Rev. Med. Chir. Soc. Med. Nat., Iai 2017 vol. 121, no.

PHARMACY ORIGINAL PAPERS

OPTIMIZATION OF THE SYNTHESIS OF SOME NEW

THIAZOLIDINE-4-ONE DERIVATIVES WITH XANTHINE SCAFFOLD

Sandra Constantin 1, Ioana Vasincu1 , Maria Apotrosoaei1 , Florentina Lupacu1,

Georgiana Tauer1, Luminia Confederat1, Andreea Iacob1, A. Sava1,
F. Buron2, S. Routier2, Lenua Profire1*
Grigore. T. Popa University of Medicine and Pharmacy Iasi
Faculty of Pharmacy
1. Department of Pharmaceutical Chemistry
University of Orlans
2. Institute of Organic and Analytical Chemistry Orlans, France
*Corresponding author. E-mail: lenuta.profire@umfiasi.ro

OPTIMIZATION OF THE SYNTHESIS OF SOME NEW THIAZOLIDINE-4-ONE DE-

RIVATIVES WITH XANTHINE SCAFFOLD (Abstract): In the last time many resear chers
were focused on synthesis of new compounds with thiazolidine-4-one scaffold based on the
important biological effects of this heterocycle. Aim: The aim of this study was to optimize
the synthesis of some new thiazolidine-4-one derivatives with xanthine scaffold in order to
obtain high yields and advanced purity. Material and methods: The synthesis was based on
a cyclization reaction between various hydrazones and thioglycolic acid. The optimization
was performed for 2-(4-methylphenyl)-3-[(1,3-dimethylxanthin-7-yl)acetamido]thiazolidine-
4-one (b) by varying different parameters such as molar ratio between reagents, solvent, ca t-
alyst, temperature, time of reaction and type of method. There were used ten chemistry pr o-
cedures for detecting the desired compound and other ones for establishing the optimal con-
ditions. The optimized method was also applied for other thiazolidine -4-one derivatives with
xanthine structure. Results: The most favorable parameters for optimal synthesis were esta b-
lished as follow: an excess of 20 equivalents of thioglycolic acid to 1 equivalent of hydr a-
zone, freshly distilled toluene as solvent, temperature of 120 C and reflux for 18 hours. The
time and temperature of reaction proved to have a key role for increased yield. Conclusions:
The optimal conditions of reaction were established in order to obtain new thiazolidine -4-
one derivatives in high yields and increased purity. Keywords: THIAZOLIDINE-4-ONE,
XANTHINE, OPTIMIZATION, SYNTHESIS.

In the last period, the interest of many
researchers was directed towards the study
of thiazolidine-4-one derivatives due to the
intense and important biological activity
proved by this heterocycle (1). The studies
proved for this scaffold many biological
effects, such as antidiabetic, antioxidant,
anti-inflammatory, anticancer, antimicrobi-
al, antiviral, anticonvulsant or antihyper-
tensive (2).
This heterocycle is usually found in the
structure of synthetic compounds, but also
it was identified in natural compounds,
such as actithiazic acid (acidomycin) which
was isolated from Streptomyces strains and
proved an intense and specific action on

438
 Optimization of the synthesis of some new thiazolidine-4-one derivatives with xanthine scaffold

Mycobacterium tuberculosis (3). method to different thiazolidine-4-one

In the literature (1) different methods
for the synthesis of thiazolidine-4-one
derivatives are described. The most used
pathway involves three components: an
amine, a carbonylic compound (aldehyde or
cetone) and thioglycolic acid and it can be
performed in one pot (fig. 1) or two steps
(fig. 2).
When the synthesis is performed in two
steps, the first reaction is based on the
condensation between the amine and car-
bonyl compounds, resulting the corre-
sponding imine, which, in the next step, it
will be cyclized in the presence of thiogly-
colic acid (fig. 2). In order to apply this
scaffolds, different parameters were varied
by the researchers, such as: time and tem-
perature of reaction, solvent (dry toluene,
benzene, dioxane, dry tetrahydrofuran,
ethanol, dimethylformamide, polypropyl-
ene glycol (4)), catalyst (silica oxychloride
(5), zinc chloride, N,N'-dicyclohexyl car-
bodiimide (6), 1-ethyl-3-(3-dimethylamino
propyl) carbodiimide,N,N-di-isopropyl-ethyl-
amine (7), N,N,N,N-tetramethyl-O-(1H-
benzotriazol-1-yl)uranium-hexafluoro-phos-
phate(8)), water extraction system (Dean
Stark apparatus), pH (sodium acetate/acetic
acid buffer (9)), methods based on green
chemistry (ultrasounds, molecular sieves).

Fig. 1. One pot synthesis for thiazolidine-4-one derivatives.

Fig. 2. Synthesis in two steps for thiazolidine-4-one derivatives.

The main objective of this study was the
optimization of the synthesis of some new
thiazolidine-4-one derivatives with xan-
thine scaffold, in view of identifying the
optimal conditions of reaction (molecular
ratio between reagents, time, temperature,
solvent, catalyst etc.).
MATERIAL AND METHODS
Reagents. N-(4-Methylbenzylidene)-2-
(1,3-dimethylxanthin-7-yl)acethydrazide
synthetized in our previous paper (10),
thioglycolic acid, organic solvents (freshly
distilled toluene and tetrahydrofuran, dime-
thylformamide - p.a. quality), zinc chlo-

439
 Sandra Constantin et al.

ride, 1-ethyl-3-(3-dimethylamino propyl) reactions and detecting the resulted com-

carbodiimide and molecular sieves were
purchased from Sigma Aldrich Company.
All reagents and solvents were used with-
out previous purification. Thin Layer
Chromatography (TLC) Silica gel 60 F 254
plates produced by Merck Company and
Proton Nuclear Magnetic Resonance ( 1 H-
NMR) spectra were used for monitoring the
pounds. The spectra were obtained in dime-
thyl sulfoxide deuterated (DMSO-d6 ) and
chloroform deuterated (CDCl 3 ), both pro-
duced by Sigma Aldrich Company. Micro-
wave irradiation was carried out in sealed
220 mL vessels placed in a Biotage Initia-
tor system, using a standard absorbance
level (300 W maximum power).

Fig. 3. Synthesis of 2-(4-methylphenyl)-3-[(1,3-dimethylxanthin-7-yl)

acetamido]thiazolidine-4-one (b).

Chemistry. 2-(4-Methylphenyl)-3-[(1,3- The reactions were monitored by TLC

dimethylxanthin-7-yl)acetamido]thiazolidine-
4-one (b) was obtained based on reaction
between N-(4-methylbenzylidene)-2-(1,3-
dimethylxanthin-7-yl)acethydrazide (a) and
thioglycolic acid (fig. 3). The synthesis was
performed by optimization of different
procedures and methods described in the
literature for cyclization between various
hydrazones and thioglycolic acid.
For the optimization of the chemistry
procedure different parameters were varied:
molar ratio between the reagents (1:1;
1:1.55; 1:2; 1:10; 1:15.2; 1:20; 1:24;
1:25.75; 1:27.3), solvent (without solvent
(11), dry toluene, dimethylformamide -
DMFA, dry tetrahydrofuran - THF), tem-
perature (room temperature - 20C, 70C,
100C, 120C, 130C, 140C, 153C, ated with a ratio between compound a and
160C, 180C), time (between 30 min and
62 hours), catalyst (zinc chloride, 1-ethyl-
3-(3-dimethylaminopropyl)carbodiimide),
type of method (classic or microwaves).
using different eluent systems: dichloro-
methane: methanol (9:1; 9.6:0.4; 9.8:0.2),
dichloromethane: acetone (7:3), ethyl ace-
tate, ethyl acetate: acetone (7:3). The struc-
ture of the compound b was proved by
NMR spectra.
RESULTS AND DISCUSSION
Chemistry
By varying different synthesis parame-
ters: ratio between reagents, catalyst, sol-
vent, temperature and time of reaction and
the applied method (classic or microwave),
10 chemistry procedures were developed
(tab. I). Freshly distilled toluene proved to
be the most favorable solvent in synthesis
of compound b. Using this solvent, associ-
thioglycolic acid of 1 eq.:1.55 eq., in mi-
crowave for 40 min, at a temperature of
160 C, the condensation reaction was car-
ried out successfully and compound b was

440
 Optimization of the synthesis of some new thiazolidine-4-one derivatives with xanthine scaffold

detected by NMR spectra. was observed that, as described in our previ-

In the next step the procedure established
for synthesis of compound b was optimized
in order to obtain the compound in high
yields and high-grade purity. The experi-
mented conditions are presented in tab II. It
ous paper (10), the highest yield (52 %) was
obtained after the reaction between 1 eq. of
hydrazone a and 20 eq. of thioglycolic acid,
at a temperature of 120 C, for 18 hours,
using freshly distilled toluene as solvent.

TABLE I
Chemistry procedures applied for synthesis of compound b
Reagents (eq.) Catalyst Time
No. Solvent T (C) Type of method b
a AT (eq.) (min/h)
1. 1 eq. 24 eq. - - 100 30 min MW nd
2. 1 eq. 27.3 eq. - - 130 42 min MW nd
3. 1 eq. 25.75 eq. - - 180 1h MW nd
dry classic + dean stark nd
4. 1 eq. 20 eq. - 140 40 h
toluene (12,13)
ZnCl 2 MW nd
5. 1 eq. 1 eq. DMFA 100 30 min
0.5 eq. (14)
ZnCl 2 28 h, 48 classic nd
6. 1 eq. 1 eq. DMFA 153
0.5 eq. h (15,16)
1 eq.; ZnCl 2 dry classic nd
7. 1 eq. 70 20 h
15.2 eq. (a pinch) THF (17)
ZnCl 2 dry classic, molecular sives nd
8. 1 eq. 1 eq. 20 20h, 40h
(a pinch) THF (18)
EDCI 20 h, 60 classic nd
9. 1 eq. 2 eq. THF 20
1.2 eq. h (19)
dry d
10. 1 eq. 1.55 eq. - 160 40 min MW
toluene
AT = thioglycolic acid; T (C) = temperature; MW = microwave; nd = nondetected; d = detected

TABLE II
Optimization of the synthesis procedure of compound b
Reagents (eq.) Time
No. T (C) Type of method
a AT (min/h) (%)
1. 1 eq. 1.55 eq. 160 40 min MW < 5%
2. 1 eq. 20 eq. 160 156 min MW < 5%
3. 1 eq. 20 eq. 160 2h MW 10,8%
4. 1 eq. 20 eq. 140 45 h classic + dean stark nd
5. 1 eq. 10 eq. 120 18 h classic < 5%
6. 1 eq. 20 eq. 120 62 h classic < 5%
7. 1 eq. 20 eq. 120 37 h classic 47,2%
8. 1 eq. 20 eq. 120 13 h classic 31,4%
9. 1 eq. 20 eq. 120 18 h classic 52%
10. 1 eq. 25 eq. 120 18 h classic 50%
AT= thioglycolic acid; T (C) = temperature; (%) = yield; MW = microwave; nd = nondetected

441
 Sandra Constantin et al.

The results showed also that the micro-
wave method was not favorable for the
synthesis of derivative b, the calculated
yield being less than 11%. On the other
hand for classic method was observed that
the increasing of the temperature was asso-
ciated with the degradation of the com-
pound, the yield being less than 5%. Refer-
ring to the time of reaction, the results
proved that a lower time than 18 hours was
not enough for a total synthesis.
The developed procedure was applied
for the synthesis of other thiazolidine-4-one
derivatives with xanthine scaffold as de-
scribed in our previous paper (10).
CONCLUSIONS
In this study, the synthesis of some new
thiazolidine-4-one derivatives with xan-
thine scaffold was developed by optimiza-
tion of the reaction between N-(4-
methylbenzylidene)-2-(1,3-
dimethylxanthin-7-yl)acethydrazide (a) and
thioglycolic acid in order to obtain 2-(4-
methylphenyl)-3-[(1,3-dimethylxanthin-7-
yl) acetamido]thiazolidine-4-one (b) in
high yield and an increased purity. The
optimization was performed by varying
different reaction parameters such as: mo-
lar ratio between reagents, time and tem-
perature of reaction, solvent, catalyst and
type of method.
ACKNOWLEDGMENTS
This paper was published under the
frame of European Social Found, Human
Resources Development Operational Pro-
gramme 2007-2013, project no.
POSDRU/159/1.5/136893 entitled: Stra-
tegic partnership for increasing the quality
of scientific research in medical universi-
ties through doctoral and postdoctoral
scholarships DocMed.Net_2.0. The
authors thank also the Campus France PHC
Brancusi program project N 38382XK for
financial support.

REFERENCES

1. Bhoi D, Bhoi UA. A complete review of thiazolidine-4-ones. J Pharm Res 2011; 44(77): 24362440.
2. Pandey Y, Sharma PK, Kumar N, Singh A. Biolgical activities of thiazolidine - A review. Int J
PharmTech Res 2011; 3(2): 980985.
3. Rajput AP, Gore RP. Synthesis, characterization and antimicrobial screening of some novel 2-(1H-
azol-1-yl)-N-(-2- (substituted phenyl)-4-oxothiazolidin-3-yl) acetamide. Int J ChemTech Res 2012;
4(3): 12121217.
4. Prasad D, Kumar A, Shukla PK, Nath M. Design, synthesis and antimicrobial evaluation of novel 2-
aryl-thiazolidin-4-one derivatives. Org Med Chem Lett 2011; 1: 410.
5. Mali JR, Pratap UR, Netankar PD, Mane RA. An efficient synthetic route for quinazolinyl 4-
thiazolidinones. Tetrahedron Lett 2009; 50: 50255027.
6. Srivastava T, Haq W, Katti SB. Carbodiimide mediated synthesis of 4-thiazolidinones by one-pot
three-component condensation. Tetrahedron 2002; 58: 76197624.
7. Apotrosoaei M, Vasincu I, Constantin S, Buron F, Routier S, Profire L. Synthesis, characterization
and antioxidant activity of some new thiazolidin-4-one derivatives. Rev Med Chir Soc Med Nat (Med
Surg J) 2014; 118(1): 213218.
8. Verma A, Saraf SK. 4-Thiazolidinone - A biologically active scaffold. Eur J Med Chem 2008; 43(5):
897905.
9. Pathak RB, Chovatia PT, Parekh HH. Synthesis, antitubercular and antimicrobial evaluation of 3-(4-
chlorophenyl)-4-substituted pyrazole derivatives. Bioorg Med Chem Lett 2012; 22: 51295133.

442
 Optimization of the synthesis of some new thiazolidine-4-one derivatives with xanthine scaffold

10. Constantin S, Lupascu FG et al. Synthesis and biological evaluation of the new 1,3-dimethylxanthine
derivatives with thiazolidine-4-one scaffold. Chem Cent J 2017; 11: 1225.
11. Vasincu I, Apotrosoaei M, Panzariu A, Buron F, Routier S, Profire L. Development and optimization
of the synthesis of new thiazolidin-4-one derivatives of ibuprofen. Rev Med Chir Soc Med Nat (Med
Surg J) 2014; 118(1): 219224.
12. Murugesan V, Makwana N et al. Rational design and synthesis of novel thiazolidin-4-ones as non-
nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg Med Chem 2014; 22(12): 31593170.
13. kla P, zsavc D et al. Synthesis, cytotoxicity, and pro-apoptosis activity of etodolac hydrazide
derivatives as anticancer agents. Arch Pharm 2013; 346: 367379.
14. Nikalje APG, Khan FK, Ghodke M. Design and synthesis of 2-(1, 3-dioxoisoindolin-2-yl)-N-(4-oxo-
2- substitutedthiazolidin-3-yl) acetamide derivatives as potential anticonvulsant agents. Eur J Med
Chem 2011; 46(11): 54485455.
15. Cacic M, Molnar M, Balic T, Draca N, Rajkovic V. Design and synthesis of some thiazolidin-4-ones
based on (7-hydroxy-2-oxo-2H-chromen-4-yl) acetic acid. Molecules 2009; 14(7): 25012513.
16. Shingalapur R V, Hosamani KM, Keri RS, Hugar MH. Derivatives of benzimidazole pharmacophore:
Synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. Eur J Med Chem 2010; 45(5):
17531759.
17. Patel HS, Patel SJ. Synthesis and Biological Activity of 2-Hydroxy-N(5-methylene-4-oxo-2-aryl-
thiazolidin-3-yl)-benzamide. Phosphorus Sulfur Silicon Relat Elem 2010; 185:16321639.
18. Thomas AB, Sharma PA et al. Green route synthesis of 4-thiazolidinone analogs of isonicotinic acid
hydrazide. Green Chem Lett Rev 2011; 4(3): 211217.
19. Rane RA, Sahu NU, Shah CP. Synthesis and antibiofilm activity of marine natural product-based 4-
thiazolidinones derivatives. Bioorg Med Chem Lett 2012; 22: 71317134.

NOUTI
NEWS

THE DIAGNOSTIC CONCORDANCE OF WHOLE SLIDE IMAGING

AND LIGHT MICROSCOPY A SYSTEMATIC REVIEW

Traditionally, light microscopy (LM) has been the reference method used in anatomic pa-
thology in the diagnosis of many diseases. However, advances in digital imaging hardware
and software have led to the development of whole slide imaging (WSI) devices. These de-
vices allow the digital capture, analysis, storage, sharing, and viewing of whole slide pathol-
ogy images. Digital pathology evolved as a practical technology in the 1980s with the deve l-
opment of telepathology technology. Initially, telepathology existed in 2 forms: static-
image telepathology and dynamic robotic telepathology. Static-image telepathology involved
the transmission of preselected regions of microscopy images. Dynamic robotic telepathol o-
gy enabled realtime image alterations by granting a remote user control of the microscope.
Since these 2 initial telepathology technologies, more than 12 types of telepathology systems
have evolved. Whole slide imaging is the latest technology used in digital pathology
(Goacher E, Randell R, Williams B, Treanor D. The Diagnostic Concordance of Whole Slide
Imaging and Light Microscopy a Systematic Review. Arch Pathol Lab Med. 2017; 141:151
161).

Doina Butcovan

443