Design, synthesis and bioactivity evaluation of thiazolidinedione derivatives as partial agonists targeting PPARγ

Article abstract of DOI:10.1016/j.bioorg.2021.105342

Thiazolidinedione (TZD) is a novel peroxides proliferator activated receptor γ (PPARγ) agonist with many side effects. Herein, we developed a series of novel TZD analogues as partial agonists targeting PPARγ. The study of anti-hyperglycemic activity and anti-inflammatory activity enabled us to identify a novel compound, 4 g, which quickly recover the blood glucose of mice at the concentration of 100 mg/kg, and show similar anti-inflammatory activity to ibuprofen at the concentration of 20 mg/kg. The competitive binding assay confirmed direct binding of 4 g to the LBD of PPARγ with IC₅₀ being 1790 nM, and dose-dependently increased the transcriptional activity of PPARγ. Besides, through computer-aided drug design software simulation docking, it was found that compound 4 g showed the best binding ability to target protein PPARγ. Furthermore, because of the introduction of benzene containing group at N3 position, the stability of H12 in the active pocket is reduced and the stability of H3 and β-fold is increased, showing the characteristics of some PPARγ agonists, based on the docking model analysis. Together, these results suggest that 4 g is a promising PPARγ agonist that deserves further investigation.

Full text of DOI:10.1016/j.bioorg.2021.105342

Bioorganic Chemistry 116 (2021) 105342
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Design, synthesis and bioactivity evaluation of thiazolidinedione
derivatives as partial agonists targeting PPARγ
,
,*
Juan Suna, Han-Yu Liub c, Yi-Heng Zhanga, Ze-Yu Fanga, Peng-Cheng Lvb
a School of Biological & Chemical Engineering, Zhejiang University of Science & Technology, Hangzhou 310023, People’s Republic of China
b The Joint Research Center of Guangzhou University and Keele Univeristy for Gene Interference and Application, School of Life Science, Guangzhou University,
Guangzhou 510006, People’s Republic of China
c College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
A R T I C L E I N F O
A B S T R A C T
Keyword:
Thiazolidinedione (TZD) is a novel peroxides proliferator activated receptor γ (PPARγ) agonist with many side
effects. Herein, we developed a series of novel TZD analogues as partial agonists targeting PPARγ. The study of
anti-hyperglycemic activity and anti-inflammatory activity enabled us to identify a novel compound, 4 g, which
quickly recover the blood glucose of mice at the concentration of 100 mg/kg, and show similar anti-
inflammatory activity to ibuprofen at the concentration of 20 mg/kg. The competitive binding assay
confirmed direct binding of 4 g to the LBD of PPARγ with IC50 being 1790 nM, and dose-dependently increased
the transcriptional activity of PPARγ. Besides, through computer-aided drug design software simulation docking,
it was found that compound 4 g showed the best binding ability to target protein PPARγ. Furthermore, because of
the introduction of benzene containing group at N3 position, the stability of H12 in the active pocket is reduced
and the stability of H3 and β-fold is increased, showing the characteristics of some PPARγ agonists, based on the
docking model analysis. Together, these results suggest that 4 g is a promising PPARγ agonist that deserves
further investigation.
Thiazolidinedione derivatives
PPARγ partial agonist
anti-hyperglycemic activity
Anti-inflammatory activity
1. Introduction
many kinds of thiazolidine-2,4-diketone compounds have been used as
anti-hyperglycemic drugs since 1997, such as pioglitazone, rosiglitazone
Diabetes is a common endocrine disease, which is characterized by a
rise in blood glucose level due to impaired glucose metabolism, that is,
when the pancreas cannot produce enough insulin or the body cannot
effectively use the insulin it produces, glucose metabolism will be
impaired [1-4]. According to the latest epidemiological data, the global
and regional impacts of diabetes in 2017 and 2045 were estimated.
According to IDF (International Diabetes Federation), in 2017, there
were 451 million (18–99 years old) diabetics in the world. These figures
are expected to increase to 693 million by 2045 [5]. Therefore, how to
prevent and treat type 2 diabetes reasonably is still an urgent problem.
Diabetes mellitus is divided into non-insulin dependent diabetes melli-
tus (NIDDM, type 2 diabetes mellitus) and insulin dependent diabetes
mellitus (IDDM, type 1 diabetes mellitus). Type 2 diabetes is the main
type of diabetes in all patients, accounting for 90–95% of the confirmed
cases of diabetes in the world [6-8].
and so on [9-12]. It has been found that thiazolidinediones can regulate
insulin tissue sensitivity and control glucose and lipid uptake and stor-
age by activating peroxides proliferator activated receptor γ (PPARγ), so
as to exert anti-hyperglycemic activity [13-18]. However, with the
application of thiazolidinediones, the over activation of PPARγ by
thiazolidinediones leads to many side effects, such as long-term
administration of rosiglitazone will cause the increase of liver trans-
aminase activity, mild edema and anemia. Therefore, the development
of new effective and safe thiazolidinedione derivatives, as a new type of
anti-hyperglycemic drugs, is still a research hotspot [19-22].
It has been reported that optimal approach to achieve insulin
sensitization did not need full agonism of PPARγ[23]. Therefore, ex-
plorations of novel PPARγ ligands with moderate modes of activation
are required for the development of therapeutic agents for insulin
resistance and T2DM. The three-dimensional structure of PPARγ mainly
consists of four parts, activation factor-1 (AF-1), DNA Binding Domain
(DBD), Hinge region, and Ligand Binding Domain (LBD) which consists
of extra ligand binding dimerization transactivation factor (AF-2). LBD
Thiazolidine-2,4-dione derivatives (TZDs) are a kind of oral antidi-
abetic drugs. Since ciglitazone, a thiazolidine-2,4-dione compound, was
reported to improve blood glucose level by increasing insulin sensitivity,
* corresponding author.
https://doi.org/10.1016/j.bioorg.2021.105342
Received 14 April 2021; Received in revised form 26 August 2021; Accepted 6 September 2021
Available online 11 September 2021
0045-2068/© 2021 Elsevier Inc. All rights reserved.

J. Sun et al.
Bioorganic Chemistry 116 (2021) 105342
provides the binding site for the ligands where hydrogen bonding in-
teractions can be seen generally between the agonists and Ser289,
His323, His449 and Tyr473 amino acid residues [24–26] Binding to
helix 12 of the LBD of PPARγ is required for full agonist activity, how-
ever, partial agonists activate PPARγ using a helix 12 independent
mechanism. Intermediate and partial agonists do not correlate with
stabilization of H12, they stabilize the β-sheet region and H3 of the LBD
instead[27-29]. Therefore, this is the key basis for the design of partial
agonists of PPARγ.
2.2. Synthesis of target compounds 4a-4i
The synthetic protocol of thiazolidinedione derivatives presented
here is shown in Scheme 1. It was synthesized for the first time and
prepared in three steps.
2.3. Crystal structures of compounds 4b
Crystals of compound 4b (CCDC number: 2011837) was obtained
from ethanol solution. Fig. 4 shows a perspective view of the monomeric
unit with the atomic numbering scheme; Fig. 5 depicts the intra-mo-
lecular and inter-molecular hydrogen bonds. Crystallographic data, de-
tails of data collection and structure refinement parameters are listed in
Table 1. The intermolecular hydrogen bond lengths (Å) and bond angles
(◦) of Compounds 4b (Å and ◦) are listed in Table 2.
In this paper, we introduce 2 - (4-bromophenyl) ꢀ 2-ethoxyl struc-
ture at N3 to eliminate the hydrogen bond with amino acids at the active
site in order to avoid over excited PPARγ activity. In addition, it is found
that the existence of double bonds will reduce the activity of the exci-
tation [30]. Therefore, the methylidene structure with different sub-
stituents is introduced at C5 to form 21 new thiazolidinedione
derivatives (Fig. 1).
Single crystals of 4b (0.13 mm × 0.18 mm × 0.11 mm) was mounted
ADMET properties are important conditions and major parts of
pharmacokinetics. Using ADME module of CAD software, we screened
21 thiazolidinedione derivatives (Supplement files) in pharmacoki-
netics. Compounds located inside the innermost oval have the best re-
sults, we obtained 9 target compounds with good pharmacokinetic
properties (Fig. 2). Finally, the 9 target compounds were obtained by
organic synthesis.
on
a
D-8 venture diffractometer equipped with graphite-
monochromated MoK
α
(λ = 0.71073 Å) radiation. For single crystal
4b, a total of 8509 reflections were collected, of which 5725 were
unique with Rint = 0.023 and 5725 observed reflections with I > 2
σ
(I)
were used in the succeeding structure calculations. The final cycle of
refinement of full matrix least-squares was converged to R = 0.0361 and
wR = 0.1081. The highest and lowest residual peaks in the final dif-
ference Fourier map are 0.47 and ꢀ 0.41 e/Å3, respectively.
2. Results and discussion
2.4. Molecular docking
2.1. Structure-Based design of small molecules
Molecular docking of the synthesized compounds was performed
using a previously reported PPAR-gamma LBD crystal structure (PDB
code 4EMA) [32]. The energy values of the 9 compounds are showed in
Fig. 6.
Partial agonists interact mainly with arm III through a hydrogen
bond with Ser342 and with arm II through several hydrophobic in-
teractions [31]. This binding mode has two simultaneous effects: a
destabilization of H12 and a stabilization of H3 that affects the
recruitment of coactivators and decreases the transactivation activity
(potential) of PPARγ[32]. As shown in Fig. 3, when INT131, a partial
agonist, binds to the LDB of PPARγ, it does not contact and stabilize helix
12 but instead wraps around helix 3 to stabilize helix 3 and the β-sheet
region. The apolar region generated by Ile341, Cys285, Gly284, and
Phe363 is also important for its interaction with the aromatic rings of
INT131. Therefore, based on the basic skeleton of thiazolidinedione, we
added 4′-bromoacetophenone skeleton at the N2 position. It can effec-
tively insert the apolar region formed by PPARγ H3 helix and act as
an“anchor”to anchor the molecule on PPARγ. Besides, the main skeleton
of thiazolidinedione can form strong hydrogen bonds to enhance the
stability of the binding of small molecules to PPARγ. At the same time,
the benzene ring with different substituents could stabilize the β-sheet
region through pi-alkyl interaction, further enhancing the affinity with
PPARγ.
Through the molecular simulation docking scoring function, it can be
found that the target compound 4 g shows the best binding ability. As we
know, the difference among target compounds is just substituent,
therefore, their binding mode is substantially identical. Since substan-
tially the same, the difference exists in the substituent. Some sub-
stituents can form the interaction force, so that the combination is
enhanced. Some affect the activity by influencing peripheral electronic
arrangement. Therefore, we choose compound 4 g for model analysis.
The molecular docking model of target compound 4 g and control
compound Rosiglitazone with target protein PPARγ is shown in Fig. 7. It
can be observed that the target compound binds well to the active site in
the form of Rosiglitazone conformation. Moreover, due to the intro-
duction of N3-containing benzene ring structure on thiazolidinedione
ring, the hydrogen bond interaction between thiazolidinedione structure
and TYR473 on target protein’s helix H12 is replaced, which reduces the
stability of helix H12. In addition, because the structure of thiazolidi-
nedione is in the middle, it is closer to helix H3, and it can be found from
Fig. 1. Structures of some compounds and strategy of designing.
2

J. Sun et al.
Bioorganic Chemistry 116 (2021) 105342
Fig. 2. ADMET properties predicted for twenty-one novel compounds. Compounds located inside the innermost oval have the best results. The nine compounds were
as follows: 4a-4i (from top to bottom, from left to right).
Fig. 3. Simulated interaction between target compounds and PPARγ.
Scheme 1. Synthetic route of target compounds. Reagents: (i) 2,4-dibromoacetophenone, K2CO3, Ethanol; (ii) Piperidine, Ethanol, 90℃.
figure that a hydrogen bond will be formed with CYS285 on helix H3,
which is more conducive to stable binding of pocket H3 and β-fold re-
gion. Fig. 8 could also confirm this result. Based on the literature reports
that some activators of PPARγ tend to stabilize the helix H3 and β - fold
region of LBD binding pocket, and reduce the stability of helix H12, our
designed target compound is consistent with the characteristics of
PPARγ partial activator, which theoretically supports high efficiency
and low toxicity [32].
2.5. Anti-hyperglycemic activity
Through four weeks of mice anti-hyperglycemic acitivity test, we
received a total of four groups of mouse blood glucose data, which is
shown in Table 3. The normal group and model group only took solvents
(Carboxymethyl Cellulose Sodium, CMC), the drug groups A1 (100 mg/
kg/d) and A2 (50 mg/kg/d) were given compound 4 g.
As shown in the Table 3, the blood glucose value of the model group
increased every week, and there was no significant difference between
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J. Sun et al.
Bioorganic Chemistry 116 (2021) 105342
Table 2
Intermolecular Hydrogen Bond Lengths (Å) and Bond Angles (◦) of Compounds
4b (Å and ◦)
Compounds
D-H… A
d(D-
H)
d (H…
d (D…
∠DHA
A)
A)
4b
Inter
C (7) –H (7) …
0.93
2.60
3.450
(6)
153′
O (2)
Fig. 4. Molecular structures of the compound 4b with atomic
numbering scheme.
Fig. 6. The molecular docking values of the 9 compounds.
experimental group and the model group, but there was no significant
difference between the experimental group and the normal group, which
proved that the blood glucose of the experimental group had returned to
the normal level, and it can be seen from the data that the effect of A1
was better than that of A2, which confirmed that the drug concentration
was relatively large, which was conducive to the recovery of blood
glucose. In terms of the magnitude of the respective trends, there was
significant difference between the experimental group and the model
group after two weeks of gavage, but there was no significant difference
between the experimental group and the normal group, which proved
that the blood glucose of the experimental group was stable and did not
cause significant hypoglycemia with the prolongation of gavage
administration time. One week after stopping gavage administration,
there was no significant difference between the experimental group and
the model group, while the experimental group has a significant dif-
ference compared with the normal group, which proved that the blood
glucose in the experimental group increased back to 20.5 ± 3.7 and 17.7
± 3.8 after stopping intragastric administration, and the blood glucose
value was unstable. It can be inferred that the compound 4 g has the
effect of lowering blood glucose. In a proper range, the higher the
concentration of the drug, the better the recovery of blood glucose, and
the longer the intragastric administration the medicine time is advan-
tageous to receive the better treatment effect.
Fig. 5. Crystal packing of the compounds 4b.
Table 1
Crystallographic data, details of data collection and structure refinement
parameters.
Compounds
4b
Empicical Formula
Formula weight
Crystal system
Space group
a (Å)
C
18H11BrFNO3S
420.25
Triclinic
P1
7.3250(8)
8.4387(9)
14.2741(16)
89.625(4)
87.826(4)
68.045(3)
817.73(16)
2
b (Å)
c (Å)
α
(o)
β (o)
γ (o)
V (Å)
Z
D calc /g cm -3
1.707
θ range (o)
2.6–27.3
420
F(000)
Reflections collected/unique
Data/restraints/parameters
Absorption coefficient (mmꢀ 1
8509/5725
5725 / 0 / 451
2.669
2.6. Anti-inflammatory activity
)
R1/ WR2[I > 2
σ
(I)]
0.0361 / 0.1081
0.0577 / 0.1081
0.804
PPARγ can inhibit inflammation in many ways. It has been reported
that PPARγ agonists can successfully treat colitis and psoriasis by
inhibiting epithelial inflammatory response [33-36]. Therefore, we
further explored the anti-inflammatory activity of the target compound,
and the data are shown in Fig. 9 and Table 4. As can be seen from the
Fig. 9, compared with the blank control group, ibuprofen in the positive
control group showed a significant ability to inhibit swelling (64%). For
our target compound 4 g, the inhibition ability was similar to that of
R1/ WR2(all date)
GOOF
the weekly blood glucose value of the model group and the initial blood
glucose value, which confirmed the stability of the model. One week
after gavage, there was
a significant difference between the
4

J. Sun et al.
Bioorganic Chemistry 116 (2021) 105342
Fig. 7. Molecular docking modeling of compound 4 g and Rosiglitazone with PPARγ. A) 2D modl of the interaction between compound 4 g and the PPARγ binding
site. B) 3D model of the interaction between compound 4 g and the PPARγ binding site. C) 2D model of the interaction between Rosiglitazone and the PPARγ binding
site. D) 3D model of the interaction between Rosiglitazone and the PPARγ binding site.
Fig. 8. Interaction diagram of active site amino acids with compounds 4a-4i.
5

J. Sun et al.
Bioorganic Chemistry 116 (2021) 105342
showed that compound 4 g was almost no ulcer.
Table 3
Anti-hyperglycemic activity values
2.8. PPARγ agonists assay
Groups
Dose mg/
kg/d
Blood glucose level(mmol/L)
0
1
2
3(week)
To further verify the targeted agonistic activity of the target com-
pound on PPARγ, We used the ELISA method to demonstrate the tar-
geted agonistic activity of the target compound 4 g against PPARγ on
293E cells. The results are shown in Table 5. The target compound 4 g
acted on the cells and caused an increase in intracellular PPARγ content
Normal
group
Model
group
A1
CMC
CMC
100
50
6.1 ±
4.8 ±
8.2 ±
7.6 ± 1.8b
1.5b
2.2b
0.4b
19.4 ±
7.3a
20.2 ±
7.5a
21.0 ±
7.3a
25.7 ±
7.5a
21.7 ±
11.5 ±
10.2 ±
20.5 ±
3.1a
3.7b
9.3b
3.7a
higher than Rosiglitazone at 62.5 and 12.5
μ
M. The increase in the
M was higher than
A2
14.8 ±
2.1a
8.8 ±
2.2b
15.9 ±
4.7b
17.7 ±
3.8a
amount of PPARγ caused by Rosiglitazone at 50
μ
compound 4 g. Through data analysis it can be determined that the
target compound acts on the cells and can increase the expression level
of PPARγ in the cells.
a: p < 0.05, significantly different from the normal group.
b: p < 0.05, significantly different from the model group.
2.9. Luciferase reporter assay
In order to verify whether compound 4 g could activate PPARγ, a
PPRE transcriptional activation reporter gene system was constructed in
293 T cells and its effect on PPARγ transcriptional activation was tested.
We found that compound 4 g increased PPARγ transcriptional activity in
a dose-dependent manner (Fig. 11). However, the effect of 12.5 μM
compound 4 g on PPARγ transcriptional activity was still weaker than
that of 1 μM Rosiglitazone, which proved that compound 4 g was a weak
PPARγ agonist.
2.10. PPARγ competitive binding assay
To verify whether compound 4 g can be used as a PPARγ ligand to
activate its transcriptional activity, we examined the ability of com-
pound 4 g to bind directly to PPARγ using a time resolved-fluorescence
Resonance Energy Transfer (TR-FRET) competitive PPARγ ligand bind-
ing assay kit. As shown in Fig. 12, Rosiglitazone showed competitive
binding with IC50 of 41 nM, compound 4 g showed concentration-
dependent competitive binding ability with IC50 of 1790 nM, indi-
cating that compound 4 g could bind PPARγ directly.
Fig. 9. Inhibition rate of ear swelling in mice after drug treatment (**: p <
0.01, remarkable significantly different from the positive group).
3. Conclusion
Table 4
Based on the structure of thiazolidinedione, 21 new thiazolidine-
dione derivatives were designed, and 9 target compounds with good
kinetic characteristics were screened by ADME module of CAD software.
Then, the target compounds were obtained by organic synthesis, and the
structures and properties of the target compounds were determined by
1H NMR and X-ray single crystal diffraction. The compound 4 g with the
best binding free energy was selected by molecular simulation docking
experiment. Using mice to test the anti-hyperglycemic ability of target
compound 4 g, it can be seen from the data that the target compound has
good anti-hyperglycemic activity and shows better anti-hyperglycemic
activity with the increase of drug concentration. In addition, based on
the relationship between the target PPARγ and the organism inflam-
mation, we further proved the anti-inflammatory activity of the target
compound through the ear swelling experiment in mice. The results
showed that the anti-inflammatory activity of compound 4 g was similar
to that of the positive control ibuprofen at the concentration of 20 mg/
kg. Besides, in vitro binding of 4 g to PPARγ was analyzed by a Lan-
thaScreen time-resolved fluorescent energy transfer (TR-FRET) PPARγ
competitive binding assay, the results showed that compound 4 g had
concentration-dependent competitive binding ability with IC50 of 1790
nM, indicating that compound 4 g could bind PPARγ directly. The
luciferase reporter assays exhibited that compound 4 g increased PPARγ
transcriptional activity in a dose-dependent manner. Finally, the binding
model between the target compound and the active site of PPARγ was
analyzed by the CAD software. We can find that the target compound 4 g
can perfectly combine with the active site. The thiazolidinedione
structure in the middle position could reduces the stability of H12 in the
Experimental data of ear swelling in mice
Indicators
0.5%
Ibuprofen +
0.5% CMC
Positive
Compound 4 g + 0.5% CMC
CMC
Blank
control
20 mg/kg
10 mg/kg
5 mg/kg
control
(10 mg/kg)
Right ear(g)
Left ear(g)
0.0566 ±
0.0041
0.0466 ±
0.0004
0.0536 ±
0.0077
0.052 ±
0.0058
0.062 ±
0.0021
0.0413 ±
0.0146
0.0396 ±
0.0052
0.0436 ±
0.0012
0.0383 ±
0.0057
0.045 ±
0.0132
Swelling
degree(g)
Swelling
rate(%)
0.0240 ±
0.0016
0.011 ±
0.0008
0.013 ±
0.0037
0.0183 ±
0.0038
0.025 ±
0.0009
73 ± 1
27 ± 2
28 ± 6
62 ± 7
70 ± 0.8
Inhibition
rate(%)
64 ± 4
63 ± 8
17 ± 9**
6 ±
0.5**
**: p < 0.01, remarkable significantly different from the positive group
ibuprofen at high concentration (20 mg/kg, 63%). Compound 4 g also
showed some inhibition ability at 10 mg/kg and 50 mg/kg. Anyway, the
target compound has anti-inflammatory activity.
2.7. Ulcerogenic activity
The mucosal damage for each stomach was examined with a
magnifying lens for the presence of macroscopically visible lesions. The
results of ulcerogenic activity are given in Fig. 10. The result was
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J. Sun et al.
Bioorganic Chemistry 116 (2021) 105342
Fig. 10. The mucosal damage for each stomach was examined with various concentrations of 4 g. (A) 5 mg/kg; (B) 10 mg/kg; (C) 20 mg/kg.
light: 12 h light and dark cycle), while maintaining a standard diet and
adequate drinking water.
Table 5
Targeting PPARγ activities
Compounds
Percentage/%
6.25 ( M)
μ
12.5 (μM)
50 (μM)
4.2. General method for the preparation of target compounds
4 g
5.24 ± 0.025
1.14 ± 0.015
6.85 ± 0.014
5.05 ± 0.036
9.08 ± 0.029
20.4 ± 0.055
Rosiglitazone
4.2.1. Synthesis of compound 3
In a 50 mL round-bottomed flask equipped with a reflux condenser
and a stirring bar, 2,4-thiazolidinedione (1 g, 8 mmol) and 2,4-dibro-
moacetophenone (2.368 g, 8 mmol) were added to the stirring abso-
lute ethanol (20 mL), and K2CO3 (0.59 g, 4 mmol) was added to the
mixture and refluxed for 12 at 65℃. Then the reactant solution was
concentrated in vacuum, and the residue was dissolved in ethyl acetate
(80 mL) and water (20 mL × 3). The organic phase was dried with
Na2SO4, concentrated, and recrystallized with ethanol to obtain the
intermediate compound 3.
4.2.2. Synthesis of target compounds (4a-4i)
In a 50 mL round-bottomed flask equipped with a reflux condenser
and a stirring bar, different substituents of benzaldehyde (0.6 mmol) and
piperidine (0.3 mmol) were added to the stirring absolute ethanol (20
mL), and compound 3 (0.6 mmol) was added to the mixture and refluxed
for 12 h at 90℃. After 12 h, product 4a-4i were filtered out of the flask.
The solid is washed with anhydrous ethanol.
4.2.2.1. 5-Benzylidene-3-(2-(4-bromophenyl)-2-oxoethyl)thiazolidine-2,4-
1
dione (4a). White powder. Mp:199.2–200.5℃. H NMR (400 MHz, d-
DMSO) δ (ppm): 7.8953 (s, 1H), 7.5478–7.5431 (s, 1H), 7.4937–7.5262
(m, 6H), 7.4493–7.4710 (m, 2H), 5.0827 (s, 2H). MS (ESI): 401
(C18H13BrNO3S, [M + H] + ) Anal. Calcd. (%) for C18H12BrNO3S: C,
53.75; H, 3.01; N, 3.48%; Found (%): C, 54.05; H, 2.89; N, 3.66%.
Fig. 11. Effect of compound 4 g and Rosiglitazone on PPARγ reporter
gene activity.
active pocket and increases the stability of H3 and β-folding, which
conforms to the characteristics of partial PPARγ agonists. Together,
these experiment results suggest that compound 4 g is a promising
PPARγ agonist. We will continue to investigate new partial PPARγ ag-
onists and establish potential functions in our future research.
4.2.2.2. 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-(2-fluorobenzylidene)thia-
zolidine-2,4-dione(4b). Mp:194.6–194.7℃.1H NMR (400 MHz, d-DMSO)
δ (ppm): 8.0234–8.0448 (m, 2H), 7.9903 (s, 1H), 7.8269–7.8483 (d, J =
8.56 Hz, 2H), 7.5116–7.6765 (m, 3H), 7.4024–7.4578 (m, 1H), 5.3583
(s, 2H). MS (ESI): 420 (C18H12BrFNO3S, [M + H] + ) Anal. Calcd. (%) for
C
18H11BrFNO3S: C, 51.44; H, 2.64; N, 3.33%; Found (%): C, 51.59; H,
4. Materials and methods
2.78; N, 2.43%.
4.1. Materials
4.2.2.3. 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-(3-fluorobenzylidene)thia-
zolidine-2,4-dione(4c). Mp:203.1–203.6℃.1H NMR (400 MHz, d-DMSO)
δ (ppm): 8.0238–8.0452 (m, 3H), 7.8284–7.8498 (d, J = 8.56 Hz, 2H),
7.6116–7.6668 (m, 1H), 7.5127–7.5747 (m, 2H), 7.3770–7.4253(m,
1H), 5.3560 (s, 2H). MS (ESI): 420 (C18H12BrFNO3S, [M + H] + ) Anal.
Calcd. (%) for C18H11BrFNO3S: C, 51.44; H, 2.64; N, 3.33%; Found (%):
C, 51.55; H, 2.59; N, 3.41%.
All chemicals (reagent grade) used were purchased from either
Aladdin (Shanghai, China) or Sangon Biotech. All the 1H NMR spectra
were recorded on a Bruker DPX 400 model spectrometer in d-DMSO, and
chemical shifts (δ) are reported as parts per million (ppm). Melting
points were determined on a Digital Melting Point apparatus (Shen-
guang., Shanghai, China). Thin layer chromatography (TLC) was per-
formed on silica gel plates (Silica Gel 60 GF254) and visualized in UV
light (254 nm and 365 nm). The Kunming male weighing 22 to 30 g at
ages of 8 to 9 weeks were used to the experiment and provided by
Xinhua Pharmaceuticals Company, Zibo, China. They were raised in
standard conditions (Room temperature: 23 ± 2℃, humidity: 55 ± 5%,
4.2.2.4. 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-(4-chlorobenzylidene)thia-
zolidine-2,4-dione (4d). Mp:180.2–181.0℃. 1H NMR (400 MHz, d-
DMSO) δ (ppm): 7.9431 (s, 1H), 7.8726–7.9136 (m, 2H), 7.7162–7.7377
(d, J = 7.4 Hz, 2H), 7.5205 (s, 4H), 5.3331 (s, 1H), 5.1827 (2H). MS
7

J. Sun et al.
Bioorganic Chemistry 116 (2021) 105342
Fig. 12. LanthaScreen TR-FRET PPAR competitive binding assay of compound 4 g and rosiglitazone.
(ESI): 436 (C18H12BrClNO3S, [M + H] + ) Anal. Calcd. (%) for
7.49 (dd, J = 6.3, 2.8 Hz, 3H), 7.37 (d, J = 3.8 Hz, 1H), 5.35 (s, 2H), 2.39
(d, J = 6.5 Hz, 3H). MS (ESI): 416 (C19H15BrNO3S, [M + H] + ) Anal.
Calcd. (%) for C19H14BrNO3S: C, 54.82; H, 3.39; N, 3.36%; Found (%): C,
55.06; H,3.12; N, 3.30%.
C
18H11BrClNO3S: C, 49.51; H, 2.54; N, 3.21%; Found (%): C, 49.72; H,
2.40; N, 3.18%.
4.2.2.5. 5-(3-Bromobenzylidene)-3-(2-(4-bromophenyl)-2-oxoethyl)thia-
zolidine-2,4-dione (4e). Mp:188.4–188.7℃. 1H NMR (400 MHz, d-
DMSO) δ (ppm): 8.3649 (s, 1H), 7.8973–7.9176 (d, J = 8.12 Hz, 2H),
7.7117–7.7314 (d, J = 7.88 Hz, 2H), 7.4595–7.5356 (m, 2H),
7.0916–7.1299 (m, 1H), 6.9973–7.0190 (m, 1H), 5.1742 (s, 2H). MS
(ESI): 480 (C18H12Br2NO3S, [M + H] + ) Anal. Calcd. (%) for
4.3. X-ray crystallography
Single crystal X-ray diffraction data were collected at room tem-
perature (293 K) by Bruker d-8 venture diffractometer. The X-ray
generator was operated at 50 kV and 35 Ma with Mo Kα radiation (k =
C
18H11Br2NO3S: C, 44.93; H, 2.30; N,2.91%; Found (%): C,45.12; H,
0.71073 Å). Data was collected using SMART software packages. The
data was simplified by SAINT-PLUS, the empirical absorption correction
is carried out by SADABS package, and the spatial group was determined
by XPREP. The crystal structure was solved by direct methods using
SIR92 and refined by full-matrix least-squares method using SHELXL97.
All non-hydrogen atoms were refined anisotropically and hydrogen
atoms have been refined in the riding mode on their carrier atoms
wherever applicable.
2.25; N, 2.71%.
4.2.2.6. 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-(4-methylbenzylidene)thia-
zolidine-2,4-dione (4f). Mp:249.2–249.7℃. 1H NMR (400 MHz, d-
DMSO) δ (ppm): 7.9767 (S, 1H), 7.8937–7.9151 (d, J = 8.56 Hz, 2H),
7.7107–7.7321 (d, J = 8.56 Hz, 2H), 7.4759–7.4962 (D, J = 8.12 Hz,
2H), 7.3080–7.3583 (m, 2H), 5.1771 (s, 2H), 2.4676 (s, 3H). MS (ESI):
416 (C19H15BrNO3S, [M + H] + ) Anal. Calcd. (%) for C19H14BrNO3S: C,
54.82; H, 3.39; N, 3.36%; Found (%): C, 54.69; H,3.32; N, 3.81%.
4.4. Establishment of STZ-induced diabetes mellitus model
4.2.2.7. 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-(2-methoxybenzylidene)
thiazolidine-2,4-dione(4 g). Mp:188.9–189.3℃. 1H NMR (400 MHz, d-
DMSO) δ 8.14 (s, 1H), 8.02 (t, J = 11.7 Hz, 2H), 8.02 (t, J = 11.7 Hz, 2H),
8.02 (t, J = 11.7 Hz, 2H), 8.02 (t, J = 11.7 Hz, 2H), 7.84 (d, J = 8.5 Hz,
2H), 7.54 (dd, J = 14.0, 7.4 Hz, 2H), 7.29 – 7.05 (m, 2H), 5.33 (s, 2H),
3.93 (s, 3H). MS (ESI): 432 (C19H15BrNO4S, [M + H] + ) Anal. Calcd.
(%) for C19H14BrNO4S: C, 52.79; H, 3.26; N, 3.24%; Found (%): C, 52.55;
H, 3.32; N, 3.35%.
This experiment was conducted in accordance with the guideline
issued by the State Food and Drug Administration (SFDA of China). The
animals were housed and cared for in accordance with the guidelines
established by the National Science Council of Republic China. All
experimental protocols were approved by Animal Care and Use Com-
mittee of Zhejiang University of Science and Technology.
The 20 mice were adaptively feed for a week, and then were fasted
for 16 h. A 1% streptozotocin (STZ) solution was prepared in a 1 mol/L
citrate buffer solution (pH = 4.5) and then injected into the peritoneum
of mice at a dose of 100 mg/kg. The control group was injected with the
same dose of citrate buffer. A week later, blood was drawn from the tail
of fasting mice to detect blood sugar concentration. The mice with the
fasting blood glucose values>11 mmol/L were considered to be suc-
cessful in the induction of type 2 diabetes and included in the study.
Finally, 15 mice were induced to Type 2 diabetes.
4.2.2.8. 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-(4-hydroxybenzylidene)
1
thiazolidine-2,4-dione(4 h). Mp:240.6–241.0℃. H NMR (400 MHz, d-
DMSO) δ (ppm): 8.0208–8.0423 (d, J = 8.6 Hz, 2H), 7.9200 (s, 1H),
7.8287–7.8501 (d, J = 8.56 Hz, 2H), 7.5449–7.5666 (d, J = 8.68 Hz,
2H), 6.9466–6.9684 (d, J = 4.72 Hz, 2H), 5.3197 (s, 2H). MS (ESI): 418
(C18H13BrNO4S, [M + H] + ) Anal. Calcd. (%) for C18H12BrNO4S: C,
51.69; H, 2.89; N, 3.35%; Found (%): C, 51.77; H, 3.05; N, 3.19%.
4.5. Effects of target compounds on STZ-induced diabetic mice
4.2.2.9. 3-(2-(4-Bromophenyl)-2-oxoethyl)-5-(3-methylbenzylidene)thia-
zolidine-2,4-dione (4i). Mp:181.8–181.9℃. 1H NMR (400 MHz, d-
DMSO) δ 8.04 (d, J = 8.6 Hz, 2H), 7.98 (s, 1H), 7.84 (d, J = 8.6 Hz, 2H),
Nine model mice were randomly divided into three groups with 3
mice in each group. In addition, 3 normal mice were randomly selected
8

J. Sun et al.
Bioorganic Chemistry 116 (2021) 105342
as normal control group. The grouping was as follows: the normal group
and model group only took solvents; the drug group was orally admin-
istered 100 mg/kg and 50 mg/kg of compound 4 g (1% CMC to prepare
the test compound), respectively. The mice were given the same dose of
solvents or compounds every day for two weeks, and their fasting blood
glucose was tested once a week. After two weeks, the compound 4 g was
discontinued and observed for one week, then the fasting blood glucose
was measured. Finally, the blood glucose values were analyzed
statistically.
4.10. Luciferase reporter assay
293 T cells were incubated in 96-well plates (1 × 104 cells/mL), and
the cells in each well were co-transfected with PPRE-Luc、PPARγ and
RXRα. A PPRE-driven luciferase reporter plasmid was applied for
examining specific activation of PPARγ binding to the PPRE. The cells
were suspended in fresh culture medium and exposed to compound 4 g
and rosiglitazone in a combination for 24 h. Then, the cells were
collected for luciferase detection.
4.11. PPARγ competitive binding assay
4.6. Anti-inflammation activity
The LanthaScreen time-resolved fluorescence resonance energy
transfer (TR-FRET) PPARγ competitive binding assay was applied ac-
cording to the manufacturer’s protocol. The FRET signal was valued by
excitation at 340 nm and emission at 520 nm for fluorescein and 490 nm
for terbium. The ability of binding to the PPARγ-LBD was measured by
the down regulation of the 520/490 nm ratio.
In male mice (20–30 g), the inflammatory activities of the tested
compounds were divided into five groups, 3 in each group. Each group
was as follows: Blank control group (0.5% CMC solution was given);
Different concentration drug groups (twice a day, continuous gavage for
3 days, the drug concentrations were 20 mg/kg, 10 mg/kg, 5 mg/kg);
Positive control group (Ibuprofen 10 mg/kg). Half an hour after the last
administration, 0.02 mL/animal of xylene was taken from the micro-
injector, and coated on the front and back sides of the right ear of mice,
0.01 mL on each side, without any treatment on the left ear. One hour
later, cut off both ears, use a 9 mm diameter hole punch to make round
ear pieces at the same place, and weigh them with an electronic balance.
The weight difference of left and right ear pieces was swelling degree.
The formula of swelling inhibition rate is as follows:
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Black control group ꢀ Drug group
Acknowledgments
Inhibition rate =
× 100%
Black control group
This work was financed by Natural Science Foundation of Zhejiang
Province (LQ20B020001) and (LY20B020003).
4.7. Ulcerogenic activity
Appendix A. Supplementary material
After measuring the anti-inflammatory activity the rats were sacri-
ficed by decapitation. The stomachs were removed, collected, opened
along the greater curvature, washed with distilled water and cleaned
gently by dipping in saline.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.105342.
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