Microwave-assisted efficient synthesis of pyrazole-fibrate derivatives as stimulators of glucose uptake in skeletal muscle cells

Article abstract of DOI:10.1016/j.bmcl.2020.127760

The design and synthesis of a series of pyrazolo[3,4-d]pyrimidinones containing fibrate side chains have been accomplished by utilizing the concept of molecular hybridization. All the synthesized compounds were evaluated for the glucose uptake stimulatory effect in L6 rat skeletal muscle cells. Four compounds (3f, 3g, 3j and 3q) were found to show significant stimulation of glucose uptake. Further these four compounds have been examined for their Glut4 translocation stimulatory effect in L6-Glut4myc myotubes. Compound 3q was found to exert maximum increase in GLUT4myc translocation.

Full text of DOI:10.1016/j.bmcl.2020.127760

Bioorg. Med. Chem. Lett. 34 (2021) 127760
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Microwave-assisted efficient synthesis of pyrazole-fibrate derivatives as
stimulators of glucose uptake in skeletal muscle cells
,
,d,
Sampa Guptaa, Amit Kumar Raib, Shubham Pandeya d, L. Ravithej Singha e, Ruchir Kantc,
,d,*
Akhilesh K. Tamrakarb, Koneni V. Sashidharaa
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
b Biochemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
c Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
d Academy of Scientific and Innovative Research, Ghaziabad 201002, U.P., India
A R T I C L E I N F O
A B S T R A C T
Keywords:
The design and synthesis of a series of pyrazolo[3,4-d]pyrimidinones containing fibrate side chains have been
accomplished by utilizing the concept of molecular hybridization. All the synthesized compounds were evaluated
for the glucose uptake stimulatory effect in L6 rat skeletal muscle cells. Four compounds (3f, 3g, 3j and 3q) were
found to show significant stimulation of glucose uptake. Further these four compounds have been examined for
their Glut4 translocation stimulatory effect in L6-Glut4myc myotubes. Compound 3q was found to exert
maximum increase in GLUT4myc translocation.
Pyrazolo[3,4-d]pyrimidinones
GLUT4myc translocation
Diabetes mellitus
Diabetes mellitus (DM) is a multifactorial metabolic syndrome
marked by high blood glucose level due to defective insulin secretion,
impaired insulin action or both.1 The chronic hyperglycemia of diabetes
is associated with relatively specific long-term microvascular compli-
cations as well as an increased threat for cardiovascular diseases (CVD).2
Diabetes has been considered as the fast growing epidemic worldwide.
Type 2 diabetes mellitus is the most common type of diabetes that ac-
counts for 90–95% of all cases of diabetes.3 Insulin resistance is the main
pathophysiological feature of type 2 diabetes mellitus, characterized by
the reduced ability of insulin sensitive tissues to respond effectively to
normal levels of insulin.4
reduced, resulting in a consequent defect in the insulin-stimulated
glucose uptake.9 Thus, interventions with ability to stimulate GLUT4
translocation are useful for the treatment of diabetes mellitus.3
Current therapeutics for diabetes are often associated with undesir-
able side effects such as, weight gain, which consequently increases the
risk of insulin resistance leading to enhance in drug dose.10 Therefore,
there is a need to introduce new and improved novel antidiabetic agents.
Large numbers of structurally diverse molecules were designed and
biologically evaluated against type 2 diabetes mellitus. In the design and
synthesis of novel antidiabetic compounds, we found several reports in
which compounds containing pyrazole and pyrimidone rings were
endowed with potent antidiabetic activity due to their unique hetero-
cyclic structure.11 For example, Balaglitazone, which contains pyr-
imidone, has been used in clinical trials to manage blood glucose levels
in type 2 diabetes mellitus.12 In addition linagliptin,13 alogliptin,14
teneligliptin, drugs from liptin family are used to treat type 2 diabetes
mellitus.15 These drugs contain either pyrazole or pyrimidone in their
structure. Narihiro et al. have reported pyrazole containing compound
showing potent glucose lowering effects.16 Eduardo et al. have designed
pyrazole containing rimonabant derivatives and evaluated them for
their antidiabetic properties.17 Vasu et al. have synthesized a novel
Insulin resistance in major insulin sensitive tissues, including skeletal
muscles, liver and fat tissue leads to imbalance of glucose homoeo-
stasis,5 resulting in establishment of hyperglycemia. Skeletal muscle has
major contribution in postprandial glucose disposal, which accounts for
more than 80% of insulin-dependent glucose disposal in human.6
Glucose uptake is the rate-limiting step in skeletal muscle.7 In skeletal
muscle cells, glucose uptake results from the enhanced translocation and
redistribution of insulin sensitive glucose transporter 4 (GLUT4) to the
cell membrane, which acts as a shuttle to move sugar across the cell
surface.8 Under insulin resistance, the translocation of GLUT4 gets
* Corresponding author at: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road,
Lucknow 226031, India.
E-mail address: kv_sashidhara@cdri.res.in (K.V. Sashidhara).
e
Present address: Fluoro-Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
https://doi.org/10.1016/j.bmcl.2020.127760
Received 16 June 2020; Received in revised form 9 December 2020; Accepted 20 December 2020
Available online 25 December 2020
0960-894X/© 2020 Elsevier Ltd. All rights reserved.

S. Gupta et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127760
Fig. 1. Designing of pyrazole-fibrate derivatives as T2DM agents.
series of fused pyrazolo[3,4-d] pyrimidinones and found them to exhibit
promising in vivo blood glucose-lowering activity.15 Gillespie et al. have
discovered potent pyrazolo[3,4-d]pyrimidine derivatives with prom-
ising pharmacokinetic profile, which reduced post-prandial glucose
levels in mice.18 Likewise, fibrates are also reported in the literature as
an interesting class of compound. Fibrates are used for the treatment of
drugs. Herein, we describe a novel and simple method to synthesize
pyrimidinone ring starting from 5-aminopyrazole-4-carboxamide 1 and
aryl aldehyde 2. With our long standing interest in the concept of mo-
lecular hybridization,21 we have hybridised pyrazole-pyrimidone moi-
ety with fibrate side chain to obtain twenty-one compounds and
evaluated them for glucose uptake stimulatory effect in skeletal muscle
cells (Fig. 1).
dyslipidemia are agonists of PPARα. It lowers plasma triglycerides via
activation of lipid catabolism. Fibrates also increase plasma HDL and are
therefore hypolipidemic agents.19 These are structurally and pharma-
cologically related to the thiazolidinediones,20 a class of anti-diabetic
Previously several methods were reported in the literature for the
synthesis of pyrazolo[3,4-d]pyrimidinones by the cyclisation of 5-ami-
nopyrazole-4-carboxamide derivatives with carboxylic acid,22 acid
Scheme 1. Synthesis of novel pyrazole-fibrate derivatives. Reagent and Conditions: a) Ethanol, reflux, 6 h, b) H2SO4, toluene 60 ◦C, 3–4 h, c) K2CO3, Acetonitrile,
reflux 3 h, d) AcOH, DDQ, 140 ◦C, MW irradiation, 30 min.
2

S. Gupta et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127760
chloride,23 ester,24 ketone,25 aldehyde26 in different reaction conditions.
Herein we are reporting the synthesis of pyrazolo[3,4-d]pyrimidinones
from 5-aminopyrazole-4-carboxamide derivatives and substituted aryl
aldehyde derivatives. The reaction proceeds via condensation of aryl
aldehyde (2a–2d) and pyrazole-4-carboxamide (1a–1e) to afford Schiff
base, followed by the cyclisation leading the formation of pyrazolo[3,4-
d]pyrimidinones derivatives. In the literature this cyclocondensation
reaction is reported in various catalytic systems and solvents such as
AcOH,26 I2/DMF,27 piperidine/EtOH,28 pTSA/benzene,29 and I2/CAN.30
Most of the reported method possessed drawbacks like prolonged reac-
tion time, low yield. Herein we report a convenient method which gives
cyclocondensation product with high yield in relatively short duration.
We found in AcOH and DDQ medium the reaction occurs within 30 min
at 140 ◦C under microwave irradiation. The pyrazole-4-carboxamides
(1a–1e) were prepared from substituted 5-amino-1-phenyl-1H-pyr-
azole-4-carbonitriles via hydrolysis in toluene medium using H2SO4
(2:1) at 60 ◦C. The substituted benzaldehydes (2a–2d) were obtained via
substitution reaction of 4-hydroxybenzaldehyde with appropriate
bromo esters in the presence of K2CO3 in acetonitrile under reflux con-
ditions. An efficient cyclocondensation reaction took place between
suitable amide derivatives (1a–1e) and substituted benzaldehyde de-
rivatives (2a–d) using DDQ in AcOH at 140 ◦C which provided final
pyrazole pyrimidone-fibrate hybrids (3a–3u) in good to excellent yields
(Scheme 1).
Table 1
Optimization of reaction conditions.a
Entry
Solvent
Catalyst
Condition
Yield
1
Toluene
Water
DMF
pTSA(20 mol%)
reflux/6h
NR
2
–
120 ◦C/8h
100 ◦C/4h
100 ◦C/6h
reflux/8h
NR
3
–
20%
44%
25%
30%
30%
40%
45%
60%
88%
90%
4
DMF
I2(0.5 equiv.)
CuCl2⋅H2O(20 mol%)
–
5
EtOH
DMSO
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
6
120 ◦C/8h
120 ◦C/6h
120 ◦C/8h
120 ◦C/8h
140 ◦C/ 8 h
140 ◦C/8 h
140 ◦C/30 min
7
–
8
I2(0.5 equiv.)
KMnO4(1 equiv.)
DDQ(1 equiv.)
DDQ(2 equiv.)
DDQ(2 equiv.)
9
10
11
12b
Bold represents optimized reaction conditions.
a
All reactions were carried out using 1a (0.5 mmol), 1b (0.5 mmol), solvent
(4 mL) at indicated time.
To optimize the reaction conditions for the synthesis of pyrazole
pyrimidone-fibrate hybrid, the reactions were carried out using car-
boxamide intermediates (1a) and substituted benzaldehydes derivative
b
Microwave irradiation, NR no reaction.
Scheme 2. Synthetic strategy for the synthesis of mini library of compounds.
3

S. Gupta et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127760
Fig. 2. ORTEP diagram drawn with 30% ellipsoid probability for non-H atoms
of the crystal structure of compound 3k determined at 293 K.
Table 2
Effect on in vitro glucose uptake in L6-GLUT4myc skeletal muscle cells of
compound 3a–3u.
Compound number
Fig. 3. Effect of compounds on Glut4 translocation in L6-Glut4myc myotubes.
All the experiments were done in triplicate and expressed as mean ± SE. *p <
0.05 relative to the un-stimulated control.
% Glucose uptake stimulationa
3a
ꢀ 8.60
13.10
ꢀ 16.80
23.70
ꢀ 1.60
34.00
34.40
ꢀ 14.70
ꢀ 17.20
34.40
5.00
3b
88% (entry 11). The 2 equiv. of DDQ is required in the reaction probably
due to inhibition the activity of DDQ molecule by water molecule
formed in the cyclisation between 1a and 2a. To optimize the reaction
time, the reaction was then carried out under microwave (MW) irradi-
ation. Interestingly, the product was formed within 30 min with 90%
yields (entry 12). This was considered as optimal reaction codition. With
the optimum conditions in hand, a variety of pyrazolo[3,4-d]pyr-
imidinones derivatives were then synthesized and the results are sum-
marized in Scheme 2.
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
12.90
ꢀ 12.80
ꢀ 8.30
10.40
2.90
3m
The structures of synthesized compounds were characterized by 1H
NMR, 13C NMR and mass spectral techniques, which were found to be in
good agreement with the proposed structures. The structure of 3k was
further confirmed by X-ray crystallography (Fig. 2).
3n
3o
3p
3q
54.00
0.60
3r
All the synthesized pyrazole-pyrimidone-fibrate hybrids (3a–3u)
were screened for their effect on glucose uptake in L6 rat skeletal muscle
cells. For the compounds that were found active in primary screening,
their dose-dependent effect on glucose uptake were also determined.
3s
0.60
3t
6.40
3u
2.90
Metforminb
48.0
Bold represents compounds considered as lead for further analysis.
a
b
Glucose uptake activity of compounds was done at 10 µM concentration.
Metformin used was at 500 µM concentration.
(2a) as model substrate. The reaction conditions were optimized by
changing catalyst and the solvent. The results are summarized in
Table 1. Initially, 20 mol% of pTSA as catalyst in toluene under reflux
condition failed to give any product. Likewise, no product formation was
observed when water was used as solvent (entries 1 and 2). However,
using DMF as solvent afforded slight formation of product (20%) after 4
h at 90–100 ◦C but most of the reactant was recovered (entry 3).
Repeating the same reaction using I2 (0.5 equiv.) as catalyst gave 44% of
product (entry 4). Further, 20 mol% of CuCl2 as catalyst in refluxing
ethanol as medium offered 25% of 3a (entry 5). Replacing, DMSO as
solvent at 120 ◦C for 8 h does not favor the reaction by giving only 30%
yields (entry 6). Subsequently, AcOH was choosen as solvent without
presence of any catalyst resulted 30% of 3a (entry 7). Therefore, in the
same solvent the reaction was carried out using I2 (entry 8) and KMnO4
(entry 9) as catalysts yielded 40% and 45% of product, respectively.
Replacing the catalysts with DDQ (1 equiv.) at 140 ◦C for 8 h displayed a
better result than KMnO4 and I2 by giving 60% of yields. Surprisingly,
increasing the amount of DDQ to 2 equiv., improved the yield of 3a to
Fig. 4. Effect of compounds on insulin-stimulated Glut4 translocation in L6-
Glut4myc myotubes. All the experiments were done in triplicate and
expressed as mean ± SE.
4

S. Gupta et al.
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127760
withdrawing group. The free –NH of pyrimidone ring i.e. R4 = H is
crucial for activity over –Me protected nitrogen. In the case of R2 and R3,
presence of –Me group is found beneficial for activity when n = 1.
However, when R2 = R3 = H, the n is optimized to 3 for the most active
compound. This SAR allows modification of a potent compound’s ac-
tivity by changing its chemical structure and test the modifications for
their biological effects. This study will be helpful for further developing
these molecules with better activity. The pictorial representation of this
SAR is shown in Fig. 5.
In conclusion, we have designed and synthesized novel pyrazole-
fibrate derivatives. The synthetic strategy used is concise, efficient,
high yielding and flexible enough to create diversity. In our study, we
have tested the glucose uptake stimulatory effect of the synthesized
compounds. Four compounds (3f, 3g, 3j and 3q) were found to show
significant stimulation of glucose uptake with respective 1.34 (p < 0.01),
1.34 (p < 0.01), 1.34 (p < 0.01) and 1.54 (p < 0.05) fold increase at 10
μ
M concentration. Taking these compounds, we evaluated the effect of
active compounds on Glut4 translocation in L6-Glut4myc myotubes.
Compound 3q exhibited maximum GLUT4myc translocation. Further
studies with detailed mechanistic and pharmacokinetic studies are
ongoing in our lab to establish structure-activity relationship and opti-
mize GLUT4 translocation stimulatory activity.
Fig. 5. Pictorial representation of structural activity relationship (SAR).
Skeletal muscles are the major insulin-target tissues responsible for
the maintenance of whole-body glucose homeostasis. In skeletal muscle,
the rate of glucose uptake determines its utilization rate and gets
impaired under diabetic stage. Thus, to assess the in vitro antidiabetic
potential, all the synthesized compounds (3a–3u) were evaluated for
their effect on glucose uptake in L6-GLUT4myc skeletal muscle cells, at a
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.
single dose of 10 μM concentration. The results of the glucose uptake
stimulatory effect of compounds are summarized in Table 2. Among all
the tested compounds, 3f, 3g, 3j and 3q showed significant stimulation
of glucose uptake with 1.34 (p < 0.01), 1.34 (p < 0.01), 1.34 (p < 0.01)
Acknowledgments
and 1.54 (p < 0.05) fold increase, respectively, at 10 μM concentration.
The authors acknowledge CSIR-CDRI, Govt. of India, for financial
and infrastructural support. Instrumentation facilities from SAIF, CDRI,
are gratefully acknowledged. We acknowledge Dr. S.P. Singh (Technical
Officer), CSIR-CDRI, for technical assistance. We thank Dr. Tejender S.
Thakur of Molecular and Structural Biology Division, CSIR-Central Drug
Research Institute for supervising the X-ray Data collection and structure
determination of our compound reported in this paper. The author SG,
LRS acknowledge CSIR, New Delhi and SP is thankful to UGC, AKR is
thankful to ICMR, New Delhi for the financial assistance in the form of
fellowships. The authors declare no competing financial interests. This is
CSIR-CDRI manuscript number 10169.
Interestingly, compound 3q was found to be the most potent in the se-
ries. Metformin was used as a positive control, which showed 1.48-fold
increase in glucose uptake at 500 μM concentration.
In skeletal muscle, an increase in glucose uptake is associated with
enhanced translocation of GLUT4 to cell membrane, where they facili-
tate the entry of glucose inside the cell. In a quest to assess the effect of
compounds to stimulate GLUT4 translocation to the cell surface, L6-
Glut4myc cells were treated with the compounds 3f, 3g, 3j and 3q at 10
µM concentration for 16 h, followed by measurement for cell surface
level of GLUT4myc. As shown in Fig. 3, treatment with the compounds
caused a significant increase in the surface level of GLUT4myc (p < 0.05
vs. control) under basal conditions. Metformin, a known anti-diabetic
drug was used as the positive control, which brought about 1.45-fold
increase under identical experimental conditions.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2020.127760.
Subsequently, we tested the effect of compounds on insulin response
to increase GLUT4 translocation in muscle cells. Cells were treated with
compounds for overnight period with the final three hours in serum-free
medium. Then cells were stimulated with 100 nM insulin for 20 min, and
the surface level of GLUT4myc was monitored. As shown in Fig. 4, in-
sulin alone caused 2.5-fold increase in the surface level of GLUT4myc;
prior treatment with compounds did not cause any significant difference
in insulin-induced GLUT4myc translocation. Among the four com-
pounds, 3g was found to exert maximum increase in GLUT4myc
translocation.
References
1
Mitra A. Some salient points in dietary and life-style survey of rural Bengal
particularly tribal populace in relation to rural diabetes prevalence. Stud Ethno-Med.
2008;2:51–56.
2
3
Korthikunta V, Pandey J, Singh R, et al. In vitro anti-hyperglycemic activity of 4-
hydroxyisoleucine derivatives. Phytomedicine. 2015;22:66–70.
Khan MF, Dixit P, Jaiswal N, Tamrakar AK, Srivastava AK, Maurya R. Chemical
constituents of Kigelia pinnata twigs and their GLUT4 translocation modulatory
effect in skeletal muscle cells. Fitoterapia. 2012;83:125–129.
The structure-activity relationship (SAR) correlates the series of
compounds with similar structural properties and its biological activity.
The analysis of SAR facilitates the discovery of the chemical groups
responsible for biological activity. Based on the in vitro glucose uptake
stimulatory effect, we can give a brief structure-activity relation of
synthesized compounds. In this screening process, we have found
compound 3f, compound 3g, compound 3j and compound 3q were
active. While correlating this activity with structures of the compounds
it has been found that electron-donating groups like 4-OMe, 3, 4
dimethyl groups are preferred for activity on R1 rather than any electron
4
Boden G, Shulman G. Free fatty acids in obesity and type 2 diabetes: defining their
role in the development of insulin resistance and β-cell dysfunction. Eur J Clin
Investig. 2002;32:14–23.
5
6
Hoehn KL, Hohnen-Behrens C, Cederberg A, et al. IRS1-independent defects define
major nodes of insulin resistance. Cell Metab. 2008;7:421–433.
DeFronzo R, Jacot E, Jequier E, Maeder E, Wahren J, Felber J. The effect of insulin on
the disposal of intravenous glucose: results from indirect calorimetry and hepatic and
femoral venous catheterization. Diabetes. 1981;30:1000–1007.
Ziel FH, Venkatesan N, Davidson MB. Glucose transport is rate limiting for skeletal
muscle glucose metabolism in normal and STZ-induced diabetic rats. Diabetes. 1988;
37:885–890.
7
8
Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of
sugar transport proteins. Br J Nutr. 2003;89:3–9.
5

S. Gupta et al.
Petersen KF, Shulman GI. New insights into the pathogenesis of insulin resistance in
Bioorganic & Medicinal Chemistry Letters 34 (2021) 127760
9
J Med Chem. 2018;143:1981–1996.(b) Singh LR, Kumar A, Upadhyay A, et al.
Discovery of coumarin-dihydroquinazolinone analogs as niacin receptor 1 agonist
with in-vivo anti-obesity efficacy. Eur J Med Chem. 2018;152:208–222.(c)
Sashidhara KV, Singh LR, Palnati GR, Avula SR, Kant R. A catalyst-free one-pot
protocol for the construction of substituted isoindolinones under sustainable
conditions. Synlett. 2016;27:2384–2390.
humans using magnetic resonance spectroscopy. Obesity. 2006;14:34S–40S.
10 Campbell RK. Type 2 diabetes: where we are today: an overview of disease burden,
current treatments, and treatment strategies. J Am Pharm Assoc. 2009;49:S3–S9.
11 Juillerat-Jeanneret L. Dipeptidyl peptidase IV and its inhibitors: therapeutics for type
2 diabetes and what else? J Med Chem. 2013;57:2197–2212.
12 Agrawal R, Jain PN, Dikshit S. Balaglitazone: a second generation peroxisome
proliferator-activated receptor (PPAR) gamma (γ) agonist. Mini-Rev Med Chem. 2012;
12:87–97.
22 Gellibert F, Fouchet M-H, Nguyen V-L, et al. Design of novel quinazoline derivatives
and related analogues as potent and selective ALK5 inhibitors. Bioorg Med Chem Lett.
2009;19:2277–2281.
13 Graefe-Mody U, Friedrich C, Port A, et al. Effect of renal impairment on the
pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes
Metab. 2011;13:939–946.
23 Davoodnia A, Anvari L, Tavakoli-Hoseini N. Microwave synthesis of new pyrazolo
[3,4-d] pyrimidin-4-ones in solvent-free condition. Asian J Chem. 2011;23:3683.
24 Markwalder JA, Arnone MR, Benfield PA, et al. Synthesis and biological evaluation
of 1-aryl-4, 5-dihydro-1 H-pyrazolo [3, 4-d] pyrimidin-4-one inhibitors of cyclin-
dependent kinases. J Med Chem. 2004;47:5894–5911.
14 Deacon CF. Alogliptin, a potent and selective dipeptidyl peptidase-IV inhibitor for
the treatment of type 2 diabetes. Curr Opin Invest Drugs. 2008;9:402–413.
15 Sagar SR, Agarwal JK, Pandya DH, Dash RP, Nivsarkar M, Vasu KK. Design, synthesis
and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in
diabetes. Bioorg Med Chem Lett. 2015;25:4428–4433.
25 Mohammed S, Vishwakarma RA, Bharate SB. Iodine catalyzed oxidative synthesis of
quinazolin-4 (3H)-ones and pyrazolo [4,3-d] pyrimidin-7 (6H)-ones via amination of
sp3 C-H bond. J Org Chem. 2015;80:6915–6921.
16 Toda N, Hao X, Ogawa Y, et al. Potent and orally bioavailable GPR142 agonists as
novel insulin secretagogues for the treatment of type 2 diabetes. ACS Med Chem Lett.
2013;4:790–794.
26 Heravi MM, Motamedi R, Bamoharram FF, Seify N. A catalytic method for synthesis
of 6-aryl-1H-pyrazolo [3,4-d] pyrimidin-4 [5H]-ones by heteropolyacids: H14
[NaP5W29MoO110] and H3PMo12O40. Catal Commun. 2007;8:1467–1471.
27 Hassan GS, Rahman DEA, Nissan YM, Abdelmajeed EA, Abdelghany TM. Novel
pyrazolopyrimidines: synthesis, in vitro cytotoxic activity and mechanistic
investigation. Eur J Med Chem. 2017;138:565–576.
´
´
17 Hernandez-Vazquez E, Salgado-Barrera S, Ramírez-Espinosa JJ, Estrada-Soto S,
′
´
Hernandez-Luis F. Synthesis and molecular docking of N -arylidene-5-(4-
chlorophenyl)-1-(3, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazides as
novel hypoglycemic and antioxidant dual agents. Bioorg Med Chem. 2016;24:
2298–2306.
28 El-Enany MM, Kamel MM, Khalil OM, El-Nassan HB. Synthesis and antitumor activity
of novel 6-aryl and 6-alkylpyrazolo [3,4-d] pyrimidin-4-one derivatives. Eur J Med
Chem. 2010;45:5286–5291.
18 Gillespie P, Goodnow RA, Saha G, et al. Discovery of pyrazolo [3,4-d] pyrimidine
derivatives as GPR119 agonists. Bioorg Med Chem Lett. 2014;24:949–953.
19 Wang Y-X. PPARs: diverse regulators in energy metabolism and metabolic diseases.
Cell Res. 2010;20:124.
29 Babu Katiyar S, Kumar A, Chauhan PM. Facile synthesis of pyrazolo [3,4-d]
pyrimidines and pyrimido [4,5-d] pyrimidin-4-one derivatives. Synth Commun. 2006;
36:2963–2973.
20 Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and
type II diabetes. Diabetes. 1996;45:1661–1669.
30 Rahmouni A, Souiei S, Belkacem MA, Romdhane A, Bouajila J, Jannet HB. Synthesis
and biological evaluation of novel pyrazolopyrimidines derivatives as anticancer and
anti-5-lipoxygenase agents. Bioorg Chem. 2016;66:160–168.
21 (a) Gupta S, Maurya P, Upadhyay A, et al. Synthesis and bio-evaluation of indole-
chalcone based benzopyrans as promising antiligase and antiproliferative agents. Eur
6