Synthesis and antidiabetic evaluation of 5-(2-methoxy-6-pentadecylbenzylidene)-3-alkyl/aryl substituted thiazolidine-2, 4-dione derivatives

Article abstract of DOI:10.14233/ajchem.2018.21168

Compounds containing the thiazolidinedione moiety have been found to exhibit various pharmacological and biological activities viz., COX-2 inhibitor, antihyperglycemic, anti-inflammatory, antioxidant, cytotoxic, antimicrobial etc. The present paper descri

Full text of DOI:10.14233/ajchem.2018.21168

Asian Journal of Chemistry; Vol. 30, No. 6 (2018), 1231-1236
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21168
Synthesis and Antidiabetic Evaluation of 5-(2-Methoxy-6-pentadecylbenzylidene)-3-alkyl/aryl
substituted thiazolidine-2,4-dione Derivatives
3
M. UPENDAR REDDY1,2,* and M.C. SOMASEKHARA REDDY
1Department of Chemistry, Rayalaseema University, Kurnool-518 007, India
2Dr. J.C.R. Bio, Plot No. 79/80, Survey No-12, Chengicherla Village, Cherlapalli Phase III Industrial Park, Hyderabad-500 039, India
3Department of Basic Sciences, G.P.R. Engineering College (Autonomous), Kurnool-518 007, India
*Corresponding author: E-mail: upendram2509@gmail.com
Received: 5 December 2017;
Accepted: 16 January 2018;
Published online: 30 April 2018;
AJC-18871
Compounds containing the thiazolidinedione moiety have been found to exhibit various pharmacological and biological activities viz.,
COX-2 inhibitor, antihyperglycemic, anti-inflammatory, antioxidant, cytotoxic, antimicrobial etc. The present paper describes the synthesis
of 5-(2-methoxy-6-pentadecylbenzylidene)-3-alkyl/aryl-substituted thiazolidine-2,4-dione derivatives (6a-6k) in five synthetic steps utilizing
anacardic acid as starting material. The key steps involves (i) methylation of anacardic acid in presence of dimethyl carbonate in sealed
tube (ii) methylester reduction in presence of sodium borohydride in refluxing 2-methyl-tetrahydrofuran (iii) oxidation of 1° alcohol in
presence of CuBr, 2,2-bipyridine, TEMPO (iv) Condensation reaction of aldehyde with thiazolidinedione followed by alkylation. The newly
synthesized 3-substituted N-alkyl/aryl-thiazolidine derivative were evaluated for antidiabetic property (alloxan induced diabetic mice),
compounds 6a, 6b, 6c showed significant decrease in fasting blood glucose (FBG) levels (when compared to standard drug with insulin).
Keywords: Anacardic acid, Dimethyl carbonate, Thiazolidine-2,4-dione, Synthesis.
protective [15], antiproliferative [16], antitumor [17], MurD
ligase inhibitor [18], monoamine oxidase B (MAO-B) inhibitor
[19], antimalarial [20] and chemotherapeutic activities [21].
Anacardic acid (Fig. 1), a major component of natural
cashew nut shell liquid (CNSL), has attracted great research
interest due to its biological activities such as antitumor, anti-
oxidant, gastro-protective and antibiotic. In addition, it has
been used as a synthon for the production of a variety of
biologically active compounds with increased efficiency and
some of them out perform their corresponding standard
material [22]. Besides the biological activities, anacardic acid
has rece-ntly been found to be a potential candidate as a
capping agent for the development of nanomaterials [23,24].
INTRODUCTION
Diabetes mellitus is a heterogenous group of disorder,
characterized by a state of chronic hyperglycemia, ensuing
from a diversity of etiologies either environmental and genetics,
acting jointly [1]. Characteristically, diabetes is a long term
metabolic disorder with a number of complication including
cardiovascular, renal, neurological, ocular and other such
consistent problems [1]. Diabetes mellitus is one of the major
health problems in the world today. The incidence of the
disease currently is estimated to reach 300 million by the year
2025. Most cases will be of Type 2 diabetes mellitus, which
sturdily connected with a sedentary life style and obesity [2].
During the last decades substituted thiazolidinediones received
attention in the field of diabetes. Several thiazolidinediones
serve as basic pharmacophore for various biological profiles
i.e. antidiabetic, anticancer [3], antimalarial [4], aldose
reductase [5] and anti-inflammatory [6], etc.
OH
O
OH
Thiazolidinedione scaffold has been recognized to play
an important position in medicinal chemistry [7,8]. Compounds
containing thiazolidinedione moiety have been found to demon-
strate an extensive assortment of biological activities viz., COX-2
inhibitor [9], antihyperglycemic [10], anti-inflammatory [11],
antioxidant [12], cytotoxic [13], antimicrobial [14], neuro-
Fig. 1. Structure of anacardic acid
These observations promoted us to synthesize a new series
of thiazolidinedione with higher biological activity. In the present
paper, the synthesis and screening of novel thiazolidinedione
derivatives embedded with anacardic acid motif for anti-

1232 Reddy et al.
Asian J. Chem.
diabetic activity was performed. The structures of the various
synthesized compounds were assigned on the basis of mass,
IR and 1H NMR spectral data. These compounds were screened
for their antidiabetic activity by using alloxan induced insulin
resistance in rats.
24H), 0.89 (t, J = 7.2 Hz, 3H, D2O exchangeable OH); ESIMS:
m/z, 349 [M+H]+.
Preparation of 2-methoxy-6-pentadecylbenzaldehyde
(4): To a stirred solution of 2-methoxy-6-pentadecylphenyl)-
methanol (3, 2 g, 5.74 mmol) in acetone (30 mL) was added
sequentially CuBr (10 mol %), bpy (2,2’-bipyridine, 10 mol
%) and TEMPO (10 mol %) while the solution was stirred for
15 min and then N-methyl imidazole (10 mol %) was added.
The reaction mixture was stirred rapidly while open to the air
for 2 h (until the reaction is complete). The reaction mixture
was diluted with water (50 mL) and extracted with pentane
(3 × 30 mL), the organic layer was separated and dried over
anhydrous Na2SO4, filtered and evaporated to afford 2-methoxy-
6-pentadecylbenzaldehyde (4). Pale yellow solid;Yield: 1.4 g
(71 %); m.p.: 70-72 °C; IR (KBr, νmax , cm–1): 1687 (C=O stret-
ching), 1589 (C-O stretching); 1H NMR (CDCl3, 400 MHz):
δ, 10.62 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 8.4 Hz,
2H), 3.88 (s, 3H), 2.92 (t, J = 8.0 Hz, 2H), 1.51-1.57 (m, 2H),
1.25 (brs, 24H), 0.88 (t, J = 6.8 Hz, 3H); ESI-MS: m/z,347.29
[M+H]+.
EXPERIMENTAL
The uncorrected melting points of compounds were taken
in an open capillary in a paraffin bath. All reagents used were
commercial and laboratory grade, melting points were deter-
mined in open capillaries and are uncorrected. IR spectra were
recorded on potassium bromide disks on a Perkin-Elmer 383
spectrophotometer. 1H NMR spectra were obtained on Varian
400 MHz instrument and Varian 400 MHz, with TMS as
internal Standard and chemical shifts are expressed in δ ppm
solvent used in CDCl3 and mass spectrum on a Hewelett Packard
mass spectrometer operating at 70 ev, purity of the compounds
were checked by TLC, which is performed with E. Merck pre
coated silica gel plates (60 F-254) with iodine as a developing
agent.Acme, India silica gel, 60-120 mesh for column chromato-
graphy is used.
Preparation of methyl (2-methoxy-6-pentadecyl)benzoate
(2): In a sealed tube vessel, was added 2-hydroxy-6-penta-
decylbenzoic acid (1, 10 g, 28.70 mmol), 2-methyl tetra-
hydrofuran (60 mL), dimethylcarbonate (5.17 g, 57.40 mmol)
followed by DBU (0.44 g, 2.90 mmol) and the cap was screwed
tightly. The reaction mixture was heated to 140 °C for 17 h.
After cooling, the reaction contents was diluted with cyclopentyl
methyl ether (25 mL), washed with 10 % solution of sodium
bicarbonate solution (3 × 15 mL), washed with 1 M HCl (3 × 25
mL) and with water (3 × 25 mL), dried over sodium sulphate,
filtered and concentrated to afford methyl 2-methoxy-6-
pentadecylbenzoate (3). Pale yellow solid;Yield: 9.0 g, 84 %;
m.p.: 36-37 °C; IR (KBr, νmax , cm–1): 3004 (Ar-CH str, 2921
(-CH str), 1732 (-C=O str), 1460 (-C=C-, str), 1105 (-C-OC-,
str); 1H NMR (400 MHz, CDCl3) δ: 7.25 (t, J = 8.0 Hz, 1H),
6.82 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.90 (s,
3H), 3.81 (s, 3H), 2.53 (t, J = 8.0 Hz, 2H), 1.53-1.60 (m, 2H),
1.25 (brs, 24H), 0.88 (t, J = 6.8 Hz, 3H); ESI-MS: m/z, 377
[M+H]+.
Preparation of (2-methoxy-6-pentadecylphenyl)-
methanol (3): To a stirred suspension of methyl 2-methoxy-
6-pentadecylbenzoate (2, 5.0 g, 13.28 mmol) in 2-methyl THF
(75 mL) was added sodium borohydride (2 g, 52.86 mmol)
and heated under reflux for 1 h. The above reaction mixture
was diluted with methanol (75 mL) and was further refluxed
for 1 h. The reaction mixture was cooled to room temperature
and quenched with a saturated solution of NH4Cl (50 mL) for
2 h and diluted with isopropylacetate. The organic extracts
was washed with water followed by brine solution, dried over
Na2SO4 and concentrated under reduced pressure to obtain
(2-methoxy-6-pentadecylphenyl)methanol (3). Off white solid;
Yield: 3 g, 81 %; m.p.: 60-62 °C; IR (KBr, νmax , cm–1): 3367 (-
OH str), 3004 (Ar-CH,str), 2853 (-CH str), 1457 (-C=C, str),
1080 (-C-O-C, str); 1H NMR (400 MHz, CDCl3) δ: 7.20 (t, J
= 8.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 8.0 Hz,
1H), 4.75 (d, J = 6.4 Hz, 2H), 3.87 (s, 3H), 2.68 (t, J = 6.4 Hz,
2H), 2.37 (t, J = 6.4 Hz, 1H), 1.53-1.58 (m, 2H), 1.27 (brs,
Preparation of (E)-5-(2-methoxy-6-pentadecylbenzyli-
dene)thiazolidine-2,4-dione (5): To a solution of compound
4 (1.0 g, 2.890 mmol) in toluene (15 mL) was added thiazoli-
dinedione (339 mg, 2.89 mmol), ammonium acetate (669 mg,
8.670 mmol) and acetic acid (1 mL) at room temperature.
Reaction mixture was refluxed for 3 h, reaction mixture was
distilled off crude compound was re-dissolved in ethyl acetate
(50 mL) with water (50 mL), brine solution (20 mL) dried
over anhydrous Na2SO4, filtered and evaporated under vacuum
to obtain 5-(2-methoxy-6-pentadecyl-benzylidene)thiazolidine-
2,4-dione (5). Cream colour solid; Yield: 650 mg, (50.4 %);
m.p.: 82-83 °C; IR (KBr pellet, cm–1): 3184 (Ar-CH, str), 2912
(-CH str), 1739, 1699 (C=O str, thiazolidine carbonyl), 1597
1
(-C=C- str), 1078 (-C-O-C str), 763 (C-SC- str); H NMR
(CDCl3, 400 MHz): δ 7.92 (s, 1H), 7.22 (dd, J = 7.6, 16 Hz,
1H), 6.80 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 5.66 (s,
2H), 3.80 (s, 3H), 2.58 (t, J = 7.6 Hz, 2H), 1.48-1.44 (m, 2H),
13
1.21-1.17 (m, 24H), 0.80 (t, J = 7.6 Hz, 3H); C NMR (100
MHz, CDCl3), δ: 167.5, 165.8, 155.8, 143.7, 130.2, 130.2, 125.8,
121.1, 119.3, 107.5, 54.0, 32.7, 30.9, 30.0, 29.0, 28.6 (6C), 28.5,
28.4, 28.3 (2C), 21.6, 13.0; MS (ESI) m/z: 446.1 [M+H]+.
General procedure for the N-alkylation of (E)-5-(2-
methoxy-6-pentadecylbenzylidene)thiazolidine-2,4-dione
(5) to produce corresponding N-alkyl/aryl substituted-
thiazolidine-2,4-dione derivatives: To a stirred solution of
compound 5 (100 mg, 0.225 mmol) in DMF (1 mL) was added
potassium carbonate (0.27 mmol) followed by the correspon-
ding alkyl bromides (0.225 mmol), benzyl bromide (0.225
mmol) and phenacyl bromide (0.225 mmol) and heated to 80 °C
for 1-3 h. After the completion of the reaction (monitored by
TLC), the reaction mixture was diluted with water and extracted
with ethylacetate (2 × 5 mL). The organic layer was washed
with water (3 × 5mL) followed by brine solution, separated
and dried over Na2SO4, filtered and evaporated under reduced
pressure to obtain the corresponding 2,4-thiazolidine derivatives
6a-6k.
(E)-5-(2-methoxy-6-pentadecylbenzylidene)-3-ethyl-
thiazolidine-2,4-dione (6a): Pale yellow viscous liquid;Yield:

Vol. 30, No. 6 (2018)
Synthesis and Antidiabetic Evaluation of Substituted Thiazolidine-2,4-dione Derivatives 1233
1
88 %; H NMR (CDCl3, 400 MHz): δ 8.0 (s, 1H), 7.30 (dd,
J = 7.6, 10.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.78 (d, J =
7.6 Hz, 1H), 3.84 (s, 2H), 3.80 (q, J = 6.8 Hz, 2H), 2.62 (t, J
= 7.6 Hz, 2H), 1.58-1.52 (m, 2H), 1.38-1.22 (m, 27H), 0.90
(t, J = 7.6 Hz, 3H); MS (ESI) m/z : 474.1 (M-H)+.
(E)-5-(2-methoxy-6-pentadecylbenzylidene)-3-(4-
chlorobenzyl)thiazolidine-2,4-dione (6h):Yellow oily liquid;
Yield: 86 %; 1H NMR (CDCl3, 400 MHz): δ 7.98 (s, 1H), 7.90
(d, J = 7.2 Hz, 2H), 7.56 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.8
Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H),
4.88 (s, 2H), 3.80 (s, 3H), 2.62 (t, J = 6.8 Hz, 2H), 1.48-1.42
(m, 2H), 1.32-1.26 (m, 24H), 0.90 (t, J = 7.6 Hz, 3H); ESI-
MS: m/z, 570.3 [M+H]+.
4-[{(E)-5-(2-methoxy-6-pentadecylbenzylidene)-2,4-
dioxothiazolidin-3-yl}methyl]benzonitrile (6i): Pale yellow
solid; Yield: 84 %; m.p.: 118-119 °C; 1H NMR (CDCl3, 400
MHz): δ 8.01 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.52 (d, J =
7.2 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.0 (d, J = 7.8 Hz, 1H),
6.90 (d, J = 7.8 Hz, 1H), 4.90 (s, 2H), 3.82 (s, 3H), 2.60 (t, J
= 6.8 Hz, 2H), 1.50-1.42 (m, 2H), 1.30-1.26 (m, 24H), 0.90
(t, J = 7.6 Hz, 3H); ESI-MS: m/z, 561.0 [M+H]+.
(E)-5-(2-Hexadecyl-6-methoxy-benzylidene)-3-(2-oxo-
2-phenyl-ethyl)-thiazolidine-2,4-dione (6j): Colourless viscous
liquid;Yield: 78 %; 1H NMR (CDCl3, 400 MHz): δ 8.06-7.78
(m, 5H), 7.96 (s, 1H), 7.40 (t, J = 7.6, 1H), 6.92 (d, J = 7.6
Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 5.26 (s, 2H), 3.80 (s, 3H),
2.60 (t, J = 7.6 Hz, 2H), 1.50 (t, J = 7.8 Hz, 2H), 1.20-1.14
(m, 24H), 0.88 (t, J = 7.6 Hz, 3H); ESI-MS: m/z, 564.1 [M+H]+.
(E)-3-[2-(4-Bromo-phenyl)-2-oxo-ethyl]-5-(2-hexadecyl-
6-methoxy-benzylidene)thiazolidine-2,4-dione (6k): Pale
yellow visous liquid;Yield: 80 %; 1H NMR (CDCl3, 400 MHz):
δ 8.06 (d, J = 8.2 Hz, 2H), 8.0 (s, 1H), 7.80 (d, J = 8.2 Hz,
2H), 7.40 (t, J = 7.6, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.90 (d,
J = 7.6 Hz, 1H), 5.30 (s, 2H), 3.84 (s, 3H), 2.64 (t, J = 7.6 Hz,
2H), 1.52 (t, J = 7.8 Hz, 2H), 1.22-1.18 (m, 24H), 0.82 (t, J =
7.6 Hz, 3H); ESI-MS: m/z, 642.1 [M+H]+.
(E)-5-(2-methoxy-6-pentadecylbenzylidene)-3-propyl-
thiazolidine-2,4-dione (6b): Pale yellow viscous liquid;Yield:
85 %; IR (KBr pellet, cm–1): 2916 (-CH str), 1732 (-C=O, ethyl-
ester carbonyl), 1691,1604 (C=O str, thiazolidine carbonyl),
1593 (-C=C- str), 1026 (-C-O-C str), 800 (C-S-C str); 1H NMR
(CDCl3, 400 MHz): δ 8.0 (s, 1H), 7.30 (dd, J = 7.6, 10.8 Hz,
1H), 6.90 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 3.82
(s, 2H), 3.75 (q, J = 6.8 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H),
1.58-1.52 (m, 2H), 1.38-1.22 (m, 24 H), 0.98 (t, J = 6.8Hz,
3H), 0.92 (t, J = 6.8 Hz, 3H); ESI-MS: m/z, 488.1 [M-H]+.
Ethyl 2-[(E)-5-(2-methoxy-6-pentadecylbenzylidene)-
2,4-dioxothiazolidin-3-yl]acetate (6c): Pale yellow solid;
Yield: 78 %; m.p.: 50-51 °C; IR (KBr pellet, cm–1): 2918 (-CH
str), 1732 (-C=O str, ethylester group), 1691, 1604 (-C=O,
thiazolidine group), 1593 (-C=C- str), 1026 (-C-O-C str), 800
(C-S-C str); 1H NMR (CDCl3, 400 MHz): δ 7.98 (s, 1H), 7.22
(dd, J = 8.0, 16 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.70 (d, J =
7.6 Hz, 1H), 4.38 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H),
2.58 (t, J = 7.6 Hz, 2H), 1.48-1.44 (m, 2H), 1.21-1.17 (m,
24H), 0.80 (t, J = 7.6 Hz, 3H); ESI-MS: m/z,532.5 [M+H]+.
(E)-5-(2-Methoxy-6-pentadecylbenzylidene)-3-benzyl-
thiazolidine-2,4-dione (6d): Colourless viscous liquid;Yield:
82 %; 1H NMR (CDCl3, 400 MHz): δ H NMR (CDCl3, 400
1
MHz): δ 7.98 (d, J = 8.0 Hz, 1H), 7.34-7.28 (m, 5H), 7.20
(dd, J = 7.8, 10.4 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.68 (d,
J = 7.8 Hz, 1H), 4.80 (s, 2H), 3.82 (s, 3H), 2.62 (t, J = 7.6 Hz,
2H), 1.44 (t, J = 7.6 Hz, 2H), 1.28-1.20 (m, 24H), 0.80 (t, J =
7.6 Hz, 3H); ESI-MS: m/z, 554.1 [M+H]+.
Pharmacological experimental section [25,26]
Experimental animals: Swiss albino mice weighing 25-
30 g were used for this study. Animals were grouped and housed
for one week to acclimatize to laboratory conditions before
starting the experiment. Animals were fed with standard diet
and water ad libitum and standard laboratory conditions. 12 h
prior to an experiment; the animals were deprived of food but
not water.All the experimental procedures were carried out
accordance with CPCSEA guidelines. The InstitutionalAnimal
Ethics Committee was approved the experimental protocol.
Induction of diabetes: To the overnight-fasted Swiss
albino mice was injected with alloxan monohydrate (150 mg/
kg) in saline buffer administer through intraperitoneally. In
order to prevent hypoglycaemia after injection of alloxan,
animals were fed with 20 % w/v glucose solution. After 72 h
the fasting blood glucose levels (FBG) were determined by
using ONETOUCH select simple (J&J) Glucometer strips
(diabetic control, Table-1). Mice with < 250 mg/dl were excluded
from experiment and mice with > 250 mg/dl are selected to
diabetic study and divide them into groups.
2-[{(E)-5-(2-Methoxy-6-pentadecylbenzylidene)-2,4-
dioxothiazolidin-3-yl}methyl]benzonitrile (6e): Off white
solid;Yield: 86 %; m.p.: 92-93 °C; 1H NMR (CDCl3, 400 MHz):
1
δ H NMR (CDCl3, 400 MHz): δ 8.0 (s, 1H), 7.90 (d, J = 8.0
Hz, 1H), 7.70 (t, J = 8.2 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.40
(d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.0 (d, J = 7.6 Hz,
1H), 6.90 (d, J = 7.6 Hz, 1H), 5.0 (s, 2H), 3.82 (s, 3H), 2.62 (t,
J = 7.6 Hz, 2H), 1.52-1.48 (m, 2H), 1.35-1.12 (m, 24H), 0.92
(t, J = 7.6 Hz, 3H); ESI-MS: m/z, 561.2 [M+H]+.
3-[{(E)-5-(2-Methoxy-6-pentadecylbenzylidene)-2,4-
dioxothiazolidin-3-yl}methyl]benzonitrile (6f): Off white
solid;Yield: 82 %; m.p.: 90-91 °C; 1H NMR (CDCl3, 400 MHz):
δ 7.96 (d, J = 8.0 Hz, 1H), 7.40-7.36 (m, 4H), 7.26 (dd, J =
7.8, 10.2 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 7.8
Hz, 1H), 4.84 (s, 2H), 3.86 (s, 3H), 2.66 (t, J = 7.6 Hz, 2H),
1.46 (t, J = 7.6 Hz, 2H), 1.26-1.20 (m, 24H), 0.82 (t, J = 7.6
Hz, 3H); ESI-MS: m/z, 561.3 [M+H]+.
(E)-5-(2-Methoxy-6-pentadecylbenzylidene)-3-(3-
chlorobenzyl)thiazolidine-2,4-dione (6g): Off white solid;
Yield: 82 %; m.p.: 101-102 °C; 1H NMR (CDCl3, 400 MHz):
δ 7.98 (d, J = 8.0 Hz, 1H), 7.38-7.34 (m, 4H), 7.24 (dd, J =
7.8, 11.0 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 7.8
Hz, 1H), 4.80 (s, 2H), 3.82 (s, 3H), 2.62 (t, J = 7.6 Hz, 2H),
1.44 (t, J = 7.6 Hz, 2H), 1.24-1.18 (m, 24H), 0.80 (t, J = 7.6
Hz, 3H); ESI-MS: m/z, 570.1 [M+H]+.
Protocol for animal:Animals were separated into 13 sets
of 6 mice (n = 6): (i) diabetic animals (vehicle) labeled as set-
1, received 1 mL of CMC (0.5 %); (ii) diabetic animals labeled
as set-2, received insulin as a standard 2IU/kg SC.50 mg/Kg.
(iii) Set (3-13) diabetic animals received compounds 6a-k in
a single dose (10 mg/kg body weight per oral) respectively
for seven days incessantly.

1234 Reddy et al.
Asian J. Chem.
TABLE-1
FBG LEVELS OF THIAZOLIDINE DERIVATIVES (6a-k)
Groups
Control
Insulin
6a
6b
6c
6d
6e
6f
6g
After 1st day of treatment
After 3rd day of treatment
After 7th day of treatment
Hyperglycemic activity (%)
93 1.29
92.5 1.84
108.8 3.497***
222.0 2.45*
210.3 1.11***
187.8 4.32***
224.0 6.41***
288.0 4.52*
95.5 2.02
–
321.8 4.76***
304.3 3.65ns
288.0 3.12**
286.5 5.31*
303.3 6.03*
317.3 5.16ns
310.3 3.10**
292.8 4.0ns
284.3 3.11**
310.3 6.86ns
315.3 4.95ns
280.5 2.11**
108.3 2.689***
120.0 1.10***
115.3 1.931***
113.0 3.440***
136.0 4.54***
226.5 2.781***
214.5 1.454***
147.3 1.931***
157.5 3.663***
208.5 5.951***
133.0 3.16***
118.0 2.520***
66.34
60.52
60.06
60.55
55.15
28.61
30.07
49.69
44.60
32.80
57.80
57.93
242.0 5.54*
222.3 3.11***
247.0 2.58***
293.0 6.02*
214.0 3.62***
194.8 4.32***
6h
6i
6j
6k
Data are expressed as mean SEM (n = 4) and analyzed by one way ANOVA followed by Tukey's multiple comparison test. ***P < 0.001, **P <
0.01, *P < 0.05 as compared to the diabetic control group.
Measurement of blood glucose levels: Each individual
reading was noted by withdrawing blood sample from the tail
vain. Measurement of blood glucose was taken at intervals of
0, 3rd and 7th day. By snipping the tip of the tail, blood samples
were withdrawn from a tail vein and the blood glucose level was
measured at the end of 0, 3rd and 7th day (by Accu Sure Blood
Glucose Monitoring System, Dr. Gene Health & Wellness.
five steps utilizing anacardic acid as starting material [27].
Methylation of anacardic acid (1) was achieved in presence of
dimethyl carbonate [28], 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) in 2-Me THF in sealed tube at 140 °C for 17 h produced
methyl (2-methoxy-6-pentadecyl)benzoate (2) in 84 % yield.
Sodium borohydride reduction of 2-methoxy-6-pentadecyl-
benzoate (2) in presence of 2-Me THF at reflux for 1 h yielded
(2-methoxy-6-pentadecylphenyl)methanol (3) in 81 %. The
oxidation of alcohol 3 [29] was carried out in presence of CuBr,
2,2-bipyridine, TEMPO, N-methyl imidazole in acetone at
room temperature resulted in the formation of 2-methoxy-6-
pentadecylbenzaldehyde 4 in 71 % yield. Condensation of
RESULTS AND DISCUSSION
The synthesis of 5-(2-methoxy-6-pentadecylbenzylidene)-
3-alkyl/aryl-substituted thiazolidine-2,4-dione derivatives (6a-6k)
is illustrated in Scheme-I. These derivatives were prepared in
OMe
OMe
OH
OMe
COOH
C15H31
COOMe
C15H31
CHO
b
a
OH
c
C15H31
C15H3
1
2
3
1
4
O
O
O
O
S
R-Br
e
S
d
NH
N
R
C15H31
O
O
C15H31
6a-6k
5
CN
CN
O
O
b
a
c
e
f
d
Br
R =
Cl
Cl
CN
Br
Br
O
g
h
i
O
j
k
Experimental conditions: (a) dimethyl carbonate, DBU, 2-Me THF, 140 °C, sealed tube; (b) NaBH4, 2-MeTHF, reflux, 1 h;
c) CuBr, 2,2’-bipyridine, TEMPO, N-methyl imidazole, acetone, room temperature, 2 h; d) thiazolidinedione,
ammonium acetate, acetic acid, toulene, reflux, 3 h; e) R-Br/Ar-CH2-Br, K2CO3, DMF, 80 °C, 1-3 h
Scheme-I: Synthesis of novel thiazolidine-2,4-dione derivatives 6a-k

Vol. 30, No. 6 (2018)
Synthesis and Antidiabetic Evaluation of Substituted Thiazolidine-2,4-dione Derivatives 1235
aldehyde 4 with thiazolidinedione in presence of ammonium
acetate and acetic acid (catalytic quantity) in toluene at reflux
for 3 h gave (E)-5-(2-methoxy-6-pentadecylbenzylidene)thia-
zolidine-2,4-dione (5). Reaction of thiazolidine-2,4-dione (5)
with corresponding alkyl bromides, benzyl bromides and phenacyl
bromides in presence of potassium carbonate in DMF at 80 ºC
for 1-3 h resulted in the formation of corresponding N-alkylated
thiazolidine-2,4-dione derivatives 6a-6k. The structures of newly
scopic techniques. Furthermore, these compounds have been
evaluated for their antidiabetic property, compounds 6a, 6b
and 6c with substitution ethyl, propyl and ethylacetoacetate
showed significant decrease in fasting blood glucose levels
when compared to standard drug with insulin.
REFERENCES
1. P.R. Shashikant, K. Prajact, N.S. Dighe, S.B. Bhawar, N. Ana and P.
Ashwini, Asian J. Res. Chem., 2, 123 (2009).
2. C.H. Jithendra and P. Muralidharan, Int. J. Green Pharm., 3, 66 (2009);
https://doi.org/10.4103/0973-8258.49378.
3. S. Kim, J.J. Lee and D.S. Heo, Biochem. Biophys. Res. Commun., 406,
389 (2011);
https://doi.org/10.1016/j.bbrc.2011.02.052.
4. N.C. Desai, U.P. Pandit and A. Dodiya, Expert Opin. Ther. Pat., 25,
479 (2015);
https://doi.org/10.1517/13543776.2014.1001738.
5. O. Bozdag-Dündar, N.D. Evcimen, M. Ceylan-Ünlüsoy, R. Ertan and M.
Sarikaya, Med. Chem. Res., 16, 39 (2008);
1
synthesized derivatives 6a-k were determined by H NMR,
mass and IR spectral data. As a representative example the 1H
NMR of ethyl 2-[(E)-5-(2-methoxy-6-pentadecylbenzylidene)-
2,4-dioxothiazolidin-3-yl]acetate (6c) is discussed here, the
proton signals resonating in the aromatic region 7.98 ppm (singlet,
1H), 7.22 ppm (double doublet, 1H), 6.80 ppm (doublet, 1H),
6.70 ppm (doublet, 1H) is assigned to the olefin bridge proton
(linking AA and thiazolidine ring) and anacardic acid ring
protons respectively. The proton signals resonating in the
aliphatic region viz., 4.38 ppm (singlet, 2H), 3.80 ppm (singlet,
3H) corresponds to the methylene (-CH2) and methoxy groups,
while the protons resonating at 4.18 ppm (quartet, 2H), 2.58
ppm (triplet, 3H) and 0.80-1.48 ppm is assigned to ethylester
group and anacardic acid side chain protons respectively.
IR interpretation 6c: A strong characteristic band in the
region 1732 cm-1 corresponds to C=O stretching vibrations of
ethyl ester functional group while the peaks in the region 1691
and 1604 cm-1 is assigned to the C=O stretching vibrations of
thiazolidine ring. The remaining aliphatic and aromatic stret-
ching bands appeared in the expected region.
https://doi.org/10.1007/s00044-007-9008-9.
6. L.R. de Magalhães, I.B.V. Alves, E. dos Santos, V.B.R. da Silva, L.C.A.
da Silva, A.L. da Silva, L.C.L. de Oliveira, A.C.N. da Cruz, B.I.M. da
Silva, L.F.C. da Costa Leite, M.H. Zaldini, I. da Rocha Pitta, T.G. da Silva
and M. do Carmo Alves de Lima, Br. J. Pharm. Res., 4, 1739 (2014);
https://doi.org/10.9734/BJPR/2014/11294.
7. D. Patel, P. Kumari and N. Patel, Med. Chem. Res., 21, 2926 (2012);
https://doi.org/10.1007/s00044-011-9822-y.
8. M.R. Shiradkar, M. Ghodake, K.G. Bothara, S.B. Bhandari, A. Nikalje
and K.C. Akula, ARKIVOC, 58 (2007);
https://doi.org/10.3998/ark.5550190.0008.e08.
9. A.M. Ali, G.E. Saber, N.M. Mahfouz, M.A. El-Gendy, A.A. Radwan
and M.A. Hamid, Arch. Pharm. Res., 30, 1186 (2007);
https://doi.org/10.1007/BF02980259.
The 13C NMR of 6c is in accordance with the desired struc-
ture, the signals in the region 168.6, 166.4, 165.6 ppm is assigned
to carbonyl signal of ethylester group and 2,4-thiazolidine
dione ring, respectively. The remaining carbon signals of the
aromatic and aliphatic groups were found to be in the expected
region. ESI-MS spectrum carrying a base peak at m/z 532.5
[M+1]+ is in agreement with the formation of compound 6c.
Similarly, the remaining compounds 6a-k has been fully
characterized as per the above description.
Antidiabetic activity: Alloxan administration signifi-
cantly elevated the fasting blood glucose levels (FBG) levels
in all groups. Treatment with thiazolidine-2,4-dione derivatives
(6a-k) are continued for 7 days.After the 7th day of treatment, it
was observed that some of the significantly reduced the FBG
levels when compared to diabetic mice (analyzed by glucometer
strips analysis). Out of all synthetic compounds the compounds
6a, 6b, 6c showed significant decrease in FBG levels (when
compared to standard drug with insulin) and in terms of hyper-
glycemic percentage, 60.52, 60.06 and 60.55 %, respectively
these compounds displayed good antidiabetic activity while
the compounds 6d, 6j and 6k displayed moderate antidiabetic
activity with 55.15, 57.80 and 57.93 % of hypoglycemic
activity. The remaining compounds in the series 6e-6i displayed
poor antidiabetic activity.
10. B.B. Lohray, V. Bhushan, B.P. Rao, G.R. Madhavan, N. Murali, K.N. Rao,
A.K. Reddy, B.M. Rajesh, R. Chakrabarti, R.K. Vikramadithyan, P.G.
Reddy, R. Rajagopalan, R.N.V.S. Mamidi, H.K. Jajoo and S. Subramaniam,
J. Med. Chem., 41, 1619 (1998);
https://doi.org/10.1021/jm970444e.
11. C. Prabhakar, G. Madhusudhan, K. Sahadev, C.M. Reddy, M. Sarma,
G.O. Reddy, R. Chakrabarti, C.S. Rao, T.D. Kumar and R. Rajagopalan,
Bioorg. Med. Chem. Lett., 8, 2725 (1998);
https://doi.org/10.1016/S0960-894X(98)00485-5.
12. K.A. Reddy, B. Lohray, V. Bhushan, A.S. Reddy, P.H. Kishore, V.V.
Rao, V. Saibaba, A.C. Bajji, B.M. Rajesh, K.V. Reddy, R. Chakrabarti
and R. Rajagopalan, Bioorg. Med. Chem. Lett., 8, 999 (1998);
https://doi.org/10.1016/S0960-894X(98)00159-0.
13. V. Patil, K. Tilekar, S. Mehendale-Munj, R. Mohan and C. Ramaa,
Eur. J. Med. Chem., 45, 4539 (2010);
https://doi.org/10.1016/j.ejmech.2010.07.014.
14. C.G. Bonde and N.J. Gaikwad, Bioorg. Med. Chem., 12, 2151 (2004);
https://doi.org/10.1016/j.bmc.2004.02.024.
15. A.M. Youssef, M. Sydney White, E.B. Villanueva, I.M. El-Ashmawy
and A. Klegeris, Bioorg. Med. Chem., 18, 2019 (2010);
https://doi.org/10.1016/j.bmc.2010.01.021.
16. A. Natarajan,Y. Guo, F. Harbinski,Y.-H. Fan, H. Chen, L. Luus, J. Diercks,
H.Aktas, M. Chorev and J.A. Halperin, J. Med. Chem., 47, 4979 (2004);
https://doi.org/10.1021/jm0496234.
17. H.N. Hafez andA.R. El-Gazzar, Bioorg. Med. Chem. Lett., 19, 4143 (2009);
https://doi.org/10.1016/j.bmcl.2009.05.126.
18. T. Tomasic, N. Zidar, M. Mueller-Premru, D. Kikelj and L.P. Masic,
Eur. J. Med. Chem., 45, 1667 (2010);
https://doi.org/10.1016/j.ejmech.2009.12.030.
19. R.T. Carroll, D.E. Dluzen, H. Stinnett, P.S. Awale, M.O. Funk and W.J.
Geldenhuys, Bioorg. Med. Chem. Lett., 21, 4798 (2011);
https://doi.org/10.1016/j.bmcl.2011.06.060.
20. N. Sunduru, K. Srivastava, S. Rajakumar, S.K. Puri, J.K. Saxena and
P.M.S. Chauhan, Bioorg. Med. Chem. Lett., 19, 2570 (2009);
https://doi.org/10.1016/j.bmcl.2009.03.026.
Conclusion
We have designed and synthesized some novel 5-(2-
methoxy-6-pentadecylbenzylidene)-3-alkyl/aryl-substituted
thiazolidine-2,4-dione derivatives (6a-6k) utilizing anacardic
as starting material. The structural determination of these deriva-
tives have been confirmed by 1H NMR, mass and IR spectro-
21. Sucheta, S. Tahlan and P.K. Verma, Chem. Cent. J., 11, 130 (2017);
https://doi.org/10.1186/s13065-017-0357-2.

1236 Reddy et al.
Asian J. Chem.
22. M.T. Trevisan, S.B. Pfundstein, R. Haubner, G. Wurtele, B. Spiegelhalder,
H. Bartsch and R.W. Owen, Food Chem. Toxicol., 44, 188 (2006);
https://doi.org/10.1016/j.fct.2005.06.012.
23. S.S. Mlowe, R.R. Pullabhotla, E.B. Mubofu, F.N. Ngassapa and N.N.
Revaprasadu, Int. Nano Lett., 4, 106 (2014);
26. D. Kumar, S. Kumar, S. Kohli, R. Arya and J. Gupta, Asian Pac. J. Trop.
Med., 4, 900 (2011);
https://doi.org/10.1016/S1995-7645(11)60215-0.
27. P.V. Swamy, K.B. Chandrasekhar and K.C. Pullaiah, China J. Appl.
Chem., 32, 492 (2015).
https://doi.org/10.1007/s40089-014-0106-7.
28. W.-C. Shieh, S. Dell and O. Repic, J. Org. Chem., 67, 2188 (2002);
https://doi.org/10.1021/jo011036s.
29. N.J. Hill, J.M. Hoover and S.S. Stahl, J. Chem. Educ., 90, 102 (2013);
https://doi.org/10.1021/ed300368q.
24. S. Mlowe,A.A. Nejo,V.S.R.R. Pullabhotla, E.B. Mubofu, F.N. Ngassapa,
P. O’Brien and N. Revaprasadu, Mater. Sci. Semicond. Process., 16, 263
(2013);
https://doi.org/10.1016/j.mssp.2012.10.017.
25. M. Misra and U. Aiman, Indian J. Pharmacol., 44, 538 (2012);
https://doi.org/10.4103/0253-7613.99348.