New thiazolidinedione-5-acetic acid amide derivatives: Synthesis, characterization and investigation of antimicrobial and cytotoxic properties

Article abstract of DOI:10.1007/s00044-011-9598-0

The present work describes the synthesis, antimicrobial and cytotoxic activity of 2,4-thiazolidinedione- 5-acetic acid amides 3a-n. The structures of the compounds were confirmed by IR, ¹H, ¹³C NMR and elemental analysis. All compounds were tested for antimicrobial activity by twofold serial dilution technique. The preliminary results revealed that the compound 3d exhibits promising antibacterial and antifungal activity. The cytotoxic (MTT) activity of 2,4-thiazolidinedione-5-acetic acid amides were tested in four tumour cell lines. We found that compound 3j inhibited proliferation of HeLa, HT29, A549 and MCF-7 cell lines with IC₅₀ values of 33, 35, 30 and 36 μM, respectively. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9598-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:816–824
DOI 10.1007/s00044-011-9598-0
ORIGINAL RESEARCH
New thiazolidinedione-5-acetic acid amide derivatives: synthesis,
characterization and investigation of antimicrobial and cytotoxic
properties
•
Shankar G. Alegaon Kallanagouda R. Alagawadi
Received: 26 November 2010 / Accepted: 4 February 2011 / Published online: 17 February 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The present work describes the synthesis,
antimicrobial and cytotoxic activity of 2,4-thiazolidine-
dione-5-acetic acid amides 3a–n. The structures of the
compounds were confirmed by IR, 1H, 13C NMR and
elemental analysis. All compounds were tested for anti-
microbial activity by twofold serial dilution technique. The
preliminary results revealed that the compound 3d exhibits
promising antibacterial and antifungal activity. The cyto-
toxic (MTT) activity of 2,4-thiazolidinedione-5-acetic acid
amides were tested in four tumour cell lines. We found that
compound 3j inhibited proliferation of HeLa, HT29, A549
and MCF-7 cell lines with IC50 values of 33, 35, 30 and
36 lM, respectively.
problem encountered in developing safe and efficient
antifungal. On the other hand, Mycobacterium tuberculosis
remains a leading infectious cause of death in the world
today. The incidence of tuberculosis is increasing world-
wide, partly due to poverty and inequity and partly to the
HIV/AIDS pandemic, which greatly increase the risk of
infection proceeding to overt disease (Grange and Zumla,
2002).
The 2,4-thiazolidinedione (TZD) moiety is extensively
utilised as a carboxylic acid mimetic to improve the met-
abolic stability and therapeutic profile of bioactive agents
(Boyd, 2007; Mclntyre et al., 2007; Elte and Blickle,
2007). During recent years there has been a vast investi-
gation on different classes of 2,4-thiazolidinediones, many
of which were found to have an extensive spectrum of
pharmacological activities such as antibacterial and anti-
fungal (Ayhan-kilcigil and Atlantar, 2000; Heerding et al.,
2003; Tuncbilek and Atlantar, 2006; Bozdag-Dundar et al.,
2007), cardiotonic (Andreani et al., 1993), anti-oedematus
and analgesic (De-Lima et al., 1994), cyclooxygenase and
lipoxygenase inhibitory (Boschelli et al., 1992), rosiglit-
azone and pioglitazones (TZD), lower plasma glucose
levels by acting as ligands for the peroxisome proliferator-
activated receptors (PPARs). In addition, this class of
compounds have several other potentially beneficial effects
including change in lipid profile, blood pressure lowering
and anti-inflammatory effects (Kalaitzidis et al., 2009).
TZDs target vascular cells (Kurebayashi et al., 2005), and
monocytes/macrophages (Jiang et al., 1998; Ricote et al.,
1998) inhibit the production of pro-inflammatory cytokines
as well as the expression of inducible nitric oxide synthase
and cell adhesion molecules. These drugs may also be
beneficial in multiple sclerosis and neurodegenerative dis-
eases, including Alzheimer’s and Parkinson’s at least par-
tially due to their anti-inflammatory activity (Heneka and
Keywords Thiazolidinedione Á Antibacterial activity Á
Antifungal activity Á Cytotoxic activity
Introduction
Since resistance of pathogenic bacteria towards available
antibiotics is rapidly becoming a major worldwide prob-
lem, the design of new compounds to deal with resistant
bacteria has become one of the most important areas of
antibacterial research today. In addition, primary and
opportunistic fungal infections continue to increase rapidly
because of the increased number of immunocompromised
patients. As known, not only biochemical similarity of
human cell and fungi forms a handicap for selective
activity, but also the easily gained resistance is the main
S. G. Alegaon (&) Á K. R. Alagawadi
Department of Pharmaceutical Chemistry, KLE University’s
College of Pharmacy, Belgaum 590 010, Karnataka, India
e-mail: shankar_alegaon@yahoo.co.in
123

Med Chem Res (2012) 21:816–824
817
Landreth, 2007). On the other hand, thiadiazole nucleus
constitutes the active part of several biological active
compounds, including antibacterial, antifungal (Mod-
zelewska-Banachiewicz et al., 2004; Foroumadi et al.,
2005a; Kadi et al., 2007), antitubercular (Solak and Rollas,
2006; Mamolo et al., 2003; Foroumadi et al., 2005c),
analgesic (Schenone et al., 2006), anti-inflammatory (Far-
ghaly et al., 2000; Kadi et al., 2007; Schenone et al., 2006),
antidepressant (Varvaresou et al., 1998), leishmanicidal
(Foroumadi et al., 2005b) agents. In view of these facts, we
have designed and synthesised a number 2-(2,4-dioxo-1,3-
thiazolidin-5-yl)-N-(5-substituted-1,3,4-thiadiazol-2-yl)acet-
amide derivatives. The objective of this study was to
investigate the benefits of such hybridization on the
anticipated biological activities, and to determine whether
this would lead to added synergistic biological activity of
the target molecules.
a series of 2-amino-5-substituted-1,3,4-thiadiazols. The
structures and physicochemical data of final compounds
are illustrated in Table 1.
The IR spectra of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-
(5-substituted-1,3,4-thiadiazol-2-yl)acetamides (3a–n) exhib-
ited a absorption band in the region of 3566–3233 cm-1
attributable to the stretching vibration of NH, and around
1690 cm-1 to the carbonyl carbon. The 2,4-thiazolidinedione-
5-acetic acid and their derivatives contain diastereotopic pro-
tons of methylene group, that is why the fragment CHAHBCHX
is presented in 1H NMR spectra as ABX spin system, which
appears as doublet of doublet at *3.05–3.48 ppm, and
*4.85 ppm with coupling constant JAB = 15.01–17.76 Hz,
JAX = 6.9–10.75 Hz, JBX = 3.4–5.5 Hz. High value of JAB
agreed with the data of Takahashi (‘‘carbonyl effect’’) for
structurally related 2-thioxo-4-thiazolidinone-acetic acids
(Takahashi, 1964).
In order to predict the drug likeliness of the synthesised
compounds on the guidelines of Lipinski rule of 5 (Molec-
ular weight B 500, log P B 5, HBD B 5 and HBA B 10)
study was carried out using Pallas software (Pallas, 2010)
the result are given in Table 2. The relevance of the syn-
thesised molecules with respect to Lipinski rule of five is as
follows.
Results and discussion
Chemistry
2,4-Thiazolidinedione-5-acetic acid, prepared from thio-
urea and maleic anhydride in presence of concentrated
hydrochloric acid (Zimenkovskii et al., 2006). 2-(2,4-Di-
oxothiazolidin-5-yl)acetyl chloride was prepared from the
2,4-thiazolidinedione-5-acetic acid and SOCl2, without
isolation further reacted with 5-substituted-2-amino-1,3,4-
thiadiazols as Scheme 1. Several procedures are available
for the one-step synthesis of 2-amino-5-substituted-1,3,4-
thiadiazols (Tu et al., 2008) derivatives. Yet the reaction of
substituted aryl acid with thiosemicarbazide in presence of
dehydrating agent phosphorus oxychloride (POCl3) affords
Molecular weight of the compound is important in drug
action, if the molecular weight increases beyond a limit,
the bulkiness of the compounds also increases, which will
affect the drug action (affect the drug receptor/DNA
interactions). Molecular weight of compounds lie between
326.29 and 424.28 show that it follows Lipinski rule of 5.
So the bulkiness of the compounds is in optimum limit for
the action.
Pharmacokinetic property optimization is a rather
complex undertaking that is likely to require changes in
Scheme 1 Reagents and
conditions: (a) POCl3, 110°C;
(b) 0–40°C; (c) HCl 100°C;
(d) (I) SOCl2, dioxane, (II)
1a–n, Et3N, dioxane
H
N
H
N
(a)
N N
S
H
H
N
H
H
R
COOH
+
R
N
S
H
(1 a-m)
H
H
(b)
N N
H
N
N
H
(CF3CO)2O
+
N
H
F3C
N
S
H
S
H
(1n)
H
N
O
O
O
H
H
H
N
N
S
O
(c)
N
(d)
O
O
N
N
Ar
+
H
H
S
N
H
O
S
O
O
S
OH
(3 a-n)
(2)
123

818
Med Chem Res (2012) 21:816–824
Table 1 Physical constants of the compounds 3a–n
O
N
Ar
H
O
N
N
N
S
S
H
O
Compounds
Ar
Yield (%)
M.p. (°C)
Molecular weight
Molecular formula
3a
3b
3c
3d
3e
3f
C6H5
66
59
61
55
62
58
54
69
62
52
56
50
54
49
256–257
261–262
247–248
239–240
231–232
260–261
237–238
249–250
241–242
260–261
248–249
241–242
256–257
298–299
334
368
413
352
368
348
364
364
394
424
379
379
379
402
C13H10N4O3S2
C13H9ClN4O3S2
C13H9BrN4O3S2
C13H9FN4O3S2
C13H9ClN4O3S2
C14H12N4O3S2
C14H12N4O4S2
C14H12N4O4S2
C15H14N4O5S2
C16H16N4O6S2
C13H9N5O5S2
C13H9N5O5S2
C13H9N5O5S2
C8H5F3N4O3S2
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
2-Cl-C6H4
4-CH3-C6H4
3-OCH3-C6H4
4-OCH3-C6H4
3, 4-OCH3-C6H3
3,4,5-OCH3-C6H2
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
CF3
3g
3h
3i
3j
3k
3l
3m
3n
interaction. Number of HBAs (B10) and HBDs (B5) in the
proposed compounds obeys the Lipinski rule of 5, so it may
have good absorption or permeability properties through
the biological membrane.
Table 2 Drug likeliness of the 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-
(5-substituted-1,3,4-thiadiazol-2-yl)acetamides (3a–n)
Compound TPSA
MW
log P HBD HBA Rule-5
violation
Dissolution is highly interdependent influences of
aqueous solubility, ionizability (pKa) and lipophilicity
(log P). Furthermore, log P is a crucial factor governing
passive membrane partitioning, influencing permeability
opposite to its effect on solubility. The log P values of the
synthesised compounds lie in between 0.45 and 2.22.
3a
3b
3c
3d
3e
3f
101.05 334.39 1.43
101.05 368.83 2.06
101.05 413.28 2.22
101.05 352.38 1.70
101.05 368.83 2.06
101.05 348.42 1.97
110.28 364.42 1.43
110.28 364.42 1.43
119.51 394.45 1.30
128.75 424.48 1.17
146.87 379.39 1.34
146.87 379.39 1.34
146.87 379.39 1.34
101.05 326.29 0.45
2
2
2
2
2
2
2
2
2
2
2
2
2
2
7
7
0
0
0
0
0
0
0
0
0
0
0
0
0
0
7
7
7
7
3g
3h
3i
8
Pharmacology
8
9
Antimicrobial activity
3j
10
10
10
10
7
3k
3l
The synthesised compounds were tested for their in vitro
antibacterial activity against the Gram-positive Staphylo-
coccus aureus (ATCC25923), Enterococcus faecalis (ATC
C35550), Gram-negative Escherichia coli (ATCC35218),
Pseudomonas aeruginosa (ATCC25619) bacteria and
Candida albicans (ATCC2091), Aspergillus flavus (NCIM
No. 524), Aspergillus niger (ATCC6275) and Cryptococ-
cus neoformans (Clinical isolate) fungi. The MIC values
were determined by using the twofold serial dilution
technique (National Committee for Clinical Laboratory
Standards, 2000) in Mueller–Hinton broth and Sabouraud
dextrose agar for the antibacterial and antifungal assays,
3m
3n
TPSA polar surface area, MW molecular weight, HBD hydrogen bond
donors, HBA hydrogen bond acceptor, Lipinski rule of 5 (Molecular
weight B 500, log P B 5, HBD B 5 and HBA B 10)
those molecular determinants that are responsible for
binding affinity and specificity like hydrogen bonds.
Hydrogen bond acceptor (HBA) and hydrogen bond donor
(HBD) groups in the compound optimise the drug receptor
123

Med Chem Res (2012) 21:816–824
819
position of phenyl ring were found to enhance the anti-
bacterial potency significantly. Thus, the compounds 3b
and 3c active against Gram-positive especially Staphylo-
coccus aureus at 4–8 lg/ml concentration, while 3d which
has electron withdrawing –F functional group substituted at
the para position of phenyl ring exerted excellent anti-
bacterial activity by inhibiting the growth of all the tested
bacterial strains at 4–8 lg/ml.
Table 3 Results of antibacterial and antifungal activities of com-
pounds (3a–n) [minimum inhibitory concentration (MIC) values]
O
N
Ar
H
O
N
N
N
S
S
H
O
Compounds like 3k, 3l, and 3m showed moderate
antibacterial activity against all the tested bacterial strains.
Antifungal results indicated that compounds 3b–d exhibit
good activity against all the tested fungal strains.
Compound Ar
E.c P.a S.a E.f C.a C.n A.f A.n
3a
3b
3c
3d
3e
3f
C6H5
64 64 32 64 64 64 64 64
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
2-Cl-C6H4
32 32
32 32
4
8
4
32 16 16 16 16
32 16 16 16 16
Cytotoxic activity
8
8
4
8
8
8
4
32 32 16 16 16 16 32 16
In vitro cytotoxic studies of thiazolidinedione-5-acetic acid
amide derivatives 3a–n were carried out on different can-
cer cell lines and results of cytotoxicity studies were
summarised in Table 4. Among the 14 compounds 3j
which was 3,4,5-trimethoxyphenyl, exhibited the good
inhibitory activity against HeLa, HT29, A549 and MCF-7
cell lines, with the inhibitory concentration (IC50) values of
33, 35, 30 and 36 lM, respectively. Compounds 3g, 3h and
3i showed moderate cytotoxic activities against all tested
human tumour cell lines with IC50 values of 35–60 lM. In
general, structures with donor substituents showed activity,
the position of substituents appears to play an important
role in activity too.
4-CH3-C6H4
16 16
16 32
8
4
4
8
4
16 32 32 32
16 16 16 32
16 16 32 16
3g
3h
3i
3-OCH3-C6H4
4-OCH3-C6H4
32 16 16
3,4-OCH3-C6H3 16 16 16 32 16 16 16 32
3j
3,4,5-OCH3-
C6H2
16 16 16 16 16 32 16 16
3k
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
CF3
64 64 32 64 64 64 64 16
64 32 32 64 64 64 64 64
64 64 32 32 64 64 32 64
32 32 32 32 16 16 32 16
3l
3m
3n
Amp.
Cip.
Ket.
NT NT 2
NT NT NT NT NT NT
NT NT NT NT 2
2
NT NT NT NT
2
2
2
1
2
E.c, Escherichia coli; P.a, Pseudomonas aeruginosa; S.a, Staphylo-
coccus aureus; E.f, Enterococcus faecalis; C.a, Candida albicans;
C.n, Cryptococcus neoformans; A.f, Aspergillus flavus; A.n, Asper-
gillus niger; NT, not tested; Amp., ampicillin; Cip., ciprofloxacin;
Ket., ketoconazole
Table 4 In vitro cytotoxicity of compounds (3a–n) against four
different human cancer cell lines (IC50, lM)
Compound Ar
HeLa HT29 A549 MCF7
respectively. Ampicillin and ciprofloxacin were used as the
reference antibacterial agents; ketoconazole was used as
the reference antifungal agents. All the biological results of
the tested compounds are given in Table 3. The combined
data were reported that the synthesised compounds (3a–
n) showing MIC values between 64 and 4 lg/ml were able
to have an in vitro inhibitory effect against the screened
microorganisms.
3a
C6H5
62
62
52
50
60
50
54
42
40
78
64
60
42
66
58
56
44
42
35
68
72
60
50
4
80
60
68
50
62
46
60
45
35
30
72
78
68
60
2
80
68
72
60
84
52
58
42
38
36
78
67
72
62
3
3b
3c
4-Cl-C6H4
4-Br-C6H4
3d
3e
4-F-C6H4
2-Cl-C6H4
3f
4-CH3-C6H4
3-OCH3-C6H4
4-OCH3-C6H4
3,4-OCH3-C6H3
3g
3h
3i
All compounds were found to be active against Gram-
positive bacteria especially Staphylococcus aureus at
4–32 lg/ml concentration. Compound 3a which has no
substitution at the para position of phenyl ring attached to
5th position of the thiadiazole moiety did not promote
much activity against the tested microbial strains, whereas
compounds 3f–j which have electron donating –CH3 group
at the para position of phenyl ring and –OCH3 group at
different position of the phenyl ring exhibits moderate
activity. The introduction of –Cl, –Br groups at the para
3j
3,4,5-OCH3-C6H2 33
3k
3l
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
CF3
50
68
50
42
7
3m
3n
Cisplatin
Cell lines include cervical carcinoma (HeLa), colorectal cancer
(HT29), lung cancer (A549) and breast adenocarcinoma (MCF-7)
123

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Med Chem Res (2012) 21:816–824
Conclusion
M.p.: 225–227°C; IR (KBr, v, cm-1); 3590, 3126 (vNH),
1620 (vC=N), 690(vC–S); 1H NMR (400 MHz, d, ppm,
DMSO-d6): 7.76 (s, 2H), 7.5 (m, 5H).
We report the synthesis of a series of 2,4-thiazolidinedione-
5-acetic acid amides in good yields and are characterised
by their physical and analytical data. The antibacterial and
antifungal studies carried out to by twofold serial dilution
technique. The preliminary structural-activity relationship
study showed that 4-fluorophenyl and 3,4,5-trimethoxy-
phenyl ring are important for activity and selectivity of 2,4-
thiazolidinedione-5-acetic acid amides. Moreover, the
cytotoxic activity of this series suggests that 2-(2,4-dioxo-
1,3-thiazolidin-5-yl)-N-(5-(-3,4,5-trimethoxyphenyl)-1,3,4-
thiadiazol-2-yl)acetamide 3j offers a novel template for
development of a new class of anticancer agents.
Synthesis of 5-(4-chlorophenyl)-1,3,4-thiadiazol-2-amine
1b This compound was obtained as white solid in a yield
of 75%. M.p.: 212–214°C; IR (KBr, v, cm-1); 3345, 3156
(vNH), 1626 (vC=N), 685(vC–S); 1H NMR (400 MHz, d,
ppm, DMSO-d6): 7.50 (d, J = 6.56 Hz, 2H), 7.47 (d,
J = 6.23 Hz, 2H), 7.44 (s, 2H).
Synthesis of 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine
1c This compound was obtained as white solid in a yield
of 74%. M.p.: 225–226°C; IR (KBr, v, cm-1); 3394, 3136
(vNH), 1626 (vC=N), 665(vC–S); 1H NMR (400 MHz, d,
ppm, DMSO-d6): 7.78-7.82 (dd, J1 = 8.42 Hz, J2 =
16.63 Hz, 4H), 7.44(s, 2H).
Experimental protocols
General conditions
Synthesis of 5-(4-fluorophenyl)-1,3,4-thiadiazol-2-amine
1d This compound was obtained as white solid in a yield
of 80%. M.p.: 232°C; IR (KBr, v, cm-1); 3294, 3156 (vNH),
1633 (vC=N), 682(vC–S); 1H NMR (400 MHz, d, ppm,
DMSO-d6): 7.79–7.84 (dd, J1 = 6.36 Hz, J2 = 8.46 Hz,
2H), 7.42 (s, 2H), 7.28–7.34 (m, 2H).
Unless otherwise noted, materials were obtained from
commercial suppliers and used without further purification.
Melting point was determined by electrothermal melting
point apparatus and is uncorrected. All reactions were
monitored by thin-layer chromatography (TLC) on 0.25 mm
silica gel (60GF-254) plates and visualised with UV light.
Column chromatography was performed on silica gel
(200–300mesh). Infra red (IR)spectra was recorded on using
Synthesis of 5-(2-chlorophenyl)-1,3,4-thiadiazol-2-amine
1e This compound was obtained as white solid in a yield
of 82%. M.p.: 228–230°C; IR (KBr, v, cm-1); 3384, 3136
(vNH), 1643 (vC=N), 672(vC–S); 1H NMR (400 MHz, d,
ppm, DMSO-d6): 7.97–8.01 (m, 2H), 7.57–7.60 (m, 1H),
7.44–7.47 (m, 1H), 7.42 (s, 2H).
1
KBr disk on a Nicolet MX-1 FTIR spectrophotometer, H
and 13C NMR spectra were recorded on AMX-400, Bruker-
400 liquid-state NMR spectrometer using tetramethylsilane
(TMS) as internal standard (chemical shift in d ppm). Ele-
mental analysis was carried out using a Perkin Elmer
2400-CHN Analyzer. Spectral analysis was carried out by
Sophisticated Analytical Instruments Facility (SAIF) divi-
sion of Indian Institute of Science, Bangalore, India.
Synthesis of 5-(4-methylphenyl)-1,3,4-thiadiazol-2-amine
1f This compound was obtained as white solid in a yield
of 88%. M.p.: 212°C; IR (KBr, v, cm-1); 3578, 3143 (vNH),
1651 (vC=N), 681(vC–S); 1H NMR (400 MHz, d, ppm,
DMSO-d6): 7.60–7.63 (d, J = 9.96 Hz, 2H), 7,31 (s, 2H),
7.26 (d, J = 7.93 Hz, 2H), 2.32 (s, 3H, CH3).
Chemistry
General procedure for synthesis of 5-substituted-1,3,4-
thiadiazol-2-amine 1a–m (Tu et al., 2008)
Synthesis of 5-(3-methoxyphenyl)-1,3,4-thiadiazol-2-amine
1g This compound was obtained as light yellow solid in a
yield of 84%. M.p.: 220°C; IR (KBr, v, cm-1); 3448, 3155
1
A stirring mixture of benzoic acid (50 mmol), thiosemi-
carbazide (50 mmol) and phosphorus oxychloride (15 ml)
was heated at 75°C for 1 h. After cooling to room tem-
perature, water was added; the reaction mixture was further
refluxed for 4 h. After cooling, the mixture was basified to
pH 8 by the dropwise addition of 50% potassium hydroxide
solution under stirring. Thus, obtained precipitate was fil-
tered and recrystallised from ethanol.
(vNH), 1650 (vC=N), 1231 (vAr–O–C), 676(vC–S); H NMR
(400 MHz, d, ppm, DMSO-d6): 7.25–7.35 (m, 3H),
6.97–7.01 (dd, 1H), 7,40 (s, 2H), 3.79 (s, 3H, OCH3).
Synthesis of 5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine
1h This compound was obtained as light yellow solid in a
yield of 80%. M.p.: 196°C; IR (KBr, v, cm-1); 3548, 3126
1
(vNH), 1660 (vC=N), 1243 (vAr–O–C), 676(vC–S); H NMR
(400 MHz, d, ppm, DMSO-d6): 7.62 (d, J = 7.83 Hz, 2H),
7.50 (d, J = 8.01 Hz, 2H), 7,27 (s, 2H), 3.53 (s, 3H,
OCH3).
Synthesis of 5-phenyl-1,3,4-thiadiazol-2-amine 1a This
compound was obtained as white solid in a yield of 78%.
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Med Chem Res (2012) 21:816–824
821
Synthesis of 5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazol-2-
amine 1i This compound was obtained as white solid in a
yield of 79%. M.p.: 210°C; IR (KBr, v, cm-1); IR (KBr, v,
cm-1); 3578, 3156 (vNH), 1640 (vC=N), 1258 (vAr–O–C),
670(vC–S); 1H NMR (400 MHz, d, ppm, DMSO-d6):
8.65–8.69 (m, 3H), 7.61 (s, 2H), 3.71 (s, 3H, OCH3), 3.70
(s, 3H, OCH3).
cooled water, and recrystallised from water to yield 2,4-
dioxothiazolidine-5-acetic acid.
1
IR (KBr, v, cm-1): 3227 (vNH), 2850, 1690 (vC=O); H
NMR (400 MHz, d, ppm, DMSO-d6): 12.60 (s, 1H), 11.90
(s, 1H), 4.86 (m, 1H), 3.03 (dd, J = 15.23 Hz, J = 4.6 Hz,
1H), 2.89 (dd, J = 11.46 Hz, J = 4.2 Hz, 1H).
General procedure for synthesis of 2-(2,4-dioxo-1,3-
thiazolidin-5-yl)-N-(5-substituted-1,3,4-thiadiazol-2-
yl)acetamide 3a–n
Synthesis of 5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazol-2-
amine 1j This compound was obtained as greyish solid in
a yield of 90%. M.p.: 206°C; IR (KBr, v, cm-1); 3590,
1
3126 (vNH), 1620 (vC=N), 1266 (vAr–O–C), 690(vC–S); H
A mixture of 2,4-dioxothiazolidine-5-acetic acid (50 mmol)
and 1.2 g of thionyl chloride in 5 ml of dioxane was heated
under reflux for 5 h, cooled, and treated with 15 ml of hex-
ane. The precipitate was separated by filtration and used
without further purification. To a solution of corresponding
5-substituted-1,3,4-thiadiazol-2-amine (10 mmol) and 1 ml
of triethylamine in 10 ml of anhydrous dioxane was added
the solution of acid chloride (50 mmol) in 10 ml of same
solvent. The mixture was heated for 10 min at 100°C,
cooled, and diluted with 100 ml of water. The precipitate
was separated by filtration and recrystallised with appro-
priate solvent.
NMR (400 MHz, d, ppm, DMSO-d6): 7.85 (s, 2H), 6.95 (s,
2H, NH2), 3.83 (s, 6H, OCH3), 3.80 (s, 3H, OCH3).
Synthesis of 5-(2-nitrophenyl)-1,3,4-thiadiazol-2-amine 1k
This compound was obtained as yellow solid in a yield of
73%. M.p.: 242°C; IR (KBr, v, cm-1); 3577, 3132 (vNH),
1667 (vC=N), 676(vC–S); 1H NMR (400 MHz, d, ppm,
DMSO-d6): 8.41–8.48 (m, 1H), 8.27 (d, J = 8.84 Hz, 2H),
8.01 (m, 1H), 7.70 (s, 2H).
Synthesis of 5-(3-nitrophenyl)-1,3,4-thiadiazol-2-amine 1l
This compound was obtained as light yellow solid in a
yield of 71%. M.p.: 219°C; IR (KBr, v, cm-1); 3532, 3151
(vNH), 1637 (vC=N), 651(vC–S); 1H NMR (400 MHz, d,
ppm, DMSO-d6): 7.99 (d, J = 8.14 Hz, 2H), 7.75–7.87 (m,
2H), 7.70 (s, 2H).
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-phe-
nyl-1,3,4-thiadiazol-2-yl)acetamide 3a This compound
was obtained as white solid in a yield of 66%. M.p.: 256°C;
IR (KBr, v, cm-1): 3325, 3255 (vNH), 2881, 1699 (vC=O);
1H NMR (400 MHz, d, ppm, DMSO-d6): 12.90 (s, 1H),
12.10 (s, 1H), 7.95–7.92 and 7.51 (m, 5H), 4.80 (m, 1H),
3.42 (dd, J = 17.11 Hz, J = 4.71 Hz, 1H), 3.29 (dd,
J = 16.12 Hz, J = 4.32 Hz, 1H). 13C NMR (100 MHz, d,
ppm, DMSO-d6): 169.23, 166.78, 165.63, 162.45, 152.65,
132.12, 129.33, 128.31, 126.34, 51.02, 35.12. Calcd. for
C13H10N4O3S2: C, 46.70; H, 3.01; N, 16.76; Found: C,
46.65; H, 3.00; N, 16.84%.
Synthesis of 5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine 1m
This compound was obtained as yellow solid in a yield of
78%. M.p.: 260°C; IR (KBr, v, cm-1); 3568, 3147 (vNH),
1658 (vC=N), 656(vC–S); 1H NMR (400 MHz, d, ppm,
DMSO-d6): 8.29 (d, J = 8.92 Hz, 2H), 7.98 (d,
J = 8.92 Hz, 2H), 7.69 (s, 2H).
Synthesis of 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine
1n A mixture of trifluoroaceticacid anhydride (50 mmol),
thiosemicarbazide (50 mmol) was heated at 40°C on a
water bath for 1 h. The reaction mixture was cooled,
diluted with water and made alkaline with ammonia; the
crystalline precipitate was recrystallised with ethanol gave
white crystals in a yield of 81%. M.p.: 226°C; IR (KBr, v,
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-4-chloro-
phenyl-1,3,4-thiadiazol-2-yl)acetamide 3b This compound
was obtained as light brown solid in a yield of 59%. M.p.:
261°C; IR (KBr, v, cm-1): 3566, 3498 (vNH), 2966, 1690
1
(vC=O); H NMR (400 MHz, d, ppm, DMSO-d6): 12.89 (s,
1H), 12.12 (s, 1H), 7.55 (d, J = 6.71 Hz, 2H), 7.51 (d,
J = 7.26 Hz, 2H), 4.78 (m, 1H), 3.41 (dd, J = 15.53 Hz,
J = 4.61 Hz, 1H), 3.27 (dd, J = 17.13 Hz, J = 4.82 Hz,
1H). 13C NMR (100 MHz, d, ppm, DMSO-d6): 170.03,
168.21, 166.53, 162.13, 153.19, 133.23, 129.74, 128.17,
126.89, 50.12, 34.09. Calcd. for C13H9ClN4O3S2: C, 42.34;
H, 2.46; N, 15.19; Found: C, 42.26; H, 2.40; N, 15.29%.
1
cm-1); 3468 (vNH), 1647 (vC=N); H NMR (400 MHz, d,
ppm, DMSO-d6): 7.96 (s, 2H).
Synthesis of 2,4-dioxothiazolidine-5-acetic acid 2
(Zimenkovskii et al., 2006)
A mixture of thiourea (25 mmol) and maleic anhydride
(25 mmol) in 15 ml of concentrated hydrochloric acid was
refluxed for 5 h. After cooling down to room temperature,
the precipitate was separated by filtration, washed with
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-4-bromo-
phenyl-1,3,4-thiadiazol-2-yl)acetamide 3c This compound
123

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Med Chem Res (2012) 21:816–824
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-3-
methoxyphenyl-1,3,4-thiadiazol-2-yl)acetamide 3g This
compound was obtained as brown solid in a yield of 54%.
M.p.: 237°C; IR (KBr, v, cm-1): 3357, 3241 (vNH), 2979,
1689 (vC=O); 1H NMR (400 MHz, d, ppm, DMSO-d6):
12.87 (s, 1H), 12.21 (s, 1H), 7.35–7.32 (m, 3H), 7.16–7.9
(m, 1H), 4.83 (m, 1H), 3.80 (s, 3H, OCH3), 3.31 (dd,
J = 17.34 Hz, J = 4.23 Hz, 1H), 3.05 (dd, J = 15.71 Hz,
J = 4.78 Hz, 1H). 13C NMR (100 MHz, d, ppm, DMSO-
d6): 171.76, 168.12, 165.97, 161.78, 151.61, 132.87,
130.12, 129.23, 128.31, 127.13 126.44, 56.28, 50.34,
34.45. Calcd. for C14H12N4O4S2: C, 46.15; H, 3.32; N,
15.37; Found: C, 46.11; H, 3.24; N, 15.45%.
was obtained as brown solid in a yield of 61%. M.p.:
247°C; IR (KBr, v, cm-1): 3362, 3271 (vNH), 2942, 1693
(vC=O); H NMR (400 MHz, d, ppm, DMSO-d6): 12.99 (s,
1H), 12.13 (s, 1H), 7.78–7.74 (m, 4H), 4.81 (m, 1H), 3.39
(dd, J = 16.52 Hz, J = 4.71 Hz, 1H), 3.08 (dd,
J = 17.11 Hz, J = 4.36 Hz, 1H). 13C NMR (100 MHz, d,
ppm, DMSO-d6): 169.87, 167.01, 164.21, 162.09, 153.12,
135.11, 129.89, 128.45, 126.61, 51.18, 34.41. Calcd. for
C13H9BrN4O3S2: C, 37.78; H, 2.20; N, 13.56; Found: C,
37.70; H, 2.18; N, 13.63%.
1
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-4-fluo-
rophenyl-1,3,4-thiadiazol-2-yl)acetamide 3d This com-
pound was obtained as light yellow solid in a yield of
55%. M.p.: 239°C; IR (KBr, v, cm-1): 3434, 3246 (vNH),
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-4-
methoxyphenyl-1,3,4-thiadiazol-2-yl)acetamide 3h This
compound was obtained as white solid in a yield of 69%.
M.p.: 249°C; IR (KBr, v, cm-1): 3561, 3315 (vNH), 2955,
1698 (vC=O); 1H NMR (400 MHz, d, ppm, DMSO-d6):
13.00 (s, 1H), 12.15 (s, 1H), 7.59 (d, 2H), 7.52 (d, 2H),
4.78 (m, 1H), 3.89 (s, 3H, OCH3), 3.43 (dd, J = 16.21 Hz,
J = 4.78 Hz, 1H), 3.07 (dd, J = 15.12 Hz, J = 4.65 Hz,
1H). 13C NMR (100 MHz, d, ppm, DMSO-d6): 170.29,
168.81, 165.24, 163.11, 153.32, 130.11, 129.24, 128.22,
125.41, 54.21, 49.89, 34.31. Calcd. for C14H12N4O4S2: C,
46.15; H, 3.32; N, 15.37; Found: C, 46.10; H, 3.26; N,
15.43%.
1
2963, 1698 (vC=O); H NMR (400 MHz, d, ppm, DMSO-
d6): 12.90 (s, 1H), 12.10 (s, 1H), 7.71 (d, 2H), 7.67 (d,
2H), 4.83 (m, 1H), 3.33 (dd, J = 17.41 Hz, J = 4.43 Hz,
1H), 3.06 (dd, J = 15.23 Hz, J = 4.62 Hz, 1H). 13C
NMR (100 MHz, d, ppm, DMSO-d6): 171.23, 167.12,
165.13, 163.15, 151.45, 132.34, 129.78, 128.11, 126.69,
50.72, 33.09. Calcd. for C13H9FN4O3S2: C, 44.31; H,
2.57; N, 15.90; Found: C, 44.23; H, 2.51; N, 15.98%.
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-2-chloro-
phenyl-1,3,4-thiadiazol-2-yl)acetamide 3e This compound
was obtained as white solid in a yield of 62%. M.p.: 231°C;
IR (KBr, v, cm-1): 3421, 3233 (vNH), 2982, 1690 (vC=O);
1H NMR (400 MHz, d, ppm, DMSO-d6): 12.89 (s, 1H),
12.00 (s, 1H), 8.01–7.92 (m, 4H), 4.81 (m, 1H), 3.43 (dd,
J = 17.14 Hz, J = 4.20 Hz, 1H), 3.19 (dd, J = 15.51 Hz,
J = 4.34 Hz, 1H). 13C NMR (100 MHz, d, ppm, DMSO-
d6): 168.97, 165.86, 164.34, 161.56, 151.875, 136.31,
133.32, 129.59, 128.38, 127.78, 126.28, 50.11, 35.29.
Calcd. for C13H9ClN4O3S2: C, 42.34; H, 2.46; N, 15.19;
Found: C, 42.24; H, 2.39; N, 15.28%.
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-(-3,4-
dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide 3i This
compound was obtained as white solid in a yield of 62%.
M.p.: 241°C; IR (KBr, v, cm-1): 3448, 3278 (vNH), 2957,
1698 (vC=O); 1H NMR (400 MHz, d, ppm, DMSO-d6):
12.97 (s, 1H), 12.21 (s, 1H), 7.31–7.27 (m, 3H), 4.78 (m,
1H), 3.83 (s, 3H, OCH3), 3.80 (s, 3H, OCH3). 3.41 (dd,
J = 17.26 Hz, J = 4.47 Hz, 1H), 3.12 (dd, J = 15.44 Hz,
J = 4.53 Hz, 1H). 13C NMR (100 MHz, d, ppm, DMSO-
d6): 171.33, 169.28, 165.11, 162.47, 152.31, 130.79,
129.66, 127.38, 126.12, 124.21, 57.37, 51.45, 49.23, 33.97.
Calcd. for C15H14N4O5S2: C, 45.68; H, 3.58; N, 14.20;
Found: C, 45.69; H, 3.53; N, 14.31%.
Synthesis
of
2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-
4-methylphenyl-1,3,4-thiadiazol-2-yl)acetamide 3f This
compound was obtained as light yellow solid in a yield
of 58%. M.p.: 260°C; IR (KBr, v, cm-1): 3372, 3259
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-(-3,4,
5-trimethoxyphenyl)-1,3,4-thiadiazol-2-yl)acetamide 3j This
compound was obtained as light yellow solid in a yield of
52%. M.p.: 260°C; IR (KBr, v, cm-1): 3412, 3253 (vNH),
1
(vNH), 2961, 1697 (vC=O); H NMR (400 MHz, d, ppm,
DMSO-d6): 12.89 (s, 1H), 12.00 (s, 1H), 7.62 (d,
J = 7.4 Hz, 2H), 7,52 (d, J = 6.7 Hz, 2H), 4.82 (m,
1H), 3.39 (dd, J = 16.87 Hz, J = 4.69 Hz, 1H), 3.08
(dd, J = 15.54 Hz, J = 4.81 Hz, 1H), 2.63 (s, 3H,
CH3),. 13C NMR (100 MHz, d, ppm, DMSO-d6): 169.65,
167.21, 165.28, 161.64, 151.73, 131.19, 130.11 129.37,
128.21, 51.02, 35.12 29.15. Calcd. for C14H12N4O3S2: C,
48.26; H, 3.47; N, 16.08; Found: C, 48.27; H, 3.41; N,
16.20%.
1
2966, 1700 (vC=O); H NMR (400 MHz, d, ppm, DMSO-
d6): 12.81 (s, 1H), 12.14 (s, 1H), 7.21 (d, 2H), 4.81 (m,
1H), 3.87 (s, 6H, 2OCH3), 3.71 (s, 3H, OCH3). 3.38 (dd,
J = 16.43 Hz, J = 4.32 Hz, 1H), 3.27 (dd, J = 15.23 Hz,
J = 4.6 Hz, 1H). 13C NMR (100 MHz, d, ppm, DMSO-
d6): 170.23, 169.67, 166.71, 163.67, 152.39, 131.28,
129.57, 128.49, 125.38, 108.34, 57.34, 50.89, 33.29. Calcd.
123

Med Chem Res (2012) 21:816–824
823
for C16H16N4O6S2: C, 45.28; H, 3.80; N, 13.20; Found: C,
45.26; H, 3.76; N, 13.23%.
Calcd. for C8H5N4O3S2: C, 29.45; H, 1.54; N, 17.17;
Found: C, 29.40; H, 1.51; N, 17.56%.
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-2-
nitrophenyl-1,3,4-thiadiazol-2-yl)acetamide 3k This com-
pound was obtained as light yellow solid in a yield of 56%.
M.p.: 248°C; IR (KBr, v, cm-1): 3423, 3304 (vNH), 2946,
1688 (vC=O); 1H NMR (400 MHz, d, ppm, DMSO-d6):
12.92 (s, 1H), 12.18 (s, 1H), 7.72–7.69 (m, 4H), 4.44 (m,
1H), 3.42 (dd, J = 16.37 Hz, J = 4.23 Hz, 1H), 3.08 (dd,
J = 17.13 Hz, J = 4.47 Hz, 1H). 13C NMR (100 MHz, d,
ppm, DMSO-d6): 170.87, 168.78, 164.25, 163.49, 150.87,
142.31, 130.78, 128.11, 126.65, 125.12, 121.43, 50.72,
32.28. Calcd. for C13H9N5O5S2: C, 41.16; H, 2.39; N,
18.46; Found: C, 41.15; H, 3.33; N, 18.53%.
Microbiology
For the antibacterial and antifungal activity, the com-
pounds were dissolved in dimethylsulfoxide (DMSO).
Further dilutions of the compounds and standard drugs in
the test medium were prepared at the required quantities of
128, 64, 32, 16, 8, 4, 2, 1 lg/ml concentrations with
Mueller–Hinton broth and Sabouraud dextrose broth. The
minimum inhibitory concentrations (MICs) were deter-
mined using the twofold serial dilution technique (National
Committee for Clinical Laboratory Standards, 2000). A
control test was also performed containing inoculated broth
supplemented with only DMSO at the same dilutions used
in our experiments and found inactive in the culture med-
ium. All the compounds were tested for their in vitro
growth inhibitory activity against different bacteria and
fungi.
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-3-
nitrophenyl-1,3,4-thiadiazol-2-yl)acetamide 3l This com-
pound was obtained as light yellow solid in a yield of 50%.
M.p.: 241°C; IR (KBr, v, cm-1): 3453, 3219 (vNH), 2982,
1697 (vC=O); 1H NMR (400 MHz, d, ppm, DMSO-d6):
13.12 (s, 1H), 12.13 (s, 1H), 7.78 (d, 2H), 7.74–7.72 (m,
2H), 4.31 (m, 1H), 3.41 (dd, J = 16.41 Hz, J = 4.38 Hz,
1H), 3.21 (dd, J = 15.43 Hz, J = 4.78 Hz, 1H). 13C NMR
(100 MHz, d, ppm, DMSO-d6): 171.91, 167.57, 163.41,
162.12, 151.13, 141.54, 130.38, 128.87, 126.11, 124.42,
51.76, 34.81. Calcd. for C13H9N5O5S2: C, 41.16; H, 2.39;
N, 18.46; Found: C, 41.14; H, 3.34; N, 18.54%.
Antibacterial and antifungal activity
The cultures were obtained from Mueller–Hinton broth for
all the bacterial strains after 24 h of incubation at
37 1°C. Fungi were maintained in Sabouraud dextrose
broth after incubation for 24 h at 25 1°C. Testing was
carried out in Mueller–Hinton broth and Sabouraud dex-
trose broth at pH 7.4 and the twofold serial dilution tech-
nique was applied. The final inoculums size was 105 CFU/
ml for the antibacterial assay and 104 CFU/ml for the
antifungal assay. A set of tubes containing only inoculated
broth was used as controls. For the antibacterial assay after
incubation for 24 h at 37 1°C and after incubation for
48 h at 25 1°C for antifungal assay, the tube with no
growth of microorganism was recorded to represent the
MIC expressed in lg/ml. Every experiment in the anti-
bacterial and antifungal assay was replicated twice.
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-4-
nitrophenyl-1,3,4-thiadiazol-2-yl)acetamide 3m This com
pound was obtained as light yellow solid in a yield of 54%.
M.p.: 256°C; IR (KBr, v, cm-1): 3418, 3312 (vNH), 2944,
1691 (vC=O); 1H NMR (400 MHz, d, ppm, DMSO-d6):
12.92 (s, 1H), 12.14 (s, 1H), 8.27 (d, J = 7.2 Hz, 2H), 7.98
(d, J = 6.23 Hz,2H), 4.12 (m, 1H), 3.42 (dd, J =
15.83 Hz, J = 4.62 Hz, 1H), 3.13 (dd, J = 16.41 Hz, J =
4.23 Hz, 1H). 13C NMR (100 MHz, d, ppm, DMSO-d6):
169.24, 167.98, 165.46, 161.59, 150.22, 130.54, 128.43,
126.63, 125.65, 52.43, 34.21. Calcd. for C13H9N5O5S2: C,
41.16; H, 2.39; N, 18.46; Found: C, 41.17; H, 3.35; N,
18.50%.
Cytotoxic activity evaluation
The MTT [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl-tetra-
zolium bromide] cell proliferation assay (Mosmann, 1983)
was used to evaluate cytotoxic activity of the synthesised
compounds against four human cancer cell lines including
HeLa (cervical carcinoma), HT29 (colorectal cancer),
A549 (lung cancer) and MCF-7 (breast adenocarcinoma)
cell lines. The inhibition of the cell proliferation was
determined 24 h after cells were exposed to the tested
compounds. The IC50 (the concentration that causes 50%
growth inhibition) values were determined.
Synthesis of 2-(2,4-dioxo-1,3-thiazolidin-5-yl)-N-(5-tri-
fluoromethyl-1,3,4-thiadiazol-2-yl)acetamide 3n This
compound was obtained as white solid in a yield of 49%.
M.p.: 198°C; IR (KBr, v, cm-1): 3417, 3319 (vNH), 1689
1
(vC=O); H NMR (400 MHz, d, ppm, DMSO-d6): 13.00 (s,
1H), 12.23 (s, 1H), 4.33 (m, 1H), 3.43 (dd, J = 17.38 Hz,
J = 4.78 Hz, 1H), 3.11 (dd, J = 15.33 Hz, J = 4.23 Hz,
1H). 13C NMR (100 MHz, d, ppm, DMSO-d6): 170.45,
168.33, 165.27, 156.85, 150.18, 121.44, 50.12, 34.21.
123

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