Antihyperglycemic activity of chalcone based novel 1-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl} thioureas

Article abstract of DOI:10.1080/00397911.2018.1539178

The present study describes the synthesis of novel chalcone based 1-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl} thioureas (4a-c) using Claisen Schmidt condensation and investigates their protective role in diabetic conditions and associated oxidative

Full text of DOI:10.1080/00397911.2018.1539178

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Antihyperglycemic activity of chalcone based novel
1-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl}
thioureas
Satarupa Acharjee, Tapan Kumar Maity, Subir Samanta, Supriya Mana, Tania
Chakraborty, Tanushree Singha & Arijit Mondal
To cite this article: Satarupa Acharjee, Tapan Kumar Maity, Subir Samanta, Supriya Mana,
Tania Chakraborty, Tanushree Singha & Arijit Mondal (2018): Antihyperglycemic activity of
chalcone based novel 1-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl} thioureas, Synthetic
Communications, DOI: 10.1080/00397911.2018.1539178
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https://doi.org/10.1080/00397911.2018.1539178
Antihyperglycemic activity of chalcone based novel
1
-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl} thioureas
a,b
a
c
Satarupa Acharjee , Tapan Kumar Maity , Subir Samanta ,
d
d
a
b
Supriya Mana , Tania Chakraborty , Tanushree Singha , and Arijit Mondal
a
Department of Pharmaceutical Technology Synthetic and Natural Product Research Laboratory,
b
Jadavpur University, Kolkata, West Bengal, India; Department of Pharmacy, NSHM Knowledge Campus,
Kolkata-Group of Institutions, Kolkata, West Bengal, India; Department of Pharmaceutical Sciences and
Technology, Birla Institute of Technology, Mesra, Jharkhand, India; Department of Pharmacology,
c
d
NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal, India
ABSTRACT
ARTICLE HISTORY
The present study describes the synthesis of novel chalcone based
Received 7 August 2018
1
-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl} thioureas (4a-c)
using Claisen Schmidt condensation and investigates their protective
role in diabetic conditions and associated oxidative stress. Spectral
properties for the synthesized compounds were studied. Novel
compounds were screened for antihyperglycemic effect in streptozo-
tocin (STZ)-induced diabetic rats in a 6 week study and compound
KEYWORDS
Apoptosis; blood glucose
lowering effect; catalase;
chalcone; streptozotocin
4
b exhibited significant (p ꢀ .05) results similar to the standard drug
glipizide. Treatment of diabetic animals with compound 4b (10 and
0 mg/kg, body weight) for 12 weeks, reduced the increased blood
2
glucose level significantly (p ꢀ .01) and restored attenuated serum
biochemical parameters to normal levels. Altered antioxidant enzyme
activity was also considerably (p ꢀ .01) restored to the standard
normal range. b-apoptotic TUNEL assay indicated that compound 4b
(
AI: 1.2 ± 0.05) could prevent further b-cell death in the pancreas of
diabetic animals in a dose-dependent manner, which highlights its
potentiality as an effective antihyperglycemic agent.
GRAPHICAL ABSTRACT
Introduction
Diabetes is one of the major endocrine disorders of multiple etiologies and
characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and
[
1]
protein metabolism resulting from defects in insulin secretion, insulin action or both.
CONTACT Arijit Mondal
arijit_ncp@rediffmail.com
Department of Pharmacy, NSHM Knowledge Campus, Kolkata-
Group of Institutions, 124 BL Saha Road, Kolkata, West Bengal 700053, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
S. ACHARJEE ET AL.
Diabetes is becoming the third “silent killer” of mankind, after cancer and cardiovascular
[
2]
diseases, because of its high prevalence, morbidity, and mortality. Type-2 diabetes is
the most common form prevalent in 90–95% of diabetic patients and is characterized by
[
3]
insulin resistance in liver and peripheral tissues together with pancreatic b-cell defects.
According to the World Health Organization (WHO), diabetes deaths will get doubled
by 2030 and 80% of this numerical increase will occur in developing countries including
[
4]
India.
The treatment of diabetes is currently managed by exercise, calorie intake and
oral hypoglycemics, prominent among them being sulfonylurea, biguanides, and
thiazolidinones. Though treatment with a highly active thiazolidinone class of drugs has
considerably improved the clinical situation, adverse effects of hepatotoxicity, weight
gain, and edema still persist. Hence, there is a persistent need for exploration of new
molecular targets and strategies to develop safer and effective anti-hyperglycemic, which
can also cater to the management of long-term complications of type-2 diabetes mellitus
(
T2DM). During research into new anti-diabetic molecules, aminoalkyl guanidine
[
5]
analogs were reported as potential anti-hyperglycemic and food intake reducing agent.
3
pyridine-2-yl-thioureido alkanoic acid esters were first reported as less toxic but potent
[
6]
anti-diabetic agents compared to 3-guanidino propionic acid.
A recent literature survey has also highlighted the design and synthesis of a novel
hybrid moiety comprising of sulfonyl urea and thiourea moiety responsible for hypogly-
cemic action with benzene sulfonamide group proved to possess thromboxane A receptor
2
[
7]
(
TPs) antagonistic action to cater to diabetes-induced cardiac complications.
Diabetic complications are further aggravated due to oxidative stress, which plays an
important role in causing insulin resistance, b-cell dysfunction, and impaired glucose
[
8]
tolerance.
Lower levels of antioxidant enzymes such as catalase and glutathione
peroxidase in the b-cells of the pancreas in diabetic conditions make them susceptible
to be attacked by reactive oxygen species (ROS) reported to be produced during
[
8,9]
oxidative stress.
Hence, hyperglycemic conditions increase the overall oxidative
burden, which in turn promotes the release of several pro-inflammatory cytokines caus-
[
8,10]
ing the apoptosis of b-cells.
Prolonged exposure of human islets to hyperglycemic
[
11]
conditions has been reported to increase b-cell apoptosis in a dose-dependent manner.
Thus, a decrease in the total number of b-cells either by uncontrolled apoptosis or
disruptions in the normal homeostatic control could lead to a decrement in the b-cell
[
12]
mass.
level might prevent further b-cell damage and produce beneficial effects in diabetes.
Several studies have demonstrated significant anti-hyperglycemic as well as the
This suggests that compounds which can enhance antioxidant enzyme activity
[
13]
[
14]
[15]
hypoglycemic effect of natural,
synthetic naphthyl chalcones
as well as chalcone
coupled with aryloxypropanolamine and sulfonamide moiety in in-vitro and in-vivo
[
16–18]
models.
alleviate oxidative stress-related manifestations.
Anti-hyperglycemic activity of hybrid moieties involving thiazolidinones with
Chalcones have also shown promising anti-oxidant activity which can
[
19]
[
20]
[21]
chalcone
and sulfonyl ureas has been reported.
Chalcones have demonstrated their
modulatory effect on all major targets namely PTB1B, PPARc, a-glucosidase, DPP-4, and
[
21,22]
aldose reductase and are prospective candidates amongst all other present ligands.
[
23]
0
0
[24]
Recently series of hydroxy bis-chalcones,
3 ,5 -digeranylated chalcone
and

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3
chalcone-triazole derivatives have been reported to exhibit good a-glucosidase inhibitory
activities and stronger effect in reducing glucose level compared to the standard drug,
[
25]
acarbose.
Also, chalcones bearing electron donating or electron withdrawing substitu-
[
26]
tions were prepared and their glucose uptake activity was evaluated.
Chalcones with
chloro, bromo, iodo, and hydroxy substitutions at position 2 on A-ring exhibited the
highest activity with glucose median concentration better than that of pioglitazone and
[
26]
rosiglitazone.
Similarly, another reported series of chalcones suggested that presence
of 3,4-methylenedioxy group on ring B and nitro/methoxy substituent on ring A in dif-
ferent positions exhibited a significant antihyperglycemic effect similar to that of lispro
[
27]
[20]
insulin and tolbutamide.
Hsieh et al.
SARs and research findings published by Jung et al.
and
[
26]
have also reiterated the significance of 4-alkoxy substitution on ring B of
chalcones eliciting potent PPAR c agonistic activity. Six trihydroxy chalcone derivatives
were found to be promising candidates for PTB1B inhibition and the results concluded
[
28]
that the electron donating groups on B ring showed better inhibitory activity.
To the best of our knowledge, there are no scientific reports on chalcone based novel
thioureas as an anti-diabetic molecule. Based on the promissory effect of chalcones as
well as thioureas individually in glucose lowering effect in hyperglycemic rats, the aim
of this study was to synthesize chalcone based novel thiourea derivatives and to evaluate
the anti-diabetic activity in streptozotocin (STZ) -induced diabetic rats
Results and discussion
Chemistry
1
The structures of the synthesized compounds were established by IR, H- & 13C-NMR
and mass spectral analysis. In the FT-IR spectra of compounds (4a–c), it was possible to
ꢁ
1
observe the absorptions between 3263 and 3453 cm
absorptions at 1638-60 cm
relating to -NH stretch and
ꢁ
1
from a, b unsaturated carbonyl moiety stretching.
Thiocarbonyl is less polar than the carbonyl group, and consequently, the band is not
1
intense and it is located at lower frequencies than carbonyl. The H-NMR spectra for all
synthesized compounds show the signals of aromatic protons of nitrogen in the range of
8.2–10.0 ppm. The signals for aromatic hydrogens are between 7.0 and 8.3 ppm. In these
same regions are the vinylic protons of trans olefinic protons which have larger coupling
constants than those of cis isomers. The 13C-NMR data of compounds (4a–c) showed a
characteristic peak for ꢁNHCSNH from d180-181 and C¼O peak at d187–189. The
vinylic carbons Ca and Cb showed characteristic peaks at d119–146. The OCH carbons
3
of 4b showed distinct peaks at d55 ppm. The ESI-Mass data shows the presence of M þ 1
and pseudomolecular M þ 23 ions (spectras provided in the supplementary file).
All the novel compounds (4a–c) were screened for in vivo antihyperglycemic activity
for 6 weeks. Diabetes was induced in Wistar rats by injecting STZ intraperitoneally
(50 mg/kg, body weight). Rats showing high blood glucose level of 260–300 mg/dl were
selected for the study. Results suggested that the synthesized compounds had significant
(
p ꢀ .05) normalizing effect of blood glucose level (BGL) post 6 weeks. Amongst the
three compounds, compound 4b was significantly comparable (p ꢀ .01) to the standard
drug, glipizide as shown in (Table S6, Fig. S8, supplementary file). Oral Glucose
tolerance tests were carried out to test whether these compounds can cope up with the

4
S. ACHARJEE ET AL.
sudden increase in glucose load. Oral treatment by compounds 4(a-c) caused a
significant (p ꢀ .05) decrease in the hyperglycemia peak after glucose loading in rats.
Percentage reduction of elevated BGL by compounds 4a and 4c was quite fast in the
range of 47–55% compared to 19% exhibited by glipizide over a period of 1 hr (post
glucose load) followed by 66% and 40% respectively. Compound 4b exhibited a slow
but sustained reduction of elevated BGL (27% in 60 min, 74% in 2 h), a better profile
compared to glipizide (60% in 2 hours) as shown in Figure S9, Table S7 (Supplementary
file). Based on the superior performance of compound 4b, it was selected for long-term
antidiabetic study in STZ-induced diabetic rat model for 12 weeks.
Acute toxicity studies on male Wistar albino rats (90–120 g) revealed that the LD50
for the oral administration of the drug was found to be in between >5 and 50 mg/kg of
[
29,30]
body weight, according to class 2 of ATC methodology.
The animals were treated
with doses of 10 mg/kg and 20 mg/kg, body weight with no lethality and toxic reactions.
In vivo antidiabetic study results for 12 weeks showed, that continuous treatment by
compound 4b at two different dose levels (10 and 20 mg/kg, body weight) reduced the
elevated blood glucose levels(BGL) significantly (p ꢀ .01) (Fig. 1A). In the oral glucose
tolerance test (OGTT), performed on the sixth week of treatment, compound 4b caused
a rapid and significant (p ꢀ .001) decrease (21% at 10 mg/kg and 52% in 20 mg/kg) in
BGL levels, in a dose-dependent manner. Interestingly, compound 4b resembled the
pattern exhibited by standard drug glipizide, which showed 48% decline in BGL, 60 min
post-glucose pulse (Fig. 1B). The above finding suggests, that compound 4b may have
therapeutic potential in post-prandial hyperglycemia.
The effect of compound 4b on antioxidant enzyme activity was monitored.
Administration of 20 mg/kg dose of compound 4b to diabetic rats resulted in a signifi-
cant decrease (p ꢀ .01) of thiobarbituric acid reactive substances (TBARS), superoxide
dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) to near-control levels
which indicated improved oxidative status in the pancreatic tissues (Fig. 1C). Oral
administration of test compound to diabetic groups CI and C2 restored the altered
levels of blood urea nitrogen (BUN) (p ꢀ .05), creatinine (p ꢀ .01), serum triglycerides
(
p ꢀ .05) to equilibrium (Fig. 1D,1E and 1H) post 9–12 weeks suggesting its renoprotec-
tive potential in long-term diabetic complications.
In order to further study and establish the regenerative potential of compound 4b in
pancreatic islet cells, we investigated its effect in the prevention of rate of b-cell apop-
tosis in the pancreas of diabetic rats by TUNEL assay as shown in Table 1. Compound
4
b (20 mg/kg) showed significantly reduced (p < .01) apoptotic index (1.2 ± 0.05)
compared to that of STZ control (15.5 ± 0.02) in a dose-dependent manner as shown in
Figure 2. Higher apoptotic index in the diabetic state compared to low apoptotic index
in treated rats suggests that compound 4b by its anti-apoptotic effect could prevent
further b-cell death in the pancreas of diabetic animals and thus be partly accountable
for the increase in b-cell number.
Conclusions
Thus, the present study demonstrates the anti-hyperglycemic potential of compound 4b,
a representative of chalcone based novel thioureas, in STZ-induced diabetic rats and

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Figure 1. Effect of compound 4b on blood glucose (1A), OGTT (1B), antioxidant enzyme activity (1C),
and BUN (1D) level in STZ-induced diabetic rats over a period of 12 weeks. Effect of compound 4b
on serum triglycerides (1E), HDL cholesterol (1F), LDL cholesterol (1G) and creatinine (1H) level in
STZ-induced diabetic rats over a period of 12 weeks.
provides evidence that the protective effects are possibly due to the restoration of
biochemical and antioxidant status and suppression of apoptotic events in the pancreas
tissue. The improvement in the lipid and renal profile in diabetic animals after
treatment with the novel compound 4b suggests they could be beneficial in preventing
long-term diabetic complications as well. Further detailed in vivo studies need to be done
to provide insights into the explicit molecular mechanism underlying their actions.

6
S. ACHARJEE ET AL.
Table 1. Apoptotic value of pancreatic tissue sections.
Groups
Apoptotic Index (AI)
ꢂꢂ
CC (Control rats)
DC (Diabetic control rats)
C1(Compound 4b) 10 mg/kg b.w
C2 (Compound 4b) 20 mg/kg b.w
Standard Glipizide (1mg/kg b.w./day)
0.6 ± 0.01
15.5 ± 0.02
ꢂ
5.6 ± 0.01
1.2 ± 0.05
ꢂꢂ
ꢂꢂ
0.8 ± 0.03
Approximately 200 cells were counted per field, five fields were examined per slide and five slides were examined per
group. The percentage of TUNEL-positive apoptotic cells was denoted as an apoptotic index (AI). Results are analyzed
by t-test and one-way analysis of variance (ANOVA) confirmed by post hoc Dennett’s test. Values are given as
ꢂꢂ
ꢂ
mean ± SEM for each group’s animals. p < .01 and p < .05, significant differences when compared with diabetic
control animals.
Figure 2. Immunohistochemistry photomicrographs of apoptotic cells in pancreatic sections (40X)
of rats. Brown stained cells indicate apoptosis. Arrow represents the expression of TUNEL-positive
apoptotic cells. Section A shows a normal histological section with well-arranged cells. Section B
shows the marked increment of apoptotic events in the pancreatic section of STZ-induced diabetic
rats. Section C shows the TUNEL-positive apoptotic cells moderately expressed in a pancreatic section
of diabetic rat treated by compound 4b (10 mg/kg). Section D depicts minimal expression of
apoptotic cells in a pancreatic section of diabetic rat treated by compound 4b (20 mg/kg). In the case
of standard Glipizide (1 mg/kg) (E), showed normal apoptotic events of pancreatic sections of
diabetic rats.
Experimental
Chemistry
The synthetic route used to synthesize title compounds as outlined in Figure 3. Three
test compounds 1-{3-[3-(substituted phenyl) prop-2-enoyl] phenyl} thioureas [4a-c]
were prepared by Claisen Schmidt condensation between substituted acetophenone [1]
[
31]
and substituted aromatic aldehydes in methanol under basic conditions.

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Synthetic procedure of 1-{3-[3-phenyl) prop-2-enoyl] phenyl} thioureas (4a–c)
N-[(3-acetylphenyl) carbamothioyl] benzamide [3] (2.98 g, 10 mmol) was dissolved
in 15–20 ml of 95% ethanol. NaOH solution (1 g, 50 mmol) was added dropwise to
solubilizes compound 3. Substituted benzaldehydes (10 mmol) separately dissolved in
[
31]
10 ml of ethanol was then added and the reaction mixture was stirred for 24–48 h
as
represented in Figure 3. The reaction mixture was poured into ice-cold water, acidified
with 6 N HCl using pH indicator paper till it becomes neutral. The mixture was
extracted with 200 ml of ether and the ether extract was washed with saturated
NaHCO . The extract was dried until the solvent evaporates off and the solid product
3
was recrystallized with acetone/methanol to get yellow to orange-colored crystals.
Spectral data of 1-{3-[3-phenyl) prop-2-enoyl] phenyl} thioureas (4a)
ꢃ
Yellowish solid, Yield 50%; mp 138–140 C (from methanol); IR ꢀ
3338 (aromatic-
max
ꢁ
1
1
NH), 1674 (ꢁCO) cm ; H-NMR (DMSO-d6, 300 MHz): d ¼ 8.29 (d, 2 H, aromatic
0
0
H2 -6 , J ¼ 8.86 Hz), 8.20 (br s, 1 H, NH), 8.06 (d, 1 H, H , J ¼ 9 Hz), 7.8 (d, 2 H, aromatic
ß
0
0
H3 -5 , J ¼ 8.86 Hz), 7.74 (d, 4 H, aromatic H2ʺ-6ʺ , J ¼ 8.55 Hz), 7.68 (d, 1 H, H ,
a
J ¼ 9 Hz), 7.40 (d, 2 H, aromatic H3ʺ-5ʺ , J ¼ 8.55 Hz) ppm. 13C-NMR (DMSO-d6,
4
1
(
00 MHz): d ¼ 188.1 (ꢁCO), 181.6 (ꢁNHCSNH), 144.4 (C ), 135.2 (C4ʺ), 129.9 (C3ʺ5ʺ),
b
0
0
0
0
30.9 (C2ʺ6ʺ), 129.3 (C1 ), 122.4 (C4 ), 129.2 (C 3 5 ), 121.5 (C ), 122.4 (C1ʺ), 121.5
a
0
0
þ
C2 6 ) ppm. ESI-MS (m/z) [M þ23]: 305.23. Analytically calculated (%) for C H N OS:
16 14 2
C, 68.06; H, 5.0; N, 9.92, S, 11.36. Found: C, 67.84; H, 4.9; N, 9.90, S, 11.28.
0
Spectral data of 1-{3-[3-(4 -methoxy phenyl) prop-2-enoyl] phenyl} thioureas (4b)
ꢃ
Light brownish solid, yield 70%; mp: 170–172 C (from methanol); IR ꢀ
(
3453
max
ꢁ
1 1
aromatic-NH), 1638 (ꢁCO) cm ; H-NMR (DMSO-d6, 300 MHz): d ¼ 8.19 (1 H, br,
s, NH), 8.07 (1 H, d, H , J ¼ 8.7 Hz), 7.83 (2 H, d, H2ʺ-6ʺ, J ¼ 8.7 Hz), 7.91 (2 H, d,
ß
Figure 3. Reagents and conditions: (i) acetone (ii) reflux 10–15 min (iii) reflux (iv) 30 min-1 hr (v)
4-amino acetophenone (vi) 40% NaOH; stirring (vii) RT (viii) substituted benzaldehyde.

8
S. ACHARJEE ET AL.
0
0
aromatic H2 -6 , J ¼ 7.2 Hz), 7.61 (2 H, d, aromatic H3ʺ-5ʺ, J ¼ 8.7Hz), 7.49 (2 H, d,
0
0
aromatic H3 -5 , J ¼ 7.2Hz), 6.95 (1 H, d, H , J ¼ 8.7Hz), 3.85 (3 H, s, ꢁCOCH ) ppm.
a
3
1
3
0
C-NMR (DMSO-d6, 400 MHz): d ¼ 188.0 (ꢁCO), 181.6 (-NHCSNH), 161.7 (C4 ),
0
0 0
1
1
44.3 (C ), 135.0 (C4ʺ), 130.0 (C2ʺ C6ʺ), 128.2 (C3ʺ5ʺ), 128.9 (C1 ), 127.8 (3 5 ),
b
0
0
þ
20.0 (C ), 114.8 (C1ʺ), 119.9 (C2 6 ), 55.8 (-OCH ) ppm. ESI-MS (m/z) (M þ69): 380.
a
3
Analytically calculated (%) for C H N O S: C, 65. 36, H, 5.16, N, 8.97, S, 10.26.
1
7
16 2 2
Found: C, 65.30, H, 5.00; N, 8.23, S, 10.0.
0
Spectral data of 1-{3-[3-(4 -chloro phenyl) prop-2-enoyl] phenyl} thioureas (4c)
ꢃ
Deep yellowish solid, Yield: 65%; m.p: 160–174 C (from methanol); IR (KBr) ꢀ
max
ꢁ
1 1
3
8
1
1
1
341(NH) 1671 (CO) cm , H-NMR (300 MHz, DMSO-d6): d ¼ 10.07 (br s, 1 H, NH),
.12 (d, 1 H, H , J ¼ 8 Hz), 7.90–7.99 (m, 4 H, Ar-H), 7.67–7.74 (m, 4 H, Ar-H), 7.51 (d,
a
1
3
H, H , J ¼ 8 Hz) ppm. C-NMR (DMSO-d6, 400 MHz): d ¼ 187.7 (ꢁCO), 144.6 (C ),
b
b
0
0
0
þ
0 0
31.0 (C4ʺ), 131.0 (C4 ), 130.5 (C3 5 ), 129.4 (C2ʺ6ʺ), 130.9 (C2 6 ), 124.0 (C3ʺ5ʺ),
19.1 (C ) ppm. ESI-MS (m/z): (M þ23): 339.16. Analytically calculated (%) for
a
C H ClN OS: C, 60.66; H, 4.14; N, 8.84, S, 10.12. Found: C, 61.05; H, 4.10; N, 8.78,
1
6
13
2
S, 10.20%.
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