Synthesis, in vitro and in silico studies of a PPARγ and GLUT-4 modulator with hypoglycemic effect

Article abstract of DOI:10.1016/j.bmcl.2014.07.068

Compound {4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetyl)amino]phenoxy}acetic acid (1) was prepared and the in vitro relative expression of PPARγ, GLUT-4 and PPARα, was estimated. Compound 1 showed an increase of 2-fold in the mRNA

Full text of DOI:10.1016/j.bmcl.2014.07.068

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, in vitro and in silico studies of a PPAR
modulator with hypoglycemic effect
c and GLUT-4
Gabriel Navarrete-Vázquez a, , Héctor Torres-Gómez a,b, Sergio Hidalgo-Figueroa a,
Juan José Ramírez-Espinosa a, Samuel Estrada-Soto a, José L. Medina-Franco c, Ismael León-Rivera d,
Francisco Javier Alarcón-Aguilar e, Julio César Almanza-Pérez e
⇑
a Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico
b Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, D-48149 Münster, Germany
c Mayo Clinic, Scottsdale, AZ 85259, USA
d Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico
e Laboratorio de Farmacología, Depto. Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico, D.F. 09340, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Compound
{4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetyl)amino]phen-
Received 19 June 2014
Revised 22 July 2014
Accepted 24 July 2014
Available online xxxx
oxy}acetic acid (1) was prepared and the in vitro relative expression of PPAR
was estimated. Compound 1 showed an increase of 2-fold in the mRNA expression of PPAR
as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single
dose using a non insulin dependent diabetes mellitus (NIDDM) rat model. The in vivo results indicated a
significant decrease of plasma glucose levels, during the 7 h post-administration. Also, we performed a
c
, GLUT-4 and PPAR
a,
c
isoform,
Keywords:
Diabetes
PPAR
molecular docking of compound 1 into the ligand binding pocket of PPARc, showing important short con-
tacts with residues Ser289, His323 and His449 in the active site.
Ó 2014 Elsevier Ltd. All rights reserved.
Molecular docking
Peroxisome proliferator-activated receptors (PPARs) are
members of the nuclear hormone receptor superfamily, belonging
to the ligand activated transcription factors that exist in three
Multitarget therapies, which at the same time control hypergly-
cemia and inhibit progression of cardiovascular complications,
may be attractive options for the therapeutic treatment of diabe-
isoforms: PPAR
a
, PPAR
c
, and PPARb/d.1
tes. PPARa/c dual agonists are new class of drugs which have been
Each isoform regulates tissue-specific target genes acting as
lipid sensors and regulators of glucose homeostasis, such as the
fatty acid transport protein 1 (FATP1) and the solute carrier family
2 (facilitated glucose transporter), member 4 (GLUT-4).2 The
fibrate drugs (e.g., clofibrate and fenofibrate) which are hypolipi-
developed to target both PPARs in order to produce antidiabetic
and hypolipidemic effects.5 This type of compounds are examples
of the novel multitarget paradigm of drug discovery.6 The PPAR
a/
c
dual agonist tesaglitazar (Fig. 1) is well-known to reduce triglyc-
erides, to elevate cardioprotective HDL levels and consequently
demic agents, exert their effect by agonist action on PPARa. On
improve insulin sensitivity.7–9
the other hand, thiazolidine-2,4-diones (rosiglitazone and pioglit-
In our ongoing research on PPARa/c dual agonists derivatives
azone) function as insulin-sensitizing drugs, through the activation
with cardioprotective and antidiabetic activities,9 we report in this
Letter the preparation of {4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-
ylidene)methyl]phenoxy}acetyl)amino]phenoxy}acetic acid (1)
and its potential ethyl ester prodrug (2), as well as the in vitro rel-
of PPARc 3,4
.
Metabolic syndrome, an unwanted group of disorders that
includes obesity, hyperglycemia, dyslipidemia and hypertension,
contributes to the etiology of insulin resistance and diabetes.2
Therefore, the development of new compounds which interact
with PPARs constitutes an important strategy for the treatment
of diabetes and metabolic syndrome working in an effective,
specific and efficient manner.
ative expression of PPAR
the molecular docking of 1 in the active site of PPAR
a
, PPAR
c
and GLUT-4. We also describe
, and its
c
in vivo hypoglycemic effect using a streptozotocin–nicotinamide
rat model of non-insulin dependent diabetes mellitus (NIDDM).
The design of compound 1 was based on the pharmacophore of
PPAR dual agonist:9(a) An acidic head group, such as thiazolidine-
2,4-dione, carboxylic acid, or related bioisosteres; (b) a central
aromatic backbone; (c) an extra-lipophilic aromatic region; (d) a
⇑
Corresponding author. Tel.: +52 777 329 7089.
E-mail address: gabriel_navarrete@uaem.mx (G. Navarrete-Vázquez).
http://dx.doi.org/10.1016/j.bmcl.2014.07.068
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Navarrete-Vázquez, G.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.07.068

2
G. Navarrete-Vázquez et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
by recrystallization. The chemical structures of the synthesized
O
O
compounds were confirmed on the basis of their spectroscopic
and spectrometric data (NMR and mass spectra), and their purity
ascertained by microanalysis.10,11
HO
O
O
S
O
O
Tesaglitazar
Linker
To determine the effect of compounds on PPARs and GLUT-4
expression, 3T3-L1 fibroblasts were cultured in 6-well plates. After
2 days of confluence the cells were differentiated to the adipocyte
phenotype. After that, cells were treated during 24 h with 10
compounds and 2, pioglitazone (10 M) and fenofibrate
(100 M). The expression analysis was performed using SYBR
Green. Relative changes in the expression level of one specific gene
DDCt) were calculated as Ct of the test group minus Ct of the
control group and then presented as 2ꢀ
lM of
Aromatic/
Aromatic/
1
l
Acidic
Acidic
Hydrophobic
Ring 1
Hydrophobic
Ring 2
l
Moiety 2
Moiety 1
(
D
D
O
O
DDCt
.
N
O
H
O
Results summarized in Figures 2 and 3 show that compounds 1
and 2 increases significantly (about 2-fold) the levels of relative
OH
O
O
S
expression for PPAR
evant, since the activation of PPAR
c
and GLUT-4 mRNA’s. These findings are rel-
could decrease the glucose
HN
NH
O
1
c
S
O
serum levels in diabetic patients as a result of a reduction of insulin
resistance. In contrast, no change in the relative expression for
PPARa was observed with treatment of compounds 1 or 2 (Fig. 4).
Skeletal muscle glucose uptake is the rate-limiting step of glu-
cose utilization, and insulin-dependent and insulin-independent
signaling pathways physiologically regulate it, both leading to
the translocation of GLUT-4 glucose transporter to the plasma
membrane.9,12 Our data suggest that compounds 1 and 2, could
induce GLUT-4 expression.
The antidiabetic activity in vivo was measured using a strepto-
zotocin–nicotinamide NIDDM rat model.9,13–15 For this analysis,
we employed compound 2 which is the potential prodrug (ethyl
ester) form of 1. Compound 2 was employed to increase the bio-
availability of 1 according to the following rationale: Most of the
fibrates are prodrugs that, after extensive metabolism by hydroly-
sis, lead to the free carboxylic acid, which is the bioactive form.
Glibenclamide was used as hypoglycemic control (5 mg/Kg).
The antidiabetic activity of 2 was determined using a 50 mg/Kg
intragastric single dose. Compound 2 demonstrated significant
hypoglycemic activity (p < 0.05) compared to control, by lowering
glycemia ranging from 20% to 36% (Table 1). The effect was sus-
tained during the 7 h of experiment and it was comparable with
the hypoglycemic action showed by glibenclamide (a secreta-
gogue). It is important to mention that pioglitazone (an insulin
sensitizer) did not show any hypoglycemic effect under these con-
ditions of the experiment, in accordance with the research
O
HO
O
N
H
O
O
Figure 1. Pharmacophore in PPARa/c dual agonist tesaglitazar and the require-
ments fulfilled by compound 1 in two manners.
flexible spacer that connects regions (b) and (c), and allow the
structure to adopt a specific conformation (Fig. 1).9
The herein designed compound 1 matches the pharmacophoric
pattern for PPARa/c dual agonist in two manners: 1 has two acid
heads, two aromatic/hydrophobic rings and
a flexible linker
(Fig. 1).
Compound 1 was prepared starting from 4-nitrophenol (3) and
ethyl bromoacetate (4) via Williamson synthesis to give nitro-
ether 5. This compound was reduced under catalytic hydrogena-
tion with 5% Pd/C affording aniline 6, which was immediately
-chloroacetyl chloride (7), in presence of triethyl-
amine and dichloromethane as solvent, to give
8. The later compound treated with 4-hydroxybenzaldehyde (9)
under SN2 conditions led to the ether–aldehyde 10, which was con-
densed with thiazolidine-2,4-dione, following Knoevenagel reac-
tion conditions to afford compound 2 in good yields. The ethyl
ester hydrolysis of 2 with 3.5 equiv of LiOH gave desired quantita-
tive phenoxyacetic acid 1 (Scheme 1). All compounds were purified
reacted with
a
a
-chloroacetamide
O
O
OH
O
O
O
Cl
a
b
OEt
OEt
Cl
O
Br
+
+
OEt
O
7
O N
2
H2N
O N
2
6
5
4
3
c
O
O
O
O
O
OHC
OEt
OEt
OH
O
H
d
+
HN
+
Cl
N
H
S
OH
O
N
H
O
O
9
8
11
10
e
O
O
O
O
O
O
f
OEt
H
N
H
N
HN
HN
S
S
O
O
O
O
O
1
O
2
Scheme 1. Synthesis of compound 1. Reagents and conditions: (a) K2CO3, acetone, reflux; (b) H2, Pd/C 5%, ethanol; (c) Et3N, CH2Cl2; (d) K2CO3, CH3CN, reflux; (e) piperidine
(0.3 equiv), benzoic acid (0.3 equiv), toluene, Dean–Stark apparatus; (f) LiOH (3.5 equiv), THF–H2O.
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G. Navarrete-Vázquez et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
2.00
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1.75
*
1.50
*
1.25
*
1.00
0.75
0.50
0.25
0.00
Figure 4. Effect of compounds on expression of mRNA PPAR
a
.
Results are
mean SEM (n = 6).
Figure 2. Effect of compounds on expression of mRNA PPAR
c
.
Results are
mean SEM (n = 6) ⁄p < 0.01 compared with control group.
expression in rat could be associated with a marked decrease
of glucose concentrations, confirming that the level of expres-
sion of this transporter in skeletal muscle may be crucial for
the regulation of total body glucose homeostasis and insulin
action.
In order to gain an insight into the binding mode of 1, it was
docked into the catalytic site of the human PPARc (PDB ID: 1I7I)
3.0
2.5
using the program AutoDock 4.0. The docking protocol (see Supple-
mentary data) was validated by docking the co-crystal ligand
*
2.0
tesaglitazar. The root-mean square deviation (RMSD) obtained for
*
0
tesaglitazar was 1.19 ÅA. This result showed the ability of the dock-
ing protocol to reproduce the binding mode of the co-crystal
ligand.
1.5
1.0
0.5
0.0
Figures 5 and 6 show the two top ranked binding modes of 1
found by AutoDock with docking energies of ꢀ10.13 and
ꢀ9.47 kcal/mol, respectively. According to the docking results,
the first binding mode is characterized by internalization of car-
boxylic acid into the ligand binding site, making three hydrogen
interactions with the catalytic residues Ser289, His323 and
His449. Other polar contacts are made between the thiazolidine-
2,4-dione and Arg280 and Glu259 (Fig. 5).
The second binding mode is differentiated from the first one in
that carboxylic acid of 1 is located at the opposite side of the bind-
ing cavity, and the main contacts are given by the interactions
between thiazolidine-2,4-dione and the catalytic residues Ser289,
His323 and Tyr473 (Fig. 6).
Figure 7 depicts the 3D overlay of tesaglitazar (co-crystal
ligand) and compound 1. It is remarkable that both compounds
share the same binding pattern and pharmacophoric interactions
Figure 3. Effect of compounds on expression of mRNA GLUT-4. Results are
mean SEM (n = 6) ⁄p < 0.01 compared with control group.
with PPARc.
reported by Majithiya and co-workers,16,17 due to streptozotocin–
nicotinamide rat model is partially insulin-deficient and not insu-
lin resistant bioassay.
As might be expected, compound 2 did not show a significant
decrease of glycemia in the first hour post administration, due
to the ester prodrug must be activated by hydrolysis to led com-
These results contribute to explain at the molecular level, the
relevant activity of molecules in the in vitro and the in vivo tests.
As commented above, compound 1 matches the pharmacophoric
pattern of PPAR ligand in two ways: it contains two acid heads
(carboxylic acid and thiazolidine-2,4-dione), two aromatic/hydro-
phobic rings and a flexible spacer connecting them.
pound 1, which showed the best in vitro PPAR
effects. In the in vivo experiments, the increase of GLUT-4
c and GLUT-4
With the aim of anticipating potential toxicity issues of the
newly compounds herein developed, a computational prediction
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4
G. Navarrete-Vázquez et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Table 1
Percentage of variation of blood glucose concentration on streptozotocin–nicotinamide induced diabetic rats treated with a single dose of compound 2 (potential prodrug form of
1, 50 mg/Kg; intragastric administration)
Compd
Dose (mg/Kg)
Percentage of variation of glycemia SEM (mg/dL)
Zero hour
First hour
Third hour
Fifth hour
Seventh hour
2
Gli
50
5
0
0
0.0
0.0
ꢀ4.4 3.1
ꢀ20.5 6.0*
ꢀ36.7 8.0*
ꢀ31.0 6.0*
ꢀ20.5 8.0*
ꢀ36.3 8.0*
ꢀ37.5 7.1*
ꢀ43.6 9.9*
*
Values represent the mean SEM (n = 6). p < 0.05 compared with control group. The negative value indicates decrease in glycemia. Gli, glibenclamide.
Table 2
Toxicity profiles predicted for compounds 1, 2, tesaglitazar and pioglitazone
Compd
LD50 (mg/Kg)
Mouse
Probability of inhibition
(IC50 or Ki < 10 M)
CYP450 isoform
l
Rat
po
ip
po
ip
3A4
2D6
1A2
hERG
1
2
730
850
440
440
3100
1900
930
850
760
230
400
1600
1200
3600
1100
0.04
0.42
0.22
0.22
0.00
0.03
0.05
0.03
0.00
0.05
0.02
0.08
0.01
0.40
0.01
0.10
Tesaglitazar
Pioglitazone
1900
Inhibition of CYP3A4 (the major enzyme responsible for drug
metabolism in human organism), can lead to drug-drug interac-
tions and undesirable adverse effects.9,15,18 The predictions of inhi-
bition for the three main isoforms of CYP450 for compounds 1 and
Figure 5. Binding model of 1 into the active site of PPARc, representing the lowest
binding energy (ꢀ10.13 kcal/mol). Stick representation of side chains (in pink),
shows the residues that participate in the hydrogen bond network.
2 were comparable to the reference antidiabetic drugs at 10 lM,
showing satisfactory toxicity profiles. Cardiotoxicity of drug-like
compounds associated with human ether-a-go-go related gene
(hERG) channel inhibition is one of the main causes of bioactive
compounds attrition.19,20 Some thiazolidine-2,4-dione are associ-
ated with cardiovascular risks and are the leading cause for the
withdrawal of these drugs from the market.20 Compound 1 showed
very low prediction of hERG channel blockage at clinically relevant
concentrations (Ki < 10 lM), being considered as non-cardiotoxic.
In the prediction of acute toxicity, compounds 1 and 2 demon-
strated similar calculated LD50 than tesaglitazar and pioglitazone
by different administration routes, showing very low toxicity pro-
files ranging from 730 to 3100 mg/Kg.
The scaffolds of multitarget compounds 1 and 2 are partially
coincident with the structure of aldose reductase inhibitors
reported by Maccari and co-workers.21–23 This enzyme (an aldo-
keto reductase) plays a critical role in the development of chronic
diabetic problems, such as neuro-, nephro-, and retino-pathies, as
well as an increased cardiovascular risk.23 Compounds 1 and 2
were tested in silico using PASS software (Prediction of Activity
Spectra for Substances)24 showing a Pa (probability ‘to be active’)
of 0.094 and 0.064 as aldose reductase inhibitors, respectively. Pa
estimates the chance that the studied compounds are belonging
to the sub-class of active compounds (resembles the structures of
molecules, which are the most typical in a sub-set of ‘actives’ in
PASS training set. When Pa > 0.7, the chances of finding experimen-
tal activity are rather high but the compounds found may be close
structural analogs of known drugs. If we select in the range
0.5 < Pa < 0.7, the chances for detecting experimental activity will
be lower but the compounds will be less similar to known pharma-
ceutical agents. For Pa < 0.5, the chances of detecting experimental
activity will be even lower.25
Figure 6. Binding mode of compound
(ꢀ9.47 kcal/mol) into the active site of PPAR
1 with second lowest binding energy
c
.
Figure 7. Overlay of bioactive conformations of tesaglitazar (pink) and compound 1
(yellow) represented in the two top ranked binding modes.
In summary, a new hypoglycemic entity has been developed as
a promising lead compound for the treatment of diabetes. The syn-
thetic strategy is highly efficient and gave high overall yield. Com-
pound 1 is a specific PPAR
induction of the target gene GLUT-4, with predicted low toxicity
profile, multitarget effect and in vivo efficacy.
c ligand as it exhibited a marked
of toxicity was performed. The toxicity parameters of compound 1,
potential prodrug 2, tesaglitazar and pioglitazone were calculated
through the ACD/ToxSuite software, v. 2.95 (Table 2).
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G. Navarrete-Vázquez et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Calcd for C20H16N2O7S: C, 56.07; H, 3.76; N, 6.54. Found: C, 56.01; H, 3.70; N,
6.61. Ethyl {4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}-
acetyl)amino]phenoxy}acetate (2). Recrystallized from toluene. Yield: 78, mp:
250 °C (dec). 1H NMR (400 MHz, DMSO-d6): dH 1.20 (t, 3H, OCH2CH3), 4.16
(c, 2H, OCH2CH3), 4.73 (s, 2H, H-2), 4.77 (s, 2H, H-80), 6.98 (d, 2H, H-20, H-60,
J = 8.8 Hz), 7.15 (d, 2H, H-200, H-600, J = 8.8 Hz), 7.53 (d, 2H, H-30, H-50, J = 8.8 Hz),
7.58 (d, 2H, H-300, H-500, J = 8.4 Hz), 7.74 (s, 1H, H-700), 10.05 (s, broad, 1H,
CONH) ppm. 13C NMR (100 MHz, DMSO-d6) d: 14.1 (OCH2CH3), 60.6 (OCH2CH3),
64.8 (C-2), 67.0 (C-80), 114.5 (C-20, C-60), 115.5 (C-400), 120.8 (C-30, C-50), 121.2
(C-200, C-600), 121.2 (C-300, C-500), 126.1 (C-800), 131.5 (C-700), 153.7 (C-40), 159.3
(C-10), 165.5 (C-100), 167.6 (C-1200), 167.9 (C-1000), 168.5 (C-1) ppm. MS/FAB+:
m/z 456 (M+). Anal. Calcd for C22H20N2O7S: C, 57.89; H, 4.42; N, 6.14. Found:
C, 57.82; H, 4.55; N, 6.32.
Acknowledgments
This work was supported in part by the Consejo Nacional de
Ciencia y Tecnología, Mexico (CONACyT), Grant No. 100608 (CB-
2008) and Facultad de Farmacia (Universidad Autonoma del Estado
de Morelos) internal Grant. We are grateful to Narender Singh for
his technical assistance to conduct the docking.
A. Supplementary data
11. For more details, see Supplementary data.
12. Tsao, T. S.; Li, J.; Chang, K. S.; Stenbit, A. E.; Galuska, D.; Anderson, J. E.; Zierath,
J. R.; McCarter, R. J.; Charron, M. J. FASEB J. 2001, 15, 958.
13. Navarrete-Vázquez, G.; Paoli, P.; León-Rivera, I.; Villalobos-Molina, R.; Medina-
Franco, J. L.; Ortiz-Andrade, R.; Estrada-Soto, S.; Camici, G.; Díaz-Coutiño, D.;
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
07.068. These data include MOL files and InChiKeys of the most
important compounds described in this article.
14. Torres-Piedra, M.; Ortiz-Andrade, R.; Villalobos-Molina, R.; Singh, N.; Medina-
Franco, J. L.; Webster, S. P.; Binnie, M.; Navarrete-Vázquez, G.; Estrada-Soto, S.
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10. {4-[({4-[(Z)-(2,4-Dioxo-1,3-thiazolidin-5-
ylidene)methyl]phenoxy}acetyl)amino]phenoxy}acetic acid (1). Recrystallized
from ethanol. Yield: 92%, mp: >300 °C (dec). 1H NMR (400 MHz, DMSO-d6): dH
(400 MHz, DMSO-d6) d: 4.85 (s, 2H, H-2), 4.77 (s, 2H, H-80), 6.95 (d, 2H, H-20, H-
60, J = 8.8 Hz), 7.17 (d, 2H, H-200, H-600, J = 8.8 Hz), 7.51 (d, 2H, H-30, H-50,
J = 8.8 Hz), 7.56 (d, 2H, H-300, H-500, J = 8.4 Hz), 7.71 (s, 1H, H-700), 8.51 (s, broad,
1H, COOH) ppm. 13C NMR (100 MHz, DMSO-d6) d: 63.7 (C-2), 67.3 (C-80), 113.7
(C-20, C-60), 115.8 (C-400), 121.0 (C-30, C-50), 121.2 (C-200, C-600), 121.2 (C-300, C-
500), 126.1 (C-800), 131.7 (C-700), 152.5 (C-40), 160.1 (C-10), 165.5 (C-100), 167.5 (C-
1200), 168.0 (C-1000), 172.8 (C-1, COOH) ppm. MS/FAB+: m/z 429 (M+). Anal.
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Please cite this article in press as: Navarrete-Vázquez, G.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.07.068