Synthesis, antifungal and cytotoxic activities of 2-aryl-3-((piperidin-1- yl)ethyl)thiazolidinones

Article abstract of DOI:10.1016/j.ejmech.2013.03.030

A series of sixteen novel thiazolidinone derivatives were synthesized from the efficient one-pot reaction of 2-(piperidin-1-yl)ethylamine, arenealdehydes and mercaptoacetic acid in good yields. Identification and characterization of products were achieved by NMR and GC-MS techniques. The in vitro antifungal activities of all synthesized compounds were evaluated against seven fungi: Candida albicans, Candida parapsilosis, Candida guilliermondii, Cryptococcus laurentii, Geotrichum sp, Trichosporon asahii and Rhodotorula sp. The results are expressed as the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) and the best results were found against the Rhodotorula sp yeast. Two thiazolidinones (4h and 4l), MIC and MFC (16.5 μg/mL) proved to be 1.6 times more active than fluconazole and four of them (4b, 4e, 4g and 4k (MIC and MFC 25 μg/mL)) showed similar activity of standard drug to Rhodotorula sp. In addition, the cytotoxicity of thiazolidinones 4a-p was evaluated on cultured Vero cells and most of them displayed low toxicity (above 98 μg/mL). These preliminary and important results could be considered a starting point for the development of new antifungal agents.

Full text of DOI:10.1016/j.ejmech.2013.03.030

European Journal of Medicinal Chemistry 64 (2013) 74e80
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, antifungal and cytotoxic activities of 2-aryl-3-((piperidin-
1-yl)ethyl)thiazolidinones
Alice Kunzler a, Patrícia D. Neuenfeldt a, Adriana M. das Neves a, Claudio M.P. Pereira a,
Gabriela H. Marques b, Patrícia S. Nascente b, Maureen H.V. Fernandes c, Silvia O. Hübner c,
,
Wilson Cunico a
*
a Laboratório de Química Aplicada à Bioativos (LaQuiABio), Universidade Federal de Pelotas, Centro de Ciências Químicas, Farmacêuticas e de Alimentos e
CCQFA, Campus Universitário s/no, Pelotas 96010-900, RS, Brazil
b Laboratório de Micologia, Universidade Federal de Pelotas, Instituto de Biologia, UFPel, Brazil
c Laboratório de Virologia e Imunologia, Universidade Federal de Pelotas, Faculdade de Veterinária, UFPel, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of sixteen novel thiazolidinone derivatives were synthesized from the efficient one-pot reaction
of 2-(piperidin-1-yl)ethylamine, arenealdehydes and mercaptoacetic acid in good yields. Identification
and characterization of products were achieved by NMR and GCeMS techniques. The in vitro antifungal
activities of all synthesized compounds were evaluated against seven fungi: Candida albicans, Candida
parapsilosis, Candida guilliermondii, Cryptococcus laurentii, Geotrichum sp, Trichosporon asahii and Rho-
dotorula sp. The results are expressed as the Minimum Inhibitory Concentration (MIC) and Minimum
Fungicidal Concentration (MFC) and the best results were found against the Rhodotorula sp yeast. Two
Received 4 October 2012
Received in revised form
15 March 2013
Accepted 18 March 2013
Available online 26 March 2013
Keywords:
thiazolidinones (4h and 4l), MIC and MFC (16.5
conazole and four of them (4b, 4e, 4g and 4k (MIC and MFC 25
standard drug to Rhodotorula sp. In addition, the cytotoxicity of thiazolidinones 4aep was evaluated on
cultured Vero cells and most of them displayed low toxicity (above 98 g/mL). These preliminary and
m
g/mL) proved to be 1.6 times more active than flu-
Thiazolidinones
One-pot reaction
Antifungal activity
Cytotoxicity
m
g/mL)) showed similar activity of
m
Rhodotorula sp
important results could be considered a starting point for the development of new antifungal agents.
Ó 2013 Elsevier Masson SAS. All rights reserved.
1. Introduction
candidemia caused by C. albicans, Candida tropicalis and Candida
parapsilosis, with rates ranging 2e15 times higher than those re-
In the last few decades, the incidence of opportunistic fungal
infections especially invasive has increased, probably due the
expanding population with a broad list of immunocompromised
medical conditions, such as cancer, immunosuppressive therapy,
AIDS, solid-organ and hematopoietic stem cell transplantation or
still increase in premature birth, and an aging population. Between
infections caused by yeast, there is an emerging increase in those
caused by unusual fungal species, such as Candida non-albicans,
Trichosporon spp, Cryptococcus spp and Rhodotorula spp [1,2].
Candida albicans keep being the most frequent cause of fungal
infections, followed by Candida guilliermondii and Candida rugosa,
species that appear to be increasingly incidence over the years [1].
However, Diekema et al. (2012) [3] revealed a change in the
epidemiology of candidemia, with occurrence increased of Candida
glabrata. In Brazil, there has been related a higher incidence of
ported in Northern Hemisphere or Europe [4]. Infections caused by
C. parapsilosis and C. tropicalis and other yeasts, such as Tricho-
sporon and Cryptococcus species, have been also reported with high
incidence of fungemia [5e7]. Septicemia caused by Rhodotorula spp
is not so frequent, but it is highly associated with the use of
indwelling intravenous catheters in patients with serious malig-
nancies [8].
A limited number of different antifungal classes with different
mechanism of action are available for the treatment of invasive
fungal infections [9]. Nevertheless, azoles are used widely because
of their good tolerability and bioavailability. However, the large use
of azole antifungals for the treatment of fungemia has resulted in
the selection and emergence of resistant strains, especially resis-
tance to fluconazole via efflux pumps mechanism. The growing of
antifungal resistance to the commercially drugs associated with an
increase on the incidence of fungal infections causes serious
problems to the public health [5,7].
There is an urgent need for the development of new classes of
antifungal, with improvement of the pharmacodinamic and
* Corresponding author. Tel.: þ55 (53) 3275 7358; fax: þ55 (53) 3275 7354.
E-mail address: wjcunico@yahoo.com.br (W. Cunico).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.03.030

A. Kunzler et al. / European Journal of Medicinal Chemistry 64 (2013) 74e80
75
Table 1
Yields and selected physical properties of thiazolidinones 4aep.
Cl
R
N
R
Yield (%)a
91
M.p. (ꢀC)b
GCeMS m/z (%)
N
N
OH
Cl
S
4a
4b
4c
4d
4e
4f
2-F
71e74
308 (M, 2); 153 (1); 139 (2);
113 (4); 98 (100); 69 (4)
308 (M, 2); 224 (1); 139 (2);
113 (4); 98 (100); 69 (4)
308 (M, 2); 153 (1); 139 (2);
113 (3); 98 (100); 69 (3)
324 (M, 2); 155 (2); 125 (3);
98 (100); 96 (5); 69 (5)
324 (M, 1); 155 (2); 127 (2);
113 (3); 98 (100); 69 (4)
324 (M, 2); 155 (2); 125 (3);
98 (100); 69 (5)
N
N
Cl
N
N
O
N
N
3-F
83
74
75
64
55
94
95
88
86
53
59
75
97
86
91
57e61
70e73
Oil
N
Cl
O
4-F
2-Cl
Cl
3-Cl
Oil
Fig. 1. Structure of fluconazole, miconazole and the proposal thiazolidinones.
4-Cl
75e78
78e81
Oil
4g
4h
4i
2-NO2
3-NO2
4-NO2
3-OH
4-OH
2-OMe
3-OMe
4-OMe
4-Me
2,6-Cl
335 (M, 2); 166 (5); 113 (2);
98 (100); 69 (4)
335 (M, 2); 166 (1); 113 (2);
98 (100); 69 (5)
spectrum of activity or with new mechanism of action for the
treatment of fungal diseases. Besides, these new bioactive com-
pounds should be more effective, inexpensive and less toxic [10,11].
There are numerous biologically active molecules with five-
membered rings, containing two heteroatoms. The thiazolidinone
is an important and versatile scaffold that has occupied a promi-
nent position in medicinal chemistry field [12]. Numerous reports
have appeared in the literature describing a wide broad spectrum of
pharmacological properties of thiazolidinones due their synthetic
and biological versatility: antimalarial [13] antimicrobial [14], anti-
HIV [15], antitumoral [16], antioxidant [17], anti-inflammatory [18],
tuberculostatic [19], Alzheimer’s disease as muscarinic receptor 1
agonist [20] and also as antifungal [21].
Our research program has been extensively studied the chem-
istry of thiazolidinones in the last few year using conventional [22]
and non conventional methodologies, especially ultrasound irra-
diation [23]. Recently, the biological tuberculostatic of 3-
piperonilthiazolidinones [24] and the antifungal activity against
oral yeast of hydrazones (precursor to thiazolidinones) [25] were
also reported by us. So, due the important chemistry and biological
properties of this heterocyclic class, the aims of this work were the
synthesis of new thiazolidinones using the 2-aminoethylpiperidine
as amino core (Fig. 1), the evaluated of the antifungal activity
against seven yeasts and the cytotoxicity of compounds in Vero cell
lines.
Oil
335 (M, 2); 251 (1); 166 (1);
117 (1); 98 (100); 84 (5); 69 (5)
306 (M, 2); 195 (2); 151 (1);
113 (4); 98 (100); 69 (4)
306 (M, 1); 151 (3); 113 (5);
98 (100); 69 (5)
4j
109e115
210e214
57e59
Oil
4k
4l
320 (M, 4); 112 (5); 98 (100);
84 (9); 69 (8)
4m
4n
4o
4p
320 (M, 3); 151 (2); 113 (9);
98 (100); 84 (9); 69 (8)
320 (M, 2); 151 (3); 113 (5);
98 (100); 84 (8); 69 (5)
304 (M, 2); 135 (3); 113 (4);
98 (100); 84 (5); 69 (3)
359 (M, 3); 189 (5); 113 (4);
98 (100); 84 (5); 69 (2)
Oil
43e46
88e92
a
Yields of isolated compounds.
Melting points are uncorrected.
b
1 with arenealdehydes 2aep refluxing toluene in a DeaneStark
apparatus. After 2 h, the mercaptoacetic acid 3 (excess) was added
and the mixture was heated (the reactions were monitored by TLC
and GC and the complete consummation of starting materials were
found in about 3 h) to gave the corresponding thiazolidinones 4aep
in good yields. Two compounds (4n and 4p) were previously syn-
thesized as hydrochloride salt and tested their antihistaminic and
anticholinergic activities [27] When necessary the crude products
were purified by washing with hot hexane. Table 1 shows the yields
and selected physical properties of compounds 4aep.
2. Results and discussion
2.1. Chemistry
Spectral data of all compounds (1H NMR, 13C NMR and GCeMS)
are in full agreement with the proposed structures. 2D-NMR
techniques (COSY, HSQC and HMBC) helped us to assign the correct
signals. The mainly signals of 1H NMR spectra are H2 and H5 hy-
drogen’s of thiazolidinone ring. For most compounds, there is a
sobreposition of signals at region of 3.7e4.2 ppm corresponding to
diastereotopic methylene hydrogens H5 and one hydrogen of e
NCH2CH2N(C]O)e, however, they can be clearly observed in
thiazolidinone 4l with the H5a that appears as double doublets at
3.73 ppm coupling with both H5b and H2 (2J ¼ 15.6 Hz and
4J ¼ 1.6 Hz) and H5b that appears as a doublet (2J ¼ 15.6 Hz) at
Initially, the target thiazolidinones were prepared as outlined in
Scheme 1, using the previous studies carried out by us. The reaction
was carried out in one-pot and two steps reactions. The desired
thiazolidinones were obtained in both reactions, however a few
concentration of 2-aryl-1,3-oxathiolan-5-ones (common by-
product) were found in the one-pot synthesis as shown by GC
analysis [26]. According to the tests, the two steps synthesis proved
to be more efficient once this procedure afford the complete for-
mation of intermediate imine and avoid the formation of by-
product. All compounds were synthesized from reaction of amine
O
O
NH2
R
N
S
N
H
i
N
N
ii
N
+
1
53-97%
R
2a-p
R
4a-p
Scheme 1. Reagents and conditions: i. toluene, reflux, 2 h ii. HSCH2COOH 3, toluene, reflux, 3 h.

76
A. Kunzler et al. / European Journal of Medicinal Chemistry 64 (2013) 74e80
Table 2
Antifungal activity of thiazolidinones 4aep express as the minimal inhibitory concentration MIC and the minimal fungicidal concentration MFC (mg/mL).
Comp.
R
M.W.
Candida albicans
Rhodotorula ssp
C. laurentii
Geotrichum
C. parapsilosis
C. guilliermondii
T. asahii
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
FLZ
2-F
3-F
4-F
2-Cl
3-Cl
4-Cl
2-NO2
3-NO2
4-NO2
3-OH
4-OH
2-OMe
3-OMe
4-OMe
4-Me
2,6-Cl
308.4
308.4
308.4
324.9
324.9
324.9
335.4
335.4
335.4
306.4
306.4
320.5
320.5
320.5
304.4
359.3
306.1
100
150
45
75
62
62
55
50
62
36
33.5
25
33
25
50
25
16.5
30
33.5
25
16.5
33.5
33.5
37.5
30
100
100
100
100
100
100
100
100
100
100
100
100
100
100
66
>400
>400
50
50
50
50
25
100
50
>400
50
41.5
>400
>400
100
50
100
100
100
100
100
100
50
100
100
67
100
100
100
50
100
100
1
133
100
100
100
100
100
25
100
100
100
100
100
100
100
100
200
16
>400
>400
100
66.5
100
50
100
>400
100
>400
50
81
100
100
100
75
62
75
50
>400
>400
50
50
1
200
1
1
26.5
8
3.61 ppm. The H2 is shown as singlet (or a doublet with small
constant coupling due to coupling with H5a) at 5.38e6.20 ppm. The
diastereotopics hydrogens of eNCH2CH2N(C]O)e appear as four
doubletriplet signals. The 13C NMR spectra exhibit at 170e172 ppm
the signal of carbonyl group (C4), at the range of 58e64 ppm the
signal of C2, 53e55 ppm to methylenic carbons of ethyl moiety (e
NCH2CH2N(C]O)e) and about 30e33 ppm the signal of methylene
C5. The signals at aromatic region with a relative integration ex-
pected for an areneealdehyde moiety and the observation of
aliphatic signals expected for piperidine ring confirm the structure
of compounds.
fluconazole as the standard drug. Our results showed that the MIC
and MFC values found were the same for all tested compounds. The
thiazolidinones were also evaluated as their cytotoxic properties
using the Vero cells. The results of biological studies are reported in
Tables 2 and 3.
The thiazolidinones 4aep showed low antifungal activity
against C. parapsilosis, C. laurentii and C. guilliermondii (MIC and
MFC up to 65
mild MIC and MFC values (25
active than fluconazole (16
thiazolidinones 4g also showed mild activity against Geotrichum sp
(MIC and MFC 25 g/mL). A few thiazolidinones showed moderated
activity against C. albicans and T. asahii (best MIC and MFC about
45 g/mL).
The best results were found when thiazolidinones 4aep were
tested against Rhodotorula sp (Fig. 2). All MIC and MFC values found
were lower than 37.5 g/mL (exception 4f), four of them (4c, 4e, 4g
and 4k) showed the same MIC of standard drug fluconazole
(26.5 g/mL) and compounds 4h and 4l showed the highest ac-
m
g/mL), with exception for compound 4g that showed
g/mL), although about 1.5 times less
g/mL) to C. guilliermondii yeast. The
m
m
m
2.2. Biological activity
m
After the synthesis, we explore the potential antifungal activity
of all novel thiazolidinones by measure of the Minimal Inhibitory
Concentration (MIC) and the Minimal Fungicidal Concentration
(MFC) determined according to the method of M27A3 document
broth microdilution method to the organic compounds [28]. The
literature reported some thiazolidinones with potential antifungal
properties [11,14]. The structures of proposal heterocycles also have
the piperidine group, important moiety that showed antimicrobial
activity too [29e31]. So, the compounds 4aep were tested against:
C. albicans, Cryptococcus laurentii, C. parapsilosis, C. guilliermondii,
Geotrichum sp, Trichosporon asahii and Rhodotorula sp using the
m
m
tivities with MIC and MFC values of 16.5 mg/mL (1.6 times more
active than fluconazole).
The results of antifungal test did not allow us to determine a
structureeactivity relationships of thiazolidinones 4aep since the
electronic effect of substituent did not contribute significantly to
activity. Both electron-withdrawing and electron-releasing groups
Table 3
Cytotoxicity activity of thiazolidinones 4aep against monkey kidney Vero cell lines express as cell viability (%).
R
Cell viability %
3150
m
g/mL
1575
m
g/mL
787
m
g/mL
394
m
g/mL
197
m
g/mL
98
m
g/mL
49
m
g/mL
25
mg/mL
12.3 mg/mL
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
2-F
3-F
4-F
2-Cl
3-Cl
4-Cl
2-NO2
3-NO2
4-NO2
3-OH
4-OH
2-OMe
3-OMe
4-OMe
4-Me
2,6-Cl
10
13
11
22
15
11
30
2
10
11
10
5
10
17
14
16
20
13
24
7
15
13
12
17
11
11
13
10
10
27
17
38
31
15
100
15
21
60
57
30
19
33
17
11
45
60
52
31
45
28
100
60
66
100
76
67
57
73
51
32
65
84
73
71
77
68
100
75
72
100
87
72
66
87
85
75
82
92
87
94
100
74
100
94
87
100
94
100
84
95
100
100
100
100
100
84
100
100
100
100
100
100
97
100
100
100
100
100
90
100
100
100
100
100
100
100
100
100
100
97
100
100
100
84
100
100
100
100
96
100
90
100
100
100
6
11
12
7
89
100
76
100
100
100

A. Kunzler et al. / European Journal of Medicinal Chemistry 64 (2013) 74e80
77
Fig. 2. MIC and MFC (mg/mL) of thiazolidinones 4aep against Rhodotorula sp.
showed similar MIC and MFC values. The position of the substituent
in the phenyl ring (2, 3 or 4) and the presence of two substituents
(4p) did not influence in activity either.
An important observation is the cytotoxicity of all compounds
tested. The toxicity of thiazolidinones was usually observed in a
(30 m ꢁ 250
mm); helium was used as the carrier gas (56 Kpa).
Elemental analysis for compounds 4g, 4h and 4l was carried out
using a CHN EA 1110; percentages of C, H and N agreed with the
product formula (within ꢂ0.4% of theoretical values for elements).
concentration above 98
4a, 4m and 4p reduce little more than 10% of the cell viability at
98 g/mL and therefore are considered toxic ones. The compound
4f was especially toxic when compared with the others, since only
85% viability of the cells was observed at lower concentration
mg/mL (Table 3). However, the compounds
4.2. General procedure for the synthesis of thiazolidinones 4aep
m
A mixture of 2-(piperidin-2-yl)ethyl amine 1 (2 mmol) and cor-
responding arenaldehyde 2aep (2 mmol) in toluene (30 mL) was
heated at 110 ꢀC with a DeaneStark trap for 2 h. After this time, the
mercaptoacetic acid 3 (6 mmol) was added and the mixture was
heated until the complete cyclocondensation reaction, as shown by
TLC and/or GC (about 3 h). The organic layer was washed with satu-
rated NaHCO3 (3 ꢁ 30 mL), dried with MgSO4 and concentrated to
give the products as solid or oil. When necessary, the crude products
were washed with hot hexane to give the pure thiazolidinones.
(25 mg/mL) analyzed. The thiazolidinones 4g and 4j showed the
lowest cytotoxicity (above 787 mg/mL and 394 mg/mL, respectively).
3. Conclusion
In summary, novel thiazolidinones containing the piperidine
moiety were easily obtained in good yields by conventional meth-
odology. The compounds were fullycharacterized by 1H,13C NMR and
by GCeMS. All thiazolidinones were evaluated for their antifungal
activities against seven fungi and two of them (4h and 4l) displayed
mild MIC and MFC values against Rhodotorula sp. These potential
compounds were 1.6 times more activity than standard drug flu-
conazole. In addition, the thiazolidinones showed low toxic effects
in vitro to Vero cells, especially the compound 4g. These preliminary
results encourage further investigation on heterocyclic thiazolidi-
nones aiming to the development of new potent antifungal agent.
4.2.1. 2-(2-Fluorophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
one (4a)
1H NMR (CDCl3, 400 MHz):
d
7.33 (m, 1H); 7.26 (td, 1H, 3J ¼ 7.4,
4J ¼ 1.5); 7.17 (t, 1H, 3J ¼ 7.4); 7.08 (t, 1H, 3J ¼ 8.6); 6.19 (d, 1H,
4J ¼ 1.5 Hz, H2); 3.86 (dt,1H, 2J ¼ 14.0, 3J ¼ 6.6, eNCH2CH2N(C]O)e
); 3.80 (dd, 1H, 2J ¼ 15.6, 4J ¼ 1.5, H5a); 3.67 (d, 1H, 2J ¼ 15.2, H5b);
2.87 (dt, 1H, 2J ¼ 14.0, 3J ¼ 6.6, eNCH2CH2N(C]O)e); 2.61 (dt, 1H,
2J ¼ 12.5, 3J ¼ 6.2, eNCH2CH2N(C]O)e); 2.44 (m, 5H); 1.58 (m, 4H);
1.43 (m, 2H). 13C NMR (CDCl3, 100 MHz):
d
171.4 (C4); 160.4 (d, 1JCe
¼ 249); 130.4 (3JCeF ¼ 8.4); 127.9 (d, JCeF ¼ 3.1); 124.7 (d, JCe
4
4
F
2
4. Experimental protocols
¼ 3.6); 116.1 (d, JCeF ¼ 21.1) (Ph); 57.6 (C2); 55.7 and 54.3 (e
F
NCH2CH2Ne); 39.7 (2C); 32.5 (C5); 25.4 (2C); 23.9 (2C).
4.1. General
4.2.2. 2-(3-Fluorophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
All common reagents and solvents were used as obtained from
commercial suppliers without further purification. The progress of
reactions were monitored by TLC (hexane:ethyl acetate 3:1) and/or
by a Shimadzu Gas Chromatograph GC-2010, Column I.D., 0.25 mm;
Column length, 30 m; Column Head Pressure, 14 psi, program:
T0 ¼ 50 ꢀC; t0 ¼ 2.0 min; rate 16.0 ꢀC/min; Tf ¼ 250 ꢀC; tf ¼ 10.0 min;
Inj. ¼ 250 ꢀC; Det. ¼ 270 ꢀC. The melting points were determined
using open capillaries on a Fisatom model 430 apparatus and are
uncorrected. 1H and 13C NMR spectra were recorded on a Varian
Oxford AS-400 spectrometer (1H at 400.14 MHz and 13C at
100.61 MHz) and on a Bruker Ac-200F spectrometer (13C at 50 MHz,
for compounds 4d, 4f, 4g, 4i, 4j, 4l and 4m) in CDCl3 containing TMS
as in internal standard. The mass spectra were obtained on a
Hewlett Packard 6890/MSD5973 GCeMS with a splitesplitless
one (4b)
1H NMR (CDCl3, 400 MHz):
d 7.34 (m, 1H); 7.05 (m, 3H); 5.91 (s,
1H, H2); 3.82 (m, 2H, H5a and eNCH2CH2N(C]O)e); 3.71 (d, 2H,
J ¼ 15, 2, H5b and eNCH2CH2N(C]O)e); 2.83 (dt, 1H, 2J ¼ 13.6,
3J ¼ 6.6, 3J ¼ 7.0, eNCH2CH2N(C]O)e); 2.58 (dt, 1H, 2J ¼ 12.8,
3J ¼ 6.6, eNCH2CH2N(C]O)e); 2.41 (m, 4H); 1.59 (m, 4H); 1.44 (m,
2H). 13C NMR (CDCl3, 100 MHz):
d
4
171.3 (C4); 160.6 (d, 1JCeF ¼ 251);
3
2
130.6 (d, JCeF ¼ 8.1); 122.5 (d, JCeF ¼ 2.9); 116.0 (d, JCeF ¼ 21.3)
2
and 113.8 (d, JCeF ¼ 22.1) (Ph); 63.2 (C2); 55.9 and 54.4 (e
NCH2CH2Ne); 39.6 (2C); 32.7 (C5); 25.5 (2C); 23.9 (2C).
4.2.3. 2-(4-Fluorophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
one (4c)
1H NMR (DMSO-d6, 400 MHz):
d 7.31 (m, 2H); 7.08 (t, 2H,
injector and equipped with
a
HP-Innowax capillary column
3J ¼ 8.6); 5.91 (s, 1H, H2); 3.77 (m, 2H, H5a and eNCH2CH2N(C]

78
A. Kunzler et al. / European Journal of Medicinal Chemistry 64 (2013) 74e80
O)e); 3.72 (d, 1H, 2J ¼ 15.6, H5b); 2.79 (dt, 1H, 2J ¼ 14.6, 3J ¼ 6.6,
3J ¼ 6.2, eNCH2CH2N(C]O)e); 2.55 (dt, 1H, 2J ¼ 12.9, 3J ¼ 6.6,
32.7 (C5); 25.6 (2C); 23.9 (2C). Anal. Calcd for C16H21N3O3S: C, 57.29;
H, 6.31; N, 12.53. Anal. Found: C, 57.05; H, 6.41; N, 12.61.
3J ¼ 6.2, eNCH2CH2N(C]O)e); 2.38 (m, 5H); 1.58 (m, 4H); 1.44 (m,
1
2H). 13C NMR (DMSO-d6, 100 MHz):
d
171.2 (C4); 162.9 (d, JCe
4.2.9. 2-(4-Nitrophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
¼ 248),135.4 (d, 4JCeF ¼ 2.9),128.9 (d, 3JCeF ¼ 8.8) and 116.0 (d, 2JCe
¼ 21.3) (Ph); 63.3 (C2); 55.8 and 54.4 (eNCH2CH2Ne); 39.5 (2C);
one (4i)
F
1H NMR (CDCl3, 400 MHz):
d
8.26 (d, 2H, 3J ¼ 9.0); 7.48 (d, 2H,
F
32.8 (C5); 25.5 (2C); 23.9 (2C).
3J ¼ 8.6); 6.09 (s, 1H, H2); 3.86 (dt, 1H, 2J ¼ 14.0, 3J ¼ 5.4, e
NCH2CH2N(C]O)e); 3.78 (d, 1H, 2J ¼ 15.2, H5a); 3.74 (d, 1H,
2J ¼ 15.2, H5b); 2.77 (dt, 1H, 2J ¼ 14.4, 3J ¼ 5.2, eNCH2CH2N(C]O)e
); 2.57 (dt, 1H, 2J ¼ 12.9, 3J ¼ 5.8, eNCH2CH2N(C]O)e); 2.35 (m,
4.2.4. 2-(2-Chlorophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
one (4d)
1H NMR (CDCl3, 400 MHz):
d
7.40 (dd, 1H, 2J ¼ 7.8 and 3J ¼ 1.9);
5H); 1.56 (m, 4H); 1.44 (m, 2H). 13C NMR (CDCl3, 50 MHz):
d 171.3
7.29 (m, 2H); 7.17 (dd,1H, 3J ¼ 7.0, 4J ¼ 2.3); 6.37 (s,1H, H2); 3.92 (dt,
1H, 2J ¼ 14.0, 3J ¼ 5.8, eNCH2CH2N(C]O)e); 3.72 (d, 1H, 2J ¼ 15.6,
H5a); 3.64 (d, 1H, 2J ¼ 15.2, H5b); 2.83 (dt, 1H, 2J ¼ 14.0, 3J ¼ 6.6, e
(C4); 148.1, 147.4, 127.6 and 124.3 (Ph); 62.7 (C2); 56.3 and 54.5 (e
NCH2CH2Ne); 39.9 (2C); 32.6 (C5); 25.7 (2C); 23.9 (2C).
NCH2CH2N(C]O)e); 2.56 (dt, 1H, 2J
¼
12.9, 3J
¼
6.6,
e
4.2.10. 2-(3-Hydroxyphenyl)-3-(2-(piperidin-1-yl)ethyl)
NCH2CH2N(C]O)e); 2.38 (m, 5H); 1.54 (m, 4H); 1.41 (m, 2H). 13
NMR (CDCl3, 50 MHz): 171.9 (C4); 137.3, 132.7, 130.2, 129.5 and
C
thiazolidin-4-one (4j)
d
1H NMR (CDCl3, 400 MHz):
d
7.16 (t, 1H, 3J ¼ 7.8); 6.73 (t, 2H,
127.4 (Ph); 60.2 (C2); 56.1 and 54.5 (eNCH2CH2Ne); 40.1 (2C); 32.0
(C5); 25.7 (2C); 24.1 (2C).
3J ¼ 7.4); 6.66 (br,1H); 5.72 (s,1H, H2); 3.82 (dt,1H, 2J ¼ 13.6, 3J ¼ 7.4,
eNCH2CH2N(C]O)e); 3.76 (d, 1H, 2J ¼ 15.6, H5a); 3.67 (d, 1H,
2J ¼ 15.6, H5b); 2.88 (dt,1H, 2J ¼ 13.6, 3J ¼ 6.6, eNCH2CH2N(C]O)e);
2.58 (dt, 1H, 2J ¼ 10.9, 3J ¼ 7.8, eNCH2CH2N(C]O)e); 2.46 (m, 5H);
4.2.5. 2-(3-Chlorophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
one (4e)
1.59 (m, 4H); 1.43 (m, 2H). 13C NMR (CDCl3, 50 MHz):
d 171.7 (C4);
1H NMR (CDCl3, 400 MHz):
d
7.30 (m, 3H); 7.18 (m, 1H); 5.90 (d,
157.6, 140.6, 130.2, 118.0, 116.6, 116.5 and 113.4 (Ph); 63.8 (C2); 55.2
and 54.4 (eNCH2CH2Ne); 39.6 (2C); 32.8 (C5); 25.2 (2C); 23.7 (2C).
1H, 4J ¼ 1.6, H2); 3.81 (m, 2H, H5a and eNCH2CH2N(C]O)e); 3.71
(d, 1H, 2J ¼ 15.2, H5b); 2.79 (dt, 1H, 2J ¼ 13.6, 3J ¼ 5.8, e
NCH2CH2N(C]O)e); 2.53 (dt, 1H, 2J
¼
13.2, 3J
¼
5.8,
e
4.2.11. 2-(4-Hydroxyphenyl)-3-(2-(piperidin-1-yl)ethyl)
NCH2CH2N(C]O)e); 2.33 (m, 5H); 1.56 (m, 4H); 1.43 (m, 2H). 13
NMR (CDCl3, 100 MHz): 171.2 (C4); 142.1, 134.9, 130.3, 129.2, 127.0
C
thiazolidin-4-one (4k)
d
1H NMR (CDCl3, 400 MHz):
d
7.14 (d, 2H, 3J ¼ 8.6); 6.82 (d, 2H,
and 125.0 (Ph); 63.3 (C2); 56.2 and 54.5 (eNCH2CH2Ne); 39.8 (2C);
32.7 (C5); 25.8 (2C); 24.1 (2C).
3J ¼ 8.2); 5.80 (s, 1H, H2); 3.69 (m, 3H, H5a, H5b and e
NCH2CH2N(C]O)e); 2.79 (dt, 1H, 2J
NCH2CH2N(C]O)e); 2.47 (dt, 1H, 2J
¼
¼
14.0, 3J
12.9, 3J
¼
¼
6.6,
6.6,
e
e
4.2.6. 2-(4-Chlorophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
NCH2CH2N(C]O)e); 2.32 (m, 5H); 1.54 (m, 4H); 1.42 (m, 2H). 13
C
one (4f)
NMR (CDCl3, 100 MHz): d 170.2 (C4); 157.4, 128.7, 127.8 and 115.1
(Ph); 63.1 (C2); 55.2 and 53.7 (eNCH2CH2Ne); 39.1 (2C); 32.2 (C5);
25.1 (2C); 23.4 (2C).
1H NMR (CDCl3, 400 MHz):
d
7.34 (d, 2H, 3J ¼ 8.2); 7.26 (d, 2H,
3J ¼ 8.6); 5.90 (s, 1H, H2); 3.84 (dt, 1H, 2J ¼ 14.0, 3J ¼ 6.6, e
NCH2CH2N(C]O)e); 3.77 (d, 1H, 2J ¼ 16.0, H5a); 3.72 (d, 1H,
2J ¼ 16.0, H5b); 2.82 (dt, 1H, 2J ¼ 14.0, 3J ¼ 6.6, eNCH2CH2N(C]O)e
); 2.61 (dt, 1H, 2J ¼ 12.5, 3J ¼ 6.6, eNCH2CH2N(C]O)e); 2.50 (m,
4.2.12. 2-(2-Methoxyphenyl)-3-(2-(piperidin-1-yl)ethyl)
thiazolidin-4-one (4l)
5H); 1.45 (m, 4H); 1.25 (m, 2H). 13C NMR (CDCl3, 50 MHz):
d
171.1
1H NMR (CDCl3, 400 MHz):
d
7.28 (td, 1H, 3J ¼ 8.2, 4J ¼ 1.6); 7.11
(C4); 138.4, 134.7, 129.2 and 128.3 (Ph); 63.3 (C2); 56.3 and 54.5 (e
NCH2CH2Ne); 39.8 (2C); 32.8 (C5); 25.9 (2C); 24.1 (2C).
(dd, 1H, 3J ¼ 7.8, 4J ¼ 1, 6); 6.95 (t, 1H, 3J ¼ 7.4); 6.92 (t, 1H, 3J ¼ 8.2);
6.20 (d, 1H, 4J ¼ 1.5, H2); 3.86 (m, 4H, OCH3 and eNCH2CH2N(C]
O)e); 3.73 (dd, 1H, 2J ¼ 15.6, 4J ¼ 1.6, H5a); 3.61 (d, 1H, 2J ¼ 15.6,
H5b); 2.84 (dt, 1H, 2J ¼ 14.0, 3J ¼ 6.6, NCH2CH2N(C]O)e); 2.56 (dt,
1H, 2J ¼ 12.8, 3J ¼ 7.0, NCH2CH2N(C]O)e); 2.39 (m, 5H); 1.55 (m,
4.2.7. 2-(2-Nitrophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
one (4g)
1H NMR (CDCl3, 400 MHz):
d
8.13 (d, 1H, 3J ¼ 8.2); 7.70 (t, 1H,
4H); 1.42 (m, 2H). 13C NMR (CDCl3, 50 MHz):
d 171.9 (C4); 156.8,
3J ¼ 7.4); 7.51 (t, 1H, 3J ¼ 8.2); 7.30 (m, 1H); 6.59 (s, 1H, H2); 3.98 (dt,
1H, 2J ¼ 14.0, 3J ¼ 5.8, eNCH2CH2N(C]O)e); 3.70 (d, 1H, 2J ¼ 15.6,
H5a); 3.61 (d, 1H, 2J ¼ 16.0, H5b); 2.87 (dt, 1H, 2J ¼ 13.6, 3J ¼ 6.2, e
129.7, 127.7, 126.5, 120.7 and 110.9 (Ph); 58.3 (C2); 55.8 and 54.3 (e
NCH2CH2Ne); 55.4 (OCH3); 39.9 (2C); 32.5 (C5); 25.6 (2C); 24.0
(2C). Anal. Calcd for C17H24N2O2S: C, 63.72; H, 7.55; N, 8.74. Anal.
Found: C, 63.43; H, 7.61; N, 9.01.
NCH2CH2N(C]O)e); 2.67 (dt, 1H, 2J
NCH2CH2N(C]O)e); 2.45 (dt, 1H, 2J
¼
¼
12.8, 3J
12.8, 3J
¼
¼
6.6,
5.8,
e
e
NCH2CH2N(C]O)e); 2.39 (m, 4H); 1.51 (m, 4H); 1.41 (m, 2H). 13
C
4.2.13. 2-(3-Methoxyphenyl)-3-(2-(piperidin-1-yl)ethyl)
NMR (CDCl3, 50 MHz):
d
172.4 (C4); 147.0, 136.7, 134.4, 129.0, 125.8
thiazolidin-4-one (4m)
and 125.7 (Ph); 58.9 (C2); 55.8 and 54.3 (eNCH2CH2Ne); 39.8 (2C);
31.4 (C5); 25.0 (2C); 23.6 (2C). Anal. Calcd for C16H21N3O3S: C, 57.29;
H, 6.31; N, 12.53. Anal. Found: C, 57.54; H, 6.60; N, 12.55.
1H NMR (CDCl3, 400 MHz):
d
7.28 (dd, 1H, 3J ¼ 7.7, 4J ¼ 2.6); 6.88
(dd, 2H, 3J ¼ 7.9, 4J ¼ 2.1); 6.82 (d, 1H, 4J ¼ 1.9); 5.88 (s, 1H, H2); 3.79
(m, 5H, H5a, OMe, eNCH2CH2N(C]O)e); 3.70 (d, 1H, 2J ¼ 15.4,
H5b); 2.82 (dt, 1H, 2J ¼ 14.0, 3J ¼ 6.6, eNCH2CH2N(C]O)e); 2.52
(dt, 1H, 2J ¼ 12.6, 3J ¼ 7.0, eNCH2CH2N(C]O)e); 2.32 (m, 5H); 1.55
4.2.8. 2-(3-Nitrophenyl)-3-(2-(piperidin-1-yl)ethyl)thiazolidin-4-
one (4h)
(m, 4H); 1.42 (m, 2H). 13C NMR (CDCl3, 50 MHz):
d 171.3 (C4); 160.0;
1H NMR (CDCl3, 400 MHz):
d
8.20 (m, 2H); 7.67 (d, 1H, 3J ¼ 7.8);
141.2, 130.0; 119.1; 114.4; 112.3 (Ph); 63.8 (C2); 55.8 (OMe); 55.2
and 54.4 (eNCH2CH2Ne); 39.6 (2C); 32.8 (C5); 25.6 (2C); 23.9 (2C).
7.59 (t, 1H, 3J ¼ 7.8); 6.08 (d, 1H, J ¼ 1.6, H2); 3.85 (m, 2H, H5a, e
NCH2CH2N(C]O)e); 3.75 (d, 1H, 2J ¼ 15.6); 2.78 (dt, 1H, 2J ¼ 12.5,
3J ¼ 7.4, 3J ¼ 5.7, eNCH2CH2N(C]O)e); 2.59 (dt,1H, 2J ¼ 12.8, 3J ¼ 6.2,
4
4.2.14. 2-(4-Methoxyphenyl)-3-(2-(piperidin-1-yl)ethyl)
eNCH2CH2N(C]O)e); 2.38 (m, 5H); 1.58 (m, 4H); 1.44 (m, 2H). 13
C
thiazolidin-4-one (4n)
NMR (CDCl3, 100 MHz):
and 104.9 (Ph); 62.9 (C2); 56.1 and 54.5 (eNCH2CH2Ne); 39.7 (2C);
d
171.2 (C4); 142.5, 132.9, 130.2, 123.9, 122.0
1H NMR (CDCl3, 400 MHz):
d
7.24 (d, 2H, 3J ¼ 8.6); 6.89 (d, 2H,
3J ¼ 8.6); 5.85 (s, 1H, H2); 3.82 (m, 4H, eNCH2CH2N(C]O)e and

A. Kunzler et al. / European Journal of Medicinal Chemistry 64 (2013) 74e80
79
OCH3); 3.76 (m, 2H, H5a and H5b); 2.80 (dt, 1H, 2J ¼ 14.0, 3J ¼ 6.6, e
prior to removal of the specified volumes. The plates were incu-
bated at 35 ꢀC until growth was seen in the growth control sub-
culture (usually before 48 h). The MFC was the lowest drug
concentration that showed no growth.
NCH2CH2N(C]O)e); 2.50 (dt, 1H, 2J
¼
12.5, 3J
¼
7.0, e
NCH2CH2N(C]O)e); 2.28 (m, 5H); 1.55 (m, 4H), 1.42 (m, 2H). 13
NMR (CDCl3, 100 MHz): 171.1 (C4); 160.0, 131.3, 128.5 and 114.3
C
d
(Ph); 63.7 (C2); 56.1 and 54.5 (eNCH2CH2Ne); 55.3 (OCH3); 39.7
(2C); 32.9 (C5); 25.8 (2C); 24.1 (2C).
4.4. Cytotoxicity assay
4.2.15. 3-(2-(Piperidin-1-yl)ethyl)-2-p-tolylthiazolidin-4-one (4o)
4.4.1. Vero cell culture
1H NMR (CDCl3, 200 MHz):
d 7.18 (m, 4H); 5.86 (s, 1H, H2); 3.73
The Vero cells (lineage from green monkey kidney) were used to
analyze toxicityof the compounds. The cells were cultured in 96-well
plates with E-MEM (modified Eagle’s medium) supplemented with
10% (v/v) fetal bovine serum (Gibco BRL), 10 mg/mL enrofloxacin
(m, 3H, H5a, H5b and eNCH2CH2N(C]O)e); 2.79 (m, 1H, e
NCH2CH2N(C]O)e); 2.49 (m, 1H, eNCH2CH2N(C]O)e); 2.34 (m,
8H); 1.53 (m, 4H); 1.41 (m, 2H). 13C NMR (CDCl3, 50 MHz):
d 171.2
(C4); 139.0, 136.6, 129.6 and 126.9 (Ph); 63.8 (C2); 56.1 and 54.5 (e
NCH2CH2Ne); 39.7 (2C); 32.9 (C5); 25.8 (2C); 24.1 (CH3); 21.2 (2C).
(Baytril, Bayer), and 0.025 mg/mL anphotericin B (Gibco BRL). Vero
cell cultures (3 ꢁ 105 cells mLꢃ1) were allowed to attach for 24 h
before treatment with of the compounds. The culture supernatants
4.2.16. 2-(2,6-Dichlorophenyl)-3-(2-(piperidin-1-yl)ethyl)
were removed and serial dilutions (from 0.35 mg/mL to 1.23 mg/mL)
thiazolidin-4-one (4p)
of the thiazolidinones were added. Fresh E-MEM was used as nega-
tive control. Plates were maintained in a humidified atmosphere of
5% CO2, at 37 ꢀC for 72 h and the cell cytotoxicity was evaluated.
1H NMR (CDCl3, 400 MHz):
d
7.38 (m, 2H); 7.25 (dd, 1H, 3J ¼ 8.2,
3J ¼ 7.4); 6.80 (s, 1H, H2); 3.98 (dt, 1H, 2J ¼ 14.0, 3J ¼ 6.6, e
NCH2CH2N(C]O)e); 3.81 (s, 2H, H5a and H5b); 2.80 (m, 7H); 1.72
(m, 4H); 1.50 (m, 2H).13C NMR (CDCl3, 100 MHz):
d 172.1 (C4); 161.2,
4.4.2. Cytotoxicity assay
157.8, 135.0, 130.9, 130.4, and 129.0 (Ph); 67.7 (C2); 54.5 and 53.7 (e
NCH2CH2Ne); 38.4 (2C); 34.0 (C5); 23.9 (2C); 23.0 (2C).
The viability of the test cells exceeded 99% prior to cytotoxicity
assay, as determined by exclusion of the vital dye trypan blue. The
cytotoxicity of the thiazolidinones was investigated on Vero cells by
the neutral red dye uptake (NRU) assay. After treatment the culture
supernatants were removed and the cells were incubated with E-
MEM containing 3.3 mg/L neutral red. After 2 h at 37 ꢀC/5% CO2,
media was carefully removed and incorporated dye was then sol-
4.3. Antifungal assay
4.3.1. Minimal Inhibitory Concentration (MIC)
The compounds 4aep were tested against: C. albicans,
C. laurentii, C. parapsilosis, C. guilliermondii, Geotrichum sp, T. asahii
and Rhodotorula sp. The tested fungal were obtained from the
Laboratory of Micology from Department of Microbiology and
Parasitology at the Federal University of Pelotas. The yeasts were
obtained from hair and ear canal of the fungal microbiota of cats
referred to the Center for Rehabilitation of Wildlife [32].
Fungal strains were maintained on Sabouraud Dextrose Agar
(SDA) and cultures were subcultured (1% inoculum) in SDA at 35 ꢀC
for at least two days before used in screening assays. The isolates
were suspended in saline solution with the turbidity adjusted to
level 0.5 of the McFarland scale and dilutes in RPMI. After that, they
ubilized by addition of 100 mL of an aqueous solution containing
50% (v/v) ethanol and 1% (v/v) acetic acid. The absorbance at
540 nm was read on a microplate reader. The percentage of viability
was calculated as AT/AC ꢁ 100; where AT and AC are the absor-
bances of treated and control cells, respectively. The neutral red
assay is based on the initial protocol described by Borenfreund and
Puerner (1984) [33] and determines the accumulation of the
neutral red dye in the lysosomes of viable, uninjured cells.
Acknowledgments
were diluted in RPMI medium and a volume of 100
m
L was
The authors thank UFPel and FAPERGS (proc. 11/2068-7) for
financial support. Fellowships granted to A.K. and G.H.M. by CAPES
and W.C. by CNPq.
dispensed into the wells, which contained 100
concentrations of the antifungal.
mL of twice the final
Fromthe stock-solution of the drug (1.6 mg/mL), diluted in DMSO
according tothe methodology recommended by the CLSI (2008), ten
successive dilutions were sequentially dispensed into the micro
dilution plates, filling the wells in the columns numbered from 2 to
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