A DIC mediated expeditious small library synthesis and biological activity of thiazolidin-4-one and 1,3-thiazinan-4-one derivatives

Article abstract of DOI:10.1002/jhet.429

(Chemical Equation Presented) A diisopropylcarbodiimide (DIC) mediated small library of thiazolidin-4-one and 1,3-Thiazinan-4-one derivatives were efficiently synthesized using one pot three component condensation of amino acid, aldehyde, and mercapto car

Full text of DOI:10.1002/jhet.429

1084
A DIC Mediated Expeditious Small Library Synthesis and
Biological Activity of Thiazolidin-4-one and 1,3-Thiazinan-4-one
Derivatives
Vol 47
Amit Verma, Shweta S Verma, and Shailendra K Saraf*
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern India Engineering
College, Lucknow 227105, Uttar Pradesh, India
*E-mail: v.amit28@gmail.com
Received November 4, 2009
DOI 10.1002/jhet.429
Published online 13 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A diisopropylcarbodiimide (DIC) mediated small library of thiazolidin-4-one and 1,3-Thiazinan-4-one
derivatives were efficiently synthesized using one pot three component condensation of amino acid,
aldehyde, and mercapto carboxylic acid on a polymer support. The study shows significantly higher
yields of the thiazolidin-4-one derivatives thereby indicating a lower dependence on the nature of the
amino acid and aldehyde components. As an obvious extension of this protocol, the reactions were per-
formed using heterocyclic aldehydes and substituted hindered aromatic aldehydes instead of simple aro-
matic aldehydes. The synthesized library compounds were also screened for their antifungal acitivity
against these three pathogenic fungi: Candida albicans (Ca), Candida parapsilosis (Cp), and Cryptococ-
cus neoformans (Cn).
J. Heterocyclic Chem., 47, 1084 (2010).
INTRODUCTION
din-4-one and thiazinan-4-one are biologically important
scaffolds known to be associated with several biological
activities. These structures contain one S and one N
atom in skeleton as heterocyclic atoms [2–3].
The categorical imperative of modern drug discovery
is to produce better clinical candidates that are less
prone to failure at later stage. Solid phase organic syn-
thesis is regarded as one of the key disciplines for pro-
viding constant supply of chemical compounds that may
be monitored for their biological activity on the vastly
increasing number of biological targets. Solid phase or-
ganic synthesis together with high throughput synthesis
and efficient data management, undoubtedly lead to
acceleration in the process of drug discovery [1].
Several protocols for the synthesis of thiazolidin-4-
one and thiazinan-4-one derivatives are available in the
literature [4–12] (Scheme 1). Essentially these are three
component reactions involving an amine, a carbonyl
compound and a mercapto acid. The process can be ei-
ther a one-pot three-component condensation or a two-
step process. The reaction has been suggested to proceed
via imine formation followed by the attack of sulfur
nucleophile on the imine carbon. The last step involves
intramolecular cyclization with the elimination of water
to give the final compound. This step appears to be
There are numerous biologically active molecules
whose framework includes a five-membered and six-
membered ring containing two hetero atoms. Thiazoli-
C
V
2010 HeteroCorporation

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A DIC Mediated Expeditious Small Library Synthesis and Biological Activity
of Thiazolidin-4-one and 1,3-Thiazinan-4-one Derivatives
1085
Scheme 1. Schematic representation for synthesis of thiazolidin-4-one
and metathiazinan-4-one derivatives on solid support.
fluroacetic acid (TFA): dichloromethane (DCM) (1:1)
mixture, the desired products in almost quantitative
yields were obtained. It was observed that in the case of
phenylalanine, the yields were significantly lower than
that with glycine, using HBTU in both the reactions.
Fast decomposition of HBTU and steric hindrance could
be a major reason for lower yield with phenylalanine.
Previous studies suggest that the use of carboxylate
activating reagents have facilitated cyclization [19]. There-
fore it was thought to explore N, N0-diisoproplylcarbodii-
mide (DIC) as a coupling and dehydrating agent by keep-
ing N,N- dicyclohexylcarbodiimide (DCC) mediated pro-
tocol in mind, which is usually used in solid phase pep-
tide coupling reactions [20–21]. The generality of the DIC
mediated reactions have been demonstrated by synthesiz-
ing a variety of thiazolidin-4-one and thiazinan-4-one
derivatives. In previous study, it was observed that steri-
cally hindered amino acids react sluggishly during cycliza-
tion and lead to poor yields or sometimes do not react at
all. To avert these shortcomings, in this study, sterically
hindered amino acids were examined and the results
obtained were excellent (Table-2).
critical for obtaining high yields. Therefore, variations
have been affected in this step to facilitate removal of
water. Most commonly used protocols utilize azeotropic
distillation, molecular sieves, and use of other desiccants
like anhydrous zinc chloride [13], sodium sulfate [14],
or magnesium sulfate [15]. These protocols require pro-
longed heating at 70–80ꢀC for 17–20 h and give moder-
ate to good yields. More recently, an improved protocol
has been reported wherein N,N-dicyclohexylcarbodii-
mide (DCC) or 2-(1H-benzotrizole-1-yl)-1,1,3,3 tetrame-
thyluraniumhexafluorophospate (HBTU) is used as an
acid amine coupling and dehydrating agent to accelerate
intramolecular cyclization, resulting in faster reaction
and improved yields [16,17]. First time Holmes et al.
[18] reported solution and polymer-supported synthesis
of thiazolidin-4-one and thiazinan-4-one derivatives,
derived from amino acids. In amino acids, the carbox-
ylic acid function serves as an anchor group for attach-
ment to the site of support. The condensation of this
support bound amine with several aldehydes and mer-
capto acetic acids in a one-pot reaction, afforded desired
products. A series of experiments were performed using
different proportions to optimize the ratio of reactants.
The ratio of reactants in 1:2:3 for amino acid, aldehyde,
and mercapto acetic acid, respectively, as in case of so-
lution phase HBTU protocol gave poor yields. Quantita-
tive yields were obtained by using the ratio of reactants
in 1:4:6 for amino acid, aldehyde, and mercapto acetic
acid, respectively. This is in agreement with the earlier
observation by Holmes et al. In a typical experiment,
amino acid and aldehyde were shaken in dry tetrahydro-
furan (THF) for 15 min, followed by addition of mer-
capto acetic acid and HBTU, and shaking of reaction
mixture for an additional 5 h. The resin was then fil-
tered, washed successively with N,N0-dimethyl formam-
ide (DMF) (3 ꢁ 2 mL), methanol (MeOH) (3 ꢁ 2 mL),
dichloromethane (DCM) (3 ꢁ 2 mL), and diethylether
(3 ꢁ 2 mL) and dried in vacuum. After cleavage of the
final compounds from the resin by treating it with tri-
Candida albicans, Candida parapsilosis, and Crypto-
coccus neoformans are the common opportunistic fungi
responsible for infections. Out of these Candida albicans
infections may become problematic in severely immuno-
compromised patients and may induce oral candiasis,
Figure 1. The HPLC data of the final compound VI. HPLC trace of
diastereomeric thiazolidin-4-one (VI) (7.333 and 8.95 min) after TFA
cleavage from solid support at 220 nm.
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A. Verma, S. Verma, and S. Saraf
Vol 47
Table 1
oesophageal candiasis, and vaginal candiasis. Candida
parapsilosis is second to Candida albicans as a cause of
candida endocarditis. Approximately 25% of candidal en-
docarditis cases reported have been caused by Candida
parapsilosis. On the contrary Cryptococcus neoformans is
the causative agent of cryptococcosis, which is the leading
cause of morbidity and mortality due to fungi in patients
with AIDS. Thus, there is urgent need for more effective
and novel antifungal therapies. Therefore in the first
instance, synthesized library compounds were screened for
their antifungal activity, against these three pathogenic
fungi: Candida albicans (Ca), Candida parapsilosis (Cp),
and Cryptococcus neoformans (Cn).
Building blocks for solid phase synthesis.
EXPERIMENTAL
The reagents used in the study are figured in Table 1.
Unless otherwise stated, the materials were of the highest
grade available from commercial sources and used without fur-
ther purification. The solvents and reagents were purchased
from the following sources: Wang resin (1% divinylbenzene,
200–400 mesh, 0.5–1.2 mmol/g substitutions) from Novabio-
chem; Fmoc protected amino acids, N,N0-diisopropylcarbodii-
mide, piperidine, diisopropylamine, and trifluoroacetic acid
from Aldrich and mercapto acid derivatives from Lancaster.
The reactions on solid phase were optimized using polypro-
pylene syringes of 5 mL capacity (Becton and Dickinson) with
fritt (12 mm diameter and 2 mm thickness for 5 mL syringes)
inserted at the bottom of the syringes. They were shaken on an
orbital shaker (IKA-Vibrax-VXR). The syringes were capped
at the bottom with Leur positive (VSG-0419, Roland Vetter)
cap. The compounds after cleavage from the resin were dried
under N2. 1H NMR spectra were obtained on Brucker Evans
DRX-600 spectrometer and chemical shifts (d) were reported
in ppm relative to TMS. Because of solubility properties, the
solvents used was CDCl3. RP-HPLC analysis of crude prod-
ucts was carried using a 5 lm, 4.8 ꢁ 150 mm C-18 reverse-
phase column with a linear gradient of Acetonitrile:Water
(80:20 v/v) with 100 lL TFA over 25 min. The flow rate was
0.4 mL/min, and UV detection was observed at 220 nm. The
retention time of compounds has been expressed in minutes as
tR (Fig. 1). Mass spectra were recorded using electron spray
ionization (ESI) technique or FAB.
(Continued)
its absence was confirmed by colorless beads (Negative Ninhy-
drine test).
GENERAL PROCEDURE
Loading of amino acid on resin. The Wang resin
(500 mg) was swelled by shaking on an orbital shaker
(IKA-Vibrax-VXR) at 600 rpm in 5 mL DCM:DMF
(1:1) for 30 min. The resin was then filtered and washed
with DMF. The resin so obtained was then coupled with
a preactivated solution of amino acid (5 equiv., 2.825
mmol), DIC (3 equiv., 1.695 mmol, 267.38 lL) and
DMAP (3 equiv., 1.695 mmol, 207 mg) in dry DMF (2
mL) and the reaction mixture was allowed to shake at
room temperature for 6–7 h. The resin was filtered and
washed, successively, with DMF (3 ꢁ 2 mL), MeOH (3
ꢁ 2 mL), DCM (3 ꢁ 2 mL), and diethylether (3 ꢁ 2
mL) and dried in vacuum. A second repeat cycle was
made with a preactivated solution of amino acid (2
equiv., 1.13 mmol), DIC (1.5 equiv., 0.847 mmol, 133.5
lL) and DMAP (1.5 equiv., 0.847 mmol, 103.5 mg) in
dry DMF (2 mL), and the reaction mixture was allowed
to shake at room temperature for 6–7 h to achieve com-
plete loading of amino acids on resin. The resin was fil-
tered and washed, successively, with DMF (3 ꢁ 2 mL),
MeOH (3 ꢁ 2 mL), DCM (3 ꢁ 2 mL), and diethylether
(3 ꢁ 2 mL) and dried in vacuum. (Scheme 2).
Ninhydrine test for aliphatic primary amines. Ninhydrine
test is used to detect the presence and absence of free aliphatic
ANH2 group on resin beads after de-protection of Fmoc group.
The test was performed by taking small aliquot of the resin in
an eppendorf followed by the addition of few drops of follow-
ing solutions:
1. 80% solution of phenol in absolute alcohol.
2. 2% solution of aqueous KCN (0.001M) in Pyridine.
3. 5% solution of Ninhydrine in absolute alcohol.
Deprotection of Fmoc groups of resin bound amino
acids. This was carried out by treating the resin twice
with 30% (v/v) piperidine/DMF solution at room tem-
perature for 15 and 25 min, respectively. Then the resin
was filtered and washed successively with DMF (3 ꢁ 2
The eppendorf was then heated at 100ꢀC in a water bath,
for 5 min. and colour of the beads was examined. The pres-
ence of free aliphatic ANH2 group of amino acids was indi-
cated by blue resin beads (Positive Ninhydrine test), whereas
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
A DIC Mediated Expeditious Small Library Synthesis and Biological Activity
of Thiazolidin-4-one and 1,3-Thiazinan-4-one Derivatives
1087
mL), MeOH (3 ꢁ 2 mL), DCM (3 ꢁ 2 mL), and diethy-
lether (3 ꢁ 2 mL) and dried in vacuum.
mixture was filtered and the filtrate was evaporated to
dryness in vacuum.
Preparation of resin bound thiazolidin-4-one and
thiazinan-4-one derivatives. The Fmoc-deprotected
amino acids loaded Wang resin (200 mg in a polypro-
pylene syringe) was swelled in dry THF for 30 min. Af-
ter 30 min (hetero)/aromatic aldehyde (4 eq.) in THF
was added and shook on an orbital shaker (IKA-Vibrax-
VXR) at 600 rpm for 30 min. Then, an appropriate mer-
capto acid (6 eq.) was poured into the reaction mixture.
After 5 min diisopropylcarbodiimide (DIC) (4 eq.) was
added to the reaction mixture. The reaction mixture was
then allowed to shake at room temperature for 8 h. Dii-
sopropylurea (DIU) was separated during reaction was
removed by washing. The resin was then filtered,
washed successively with DMF (3 ꢁ 2 mL), MeOH (3
ꢁ 2 mL), DCM (3 ꢁ 2 mL), and diethylether (3 ꢁ 2
mL) and dried in vacuum.
ANTIFUNGAL ACTIVITY
The IC50 values of library compounds were deter-
mined against the test fungi by using micro-broth dilu-
tion technique as per guidelines of NCCLS M-27A [22].
IC50 values of standard antifungal (Miconazole) and
synthetic compounds were measured in 96 well tissue
culture plate (CellStar Greiner Bio One, Germany) using
RPMI 1640 media buffered with MOPS [3-(N-Morpho-
lino) propanesulfonic acid, Sigma]. Starting inocula of
test culture were maintained at 1.0–5.0 ꢁ 103 cfu/mL.
A solution of 2 mg/mL of library compounds in 10%
DMSO was used. Microtitre plates were incubated at
35ꢀC in a moist dark chamber and IC50 and MIC values
were recorded spectrophotometrically (Softmax pro 4.3,
Versamax microplate reader, molecular devices) after
48 h for candida albicans and candida parapsilosis and
72 h for cryptococcus neoformans. The antifungal
Cleavage of final compounds (I–XXIII). The final
compounds (Table 2) were cleaved from the resin by
treating it with TFA:DCM (1:1) mixture. The resulting
Scheme 2. DIC mediated synthesis of thiazolidin-4-one and metathiazinan-4-one derivatives. Reagents and conditions: (i) 5 mL DCM:DMF (1:1),
30 min (ii) 10 equiv. FmocAA-OH (1a–d), 5 equiv. DMAP, 5 equiv. DIC, dry DMF, rt, 600 rpm, 6h. (iii) 20% piperidine in dry DMF, rt, two
cycles of 15 and 30 min, respectively. (iv) 4 equiv. aldehyde(2a–e), 6 equiv. mercapto acid (3a–c), 4 equiv. DIC, rt, 8 h. (v) 20% TFA/DCM, rt,
1h.
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A. Verma, S. Verma, and S. Saraf
Vol 47
Table 2
Data of compounds synthesized on solid phase.
Building blocks
Entry
Amino acids
Aldehydes
Mercapto acids
Overall yieldsa (%)
M.Wt
ESI-MS m/z (MþH)þ
I
II
III
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1c
1d
1d
1a
1b
1c
1c
1b
1c
1d
2a
2b
2c
2d
2e
2a
2b
2c
2d
2a
2b
2c
2d
2e
2a
2b
2c
2a
2a
2b
2c
2b
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3c
3c
3c
3c
3b
3b
3b
98
90
96
66
95
90
63
55
30
75
42
53
28
58
89
42
68
40
80
32
62
36
40
237
267
238
271
306
251
281
252
285
327
357
328
361
396
293
323
252
265
341
371
266
371
307
238
268
239
272
307
252
282
253
286
328
358
329
362
397
294
324
253
266
342
372
267
372
308
IV
V
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
XVI
XVII
XVIII
XIX
XX
XXI
XXII
XXIII
a The overall yields are based on the initial loading of hydroxymethyl resin.
activity of library compounds has been summarized in
Table 3.
63.24, 127.11, 128.23, 129.11, 137.78, 172.35, 172.96;
minor isomer 14.38, 33.10, 53.46, 65.69, 127.11,
128.23, 129.82, 139.74, 172.35, 172.96.
2-(4-Oxo-2-phenyl-thiazolidin-3-yl)-3-phenyl-propionic acid
(X). mp 75–81ꢀC (3:1 mixture of diastereomers): IR
RESULTS AND DISCUSSION
1
(KBr) 1681.81, 1745.46; H NMR (CDCl3, 600 MHz) d
major isomer 3.23–3.27 (m, 1H, CH2-Ph), 3.31–3.48 (m,
1H, CH2-Ph), 3.66–3.76 (m, 2H, HA & HB), 3.89 (q,
J ¼ 6.0, 0.5H, CH), 5.07 (q, J ¼ 6.0, 0.5H, CH), 6.74
(bs, 1H, OH), 6.87 (s, 0.5H, C-2), 6.98 (s, 0.5H, C-2),
7.14–7.41 (m, 7H, Ar-H), 7.48 (t, J ¼ 7.2, 1H, H5-ben-
zyl), 7.68 (d, J ¼ 7.20, 2H, H2&6-Ph); 13C NMR
(CDCl3) d major isomer (32.66, 33.00), (33.10, 34.30),
(58.97, 59.25), (65.49, 65.94), (126.65, 127.12), (128.48,
128.53), (128.62, 128.69), (128.84, 129.05), (129.24,
129.45), (129.72, 132.00), (133.48, 135.77), (136.44)
137.39), (172.22, 172.49), (173.67, 174.02).
Physicochemical data. (4-Oxo-2-pyridin-2-yl-thiazoli-
din-3-yl)-acetic acid (III). mp semisolid on RT: IR (KBr)
1
1681.81, 1745.46; H NMR (CDCl3, 600 MHz) d 2.56
(bs, 1H, OH), 3.44 (d, J ¼ 18.0 Hz, 1H, NCH2), 3.76
(d, J ¼ 15.6 Hz, 1H, HA), 3.82 (dd, J ¼ 15.6, 1.2 Hz,
1H, HB), 4.39 (d, J ¼ 18.0 Hz, 1H, NCH2), 6.01 (s, 1H,
C-2), 7.40 (m, 1H, H5-Py), 7.58 (d, J ¼ 7.8 Hz, 1H, H3-
Py), 7.88 (m, 1H, H4-Py), 8.53 (d, J ¼ 4.8 Hz, 1H, H6-
Py); 13C NMR (CDCl3) d 32.18, 45.00, 63.13, 122.88,
124.72, 139.23, 147.82, 157.82, 169.73, 172.11.
2-(4-Oxo-2-phenyl-thiazolidin-3-yl)-propionic acid (VI).
mp 176–182ꢀC (3:1 mixture of diastereomers): IR (KBr)
1664.45, 1685.67, 1743.53; 1H NMR (CDCl3, 600
MHz) d major isomer 1.25 (d, J ¼ 7.8 Hz, 3H, CH3),
3.67 (d, J ¼ 16.2 Hz, 1H, HA), 3.85 (dd, J ¼ 16.2, 1.2
Hz, 1H, HB), 4.21 (q, J ¼ 7.2 Hz, 1H, CHCH3), 5.20
(bs, 1H, OH), 5.75 (s, 1H, C-2), 7.35–7.45 (m, 5H, Ph);
minor isomer, 1.41 (d, J ¼ 7.8 Hz, 3H, CH3), 3.73 (q, J
¼ 7.2 Hz, 1H, CHCH3), 3.77 (s, 2H, CH2), 5.20 (bs,
1H, OH), 5.74 (s, 1H, C-2), 7.35–7.45 (m, 5H, Ph); 13C
NMR (CDCl3) d major isomer 14.24, 32.41, 52.60,
The above findings draw attention to address the
scope and limitations of the present protocol. The work
concentrated on aldehydes having electron-donating and
electron-withdrawing substituents. It is evident from the
yields that the present method obviates the limitations
of earlier methods and is more versatile. Furthermore,
this method shows significantly higher yields of the thia-
zolidin-4-one derivatives thereby indicating a lower de-
pendence on the nature of the amino acid and aldehyde
components (Table 2). As an obvious extension of this
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A DIC Mediated Expeditious Small Library Synthesis and Biological Activity
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Table 3
IC50 values for synthesized library compounds (I–XXIII).
2,6-dihalophenyl group at C-2 position and a phenethyl
ring at N-3 position.
The results presented in this study indicate that
changes at C-2 position of thiazolidin-4-one moiety,
except for 2,6-dihalophenyl, may lead to reduction in
antifungal activity of these compounds. However, intro-
duction of phenethyl moiety at the N-3 position in the
thiazolidin-4-one ring is well-supported.
Ca IC50
[lM]
Cp IC50
[lM]
Cn IC50
[lM]
Entry
I
82.37
79.49
78.61
77.51
83.33
78.12
79.61
27.14
79.61
78.49
79.55
80.64
78.67
22.01
81.30
80.38
80.51
75.24
55.36
78.12
81.27
84.14
78.16
05.12
85.23
82.37
79.49
78.61
77.51
75.33
78.12
79.61
20.22
79.61
52.90
79.55
80.64
56.17
13.54
57.23
56.51
80.51
52.89
56.28
78.12
98.25
81.27
79.52
08.22
98.48
53.45
79.49
78.61
77.51
52.91
43.28
21.17
22.50
33.91
24.01
48.05
15.16
49.80
12.16
28.94
35.85
30.27
23.70
47.09
43.28
43.16
82.64
78.32
01.32
92.54
II
III
IV
V
VI
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VII
VIII
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protocol, the reactions were performed using heterocy-
clic aldehydes and substituted hindered aromatic alde-
hydes instead of simple aromatic aldehydes. The corre-
sponding thiazolidin-4-one derivatives were obtained in
quantitative yield. Generally, low yields of thiazolidin-
4-one derivatives were reported in the literature when
amino acids were used as a source of amine; however,
with this protocol, excellent to moderate yields were
obtained. The versatility of the protocol and to further
enhance the scope of this reaction, efforts were made on
adaptation of the method for synthesis of thiazinan-4-
one, another biologically active chromophore. It is appa-
rent from the variety of reactants that this method has
the potential to generate a battery of thiazolidin-4-one
and thiazinan-4-one derivatives by solid phase combina-
torial synthesis.
[9] Chaubey, V. N.; Singh, H. Bull Chem Soc Jpn 1970, 43,
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The results for the antifungal assay of the synthesized
library compounds are summarized in Table 3. As is
evident that out of 23 synthesized molecules, compound
XIV exhibited best inhibitions in comparison to others
with IC50 values of 22.01 lM against Ca, 13.54 lM
against Cp, and 12.16 lM against Cn.
Our studies thus suggest that activity is strongly de-
pendent on the nature of the substituent at C-2 and N-3
positions of thiazolidin-4-one ring. In particular, a high
activity level was observed for compounds possessing a
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet