Novel Piperine Derivatives with Antidiabetic Effect as PPAR-γ Agonists

Article abstract of DOI:10.1111/cbdd.12760

Piperine is an alkaloid responsible for the pungency of black pepper. In this study, piperine isolated from Piper nigrum L. was hydrolyzed under basic condition to obtain piperic acid and was used as precursor to carry out the synthesis of twenty piperine derivatives containing benzothiazole moiety. All the benzothiazole derivatives were evaluated for their antidiabetic potential by OGT test followed by assessment of active derivatives on STZ-induced diabetic model. It was observed that nine of twenty novel piperine analogues (5b, 6a-h), showed significantly higher antidiabetic activity in comparison with rosiglitazone (standard). Furthermore, these active derivatives were evaluated for their action as PPAR-γ agonists demonstrating their mechanism of action. The effects on body weight, lipid peroxidation, and hepatotoxicity after administration with active derivatives were also studied to further establish these derivatives as lead molecules for treatment of diabetes with lesser side-effects.

Full text of DOI:10.1111/cbdd.12760

Chem Biol Drug Des 2016
Research Article
Novel Piperine Derivatives with Antidiabetic Effect as
PPAR-c Agonists
1
1,
Chetna Kharbanda , Mohammad Sarwar Alam *,
Plant-derived products whether pure or in crude form
received immense attention in recent years. Several herbs
and their formulations have been listed in ancient literature
for the treatment of numerous diseases including diabetes
mellitus (11). Characterized by high blood sugar, diabetes
mellitus occurs due to impaired insulin sensitivity or secre-
tion. The statistical data according to WHO revealed that
the prevalence of diabetes which was estimated to be
1
,
1
1
Hinna Hamid *, Kalim Javed , Sameena Bano ,
1
2
3
Yakub Ali , Abhijeet Dhulap , Perwez Alam and
3
M. A. Qadar Pasha
1
Department of Chemistry, Faculty of Science, Hamdard
University, New Delhi 110 062, India
CSIR Unit for Research and Development of Information
Products, Pune 411038, India
Functional Genomics Unit, CSIR-Institute of Genomics &
Integrative Biology, Delhi, 110025, India
Corresponding authors: Mohammad Sarwar Alam,
2
2
.8% in 2000 will rise to 4.4% in 2030 (12). Therefore, the
3
regulation of fast growing diabetes mellitus has been still a
challenge for research scientists. Furthermore, the drugs
derived from natural sources are being emphasized more
than those derived from synthetic routes because of their
lesser side-effects. Piperine is one such plant-derived alka-
loid which is well known for its wide spectra of biological
activities. It is found as major constituent in the fruits of
Piper nigrum L., commonly known as black pepper. The
clinical and pharmacological studies have proved the utility
of piperine as antidepressant (13), antipyretic, analgesic,
anti-inflammatory (14), antioxidant (15), hepatoprotective
*
msalam@jamiahamdard.ac.in, msalam5555@gmail.com;
Hinna Hamid, hhamid@jamiahamdard.ac.in
Piperine is an alkaloid responsible for the pungency of
black pepper. In this study, piperine isolated from
Piper nigrum L. was hydrolyzed under basic condition
to obtain piperic acid and was used as precursor to
carry out the synthesis of twenty piperine derivatives
containing benzothiazole moiety. All the benzothiazole
derivatives were evaluated for their antidiabetic poten-
tial by OGT test followed by assessment of active
derivatives on STZ-induced diabetic model. It was
observed that nine of twenty novel piperine analogues
(16), and antidiabetic (17,18) agent. It has also been
accounted that piperine enhances the bioavailability of
several synthetic and natural drugs like sulfadiazine, strep-
tomycin, rifampicin (19), pyrazinamide, isoniazid, nateglin-
ide (20), propranolol (21), curcumin, and Boswellic acid
(
5b, 6a-h), showed significantly higher antidiabetic
activity in comparison with rosiglitazone (standard).
Furthermore, these active derivatives were evaluated
for their action as PPAR-c agonists demonstrating their
mechanism of action. The effects on body weight, lipid
peroxidation, and hepatotoxicity after administration
with active derivatives were also studied to further
establish these derivatives as lead molecules for treat-
ment of diabetes with lesser side-effects.
(
22). Moreover, it has recently been reported that piperine
exerts anti-adipogenesis effect by activating PPAR-c
receptors (23,24). As PPAR-c also plays a crucial role in
insulin sensitization (25), the present study aims at the syn-
thesis of new piperine derivatives containing benzothiazole
moiety and their evaluation for antidiabetic activity as
PPAR-c agonists.
Key words: amide linkage, antidiabetic, gene expression,
piperine, PPAR-c
Experimental Protocols
Received 9 December 2015, revised 15 February 2016 and
accepted for publication 10 March 2016
Isolation of piperine
Grounded black pepper (5 kg) was placed in cold percola-
tor and 15 L of chloroform was added to it. The extract
was filtered through Buchner funnel to remove plant mate-
rial, and the filtrate was concentrated on rotaevaporator.
Petroleum ether was slowly added to the concentrated
paste. Precipitates so obtained were filtered and crystal-
lized from methanol. Yellow-colored piperine (I) (30 g) was
Benzothiazoles have proved their biological importance in
bioorganic and medicinal chemistry, their unique bicyclic
structure allows diversified pharmacological activities, and
benzothiazole finds its utility as starting material for the
synthesis of several bioactive molecules reported as antidi-
abetic (1), antimicrobial (2), antiviral (3), antibacterial (4),
anticancer (5), anti-allergic (6), antifungal (7), anti-inflamma-
tory (8), anthelmatic, and anti-HIV agents (9,10).
1
obtained. H-NMR and melting point of the compound
were recorded and were found consistent with the
reported one (26).
ª 2016 John Wiley & Sons A/S. doi: 10.1111/cbdd.12760
1

Kharbanda et al.
General synthesis of 5-Benzo[1,3]dioxol-5-yl-
penta-2,4-dienoic acid N (substituted-
organic layer was dried on anhydrous sodium sulfate and
concentrated to give the final product as solid. The solid
product was purified from methanol to get pure compound
(Scheme 1).
0
benzothiazol-2-yl) amide (5a-j)/hydrazide (6a-j)
Piperine (1) isolated from Piper nigrum was added to 20%
alcoholic solution of potassium hydroxide and was refluxed
for 24 h. Reaction mixture was concentrated and poured
on ice. The reaction mass gradually neutralized with dil. HCl
was filtered to obtain solid. Solid product was recrystallized
from ethanol and identified as piperic acid (2). Substituted
benzothiazole reactants (3a-j, 4a-j) were synthesized using
known method (27). The weighed amount of piperic acid
In silico PPAR-c docking
Protein with Accession Number 3CS8 was selected and
downloaded from Protein Data Bank. This protein is
reported to bind with drug rosiglitazone. The protein was
imported, optimized, and minimized by removing unwanted
molecules and other defects reported by the software.
PPAR-c receptor is a dimer which has two monomers
chains (A & B). For the purpose of studies, chain B was
deleted and water molecules near the ligands were
retained. A low-energy minimized protein structure was
obtained which was used for grid generation involving
selected ligand as the reference as it signifies the binding
sites of drug with respect to the target. The generated grid
was used for docking of new molecules. Molecules drawn
in 3D form were refined by LigPrep module. The molecules
were subjected to OPLS-2005 force field to generate single
(1 mol) was dissolved in dry tetrahydrofuran. A pinch of
HOBt (10 mg) was added to reaction mixture. After half an
hour, 1.2 mole of 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide (EDC) was weighed and quickly added to reaction
mass under nitrogen atmosphere. The reaction mass was
kept on stirring for another half hour and then one equiva-
lent of other reactant (3 or 4) was added to it. Reaction mix-
ture was kept on stirring until the consumption of reactants.
The reaction mass was diluted with water, and extraction
was carried out using ethyl acetate. Corresponding desired
products (5a-j, 6a-j) were obtained from organic layer. The
Compound
a,4a,5a,6a
b,4b,5b,6b
c,4c,5c,6c
d,4d,5d,6d
e,4e,5e,6e
R
Compound
3f,4f,5f,6f
3g,4g,5g,6g
3h,4h,5h,6h
3i,4i,5i,6i
R
3
4-Cl
5-Cl
6-Cl
6-Br
6-F
4-OCH
6-OCH
3
3
3
3
6-OCH
4-CH
6-NO
2
CH
3
3
3
Scheme 1: Synthesis of piperine
derivatives.
3
3j,4j,5j,6j
2
2
Chem Biol Drug Des 2016

Novel Piperine Analogues
low-energy 3D structure while maintaining their chiralities.
Docking studies were carried using GLIDE software
mg/kg b.w. piperine, rosiglitazone, and active derivatives.
Dosing was carried out in same way for 15 days. Plasma
glucose level was scrutinized on 0, 7, and 15th day of
study by GOD-POD method.
(
Schr o€ dinger, NY, USA) with extra precision. This generates
favorable ligand poses which are further screened through
filters to examine spatial fit of the ligand in the active site.
Ligand poses which pass through initial screening are sub-
jected to evaluation and minimization of grid approximation
to generate Glide score.
Body weight
Body weight of all the diabetic animals was measured
before carrying out the in vivo antidiabetic study. Finally on
last day of study, body weights were again recorded to
understand the effect of treatment on weight.
Pharmacological evaluation
Animals
Healthy male Wistar rats were procured from Central Animal
House, Hamdard University, New Delhi. The experiments
were performed in accordance with the rules of Institutional
Animals Ethics Committee (registration number 757-
CPCSEA). Prior to the experiment, the animals were kept
on fasting for 14 h allowing access to water ad libitum only.
In vitro PPAR transactivation assay
Human embryonic kidney (HEK 293) cells were cultured in
DMEM containing 10% FBS at 37 °C in 5% CO2 humidi-
fied atmosphere until 70–80% cell confluency was
obtained. Cells were inoculated in 96-well plate containing
approximately 70 000 cells per well and transfected with
2
2
.5 lL PPRE-Luc, 6.67 lL PPAR-c, 1.0 lL Renilla, and
0 lL Lipofectamine. After 5 h of transfection, 10 lM of
In vivo antidiabetic evaluation by OGTT
test derivatives was added to cells for 24 h. Cells were
collected with the help of lysis buffer, and luciferase activ-
ity was monitored on luminometer using luciferase assay
kit according to the manufacturer’s instructions. Piperine
and rosiglitazone were taken as reference drugs.
All the synthesized derivatives were primarily evaluated for
oral glucose tolerance by earlier reported method (28).
Overnight fasted animals (130–180 g) were randomly
divided into 24 groups containing six rats per group. A
group of healthy rats was administered orally with vehicle
(10% carboxymethylcellulose) and was labeled as control.
Two groups treated with 36 mg/kg b.w. piperine and
rosiglitazone were taken as standard groups. Remaining
groups were orally administered with 36 mg/kg b.w. of
synthesized derivatives suspended in 10% CMC. All the
groups were orally given 3 g/kg b.w. glucose solution after
Gene expression
3T3-L1 cells (American Type Culture Collection) were cul-
tured to attain 70% confluency and transferred to 24-well
plate. Cells were incubated for 24 h at 37 °C and 5% CO2
and treated with 10 lM of most active compound, rosigli-
tazone as positive control and DMSO as negative control.
Treated cells were then transferred to micro-centrifuge
30 min of dosing. Plasma glucose level was tested just
prior to glucose load and after 30 and 90 min with the
help of GOD-POD kit. Working solution of each sample
was prepared as per the manufacturer’s instructions. The
wavelength of each solution and standard solution avail-
able in kit was recorded at 505 nm. Glucose concentration
in the sample can be calculated using the following
formula:
ꢀ
tubes, and total RNA was isolated by TRI Reagent
(Molecular Research Centre, Cincinnati, OH, USA). The
quantity and quality of RNA were determined on a Nano-
Drop ND-2000c spectrophotometer, and integrity was veri-
fied on a 1.5% agarose gel. The total RNA (1 lg) so
obtained was used to generate cDNA using an EZ-first
strand cDNA synthesis kit for RT (reverse transcription)–
PCR (Biological Industries, Cromwell, CT, USA). PEARL PRI-
MER software was used to design primers of PPAR-c and
b-actin for real-time PCR. Reactions were run at 95 °C for
10 min followed by 40 cycles of 95 °C for 15 second and
Glucose ðmg=dLÞ ¼ ðAbsorbance of Sample=
Absorbance of StandardÞ
ꢀ
Concentration of Standard.
6
0 °C for 1 min. Real-time PCR was performed in triplicate
on an ABI Prism 7300 Sequence Detection System
(Applied Biosystems, CA, USA) using the SYBR Green
PCR Master Mix (Applied Biosystems). PCR was repeated
two times for each gene and each sample. Relative tran-
In vivo antidiabetic activity on STZ-induced
diabetic model
Diabetes was induced by intraperitoneal administration of
fresh solution of streptozotocin (45 mg/kg b.w.) prepared
in citrate buffer (pH 4.5, 0.1 M) (29). The animals having
blood glucose level more than 250 mg/dL were divided
into fourteen groups of six animals each. Control group
comprised of healthy animals and diabetic control contain-
ing diabetic animals were administered with 1% Tween-80
only. Other groups were treated with oral dose of 36
script quantities were calculated using the C method with
t
b-actin as the endogenous reference gene.
Acute hepatotoxicity studies
Two derivatives which showed significant plasma glucose-
lowering activity were further evaluated for hepatotoxicity
Chem Biol Drug Des 2016
3

Kharbanda et al.
risk. For this purpose, three times higher dose i.e.
1
08 mg/kg b.w of selected derivatives was orally adminis-
tered to two separate groups of STZ-induced diabetic rats.
A group of three untreated diabetic rats was taken as con-
trol. Group administered orally with 108 mg/kg b.w. piper-
ine was taken as reference group. The livers of all rats
were excised after 5 h of dosing and preserved in 10%
formalin.
Lipid peroxidation assay
Lipid peroxidation effect of selected derivatives was evalu-
ated by modified thiobarbituric acid reactive species
(TBARS) assay. The liver specimen excised for hepatotoxi-
city risk evaluation was sliced and used for preparing
homogenate. The solution was prepared by adding
0
.2 mL of sodiumdodecyl sulfate (SDS; 8.1%), 1.5 mL of
acetic acid (20%), and 1.5 mL of 0.9% thiobarbituric acid
to 200 mL of homogenate. This solution was diluted with
distilled water to make the final volume of 4 mL. The mix-
ture was placed in boiling water to start reaction and then
quickly cooled. Gradually, 1 mL of distilled water and
5
.0 mL of butanol/pyridine (15:1, v/v) were added followed
by centrifugation at 10 000 9 g for 10 min. The absor-
bance of upper layer was recorded at 532 nm. To prevent
exogenous TBARS formation, 28 mL of butylated hydroxy-
toluene (1 mmol/L) was added. The quantification was
performed using
a
molar absorption coefficient of
5
ꢁ1 ꢁ1
1
.56 9 10 cm mol , and the result was expressed as
nmol malondialdehyde (MDA) per 100 mg tissue (30).
Figure 1: Docking images of piperine, rosiglitazone, and active
compounds 6c and 6d.
Results and Discussion
Docking studies
loading glucose on normal rats. The results showed that
unlike docking score, piperine did not assuage plasma
glucose level as significantly as rosiglitazone. However, of
twenty synthesized derivatives, nine derivatives (5b, 6a-h)
exhibited better alleviation in plasma glucose level than
rosiglitazone, while seven derivatives (5b, 5c, 5d, 5f-i)
improved plasma glucose level concentration as consider-
ably as rosiglitazone (Figure 2). Comparison of antidiabetic
activity of synthesized derivatives with that of piperine also
revealed that nineteen derivatives (except 6i) were more
potent antidiabetic agents than piperine.
In 2012, Coman et al. (31) reported interaction of piperine
with ligand binding domain of PPAR-c and related it with
antidiabetic potential of piperine (32). Therefore, structures
of all the synthesized piperine derivatives were docked
against ligand binding domain of PPAR-c before perform-
ing in vivo antidiabetic assay. Piperine and rosiglitazone
were taken as reference ligands. It was found that piperine
(
(
ꢁ6.5) showed higher dock score than rosiglitazone
ꢁ5.72). Captivatingly, all the derivatives except for 6i
exhibited appreciably higher docking score than rosiglita-
zone and piperine. The rigid 3D structure of compound 6i
could not be aligned into the receptor site of PPAR-c to
carry out the docking study. Rest of the derivatives
showed dock scores more than ꢁ7.00, and their docking
images exhibited that these small ligands accommodated
themselves well inside the large pocket of PPAR-c domain
resulting in high dock score (Figure 1, Table S1, support-
ing information).
To avoid the superfluous use of animals, only nine active
derivatives (5b, 6a-h) that showed more antidiabetic
potential than rosiglitazone were assessed for their effect
on plasma glucose concentration in streptozotocin (STZ)-
induced diabetic model. It was found that all these deriva-
tives possessed significantly higher antidiabetic activity in
comparison with the standards, piperine and rosiglitazone.
Additionally, the results were consistent with docking stud-
ies as well as with the results of oral glucose tolerance
test. All the derivatives restored plasma glucose level near
to normal level on 15th day of study (Figure 3). Therefore,
the in vivo study clearly illustrated that the coupling of
In vivo antidiabetic activity
The antidiabetic potential of twenty derivatives which
demonstrated high dock score was initially assessed by
4
Chem Biol Drug Des 2016

Novel Piperine Analogues
Figure 2: Antidiabetic effect of treating
Wistar rats with synthesized compounds by
oral glucose tolerance test. Data is analyzed
by one way ANOVA followed by Dunnett test
and expressed as mean ꢃ SEM from six
observations; * represents change as
compared to control; ** indicate p < 0.01 &
*
indicates p < 0.05.
Figure 3: Antidiabetic effect of active synthesized compounds on
STZ-induced diabetic animals. Data is analyzed by one way ANOVA
followed by Dunnett test and expressed as mean ꢃ SEM from six
Figure 4: In vitro PPAR-c transactivation assay on 3T3-L1 cell
line.
observations;
* represents change as compared to diabetic
control; ** indicates p < 0.01 & *** indicates p < 0.001.
In vitro PPAR transactivation assay
piperine with benzothiazole elevated antidiabetic potential
of piperine which is the main objective of study.
The consistency between docking results and in vivo
studies demonstrated that the activity of synthesized
piperine derivatives might be as a consequence of their
action on PPAR-c. The active derivatives were hence
analyzed by in vitro PPAR transactivation with intent to
validate the results of all the studies performed. The
derivatives 5b, 6a-h extensively transactivated PPAR-c
but to a lesser extent than rosiglitazone whereas piperine
exhibited very less PPAR-c transactivation (Figure 4). This
clearly affirmed the activation of PPAR-c by synthesized
derivatives. The results of in vitro PPAR-c transactivation
assay, despite in agreement with in vivo results, were less
significant. This deviation might be attributed to the syn-
ergistic effect of other genes and mediators along with
PPAR-c in in vivo systems.
Structure–activity relationship
From the results, following structure–activity relationship
was drawn:
ꢂ the derivatives containing C(O)-N-N bond were found to
be more active as antidiabetic agent and showed higher
dock score than derivatives with amide bond.
ꢂ the derivatives substituted with nitro group were least
active as antidiabetic agents.
ꢂ methyl substitution on benzothiazolyl ring imparted less
significant antidiabetic activity than ethoxy followed by
methoxy substitution.
Body weight
One of the major concerns of oral antidiabetic treatments
is increase in body weight. PPAR-c plays a vital role in
management of lipids and encompasses differentiation of
ꢂ among halide substitutions, fluoro substitution on ben-
zothiazolyl ring illustrated least antidiabetic potential.
Chem Biol Drug Des 2016
5

Kharbanda et al.
pre-adipocytes into adipocytes resulting in weight gain
Lipid peroxidation
(
33). It is therefore necessary to maintain a proper balance
Toxicity and degenerative processes are generally associ-
ated with lipid peroxidation (LPO). The results showed that
the induction of animals with STZ (diabetic control) ele-
vated lipid peroxide level by 2.43-fold. It was observed that
the derivatives 6c and 6d significantly suppressed the pro-
duction of LPO content. Derivatives 6c and 6d increased
LPO level merely by 11.29% and 8.87%, respectively,
whereas rosiglitazone exhibited comparatively less signifi-
cant inhibition and showed 38.70% increase (Figure 7).
The protective effect of these derivatives against hepato-
toxicity might be attributed to the lesser production of LPO
content after administration of these derivatives.
of pleiotropic gene, PPAR-c in order to improve glucose
homeostasis and prevent adipogenesis at the same time
(
34). However, piperine was not found to be involved in
weight gain, but the effect of synthesized derivatives on
body weight of diabetic animals post-treatment was stud-
ied carefully as they behaved as PPAR-c agonists. The
data of nine active derivatives (5b, 6a-h) is presented in
Figure 5. It was found that the treatment with active
derivatives 6a, 6c, 6d, and 6f substantially controlled and
did not allow unusual rise in body weight as observed with
rosiglitazone after 15 days of study. Weight of rats treated
with the derivatives 6a, 6c, 6d, and 6f was increasing
gradually and not abruptly unlike observed in case of mar-
keted oral treatments against diabetes. The remaining
active derivatives (5b, 6b, 6e, 6g, and 6h) also maintained
body weight but not as appreciably as derivatives 6a, 6c,
PPAR-c gene expression
The effect of the most promising antidiabetic derivatives
6c and 6d on the expression of PPAR-c target gene was
also evaluated (Figure 8). The standard drug rosiglitazone
enhanced PPAR-c expression by 1.5-folds, while piperine
was found to amplify the expression comparatively to
much less extent (0.71 folds). However, both the active
derivatives 6c and 6d exhibited 1.12- and 1.27-folds aug-
mentation in PPAR-c expression, which was found to be
more than piperine but less effective than rosiglitazone.
6
d, and 6f during the course of study.
Hepatotoxicity
Hepatic toxicity is another major drawback of oral antidia-
betic drugs and remains a major reason for drug with-
drawal from pharmaceutical development and clinical use.
In some of the initial PPAR agonists, hepatotoxicity was a
serious concern (35). Keeping these reports in view, the
effect on hepatic tissue after treatment with two most
active derivatives 6c and 6d was analyzed. The animals of
diabetic control showed enormous degeneration of tissues
and fatty changes in the liver lobule. The fatty change was
mainly seen in the centrilobular area (Figure 6). Conversely,
treating the groups with piperine, 6c, and 6d minimized
the changes caused by the induction of diabetes and pre-
sented normal histological pattern in the hepatic tissue.
Chemistry
A focused library of twenty piperine derivatives was syn-
thesized. The structures (5a-j, 6a-j) were determined by
spectral data and elemental analysis. Melting points were
determined on digital instrument and are uncorrected. The
amide coupling in 5a-j derivatives was confirmed by the
presence of singlet of NH proton in aromatic region at d
7.52–7.62 p.p.m. The coupling with substituted benzothia-
zole hydrazine (6a-j) was confirmed by the appearance of
two singlets due to NH protons, one singlet appearing in
the aromatic region (d 7.47–7.60 p.p.m.) and other at d
4
.80–4.90 p.p.m. The protons on conjugated double
bonds also appeared downfield as a multiplet in the range
of d 6.50–6.90 p.p.m. ESI-MS of all derivatives showed
+
[
M+H] peaks. Elemental analysis was carried out on
CHNS Elementar (Vario EL III). The experimental data of
each compound has been provided in supplementary
information.
Conclusion
It can be concluded from the present study that the most
of synthesized piperine derivatives are potential antidiabetic
agents with maximum effect observed for compounds 6c
and 6d. These compounds exhibited their effect by
enhancing PPAR-c gene expression. Moreover, the com-
pounds 6c and 6d did not allow unusual gain in body
weight which is generally observed in subjects suffering
from diabetes. The library of these derivatives can be
Figure 5: Change in body weight after 15 days of study on STZ-
induced diabetic rats. Data is analyzed by one way ANOVA followed
by Bonferroni ‘t’ test and expressed as mean ꢃ SEM from six
observations; * represents significant change as compared to
diabetic control; # represents significant change as compared to
normal control. ** indicates p < 0.01 & * indicates p < 0.05; ##
indicates p < 0.05 & # indicates p < 0.01.
6
Chem Biol Drug Des 2016

Novel Piperine Analogues
Figure 6: Histological study of STZ-induced
rat liver. Where; PT, Portal triad; BD, bile
duct; CV central vein; F, fatty change in
Hepatocyte.
Figure 8: PPAR-c gene expression evaluation of compounds 6c
and 6d in comparison with standards, piperine and rosiglitazone.
Data is analyzed by one way ANOVA followed by Dunnett test and
expressed as mean ꢃ SEM from three observations. * represents
change as compared to control; ** indicates p < 0.01.
Figure 7: Lipid peroxidation assay of compounds 6c and 6d.
therefore taken into further consideration to develop
prospective antidiabetic drug with fewer side-effects.
research facilities. CK is also thankful to University Grant
Commission for providing financial assistance.
Acknowledgments
Conflict of Interest
The authors wish to express their thanks to Dr G N Qazi,
Vice Chancellor, Jamia Hamdard for providing necessary
The authors have no conflict of interest.
Chem Biol Drug Des 2016
7

Kharbanda et al.
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Table S1. Dock score of all the synthesized compounds.
Chem Biol Drug Des 2016
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