,134,101,100, 76. Anal. Calcd. for C15H18N4O3S3: C, 45.22; H,
4.52; N, 14.07. Found: C, 45.10; H, 4.60; N, 14.00.
1721; 1H NMR (DMSO-d6, ppm):
d 7.78–8.05 (m, 18H, Ar, methyl-
idene and two amino protons). Anal. Calcd. for C26H18N4O6S6: C,
46.29; H, 2.67; N, 8.30. Found: C, 46.20; H, 2.60; N, 8.20.
3.1.6. 5-Ethoxymethylene-3-(4-sulfamoylphenyl)-2-thioxo-4-
thiazolidinone (8)
A mixture of 3a (2.88 g, 100 mmol) and triethyl orthoformate
(1.06 g, 100 mmol) was heated at 200 ꢁC for 1 h. The reaction
mixture was cooled. The resulting solid product was collected by
filtration and recrystallized. Yellow crystals (ethanol), Yield: 87%,
m.p. 170–172 ꢁC; IR (KBr, cmꢀ1): (NH2) 3342, 3252, (CH-aliphatic)
3.4. Formation of 4,40-bis[5(4-methoxybenzylidene)-2-thioxo-4-
thiazolidinone-3-yl]diphenylsulfone (13)
This compound was synthesized from compound 12 (4.80 g,
100 mmol) and 4-methoxybenzaldehyde (2.72 g, 200 mmol) in
a manner similar to that described for the preparation of 9. Orange
crystals (dimethylformamide), yield: 76%, m.p. >300 ꢁC; IR (KBr,
cmꢀ1): (CH-arom). 3010, (CH-aliph). 2925, CO 1692 cmꢀ1; MS: m/z
390 (Mþ), 250, 192, 154, 140, 90, 85. Anal. Calcd. for C34H24N2O6S5:
C, 56.98; H, 3.35; N, 3.91. Found: C, 56.80; H, 3.30; N, 3.80.
2992, (CO) 1711; 1H NMR (DMSO-d6, ppm):
d
1.20 (t, J ¼ 7.3 Hz, 3H,
CH3), 4.36 (q, J ¼ 7.3 Hz, 2H, CH2), 7.37–8.19 (m, 6H, Ar and NH2
protons), 8.72 (s, 1H, methine-H). Anal. Calcd. for C12H12N2O4S3: C,
41.86; H, 3.48; N, 8.13. Found: C, 41.80; H, 3.40; N, 8.00.
3.2. General procedure for preparation of 9a,b
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(100 mmol) and piperidine (100 mmol) in dioxane (20 mL) was
refluxed for 4 h. The reaction mixture was left to cool and then
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