j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 1 0 7 e1 1 1

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Original Article

Synthesis and in silico drug likeness evaluation

of N,5-disubstituted-1,3-thiazolidine-2,4-dione analogues

Naraparaju Swathi a,b,*, Thirumurthy Durai Ananda Kumar c,

Chavali Venkata Satya Subrahmanyam d, Kota Satyanarayana e
a
Sr. Assistant Professor, Dept of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Hyderabad 500 090, Andhra Pradesh,
India
b
Research and Development Cell, Jawaharlal Nehru Technological University, Hyderabad 500 072, Andhra Pradesh, India
c
Dept of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Hyderabad 500 090, Andhra Pradesh, India
d
Faculty of Pharmacy, Osmania University, Hyderabad 500 007, Andhra Pradesh, India
e
Natco Pharma Ltd., R & D, Sanath Nagar, Hyderabad 500 080, Andhra Pradesh, India

article info abstract

Article history: A series of N,5-disubstituted-1,3-thiazolidine-2,4-dione analogues (3aeh, 4aeh) were

Received 21 August 2012
Accepted 8 November 2012
Keywords:
Thiazolidine-2,4-dione
Knoevenagel condensation
DeaneStark apparatus
Topological polar surface area
prepared by knoevenagel condensation of various aromatic aldehydes with N-substituted-
1,3-thiazolidine-2,4-diones in toluene. The structures of the synthesized compounds were
established based on the IR, 1H NMR, Mass and elemental analysis data. Drug likeness of
the synthesized molecules were evaluated using online Molinspiration web JME Editor and
OSIRIS Property Explorer and were found to obey rule of thumb.
Copyright ª 2012, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights
reserved.

1. Introduction systems of therapeutic importance has been extensively

The Knoevenagel condensation is a nucleophilic addition of an
active hydrogen compound to a carbonyl group under basic
conditions.1,2 Several solid phases, solvent free organic
syntheses and various other green chemistry approaches
utilizing the same reaction have been reported in the liter-
ature.3e6 Many drugs such as lipid lowering atorvastatin,7
thiazolidine-2,4-dione class of antidiabetic agent, pioglitazone
use Knoevenagel reaction during their syntheses.8 Thiazoli-
dine-2,4-dione (TZD), one of the most important heterocyclic
studied for wide range of biological activities such as anti-dia-
betic,9 anti-inflammatory,10 anti-oxidant,11 anti-tubercular,12
anti-microbial,13 anticonvulsant14 and cytotoxic activities.15 In
light of above facts, as a part of our ongoing research on thia-
zolidine-2,4-dione analogues we made an attempt to synthesis
few N,5-disubstituted-1,3-thiazolidine-2,4-dione analogues
(3aeh, 4aeh). The synthesized compounds were evaluated for
the obeyance of Lipinski parameters (RO5), topological polar
surface area (TPSA), molar volume (MV), number of rotatable
bonds (RB), absorption percentage (% ABS) and drug score.16,17

* Corresponding author.
E-mail address: swa.pharma@gmail.com (N. Swathi).
0974-6943/$ e see front matter Copyright ª 2012, JPR Solutions; Published by Reed Elsevier India Pvt. Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jopr.2012.11.023
108 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 1 0 7 e1 1 1

2. Results and discussion Table 1 e Analytical data of compounds 3aeh, 4aeh.

Compd m. r. Yield Compd m. r. Yield
2.1. Chemistry code ( C) (%) code ( C) (%)

3a 184e186 74 4a 188e189 89
A series of N,5-disubstituted-1,3-thiazolidine-2,4-dione 3b 216e217 85 4b 194e196 78
derivatives (3aeh, 4aeh) were designed and synthesized 3c 240e242 48 4c 218e220 64
according to Scheme 1. The starting compound 1,3- 3d 221e222 71 4d 208e209 92
thiazolidine-2,4-dione (1) and the N-substituted-1,3- 3e 260e261 83 4e 248e250 68
3f 194e195 76 4f 176e177 76
thiazolidine-2,4-diones (2a, 2b) were prepared by literature
3g 211e212 72 4g 198e199 73
method with modification.18,19 The compounds 2a, 2b were
3h 190e191 69 4h 186e188 80
prepared by the reaction of methoxy phenacyl bromide/
substituted benzyl halide with 1,3-thiazolidine-2,4-dione in m. r.: melting range.
ethanolic KOH. The initial potassium salt formation was
ensured by the drop wise addition of KOH solution to the
ethanolic thiazolidine-2,4-dione (1) and stirring at rt for 2.2. Spectral analysis
15 min, which on subsequent addition of methoxy phenacyl
bromide/p-nitro benzyl bromide afforded N-substituted-1,3- The structures of the synthesized compounds were estab-
thiazolidine-2,4-dione analogues (2a, 2b). The TLC support lished based on spectral data analysis. The following obser-
for qualitative analysis was utilized and the reaction was vations are few among them: Aromatic CH stretching
found completed after 6 h of reflux with stirring. The pure vibrations at 2841e3120 cm
1, the two ketones of the dione
compounds were isolated by column chromatography. Modi- system were observed at 1602e1775 cm
1 in the IR spectrum,
fications in the reaction conditions such as performing appearance of eOH protons at d 8.9e9.3, aromatic protons at
a single step reaction for the formation of potassium salt and d 7.05e8.4, benzylidene (]CH) protons at d 7.78e8.1, methoxy
the subsequent N-alkylation rather than in two steps and (eOCH3) protons at d 3.54e3.83 and methyl (eCH3) protons at
controlled stirring before and after the addition of alkyl halide, 2.9e3.0 in 1H NMR spectrum of the synthesized compounds.
influences the reaction time and drastically decreased it to 6 h The absence of characteristic eNH peak of 1,3-thiazolidine-
when compared with the literature method.20 2,4-dione at 3200 cm
1 in IR spectra and a signal at d 12 in 1H
Further synthetic investigation as mentioned in Scheme 1 NMR confirmed the N-alkylation of 1,3-thiazolidine-2,4-dione.
is performed with N-substituted-1,3-thiazolidine-2,4-diones It was further evidenced by the appearance of molecular ion
(2a, 2b). Knoevenagel condensation of various aromatic alde- peak at m/z 265 and m/z 252 for compounds 2b and 2c
hydes with N-sustituted-1,3-thiazolidine-2,4-diones afforded respectively. Disappearance of methylene (CH2) protons at
sixteen N,5-disubstituted-1,3-thiazolidine-2,4-diones (3aeh d 4.14 and appearance of benzylidene (]CH) proton in the
and 4aeh). The carbanion formation, prerequisite for the range of d 7.34e8.0 in 1H NMR spectrum clearly indicate the
knoevenagel condensation reaction is ensured by the use of occurrence of knoevenagel condensation of aryl aldehydes
piperidine as base, while removal of water is ensured by with N-substituted-1,3-thiazolidine-2,4-diones. Molecular ion
DeaneStark apparatus.20 The compounds 4d, 4a, 3b and 3e peaks at m/z 353, m/z 388, m/z 374 and m/z 370 for compound
were obtained with 92%, 87%, 85% and 83% yield (Table 1). 3a, 3b, 4b and 4d respectively and the elemental data of

O O CHO O
1 1
R R
NH N N
R1-X R2
Ethanol, KOH Toluene, Piperidine
S O Reflux, 6 h S O Reflux, 6 h S
O
1,3-Thiazolidine- N-substituted-1,3-thiazolidine-2,4- N,5-disubstituted-1,3-thiazolidine-
-2,4 dione (1) diones (2a, 2b) 2,4-diones (3a-h, 4a-h)
R2
R2=
3a-h: R1= 4-OCH3-C6H4 - CO-CH2-
a:4H
4a-h: R1= 4-NO2-C6H5-CH2- b:4Cl
c:4NO2
d:4OCH3
e:4NMe2
f :4OH
g:4OH, 3OCH3
h:3,4OCH3

Scheme 1 e Synthetic pathway of N,5-disubstituted-1,3-thiazolidine-2,4-dione analogues.

 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 1 0 7 e1 1 1 109

compounds further confirmed the structures of the titled
compounds.
2.3. Drug like properties
Molinspiration web JME Editor21 and OSIRIS Property
Explorer22 were utilized to explore drug like properties of the
synthesized compounds. Evaluation of the synthetic
compounds for RO5 revealed that all the molecular descrip-
tors are in compliance with the rule of thumb. The TPSA, MV
and RB explains the intestinal absorption and pharmacody-
namic nature of the molecules in biophase.23 All the
compounds showed a TPSA value less than 140 Å2, indicating
their possible good permeability of the compounds in the
cellular membranes. The absorption percentage (% ABS) was
calculated according to Zhao et al.24 and were in the range of
63.9e86.44 % (Table 2). All the synthesized compounds have
a positive drug-likeness score ranging from 1.06 to 7.41. The
drug score is a cumulative term used to assess the potential of
the new drug candidates, which combines drug likeness, lip-
ophilicity, solubility, molecular weight and the risk of toxicity
into a single numerical value. A positive drug score indicates
the predominance of the pharmacophoric moieties in the
molecule. All the synthesized molecules showed a positive
value in the drug score calculation and were in the range of
0.22e0.44 for compounds 3aeh and 0.16e0.25 for compounds
4aeh.
3. Experimental
All the chemicals were procured from Merck, Sd fine-chem Ltd
and Himedia Pvt. Ltd. All the solvents and starting materials
were purified by standard methods. Melting points were
determined in DBK melting point apparatus, expressed in  C
and are uncorrected. Schimadzu digital balance, REMI
magnetic stirrer for the synthesis and hot air oven of Biotech
company for drying were used. Analytical thin layer chro-
matography (TLC) was performed on silica gel 60 plates
(Merck) and was visualized by using UV light and staining with
iodine. The IR spectrum was run on Shimadzu IR affinity 1
spectrophotometer, 1H NMR (DMSO, d ppm) was on Advance
300 MHz spectrophotometer and Mass spectra were recorded
on Shimadzu QP2010 PLUS GC-Mass spectrometer. Drug like-
ness parameters were calculated by using Molinspiration web
JME Editor and OSIRIS Property Explorer.
3.1. Synthesis of N-substituted-1,3-thiazolidine-2,4-
diones (2aeb)
A solution of potassium hydroxide in ethanol (4.2 mM) was
added drop wise to suspension of 1,3-thiazolidine-2,4-dione
(1, 4.2 mM) in ethanol. The mixture was stirred at rt for
15e20 min and then p-methoxy phenacyl bromide/p-nitro
benzyl bromide/(4.2 mM) was added. The reaction mixture
was refluxed with stirring for 6 h. The progression and
completion of the reaction is monitored by TLC. The crude
product was separated by filtration, washed with water and
diethyl ether. The compounds were purified by recrystalliza-
tion with ethanol.
N-[2-(4-methoxyphenyl)-2-oxoethyl]-1,3-thiazolidine-2,4-dione
(2a): White crystals, Yield 72%; m.p. 104e106  C; IR (KBr, cm
1):
3097, 1749, 1685, 1510, 1236, 680. 1H NMR (300 MHz, DMSO-d6,
d ppm): 8.0 (m, 2H, Ar), 7.05 (m, 2H, Ar), 5.1 (s, 2H, CH2), 4.5 (s,
2H, CH2), 3.85 (s, 3H, OCH3). MS (ESI, m/z): 265 (Mþ). Anal. Calcd.
for C12H11NO4S: C 54.33, H 4.18, N 5.28. Found: C 54.16, H 4.11, N
5.17.
N-(4-nitrobenzyl)-1,3-thiazolidine-2,4-dione (2b): White crys-
tals, Yield 75%; m.p. 115e116  C (Ref. 19, 117e118  C); IR (KBr,
cm
1): 3001, 1757, 1668, 1510, 1224, 734. 1H NMR (300 MHz,
DMSO-d6, d ppm): 8.2 (m, 2H, Ar), 7.5 (m, 2H, Ar), 4.8 (s, 2H,
CH2), 4.25 (s, 2H, CH2). Anal. calcd. for C10H8N2O4S: C 47.61, H

Table 2 e Drug-likeness data of compounds 3aeh, 4aeh.

Compd code RO5 descriptors TPSA (
A2) MV (
A3) RB % ABS Drug-likeness Drug score

M. Wt. HBA HBD Log P

3a 353.39 5 0 2.7 65.38 302.24 5 86.44 4.56 0.43

3b 388.84 5 0 3.43 65.38 315.77 5 86.44 6.19 0.36
3c 398.39 8 0 2.71 111.21 325.57 6 70.63 4.15 0.23
3d 383.42 6 0 2.81 74.62 327.78 6 83.26 5.48 0.42
3e 396.45 6 0 2.86 68.62 348.14 6 85.33 1.06 0.22
3f 369.39 6 1 2.28 85.61 310 5 79.46 5.68 0.27
3g 399.42 7 1 2.09 94.84 335.80 6 76.28 6.08 0.44
3h 413.44 7 0 2.40 83.85 353.33 7 80.07 7.41 0.41
4a 340.35 6 0 3.10 84.9 281.04 4 79.71 3.58 0.25
4b 374.79 6 0 3.78 84.9 294.58 4 79.71 5.26 0.2
4c 385.35 9 0 3.06 130.72 304.38 5 63.9 3.36 0.21
4d 370.37 7 0 3.16 94.13 306.59 5 76.53 4.7 0.24
4e 383.42 7 0 3.21 88.14 326.95 5 78.59 0.13 0.18
4f 356.35 7 1 2.63 105.13 289.06 4 72.73 4.7 0.16
4g 386.37 8 1 2.44 114.36 314.61 5 69.55 5.18 0.25
4h 400.41 8 0 2.75 103.37 332.13 6 73.34 6.57 0.24

M. Wt: molecular weight; HBA: hydrogen bond acceptor; HBD: hydrogen bond donors; TPSA: topological polar surface area; MV: molecular
volume; RB: rotatable bonds; % ABS: absorption percentage.
110 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 1 0 7 e1 1 1
3.2, N 11.11. Found: C 47.37, H 3.12, N 11.09. MS (ESI,
m/z):252 (Mþ).
3.2. Synthesis of N,5-disubstituted-1,3-thiazolidine 2,4-
diones (3aeh, 4aeh)
Equimolar amounts of substituted aryl aldehydes and N-[p-
nitro benzyl/2-(4-methoxyphenyl)-2-oxoethyl]-1,3-thiazolidine
2,4-diones (2) were suspended in 100 ml flat bottom flask con-
taining toluene and catalytic amount of piperidine. The flask is
connected to DeaneStark apparatus fitted with calcium guard
tube and refluxed with stirring for 6 h. The product precipitated
out on cooling was filtered under vacuum and washed with
mixture of cold dry toluene and dry ethanol (1:1). The progres-
sion and completion of the reaction was monitored by TLC and
data recorded in Table 1.
5-(Benzylidene)-N-[2-(4-methoxyphenyl)-2-oxoethyl]-1,3-
thiazolidine-2,4-dione (3a): Pale yellow crystals, IR (KBr, cm
1):
3120, 1686, 1604, 1400, 1205, 654. 1H NMR (300 MHz, DMSO-d6,
d ppm): 7.07e8.1 (m, 9H, Ar), 8.0 (s, 1H, ]CH), 5.2 (s, 2H, CH2),
3.85 (s, 3H, OCH3). MS (ESI, m/z):353 (Mþ). Anal. calcd. for
C19H15NO4S: C 64.58, H 4.28, N 3.96. Found: C 64.32, H 4.15,
N 3.77.
5-(4-Chlorobenzylidene)-N-[2-(4-methoxyphenyl)-2-oxoethyl]-
1,3-thiazolidine-2,4-dione (3b): Pale yellow crystals, IR (KBr,
cm
1): 3088, 1741, 1602, 1323, 1194, 740, 657. 1H NMR (300 MHz,
DMSO-d6, d ppm): 7.1e8.15 (m, 8H, Ar), 7.9 (s, 1H, ]CH), 4.9 (s,
2H, CH2), 3.9 (s, 3H, OCH3). MS (ESI, m/z): 388 (Mþ). Anal. calcd.
for C19H14ClNO4S: C 58.84, H 3.64, N 3.61. Found: C 58.63, H 3.41,
N 3.44.
N-[2-(4-Methoxyphenyl)-2-oxoethyl]-5-(4-nitrobenzylidene)-1,3-
thiazolidine-2,4-dione (3c): Yellow solid, IR (KBr, cm
1): 3020,
1732, 1678, 1573, 1265, 1214, 674. 1H NMR (300 MHz, DMSO-d6,
d ppm): 7.1e8.4 (m, 8H, Ar), 8.03 (s, 1H, ]CH), 4.78 (s, 2H, CH2),
3.7 (s, 3H, OCH3). Anal. calcd. for C19H14N2O6S: C 57.28, H 3.54,
N 7.03. Found: C 57.13, H 3.28, N 6.89.
5-(4-Methoxybenzylidene)-N-[2-(4-methoxyphenyl)-2-oxoethyl]-
1,3-thiazolidine-2,4-dione (3d): Pale yellow solid, IR (KBr, cm
1):
2985, 1741, 1681, 1436, 1174, 685. 1H NMR (300 MHz, DMSO-d6,
d ppm): 7.08e8.1 (m, 8H, Ar), 7.95 (s, 1H, ]CH), 5.23 (s, 2H, CH2),
3.8 (s, 6H, OCH3). Anal. calcd. for C20H17NO5S: C 62.65, H 4.47, N
3.65, O 20.86. Found: C 62.51, H 4.22, N 3.27, O 20.51.
5-(4-N,N-Dimethylbenzylidene)-N-[2-(4-methoxyphenyl)-2-
oxoethyl]-1,3-thiazolidine-2,4-dione (3e): Yellow solid, IR (KBr,
cm
1): 2978, 1716, 1660, 1506, 1365, 1167, 664. 1H NMR
(300 MHz, DMSO-d6, d ppm): 7.5e8.08 (m, 8H, Ar), 8.03 (s, 1H, ]
CH), 5.1 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 3.0 (s, 6H, CH3). Anal.
calcd. for C21H20N2O4S: C 63.62, H 5.08, N 7.07. Found: C 63.56,
H 5.03, N 6.98.
5-(4-Hydroxybenzylidene)-N-[2-(4-methoxyphenyl)-2-oxoethyl]-
1,3-thiazolidine-2,4-dione (3f): Pale yellow solid, IR (KBr, cm
1):
3031, 1734, 1632, 1463, 1408, 1183, 633. 1H NMR (300 MHz,
DMSO-d6, d ppm): 9.3 (s, 1H, OH), 7.7e8.2 (m, 8H, Ar), 8.1 (s, 1H,
]CH), 5.05 (s, 2H, CH2), 3.78 (s, 3H, OCH3). Anal. calcd. for
C19H15NO5S: C 61.78, H 4.09, N 3.79. Found: C 61.88, H 3.97,
N 3.66.
5-(4-Hydroxy-3-methoxybenzylidene)-N-[2-(4-methoxyphenyl)
-2-oxoethyl]-1,3-thiazolidine-2,4-dione (3g): Pale yellow solid, IR
(KBr, cm
1): 3012, 1732, 1638, 1465, 1408, 1194, 1189, 634. 1H
NMR (300 MHz, DMSO-d6, d ppm): 9.4 (s, 1H, OH), 7.5e8.1 (m,
8H, Ar), 7.9 (s, 1H, ]CH), 4.9 (s, 2H, CH2), 3.54 (s, 6H, OCH3).
Anal. calcd. for C20H17NO6S: C 60.14, H 4.29, N 3.51. Found: C
60.02, H 4.17, N 3.44.
5-(3,4-Dimethoxybenzylidene)-N-[2-(4-methoxyphenyl)-2-
oxoethyl]-1,3-thiazolidine-2,4-dione (3h): Pale yellow crystals, IR
(KBr, cm
1): 3031, 1775, 1656, 1451, 1202, 1156, 645. 1H NMR
(300 MHz, DMSO-d6, d ppm): 7.65e8.2 (m, 8H, Ar), 7.8 (s, 1H, ]
CH), 5.3 (s, 2H, CH2), 3.72 (s, 9H, OCH3). Anal. calcd. for
C21H19NO6S: C 61.01, H 4.63, N 3.39. Found: C 60.87, H 4.44,
N 3.19.
5-(Benzylidene)-N-(4-nitrobenzyl)-1,3-thiazolidine-2,4-dione
(4a): Beige colour solid, IR (KBr, cm
1): 3113, 1737, 1660, 1524,
1417, 692. 1H NMR (300 MHz, DMSO-d6, d ppm): 7.2e8.1 (m, 9H,
Ar), 8.04 (s, 1H, ]CH), 5.1 (s, 2H, CH2). Anal. calcd. for
C17H12N2O4S: C 59.99, H 3.55, N 8.23. Found: C 59.78, H 3.46,
N 8.11.
5-(4-Chlorobenzylidene)-N-(4-nitrobenzyl)-1,3-thiazolidine-2,4-
dione (4b): Pale yellow crystals, IR (KBr, cm
1): 3034, 1735, 1680,
1545, 1282, 1401, 756, 697. 1H NMR (300 MHz, DMSO-d6, d ppm):
7.5e8.3 (m, 8H, Ar), 7.98 (s, 1H, ]CH), 4.95 (s, 2H, CH2). MS (ESI,
m/z):374 (Mþ). Anal. calcd. for C17H11ClN2O4S: C 54.48, H 2.96, N
7.47, O 17.08. Found: C 54.23, H 2.65, N 7.22, O 17.01.
N-(4-Nitrobenzyl)-5-(4-nitrobenzylidene)-1,3-thiazolidine-2,4-
dione (4c): Half-white crystals, IR (KBr, cm
1): 3028, 1698, 1632,
1538, 1505, 1431, 638. 1H NMR (300 MHz, DMSO-d6, d ppm):
7.1e8.1 (m, 8H, Ar), 7.8 (s, 1H, ]CH), 4.85 (s, 2H, CH2). Anal.
calcd. for C17H11N3O6S: C 52.99, H 2.88, N 10.9. Found: C 52.79,
H 2.75, N 10.76.
5-(4-Methoxybenzylidene)-N-(4-nitrobenzyl)-1,3-thiazolidine-
2,4-dione (4d): Half-white solid, IR (KBr, cm
1): 2841, 1737, 1683,
1506, 1407, 1184, 702. 1H NMR (300 MHz, DMSO-d6, d ppm):
7.08e8.25 (m, 8H, Ar), 7.9 (s, 1H, ]CH), 4.95 (s, 2H, CH2), 3.81 (s,
3H, OCH3). MS (ESI, m/z): 370 (Mþ). Anal. calcd. for C18H14N2O5S:
C 58.37, H 3.81, N 7.56. Found: C 58.62, H 3.78, N 7.24.
5-(4-N,N-Dimethylbenzylidene)-N-(4-nitrobenzyl)-1,3-
thiazolidine-2,4-dione (4e): Yellowish orange solid, IR (KBr,
cm
1): 3007, 1732, 1681, 1508, 1342, 1303, 698. 1H NMR
(300 MHz, DMSO-d6, d ppm): 7.3e8.2 (m, 8H, Ar), 7.78 (s, 1H, ]
CH), 4.8 (s, 2H, CH2), 2.9 (s, 6H, CH3). Anal. calcd. for
C19H17N3O4S: C 59.52, H 4.47, N 10.96. Found: C 59.46, H 4.23,
N 10.85.
5-(4-Hydroxybenzylidene)-N-(4-nitrobenzyl)-1,3-thiazolidine-
2,4-dione (4f): Pale yellow solid, IR (KBr, cm
1): 3004, 1752, 1630,
1518, 1431, 1377, 638. 1H NMR (300 MHz, DMSO-d6, d ppm): 8.9
(s, 1H, OH), 7.3e8.0 (m, 8H, Ar), 7.9 (s, 1H, ]CH), 5.2 (s, 2H, CH2).
Anal. calcd. for C17H12N2O5S: C 57.3, H 3.39, N 7.86. Found: C
57.12, H 3.18, N 7.67.
5-(4-Hydroxy-3-methoxybenzylidene)-N-(4-nitrobenzyl)-1,3-
thiazolidine-2,4-dione (4g): Pale yellow solid, IR (KBr, cm
1):
2943, 1728, 1660, 1278, 1508, 1456, 1356, 693. 1H NMR (300 MHz,
DMSO-d6, d ppm): 9.03 (s, 1H, OH), 7.5e8.1 (m, 8H, Ar), 7.9 (s, 1H,
]CH), 4.8 (s, 2H, CH2), 3.7 (s, 3H, OCH3). Anal. calcd. for
C18H14N2O6S: C 55.95, H 3.65, N 7.25. Found: C 55.81, H 3.44,
N 7.13.
5-(3,4-Dimethoxybenzylidene)-N-(4-nitrobenzyl)-1,3-
thiazolidine-2,4-dione (4h): Pale yellow solid, IR (KBr, cm
1):
2996, 1698, 1633, 1553, 1411, 1163, 686. 1H NMR (300 MHz,
DMSO-d6, d ppm): 7.2e8.05 (m, 8H, Ar), 7.94 (s, 1H, ]CH), 4.9 (s,
2H, CH2), 3.83 (s, 6H, OCH3). Anal. calcd. for C19H16N2O6S: C
56.99, H 4.03, N 7. Found: C 56.89, H 4.01, N 6.94.
 j o u r n a l o f p h a r m a c y r e s e a r c h 6 ( 2 0 1 3 ) 1 0 7 e1 1 1
3.3. Drug likeness properties
The Lipinski (RO5) parameters, topological polar surface area
(TPSA), molar volume (MV) and rotatable bonds (RB) were
calculated using Molinspiration web JME editor. According to
RO5, the molecules show good oral absorption when the values
of M. Wt. <500, calculated Log P (cLog P) <5, HBD <5 and HBA
<10. The absorption percentage (% ABS) was calculated accord-
ing to Zhao et al. using the formula % ABS ¼ 109
(0.345*TPSA).
4. Conclusion
A series of 1,3-thiazolidine-2,4-dione analogues with a combi-
nation of substituents at N3- and 5-positions were synthesized
by making use of knoevenagel reaction. The characteristic eNH
peak was absent in the respective IR and 1H NMR spectrums of
the synthesized compounds and presence of benzylidene (]
CH) peak in the range of d 7.9e8.0 in the 1H NMR spectrum
confirmed the knoevenagel condensation of different aromatic
aldehydes with N-substituted-1,3-thiazolidine-2,4-diones. The
structures of the compounds were also established by mass
spectra and elemental analysis. As expected, all the synthe-
sized compounds were obeying the RO5, which explains their
possible oral absorption. The values of TPSA and the positive
drug score indicate that the compounds have potential to be
new drug candidates. Synthesis of few more analogues of
similar kind, exploring their biological activities and prediction
of their SAR is under investigation.
Conflicts of interest
All authors have none to declare.
Acknowledgments
The author NS is thankful to Gokaraju Rangaraju Educational
Society (GRES) for providing necessary laboratory facilities.
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