An expeditious, environment-friendly, and microwave-assisted synthesis of 5-isatinylidenerhodanine derivatives

Article abstract of DOI:10.2478/s11696-010-0104-9

A series of nine 5-arylidenerhodanine derivatives was prepared in good yields and purity without the use of a solvent or catalyst under microwave-assisted condensation with some substituted isatins. All 5-arylidenerhodanines were evaluated as possible inhibitors of the CK1α/β, CDK5/p25, and GSK-3α/β kinases. None of them showed substantive inhibitory activity against these kinases when evaluated at the concentration of 10 μM.

Full text of DOI:10.2478/s11696-010-0104-9

Chemical Papers 65 (3) 332–337 (2011)
DOI: 10.2478/s11696-010-0104-9
ORIGINAL PAPER
An expeditious, environment-friendly, and microwave-assisted
synthesis of 5-isatinylidenerhodanine derivatives
a
b
aAbdelmounaim Safer, Mustapha Rahmouni, Fran¸cois Carreaux,
bLudovic Paquin, Olivier Lozach, Laurent Meijer, Jean Pierre Bazureau*
c
c
b
aLaboratoire de Synth`ese et de Catalyse, Université Ibn Khaldoun, 14000 Tiaret, Algérie
bGroupe Ingénierie Chimique et Molécules pour le Vivant (ICMV), Laboratoire Sciences Chimiques de Rennes,
UMR CNRS 6226, Université de Rennes 1, Baˆt. 10A, Campus de Beaulieu,
Avenue du Général Leclerc, CS 74205, 35042 Rennes Cedex, France
cProtein Phosphorylation and Human Disease, Station Biologique de Roscoff, CNRS,
Place G. Tessier, BP 74, 29682 Roscoff Cedex, France
Received 23 April 2010; Revised 26 October 2010; Accepted 4 November 2010
A series of nine 5-arylidenerhodanine derivatives was prepared in good yields and purity without
the use of a solvent or catalyst under microwave-assisted condensation with some substituted isatins.
All 5-arylidenerhodanines were evaluated as possible inhibitors of the CK1α/β, CDK5/p25, and
GSK-3α/β kinases. None of them showed substantive inhibitory activity against these kinases when
evaluated at the concentration of 10 µM.
c
ꢀ 2011 Institute of Chemistry, Slovak Academy of Sciences
Keywords: rhodanine, isatin, Knoevenagel condensation, solvent-free microwave
Introduction
disease and other “tauopathies” inhibition by their
ability to inhibit tau aggregation (Bulic et al., 2009).
Special attention is given to the thioxothiazolidinone
core possessing a 2-oxoindole group due to the inhibi-
tions of therapeutic targets attractive for treatment
(Melnick et al., 2008; Zawahir et al., 2009; Bao &
Kimzey, 2004; McKee et al., 2004) of cancer (Fig. 1,
APE1 inhibitor). Additionally, rhodanine derivatives
show antimicrobial (Pardasani, et al., 2001; Bapodra
et al., 2002), antiviral (Zapadnyuk, 1966), anticon-
vulsant (Zapadnyuk, 1962), and antidiabetic activi-
ties (Sortino et al., 2007; Gaonkar & Shimizu, 2010).
Several rhodanines have progressed to different stages
of clinical trials. For example, epalrestat (Fig. 1) re-
duces the symptoms of diabetic neuropathy (Hotta et
al., 2006).
Numerous families of five membered heterocy-
cles have proven to be valuable in medicinal chem-
istry. 2-Sulfanylidene-1,3-thiazolidin-4-one (alterna-
tive names: 2-thioxo-4-thiazolidinone, rhodanine) is
one example of an important scaffold, with its diverse
biological activities (Lesyk & Zimenkovsky, 2004).
Several 5-alkylidene- and 5-arylidenerhodanines in-
hibit targets such as HCV NS3 protease (Sing et
al., 2001), aldose reductase (Fujishima & Tsubota,
2002), β-lactamase (Grant et al., 2000), UDP-N-
acetylmuramate/L-alanine ligase (Sim et al., 2002),
cathepsin D (Whitesitt et al., 1996), antitoxin pro-
tease (Johnson et al., 2008), PI3-kinase γ (Lanni et al.,
2007), histidine decarboxylase and Bcl-XL (Degterev
et al., 2001), and serotonin N-acetyltransferase (Szew-
czuk et al., 2007). Recently, 5-arylidenerhodanine
derivatives showed promising potential of Alzheimer’s
Due to the biological interest in this class of com-
pounds (Edwards et al., 2005; Hu et al., 2004), sev-
eral synthetic strategies for efficient formation and
*Corresponding author, e-mail: jean-pierre.bazureau@univ-rennes1.fr

A. Safer et al./Chemical Papers 65 (3) 332–337 (2011)
333
COOH
useful to a medicinal chemist for whom the reac-
tion speed and eco-friendly conditions are of great
importance (Blackwell, 2003; Larhed & Hallberg,
2001). In this context, we disclose a solvent-free
and catalyst-free microwave-assisted synthesis of novel
5-arylidene-2-thioxothiazolidinones by the Knoeve-
nagel condensation of various isatins with rhoda-
nines.
O
N
S
S
S
S
N
N
O
O
HOOC
HOOC
E
e
palrestat
APE1 inhibitor
Fig. 1. Structures of some bioactive rhodanine derivatives.
Experimental
All reagents were purchased from Acros, Aldrich
Chimie, Fluka (France) and used without further pu-
rification. Melting points were determined using a
Kofler melting point apparatus and were uncorrected.
1H (300 MHz) and 13C (75 MHz) NMR spectra were
recorded on a Bruker AC 300P spectrometer. Mass
spectra (HRMS) were recorded on a Varian MAT
311 at the ionisation potential of 70 eV. Microwave-
assisted reactions were performed in a Synthewave 402
apparatus (Merck Eurolab, France) using the stirring
option. The microwave instrument consists of a contin-
uous focused microwave power output from 0 W to 300
W. The target temperature was reached with a ramp
of 4 min and the chosen microwave power was constant
to maintain the temperature. The reaction tempera-
ture was monitored using a calibrated infrared sensor
and the reaction time included the ramp period.
Starting rhodanines, Ia–Ic, were prepared by react-
ing methyl thioglycolate with methyl isothiocyanate
or phenyl isothiocyanate at room temperature accord-
ing to an already reported procedure (Sing et al.,
2001).
Kinase activities were assayed according to the
published methodology (Polychronopoulos et al.,
2004). Three protein kinases relevant to the Alzhei-
mer’s disease were used: CK1α/β (casein kinase
1α/β), CDK5/p25 (cyclin-dependent kinase 5/p25),
and GSK-3α/β glycogen synthase kinase 3α/β. In all
assays 15 mM ATP and appropriate protein substrates
(RRKHAAIGpSAYSITA peptide for CK1α/β (Rein-
hardt et al., 2007), histone H1 for CDK5/p25 (Primot
et al., 2000), GS-1 (YRRAAVPPSPSLSRHSSPHQS-
pEDEEE) peptide for GSK-3α/β (Bach et al., 2005)
were used. IC50 values were determined from dose-
response curves.
functionalisation of rhodanine have been explored. For
alkylidene-substituted rhodanines, the most problem-
atic step is the Knoevenagel condensation with an ap-
propriate carbonyl compound. For this C-5 arylidena-
tion of rhodanine, many methods have been presented
in literature. Many of these methods suffer from one or
another limitation, such as harsh reaction conditions,
low or moderate yields, relatively long reaction times,
and a cumbersome experimental process. The Knoeve-
nagel reaction (Bourahla et al., 2007) has been accom-
plished using piperidinium benzoate (Lohray et al.,
1997) or piperidinium acetate (Carlson et al., 2006)
as catalysts in boiling toluene, sodium acetate as cata-
lyst in boiling acetic acid (Brown, 1961), piperidine as
catalyst in boiling 95 % ethanol (Mallick et al., 1971),
potassium carbonate as catalyst in dry dimethyl sul-
foxide at 25◦C (Ohishi et al., 1990), and pyrrolidine
as catalyst in dry ethanol at 75◦C (Momose et al.,
1991). Microwave irradiation was previously employed
for this reaction using piperidine as catalyst in acetic
acid using a domestic microwave oven with a multi-
mode cavity (Yang et al., 2003) but without the con-
trol of the reaction temperature.
In recent years, microwave-assisted synthesis has
become popular among synthetic organic chemists
when improving the yields of classical organic re-
actions, shortening the reaction times, and pro-
moting new reactions (Loupy, 2006). Moreover, a
microwave-assisted reaction may not require the use
of solvent, giving an eco-friendly synthesis while
offering the advantages of reduced risk of explo-
sion and easier work-up. The application of mi-
crowave technology to the rapid synthesis of po-
tentially biologically active molecules is especially
Table 1. Optimisation of reaction conditions for the preparation of IIIa under solvent-free microwave irradiation
Entry
Time/min
Temperature/◦C
Power/W
Conversiona/%
1
2
3
4
5
6
30
30
20
30
30
30
120
120
120
150
160
160
210
180
210
210
210
180
64
60
52
93
98
85
a) Conversion of Ia into IIIa was determined by 1H NMR.

334
A. Safer et al./Chemical Papers 65 (3) 332–337 (2011)
General method for the preparation of 5-(2-
oxoindolin-3-ylidene)-2-thioxothiazolidin-4-
ones (IIIa–IIIi)
Table 2. Characteristics of the compounds prepared
Compound
R1
R2
Yielda/%
M.p./◦C
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
H
C6H5
H
H
H
Cl
NO2
NO2
Cl
H
Cl
NO2
58
61
67
66
70
83
65
80
80
> 300b
> 300c
> 300
> 300
> 300d
> 300
> 300e
> 300
> 300
A cylindrical quartz reactor (ø = 1.8 cm) contain-
ing a mixture of rhodanine derivative I (5 mmol) and
isatin derivative II (5 mmol) was placed into a Syn-
thewave 402 Prolabo microwave reactor (300 W). The
stirred mixture was irradiated (after a ramp of 4 min
from 20◦C to 160◦C) at 160◦C (power level of 70 %)
for 30 min. After cooling to room temperature, ethanol
(20 mL) was added, the resulting insoluble solid was
filtered, and recrystallised from hot ethanol (15 mL)
to give the product III (> 99 % purity) which was
dried under diminished pressure (1.33 Pa) for 2 h.
H
C6H5
C6H5
Me
Me
Me
a) Isolated yield after recrystallisation; b) 285◦C (Pardasani et
al., 2001); c) 260◦C (Andreasch, 1917); d) 260–267◦C (Jones
& Hann, 1928); e) 240◦C (Pardasani et al., 2001), 308–310◦C
(Sawayama et al., 1976).
Table 3. Spectral characterisation of the prepared compounds
Compound
Spectral data
IIIaa
IIIb
IIIc
IIId
IIIe
1H NMR (DMSO-d6), δ: 13.8 (brs, 1H, NH), 10.62 b(brs, 1H, NH), 8.77 (d, 1H, J = 7.7 Hz, Haryl), 7.40 (t, 1H, J
= 7.5 Hz, Haryl), 7.07 (t, 1H, J = 7.5 Hz, Haryl), 6.94 (d, 1H, J = 7.8 Hz, Haryl
)
13C NMR (DMSO-d6), δ: 200.34, 169.90, 169.40, 144.95, 134.29, 133.26, 128.37, 124.01, 122.57, 120.38, 111.07
HRMS, m/z (found/calc.): 261.9831/261.9902 (M+, C11H6N2O2S2)
1H NMR (DMSO-d6), δ: 13.8 (brs, 1H, NH), 8.77 (d, 1H, J = 7.7 Hz, Haryl), 7.40 (t, 6H, Haryl), 7.07 (t, 1H, J =
7.5 Hz, Haryl), 6.94 (d, 1H, J = 7.8 Hz, Haryl
)
13C NMR (DMSO-d6), δ: 200.34, 169.90, 169.40, 144.95, 134.29, 133.26, 128.37, 124.01, 122.57, 120.38, 111.07
HRMS, m/z (found/calc.): 338.0209/338.0202 (M+, C17H10N2O2S2)
1H NMR (DMSO-d6), δ: 14.05 (brs, 1H, NH), 11.32 (brs, 1H, NH), 7.47 (dd, 1H, J = 8.3 Hz, J = 2.2 Hz, Haryl),
6.98 (d, 1H, J = 8.4 Hz, Haryl), 6.95 (s, 1H, Haryl
)
13C NMR (DMSO-d6), δ: 200.03, 170.03, 166.25, 143.55, 133.39, 132.32, 127.52, 126.37, 123.56, 121.64, 112.44
HRMS, m/z (found/calc.): 295.9487/295.9481 (M+, C11H5ClN2O2S2)
1H NMR (DMSO-d6), δ: 11.86 (brs, 1H, NH), 9.65 (d, 1H, J = 2 Hz, Haryl), 8.33 (dd, 1H, J = 8.6 Hz, J = 2.2 Hz,
Haryl), 7.13 (d, 1H, J = 8.7 Hz, Haryl
)
13C NMR (DMSO-d6), δ: 197.73, 170.58, 167.18, 144.30, 131.05, 130.09, 129.87, 126.87, 124.10, 121.90, 111.85
HRMS, m/z (found/calc.): 306.9719/306.9721 (M+, C11H5N3O4S2)
1H NMR (DMSO-d6), δ: 11.99 (brs, 1H, NH), 9.64 (s, 1H, Haryl), 8.36 (d, 1H, J = 8.1 Hz, Haryl), 7.64–7.49 (m,
6H, Haryl), 7.20 (d, 1H, J = 8.6 Hz, Haryl
)
13C NMR (pyridine-d5), δ: 198.42, 170.58, 168.71, 151.57, 144.30, 136.17, 131.87, 131.05, 130.09, 129.52, 126.87,
125.04, 124.10, 122.11, 121.90, 120.37, 111.85
HRMS, m/z (found/calc.): 383.0030/383.0034 (M+, C17H9N3O4S2)
IIIf
1H NMR (DMSO-d6), δ: 11.47 (brs, 1H, NH), 8.77 (d, 1H, J = 2.1 Hz, Haryl), 7.62–7.48 (m, 7H, Haryl), 7.02 (d,
1H, J = 8.5 Hz, Haryl
)
13C NMR (pyridine-d5), δ: 198.38, 168.89, 162.79, 150.10, 144.24, 135.37, 132.37, 129.84, 129.69, 129.14, 128.11,
127.15, 123.92, 122.65, 122.10, 112.08
HRMS, m/z (found/calc.): 371.9798/371.9794 (M+, C17H9ClN2O2S2)
IIIgb
IIIh
1H NMR (DMSO-d6), δ: 11.25 (brs, 1H, NH), 8.82 (d, 1H, J = 7.8 Hz, Haryl), 7.42 (t, 1H, J = 7.7 Hz, Haryl), 7.09
(t, 1H, J = 7.8 Hz, Haryl), 6.99 (d, 1H, J = 7.7 Hz, Haryl), 3.44 (s, 3H, Me)
13C NMR (DMSO-d6), δ: 198.72, 169.48, 167.58, 146.11, 133.41, 132.97, 129.13, 127.72, 122.77, 121.42, 111.15, 30.89
HRMS, m/z (found/calc.): 276.0032/276.0027 (M+, C12H8N2O2S2)
1H NMR (DMSO-d6), δ: 11.38 (brs, 1H, NH), 8.87 (s, 1H, Haryl), 7.51 (d, 1H, J = 8.5 Hz, Haryl), 7.01 (d, 1H, J =
7.5 Hz, Haryl), 3.46 (s, 3H, Me)
13C NMR (pyridine-d5), δ: 197.91, 168.86, 160.59, 151.12, 136.67, 134.52, 131.16, 129.20, 126.91, 124.65, 113.03,
31.46
HRMS, m/z (found/calc.): 309.9640/309.9637 (M+, C12H7ClN2O2S2)
IIIi
1H NMR (DMSO-d6), δ: 11.94 (brs, 1H, NH), 9.70 (s, 1H, Haryl), 8.35 (d, 1H, J = 8.4 Hz, Haryl), 7.17 (t, 1H, J =
8.6 Hz, Haryl), 3.48 (s, 3H, Me)
13C NMR (DMSO-d6), δ: 198.58, 183.09, 165.23, 136.16, 133.42, 131.92, 130.68, 123.20, 117.54, 111.88, 106.22, 33.99
HRMS, m/z (found/calc.): 320.9883/320.9878 (M+, C12H7N3O4S2)
a) NMR and mass spectral data (see Pardasani et al., 2001); b) 1H NMR data (see Pardasani et al., 2001; Sawayama et al., 1976).

A. Safer et al./Chemical Papers 65 (3) 332–337 (2011)
335
O
S
S
NH
O
S
R2
N
S
i
R1
+
O
N
O
R1
N
O
H
R2
I
II
III
Fig. 2. Synthesis of rhodanine derivatives III (for R1, R2, see Table 2). Reaction conditions: i) solvent-free microwave irradiation,
160◦C, 30 min.
Results and discussion
programme de Coopération Mixte Inter Universitaire Algéro-
Franc¸ais N◦ 03 MDU 574” for financial assistance (A.S.). Fi-
nancial support of this program carried out under the “Can-
céropôle Grand Ouest/Institut National du Cancer” by con-
tracts PRIR 04-8390 et ACI 04-2254 is gratefully acknowl-
edged. We also thank Merck Eurolab Prolabo (France) for pro-
viding the Synthewave 402 apparatus.
Initially, the microwave-assisted Knoevenagel con-
densation of commercially available rhodanine (Ia)
with isatin (IIa) using a solvent-free procedure was
studied (Table 1). Optimisation of the microwave di-
electric heating reaction conditions, using continuous
irradiation (Commarmot et al., 1985) led to the set-
ting of the reaction temperature by infrared thermom-
etry (Jacquault, 1993), showed that the irradiation of
an equimolar mixture of Ia and IIa without a solvent
or a catalyst at 160◦C (210 W) for 30 min allows their
full conversion into product IIIa. These reaction con-
ditions were subsequently applied in the Knoevenagel
condensation of N-substituted rhodanines Ib–Ic with
isatins IIb–IIc bearing an electron-withdrawing group
(Cl, NO2) in position 5 (Fig. 2).
As can be seen from the data presented in Ta-
ble 2, the yields of compounds IIIa–IIIi ranged from
58 % to 83 %. Moderate yields were obtained when
3-phenylrhodanine (Ib) was used as a reactant as a
result of its favourable solubility in the EtOH solvent
used for the recrystallisation. In the majority of cases,
good purity of the desired products was obtained (Ta-
ble 3). In order to show the advantage of the use of
a solvent-free microwave procedure, the preparation
of compound IIIb without microwave irradiation us-
ing an oil bath (160◦C) for heating was examined.
The isolated yield of compound IIIb after conventional
heating for 20 h was only 15 % compared to the 61 %
yield after 30 min under microwave irradiation.
Investigation of the in vitro bioactivity revealed
that none of the prepared compounds IIIa–IIIi was
active (IC50 > 10 µm).
References
¨
Andreasch, R. (1917). Uber substituierte Rhodanine und einige
ihrer Aldehydkondensationsprodukte. XIII. Mitteilung. Mo-
natshefte fu¨r Chemie, 38, 121–139. DOI: 10.1007/BF01526
473.
Bach, S., Knockaert, M., Reinhardt, J., Lozach, O., Schmitt,
S., Baratte, B., Koken, M., Coburn, S. P., Tang, L.,
Jiang, T., Liang, D.-C., Galons, H., Dierick, J.-F., Pinna,
L. A., Meggio, F., Totzke, F., Schächtele, C., Lerman, A.
S., Carnero, A., Wan, Y., Gray, N., & Meijer, L. (2005).
Roscovitine targets, protein kinases and pyridoxal kinase.
Journal of Biological Chemistry, 280, 31208–31219. DOI:
10.1074/jbc.M500806200.
Bapodra, A. H., Bharmal, F., & Parekh, H. (2002). Synthesis
and biological activity of 2-(3’,5’-dibromo-2’-hydroxyphenyl)-
3-aryl-5H/methyl/carboxymethyl-4-thiazolidinones. Indian
Journal of Pharmaceutical Sciences, 64, 501–504.
Bao, L., & Kimzey, A. (2004). Photochemotherapeutic com-
pounds for use in treatment of Pin1-associated states. WO
Patent No. WO2004093803. Geneva, Switzerland: World In-
tellectual Property Organization.
Blackwell, H. E. (2003). Out of the oil bath and into the
oven–microwave-assisted combinatorial chemistry heats up.
Organic & Biomolecular Chemistry, 1, 1251–1255. DOI:
10.1039/b301432k.
Bourahla, K., Derdour, A., Rahmouni, M., Carreaux, F., &
Bazureau, J. P. (2007). A practical access to novel 2-amino-
5-arylidene-1,3-thiazol-4(5H)-ones via sulfur/nitrogen dis-
placement under solvent-free microwave irradiation. Tetra-
hedron Letters, 48, 5785–5789. DOI: 10.1016/j.tetlet.2007.06.
078.
Conclusions
Brown, F. C. (1961). 4-Thiazolidinones. Chemical Reviews, 61,
463–521. DOI: 10.1021/cr60213a002.
The solvent- and catalyst-free microwave-assisted
synthesis of 5-arylidenerhodanine derivatives was opti-
mised. This simple, convenient and “green” methodol-
ogy provides the investigated compounds in excellent
yield and purity and it may represent a practical com-
plement to the methods described in literature (Grä-
nacher & Mahal, 1923; Jones & Hann, 1928; Turkevich
et al., 1982).
Bulic, B., Pickhardt, M., Schmidt, B., Mandelkow, E.-M.,
Waldmann, H., & Mandelkow, E. (2009). Development of
tau aggregation inhibitors for Alzheimer’s disease. Ange-
wandte Chemie International Edition, 48, 1740–1752. DOI:
10.1002/anie.200802621.
Carlson, E. E., May, J. F., & Kiessling, L. L. (2006). Chemical
probes of UDP-galactopyranose mutase. Chemistry & Biol-
ogy, 13, 825–837. DOI: 10.1016/j.chembiol.2006.06.007.
Commarmot, R., Didenot, D., & Gardais, J.-F. (1985). Appareil
de minéralisation pour le traitement individuel, de fa¸con au-
tomatique, d’échantillons de produits placés dans des récipi-
Acknowledgements. The authors are grateful to the “Accord

336
A. Safer et al./Chemical Papers 65 (3) 332–337 (2011)
ents. FR Patent No. FR2560686. Paris, France: Institut Na-
Lesyk, R. B., & Zimenkovsky, B. S. (2004). 4-Thiazolidones:
Centenarian history, current status and perspectives for mod-
ern organic and medicinal chemistry. Current Organic Chem-
istry, 8, 1547–1577. DOI: 10.2174/1385272043369773.
Lohray, B. B., Bhushan, V., Rao, P. B., Madhavan, G. R., Mu-
rali, N., Rao, K. N., Reddy, K. A., Rajesh, B. M., Reddy,
P. G., Chakrabarti, R., & Rajagopalan, R. (1997). Novel in-
dole containing thiazolidinedione derivatives as potent eu-
glycemic and hypolipidaemic agents. Bioorganic & Medic-
inal Chemistry Letters, 7, 785–788. DOI: 10.1016/S0960-
894X(97)00118-2.
tional de la Propriété Industrielle.
Degterev, A., Lugovskoy, A., Cardone, M., Mulley, B., Wag-
ner, G., Mitchison, T., & Yuan, J. (2001). Identification of
small-molecule inhibitors of interaction between the BH3 do-
main and Bcl-XL. Nature Cell Biology, 3, 173–182. DOI:
10.1038/35055085.
Edwards, B. S., Bologa, C., Young, S. M., Balakin, K. V.,
Prossnitz, E. R., Savchuck, N. P., Sklar, L. A., & Oprea,
T. I. (2005). Integration of virtual screening with high-
throughput flow cytometry to identify novel small molecule
formylpeptide receptor antagonists. Molecular Pharmacol-
ogy, 68, 1301–1310. DOI: 10.1124/mol.105.014068.
Fujishima, H., & Tsubota, K. (2002). Improvement of corneal
fluorescein staining in post cataract surgery of diabetic pa-
tients by an oral aldose reductase inhibitor, ONO-2235.
British Journal of Ophtalmology, 86, 860–863. DOI: 10.1136/
bjo.86.8.860.
Loupy, A. (Ed.) (2006). Microwave in organic chemistry (2nd
ed.). Weinheim, Germany: Wiley-VCH.
Mallick, S. K., Martin, A. R., & Lingard, R. G. (1971). Synthe-
sis and antimicrobial evaluation of some 5-(5-nitrofurylidene)
rhodanines, 5-(5-nitrofurylidene)thiazolidine-2,4-diones, and
their vinylogs. Journal of Medicinal Chemistry, 14, 528–532.
DOI: 10.1021/jm00288a017.
McKee, T. D., Suto, R. K., Tibbitts, T., & Sowadski, J. (2004).
Pin-1 modulating compounds and methods of use thereof.
WO Patent No. WO2004028535. Geneva, Switzerland: World
Intellectual Property Organization.
Melnick, A. M., MacKerell, A. D., Jr., & Prive, G. G. (2008).
Small molecule inhibitors of BCL6. WO Patent No. WO
2008066887. Geneva, Switzerland: World Intellectual Prop-
erty Organization.
Momose, Y., Meguro, K., Ikeda, H., Hatanaka, C., Oi, S., &
Sohda, T. (1991). Studies on antidiabetic agents. X. Syn-
thesis and biological activities of pioglitazone and related
compounds. Chemical & Pharmaceutical Bulletin, 39, 1440–
1445.
Ohishi, Y., Mukai, T., Nagahara, M., Yajima, M., Kajikawa,
N., Miyahara, K., & Takano, T. (1990). Preparations of 5-
alkylmethylidene-3-carboxymethylrhodanine derivatives and
their aldose reductase inhibitory activity. Chemical & Phar-
maceutical Bulletin, 38, 1911–1919.
Pardasani, R. T., Pardasani, P., Sherry, D., & Chaturvedi,
V. (2001). Synthetic and antibacterial studies of rhodanine
derivatives with indole-2,3-diones. Indian Journal of Chem-
istry Section B, 40, 1275–1278.
Polychronopoulos, P., Magiatis, P., Skaltsounis, A.-L., Myri-
anthopoulos, V., Mikros, E., Tarricone, A., Musacchio, A.,
Roe, S. M., Pearl, L., Leost, M., Greengard, P., & Meijer,
L. (2004). Structural basis for the synthesis of indirubins as
potent and selective inhibitors of glycogen synthase kinase-3
and cyclin-dependent kinases. Journal of Medicinal Chem-
istry, 47, 935–946. DOI: 10.1021/jm031016d.
Primot, A., Baratte, B., Gompel, M., Borgne, A., Liabeuf,
S., Romette, J.-L., Jho, E.-H., Costantini, F., & Meijer, L.
(2000). Purification of GSK-3 by affinity chromatography on
immobilized axin. Protein Expression and Purification, 20,
394–404. DOI: 10.1006/prep.2000.1321.
Reinhardt, J., Ferandin, Y., & Meijer, L. (2007). Purifica-
tion of CK1 by affinity chromatography on immobilised
axin. Protein Expression and Purification, 54, 101–109. DOI:
10.1016/j.pep.2007.02.020.
Gaonkar, S. L., & Shimizu, H. (2010). Microwave-assisted syn-
thesis of the antihyperglycemic drug rosiglitazone. Tetrahe-
dron, 66, 3314–3317. DOI: 10.1016/j.tet.2010.03.006.
¨
Gränacher, C., & Mahal, A. (1923). Uber die verwendung des
rhodanins zu organischen synthesen III. Derivate des oxin-
dols. Helvetica Chimica Acta, 6, 467–482. DOI: 10.1002/hlca.
19230060149.
Grant, E. B., Guiadeen, D., Baum, E. Z., Foleno, B. D., Jin, H.,
Montenegro, D. A., Nelson, E. A., Bush, K., & Hlasta, D. J.
(2000). The synthesis and SAR of rhodanines as novel class
C β-lactamase inhibitors. Bioorganic & Medicinal Chemistry
Letters, 10, 2179–2182. DOI: 10.1016/S0960-894X(00)00444-
3.
Hotta, N., Akanuma, Y., Kawamori, R., Matsuoka, K., Oka,
Y., Shichiri, M., Toyota, T., Nakashima, M., Yoshimura, I.,
Sakamoto, N., & Shigeta, Y. (2006). Long-term clinical ef-
fects of Epalrestat, an aldose reductase inhibitor, on diabetic
peripheral neuropathy: The 3-year, multicenter, comparative
aldose reductase inhibitor-diabetes complications trial. Dia-
betes Care, 29, 1538–1544. DOI: 10.2337/dc05-2370.
Hu, Y., Helm, J. S., Chen, L., Ginsberg, C., Gross, B., Kray-
bill, B., Tiyanont, K., Fang, X., Wu, T., & Walker, S. (2004).
Identification of selective inhibitors for the glucosyltrans-
ferase MurG via high-throughput screening. Chemistry &
Biology, 11, 703–711. DOI: 10.1016/j.chembiol.2004.02.024.
Jacquault, P. (1993). Procédé de mesure de la tempéra-
ture d’un échantillon placé dans un récipient d’un appareil
d’application de micro-ondes et appareil mettant en oeuvre
ledit procédé. FR Patent No. FR2685478. Paris, France: In-
stitut National de la Propriété Industrielle.
Johnson, S. L., Chen, L.-H., Harbach, R., Sabet, M., Savinov,
A., Cotton, N. J. H., Strongin, A., Guiney, D., & Pellecchia,
M. (2008). Rhodanine derivatives as selective protease in-
hibitors against bacterial toxins. Chemical Biology & Drug
Design, 71, 131–139. DOI: 10.1111/j.1747-0285.2007.00617.x.
Jones, H. A., & Hann, R. M. (1928). The condensation of
rhodanic acids with 5-nitro-isatin. Rhodanal-∆-5,3ꢀ-5ꢀ-nitro-
oxindoles. Journal of the American Chemical Society, 50,
2491–2493. DOI: 10.1021/ja01396a025.
Sawayama, T., Kinugasa, H., & Nishimura, H. (1976). The
structures of isatylidene 3 mercaptoacetic acid and its re-
lated compounds. Chemical & Pharmaceutical Bulletin, 24,
2305–2311.
Sim, M. M., Ng, S. B., Buss, A. D., Crasta, S. C., Goh, K.
L., & Lee, S. K. (2002). Benzylidene rhodanines as novel in-
hibitors of UDP-N-acetylmuramate/L-alanine ligase. Bioor-
ganic & Medicinal Chemistry Letters, 12, 697–699. DOI:
10.1016/S0960-894X(01)00832-0.
Lanni, T. B., Jr., Greene, K. L., Kolz, C. N., Para, K. S., Vis-
nick, M., Mobley, J. L., Dudley, D. T., Baginski, T. J., &
Liimatta, M. B. (2007). Design and synthesis of phenethyl
benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinaseγ.
Bioorganic and Medicinal Chemistry Letters, 17, 756–760.
DOI: 10.1016/j.bmcl.2006.10.080.
Larhed, M., & Hallberg, A. (2001). Microwave-assisted high-
speed chemistry: a new technique in drug discovery. Drug
Discovery Today, 6, 406–416. DOI: 10.1016/S1359-6446(01)
01735-4.
Sing, W. T., Lee, C. L., Yeo, S. L., Lim, S. P., & Sim, M. M.
(2001). Arylalkylidene rhodanine with bulky and hydropho-
bic functional group as selective HCV NS3 protease inhibitor.

A. Safer et al./Chemical Papers 65 (3) 332–337 (2011)
337
Bioorganic & Medicinal Chemistry Letters, 11, 91–94. DOI:
10.1016/S0960-894X(00)00610-7.
Yang, D.-H., Chen, Z.-C., Chen, S.-Y., & Zheng, Q.-G. (2003). A
convenient synthesis of 5-benzylidenethiazolidine-2,4-diones
under microwave irradiation without solvent. Journal of
Chemical Research, 2003, 330–331. DOI: 10.3184/030823403
103174272.
Zapadnyuk, V. I. (1966). Anticonvulsive drugs, their classifica-
tion and mechanism of action. Vrachebnoe Delo (Kiev), 10,
71–75.
Zapadnyuk, V. I. (1962). The dependence of anticonvulsion ac-
tivity and toxicity of thiohydantoin and rhodanine deriva-
tives on the chemical structure. Farmatsevticheskii Zhurnal
(Kiev), 17, 36–41.
Sortino, M., Delgado, P., Juárez, S., Quiroga, J., Abonía, R., In-
suasty, B., Nogueras, M., Rodero, L., Garibotto, F. M., Enriz,
R. D., & Zacchino, S. A. (2007). Synthesis and antifungal ac-
tivity of (Z)-5-arylidenerhodanines. Bioorganic & Medicinal
Chemistry, 15, 484–494. DOI: 10.1016/j.bmc.2006.09.038.
Swewczuk, L. M., Saldanha, S. A., Ganguly, S., Bowers, E.
M., Javoroncov, M., Karanam, B., Culhane, J. C., Hol-
bert, M. A., Klein, D. C., Abagyan, R., & Cole, P. A.
(2007). De novo discovery of serotonin N-acetyltransferase
inhibitors. Journal of Medicinal Chemistry, 50, 5330–5338.
DOI: 10.1021/jm0706463.
Zawahir, Z., Dayam, R., Deng, J., Pereira, C.,
& Nea-
Turkevich, N. M., Agaev, K. A., Steblyuk, P. N., & Sementsiv,
G. N. (1982). Thiazolidines with adamantyl substituents.
Pharmaceutical Chemistry Journal, 16, 668–670.
Whitesitt, C. A., Simon, R. L., Reel, J. K., Sigmund, S. K.,
Phillips, M. L., Shadle, J. K., Heinz, L. J., Koppel, G. A.,
Hunden, D. C., Lifer, S. L., Berry, D., Ray, J., Little, S. P.,
Liu, X., Marshall, W. S., & Panetta, J. A. (1996). Synthesis
and structure-activity relationships of benzophenones as in-
hibitors of cathepsin D. Bioorganic & Medicinal Chemistry
Letters, 6, 2157–2162. DOI: 10.1016/0960-894X(96)00393-9.
mati, N. (2009). Pharmacophore guided discovery of small-
molecule human apurinic/apyrimidinic endonuclease 1 in-
hibitors. Journal of Medicinal Chemistry, 52, 20–32. DOI:
10.1021/jm800739m.