CHEMISTRY
RESEARCH
ORIGINAL RESEARCH
Received: 6 May 2011 / Accepted: 4 November 2011 / Published online: 13 November 2011
Springer Science+Business Media, LLC 2011
123
Introduction
The development of new antimicrobial and anticancer
therapeutic agents is one of the fundamental goals in
medicinal chemistry. Cytotoxicity and genotoxicity of
anticancer drugs to the normal cells are major problems in
cancer therapy and engender the risk of inducing secondary
malignancy (Aydemir and Bilaloglu, 2003). A dose of
anticancer drug sufficient to kill tumor cells is often toxic
to the normal tissue and leads to many side effects, which
in turn, limits its treatment efficacy. In recent years, there
has been a concerned search for the discovery and development of novel selective antimicrobial and anti-tumor
agents, devoid of many of the unpleasant side effects of
conventional antimicrobial and antitumor agents. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily which
are ligand-activated transcription factors. So for, three
PPAR isotopes have been reported: PPARa, PPARb, and
PPARc. Originally, PPAR activity was thought to be limited to lipid metabolism and glucose homeostasis. Later
studies showed that PPAR activation regulates inflammatory responses, cell proliferation and differentiation, as
well as apoptosis (Houseknecht et al., 2002; Sung et al.,
2004).
Thiazolidine-2,4-dione (TZDs) are a class of insulin
sensitizing drugs which include ciglitazone, pioglitazone,
and rosiglitazone. Apart from their known antidiabetic
activity, the ability of TZDs to contribute to cancer therapy
has been evidenced by numerous in vitro and in vivo studies
(Takashima et al., 2001; Galli et al., 2004; Yoshizumi et al.,
2004; Betz et al., 2005; Turturro et al., 2004; Shiau et al.,
2005; Han and Roman 2006; Kaminskyy et al., 2009;
Li et al., 2010; Patil et al., 2010), antimicrobial and anticancer (Mohsen et al., 1985), antibacterial and antifungal
3215
Ar CHO
2 a-m
O
H
3a-m
(b)
NH
Ar
COOH
(a)
NH
S
Ar
O
H
4a-m
123
3216
Table 1 Results of antibacterial and antifungal activities of compounds 4am [minimum inhibitory concentration (MIC) values in lg/ml]
COOH
O
N
S
Ar
H
4a-m
Compound
Ar
E. c
P. a
S. a
E. f
C. a
C. n
A. f
A. n
4a
128
64
16
16
32
16
4b
128
128
16
16
16
32
16
16
32
32
64
64
32
64
16
16
32
16
32
32
32
32
16
16
16
16
32
32
16
16
64
64
32
16
16
32
32
32
128
128
32
32
16
16
16
16
32
16
16
16
32
32
Br
4c
F
4d
H3 C
4e
OCH3
4f
H3CO
4g
H3CO
H3CO
OCH3
4h
N
4i
N
4j
123
3217
Table 1 continued
Compound
Ar
4k
E. c
P. a
S. a
E. f
C. a
C. n
A. f
A. n
16
16
32
64
64
64
32
32
16
16
32
32
32
16
16
64
64
32
32
16
16
O
4l
S
4m
Amp.
NT
NT
NT
NT
NT
NT
Cip.
NT
NT
NT
NT
NT
NT
Ket.
NT
NT
NT
NT
E. c Escherichia coli; P. a Pseudomonas aeruginosa; S. a Staphylococcus aureus; E. f Enterococcus faecalis; C. a Candida albicans; C. n
Cryptococcus neoformans; A. f Aspergillus flavus; A. g Aspergillus niger; NT not tested; Amp ampicillin; Cip ciprofloxacin; Ket ketoconazole
123
3218
COOH
Table 2 continued
Compound
4l
N
S
Ar
A549
76
88
80
76
90
88
80
70
Ar
HeLa
HT29
A549
MCF-7
4a
72
88
90
100
4b
38
30
42
48
COOH
O
N
S
Br
4c
34
32
36
38
68
72
78
100
Ar
H3 C
48
4e
48
55
58
OCH3
40
4f
44
44
48
H3CO
H3CO
30
32
36
30
H3CO
OCH3
62
4h
78
80
4i
88
90
75
100
60
80
72
84
80
94
76
90
N
4j
N
4k
Compound
LogP
MW
MV
TPSA
4a
3.05
339
284
87.22
4b
3.86
418
302
76.37
4c
3.22
357
289
76.37
4d
3.50
353
301
76.37
4e
3.08
369
310
85.60
4f
3.11
369
310
85.60
4g
2.68
429
361
104.07
4h
1.88
340
280
89.26
4i
1.81
340
280
89.26
4j
1.71
340
280
89.26
4k
2.31
329
266
89.51
4l
2.95
345
275
76.37
4m
2.27
342
286
81.30
90
123
4a-m
4d
4g
MCF-7
4a-m
Compound
HT29
O
4m
Ar
HeLa
3219
COOH
O
N
S
Ar
O
H
4a-m
Compound
MW
LogP
HBD
HBA
4a
339
3.06
4b
418
3.96
4c
357
3.19
4d
353
3.45
4e
369
3.05
4f
369
2.92
4g
429
2.77
4h
340
2.05
4i
340
1.88
4j
4k
340
329
1.88
2.54
1
1
6
6
4l
345
2.90
4m
342
2.32
Conclusions
We report the synthesis of 4-((2,4-dioxothiazolidin-3yl)methyl)benzoic acid derivatives. All compounds were
evaluated for their in vitro antimicrobial and cytotoxic
activities. Antibacterial and antifungal results revealed that
most of the compounds showed significant activity whereas
compounds 4c and 4g are found to be broad spectrum
antibacterial and antifungal properties, the MIC values were
observed in the range of 24 and 28 lg/ml, respectively. In
MTT cytotoxicity studies, the compound 4g was found most
potent. In HeLa, HT29, A549, and MCF-7 cells, the IC50
values were observed in the range of 3036 lM. The results
indicates that some of functional groups such as 4-bromophenyl, 4-fluorophenyl, and 3,4,5-trimethoxyphenyl group
present in these compounds displayed role of biological
activity even most of the compounds have similar physicochemical parameters. It can be concluded that a combination of 4-((2,4-dioxothiazolidin-3-yl) methyl) benzoic acid
and substituted phenyl has caused an enhanced antimicrobial and cytotoxic effect and hence they are ideally suited
for further modification to obtain more efficacious antimicrobial and cytotoxic compounds.
Experimental protocols
General conditions
Chemistry
General method for the synthesis of 4-(5-arylidene-2,4dioxothiazolidin-3-yl) methylbenzoic acid (4am)
A mixture of (Z)-5-substituted-2,4-thiazolidinediones
(3am) (10 mmol) and potassium carbonate (20 mmol) in
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3220
acetone (100 ml) was refluxed for 45 min. Then 4-(bromomethyl) benzoic acid (20 mmol) was slowly added and
the mixture was refluxed for 4872 h. After evaporation of
the solvent under reduced pressure, the crude solid residue
was dissolved in methanol; the solution was acidified (pH
3) with HCl and was stirred at room temperature for
30 min. After evaporation to dryness in vacuum, the crude
solid was washed with H2O and recrystallized from
methanol/CHCl3 providing pure acid 4am.
4-[((Z)-5-Benzylidene-2,4-dioxothiazolidin3yl)methyl]benzoic acid (4a)
Yield 62%, mp 275277C, IR (KBr, cm-1): 3276 (OH),
1720, 1695 (C=O); 1H NMR (400 MHz, d, ppm, DMSOd6): 4.90 (s, 2H, CH2), 7.42 (d, 2H, ArH, J = 8.2 Hz),
7.497.56 (m, 3H, ArH), 7.62 (d, 2H, ArH, J = 7.4 Hz),
7.92 (d, 2H, ArH, J = 8 Hz), 7.97 (s, 1H, CH=), 12.94
(s, 1H, OH); 13C NMR (100 MHz, d, ppm, DMSO-d6):
44.37, 121.07, 127.59, 129.34, 129.64, 130.12, 130.21,
130.70, 132.86, 133.51, 140.16, 165.43, 166.90, 167.29;
Elemental Anal. Calcd for C18H13NO4S (339): C, 63.71; H,
3.86; N, 4.13. Found: C, 63.67; H, 3.85; N, 4.11.
4-[((Z)-5-(4-Bromobenzylidene)-2,4-dioxothiazolidin3yl)methyl]benzoic acid (4b)
Yield 52%, mp 262263C, IR (KBr, cm-1): 3320 (OH),
1720, 1700 (C=O); 1H NMR (400 MHz, d, ppm, DMSOd6): 5.02 (s, 2H, CH2), 7.47 (d, 2H, ArH, J = 8.1 Hz),
7.55 (d, 2H, ArH, J = 8.3 Hz), 7.65 (d, 2H, ArH,
J = 8.2 Hz), 7.81 (d, 2H, ArH, J = 8.3 Hz), 8.03(s, 1H,
CH=), 13.09 (s, 1H, OH); 13C NMR (100 MHz, d, ppm,
DMSO-d6): 46.44, 116.34, 125.37, 126.53, 127.32, 128.02,
129.66, 130.98, 132.34, 149.67, 154.55, 165.76, 167.46,
168.33; Elemental Anal. Calcd for C18H12BrNO4S (418):
C, 51.69; H, 2.89; N, 3.35. Found: C, 51.65; H, 2.86; N,
3.33.
4-[((Z)-5-(4-Fluorobenzylidene)-2,4-dioxothiazolidin3yl)methyl]benzoic acid (4c)
Yield 60%, mp 250252C, IR (KBr, cm-1): 3255 (OH),
1725, 1700 (C=O); 1H NMR (400 MHz, d, ppm, DMSOd6): 4.90 (s, 2H, CH2), 7.367.42 (m, 4H, ArH), 7.70 (d,
2H, ArH, J = 8.3 Hz), 7.90 (d, 2H, ArH, J = 6.5 Hz),
7.98 (s, 1H, CH=), 12.94 (s, 1H, OH); 13C NMR
(100 MHz, d, ppm, DMSO-d6): 47.38, 115.58, 124.36,
125.55, 127.32, 127.98, 128.79, 130.53, 131.88, 148.37,
155.16, 165.37, 166.27, 168.65; Elemental Anal. Calcd for
C18H12FNO4S (357): C, 60.50; H, 3.38; N, 3.92. Found: C,
60.47; H, 3.36; N, 3.90.
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3221
d6): 4.87 (s, 2H, CH2), 6.75 (q, 1H, J = 1.7, J = 1.6 Hz,
furan), 7.15 (d, 1H, J = 3.4 Hz, furan), 7.40 (d, 2H, ArH,
J = 8.2 Hz), 7.78 (s, 1H, CH=), 7.91 (d, 2H, ArH,
J = 8.2 Hz), 8.07 (d, 1H, J = 1.4 Hz, furan), 12.93 (s, 1H,
OH); 13C NMR (100 MHz, d, ppm, DMSO-d6): 44.50,
120.21, 123.33, 125.42, 127.33, 128.13, 129.69, 131.55,
140.72, 157.64, 162.44, 165.28, 166.23, 168.65; Elemental
Anal. Calcd for C16H11NO5S (329): C, 58.35; H, 3.37; N,
4.25. Found: C, 58.32; H, 3.33; N, 4.26.
4-[((Z)-2,4-Dioxo-5-((thiophen-2-yl)methylene)thiazolidin3yl)methyl]benzoic acid (4l)
Yield 62%, mp 258260C, IR (KBr, cm-1): 3320 (OH),
1720, 1695 (C=O); 1H NMR (400 MHz, d, ppm, DMSOd6): 4.90 (s, 2H, CH2), 7.417.43 (d, 1H, J = 3.7 Hz, thiophene), 7.60 (d, 1H, J = 1.6 Hz, thiophene), 7.76 (d, 2H,
J = 8.2 Hz, ArH), 7.797.91 (m, 2H, ArH and 1H, thiophene), 7.92 (s, 1H, CH=), 12.75 (s, 1H, OH); 13C NMR
(100 MHz, d, ppm, DMSO-d6): 44.55, 119.65, 123.60,
124.63, 127.63, 128.84, 129.61, 130.29, 139.98, 158.83,
161.38, 165.11, 166.87, 167.25; Elemental Anal. Calcd for
C16H11NO4S2 (345): C, 55.64; H, 3.21; N, 4.06. Found: C,
55.63; H, 3.20; N, 4.02.
4-[((Z)-5-((1-Methyl-1H-pyrrol-2-yl)methylene)-2,4dioxothiazolidin-3yl)methyl]benzoic acid (4m)
Yield 55%, mp 255256C, IR (KBr, cm-1): 3340 (OH),
1725, 1699 (C=O); 1H NMR (400 MHz, d, ppm, DMSOd6): 3.80 (s, 3H, CH3), 4.99 (s, 2H, CH2), 6.35 (d, 1H,
J = 3.1 Hz, pyrrol), 7.28 (m, 2H, ArH and 1H, pyrrol),
7.60 (m, 2H, ArH and 1H, pyrrol), 7.65 (s, 1H, CH=),
14.30 (s, 1H, OH); 13C NMR (100 MHz, d, ppm, DMSOd6): 32.76, 44.82, 120.92, 122.76, 125.82, 127.44, 128.02,
129.55, 131.56, 137.53, 157.44, 162.43, 165.43, 167.35,
168.63; Elemental Anal. Calcd for C17H14N2O4S (342): C,
59.64; H, 4.12; N, 8.18. Found: C, 59.62; H, 4.10; N, 8.19.
Antimicrobial activity
The cultures were obtained from MuellerHinton broth for
all the bacterial strains after 24 h of incubation at
37 1C. Fungi were maintained in Sabouraud dextrose
broth after incubation for 24 h at 25 1C. Testing was
carried out in MuellerHinton broth and Sabouraud dextrose broth at pH 7.4 and the twofold serial dilution technique 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 1C and after incubation for
48 h at 25 1C for antifungal assay, the tube with no
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3222
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