Design, synthesis, biological evaluation and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as potent pancreatic lipase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2017.06.069

A series of novel diaryl substituted pyrazolyl 2,4-thiazolidinediones were synthesized via reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinedione (TZD) and nitrobenzyl substituted 2,4-thiazolidinedione. The resulting compounds were screened in vitro for pancreatic lipase (PL) inhibitory activity. Two assay protocols were performed viz., methods A and B using p-nitrophenyl butyrate and tributyrin as substrates, respectively. Compound 11e exhibited potent PL inhibitory activity (IC₅₀?=?4.81?μM and X_i50?=?10.01, respectively in method A and B), comparable to that of the standard drug, orlistat (IC₅₀?=?0.99?μM and X_i50?=?3.72). Presence of nitrobenzyl group at N-3 position of TZD and nature of substituent at para position of phenyl ring at C-3 position of pyrazole ring notably affected the PL inhibitory activity of the tested compounds. Enzyme inhibition kinetics of 11e revealed its reversible competitive inhibition, similar to that of orlistat. Molecular docking studies validated the rationale of pharmacophoric design and are in accordance to the in vitro results. Compound 11e exhibited a potential MolDock score of ?153.349?kcal/mol. Further, the diaryl pyrazolyl wing exhibited hydrophobic interactions with the amino acids of the hydrophobic lid domain. Moreover, the carbonyl group at 2^nd position of the TZD ring existed adjacent to Ser 152 (≈3??) similar to that of orlistat. A 10?ns molecular dynamics simulation of 11e–PL complex revealed a stable binding conformation of 11e in the active site of PL (Maximum RMSD?≈?3??). The present study identified novel thiazolidinedione based leads with promising PL inhibitory activity. Further development of the leads might result in potent PL inhibitors.

Full text of DOI:10.1016/j.bmcl.2017.06.069

Accepted Manuscript
Design, Synthesis, Biological Evaluation and Molecular Modelling Studies of
Novel Diaryl Substituted Pyrazolyl Thiazolidinediones as Potent Pancreatic Li-
pase Inhibitors
S.N.C. Sridhar, Deendyal Bhurta, Dharmvir Kantiwal, Ginson George,
Vikramdeep Monga, Atish T. Paul
PII:
S0960-894X(17)30682-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.06.069
BMCL 25103
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 May 2017
24 June 2017
26 June 2017
Please cite this article as: Sridhar, S.N.C., Bhurta, D., Kantiwal, D., George, G., Monga, V., Paul, A.T., Design,
Synthesis, Biological Evaluation and Molecular Modelling Studies of Novel Diaryl Substituted Pyrazolyl
Thiazolidinediones as Potent Pancreatic Lipase Inhibitors, Bioorganic & Medicinal Chemistry Letters (2017), doi:
http://dx.doi.org/10.1016/j.bmcl.2017.06.069
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Title Page
Title:
Design, Synthesis, Biological Evaluation and Molecular Modelling Studies of Novel Diaryl
Substituted Pyrazolyl Thiazolidinediones as Potent Pancreatic Lipase Inhibitors
Authors:
Sridhar S N Ca, Deendyal Bhurtab, Dharmvir Kantiwalb, Ginson Georgea, Vikramdeep
Mongab,* Atish T. Paula,*.
Affiliations:
aLaboratory of Natural Drugs, Department of Pharmacy, Birla Institute of Technology and
Science, Pilani (Pilani campus), Pilani - 333 031, Rajasthan, India.
bDepartment of Pharmaceutical Chemistry, Rajendra Institute of Technology & Sciences,
Sirsa-125 055, Haryana, India
Corresponding authors:
Dr. Vikramdeep Monga
vikramdeepmonga@gmail.com
vikramdeepmonga@yahoo.com
Dr. Atish T. Paul
atish.paul@pilani.bits-pilani.ac.in
paulatish@gmail.com
Present Address:
Dr. Vikramdeep Monga,
Professor & Head,
Department of Pharmaceutical Chemistry,
Rajendra Institute of Technology & Sciences,
Sirsa-125055, Haryana, India
Dr. Atish T. Paul,
Assistant Professor,
3170-U, Department of Pharmacy,
Birla Institute of Technology and Science, Pilani (Pilani Campus),
Pilani - 333 031, Rajasthan, India.

Abstract
A series of novel diaryl substituted pyrazolyl 2,4-thiazolidinediones were synthesized via
reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinedione (TZD) and
nitrobenzyl substituted 2,4-thiazolidinedione. The resulting compounds were screened in
vitro for pancreatic lipase (PL) inhibitory activity. Two assay protocols were performed viz.,
methods A and B using p-nitrophenyl butyrate and tributyrin as substrates, respectively.
Compound 11e exhibited potent PL inhibitory activity (IC50 = 4.81 µM and Xi50 = 10.01,
respectively in method A and B), comparable to that of the standard drug, orlistat (IC50 = 0.99
µM and Xi50 = 3.72). Presence of nitrobenzyl group at N-3 position of TZD and nature of
substituent at para position of phenyl ring at C-3 position of pyrazole ring notably affected
the PL inhibitory activity of the tested compounds. Enzyme inhibition kinetics of 11e
revealed its reversible competitive inhibition, similar to that of orlistat. Molecular docking
studies validated the rationale of pharmacophoric design and are in accordance to the in vitro
results. Compound 11e exhibited a potential MolDock score of -153.349 kcal/mol. Further,
the diaryl pyrazolyl wing exhibited hydrophobic interactions with the amino acids of the
hydrophobic lid domain. Moreover, the carbonyl group at 2nd position of the TZD ring
existed adjacent to Ser 152 (≈ 3 Å) similar to that of orlistat. A 10 ns molecular dynamics
simulation of 11e-PL complex revealed a stable binding conformation of 11e in the active
site of PL (Maximum RMSD ≈ 3 Å). The present study identified novel thiazolidinedione
based leads with promising PL inhibitory activity. Further development of the leads might
result in potent PL inhibitors.
Keywords: Thiazolidinedione; pH indicator; Pyrazole; Knoevenagel; Molecular Modelling;
Pancreatic Lipase; Obesity; Orlistat

Graphical Abstract
Highlights
 A series of novel diaryl substituted pyrazolyl thiazolidinediones were synthesized
 Pancreatic lipase inhibition assay was performed using two methods
 Compound 11e exhibited potent and reversible competitive inhibition (IC50 = 4.81
µM)
 Molecular dynamics of 11e indicated its stable binding conformation (RMSD ≈ 3 Å)

Obesity is a multifactorial metabolic disorder, characterised by excessive deposition
of lipids in the body1. Recent statistics has projected a rapid growth in obesity with 600
million obese people worldwide2. Moreover, obesity is associated with various comorbid
conditions including diabetes mellitus and cardiovascular diseases, posing major health risk
to the obese patients3. With over 2.8 million deaths per year, obesity ranks fifth among global
deaths4. Pancreatic lipase (PL) or triacylglycerol lipase (EC 3.1.1.3), a digestive enzyme
secreted from the pancreatic exocrine, is primarily involved in the hydrolysis of dietary
lipids5. Structurally, the active site of Human PL (PDB ID: 1LPB) consists of the catalytic
triad, Ser152 - Asp176 - His263, which is enclosed within a hydrophobic lid domain
comprised of Gly 76 - Lys 80 and Leu 213 - Met 2176,7.
Orlistat, a potent PL inhibitor, remains to be the only drug approved for long term
treatment of obesity8,9. However, recent reports from the United States Food and Drug
Administration (USFDA) indicated severe adverse effects with long term administration of
orlistat, including hepatotoxicity and acute pancreatitis etc10. These events highlighted the
necessity for the development of safer and effective anti-obesity drugs.
Thiazolidinediones (TZDs) represent a renowned class of anti-diabetic medications,
used in the treatment of type II diabetes mellitus11. Further, they have also been widely
explored for their activity against obesity through PTP1b inhibition12–14. However, there are
no reports available on thiazolidinediones in relation to their PL inhibition. Previously, amide
containing compounds have been reported as potential PL inhibitors15,16. Further, we have
identified carbazolyl oxoacetamides as potential PL inhibitors in our previous study, wherein
the amide interacted with the Ser 152, while the carbazole (containing a five-membered
nitrogen heterocycle) aided in hydrophobic interactions with the lid domain17. Since TZD
possesses nitrogen centred diamide linkage (Fig. 1), we presumed TZDs to possess potential
PL inhibitory activity. In the recent years, five membered nitrogen heterocycles have gained
prominent significance in PL inhibition. Examples include oxadiazoles18,19 and 1,3-
pyrazoles20,21, wherein the molecules exhibited potential PL inhibitory activity. Considering
the above facts and the pharmacophoric requirements from our previous study17, we have
designed a pharmacophore hybrid combining the TZD with diaryl substituted pyrazoles (Fig.
1). Accordingly, the present study involved synthesis, characterization, in vitro evaluation
and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as
potent PL inhibitors.

Fig. 1. Representation of the pharmacophoric design for PL inhibition.
The synthetic route followed for the preparation of various intermediates and title
compounds 10a-f and 11a-f has been illustrated in Scheme 1 (see Supplementary data for
detailed description). The key starting materials, 3-(substituted phenyl)-1-phenyl-1H-
pyrazole-4-carbaldehydes (4a-f) were synthesized by the reaction of various acetophenones
(2a-f) with phenyl hydrazine (1) to produce corresponding hydrazones (3a–f), followed by
their Vilsmeier-Haack cyclization in the presence of DMF/POCl3 at 80-90 °C22.
Scheme 1. Reagents and conditions (i) EtOH, Glacial AcOH, reflux; (ii) DMF/POCl3, reflux, 80-90 °C, 8-10 h;
(iii) HCl, H2O, reflux, 100-110 °C, 10 h; (iv) KOH, EtOH, 18 h and (v) EtOH, piperidine, Glacial CH3COOH,
Reflux 80-90 °C, 4-6 h.

TZD (7) was obtained by the condensation of monochloroacetic acid (5) with thiourea
(6) under ice cold conditions to afford white precipitate of 2-iminothiazolidine-4-one which
upon acidification and refluxing with HCl for 10 h afforded white crystals of 2,4-TZD23. The
4-nitrobenzyl derivative of the TZD was obtained by N(3)-alkylation of TZD (7) with 4-
nitrobenzyl bromide (8) in the presence of sodium hydroxide in refluxing ethanol, leading to
formation of the intermediate, 3-(4-nitrobenzyl)thiazolidine-2,4-dione (9)24. Knoevenagel
condensation was carried out by treating equimolar ratio of thiazolidine-2,4-dione (7) or 3-(4-
nitro-benzyl)-thiazolidine-2,4-dione (9) with 1,3-diphenyl-1H-pyrazole-4-carbaldehyde (4a)
in ethanol in the presence of catalytic amount of piperidine and few drops of glacial acetic
acid by refluxing for 5-6 h. The usual work up of the reaction afforded the product (Z)-5-
((1,3-diphenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione (10a) and (Z)-5-((1,3-
diphenyl-1H-pyrazol-4-yl)methylene)-3-(4-nitrobenzyl)thiazolidine-2,4-dione (11a) in good
yield. All other compounds 10b-f and 11b-f were prepared adopting the similar
methodology25.
1
The synthesized compounds were characterized by FTIR, H and 13C NMR, mass
spectroscopy and elemental analysis data which fully supported their structural identity. The
IR spectrum of title compounds (10a-f and 11a-f) showed strong absorption bands in the
range of 1732 - 1747 cm-1and 1681 - 1689 cm-1 due to two C=O groups stretching.
Derivatives 10a-f showed typical absorption at 3397–3442 cm-1 due to NH group stretching
whereas bands due to NO2 group stretching vibrations appeared at 1521 - 1529 & 1332 -
1346 cm-1 for compounds 11a-f. Further, absorption band appeared in the range of 1592 -
1
1619 cm-1 due to C=N stretching. In the H NMR spectrum, all the products showed
characteristic singlet at δ 8.21 - 8.86 due to C5-H of pyrazole ring. Disappearance of peak due
to methylene group and appearance of arylidene (=CH-) peak further confirms the
Knoevenagel condensation between various pyrazole aldehydes and TZD (7) or 3-(4-
nitrobenzyl)thiazolidine-2,4-dione (9). Proton of arylidene group appeared either as singlet or
1
multiplet in the range of 7.43 - 7.99. In the H NMR spectrum, =CH- proton was deshielded
more (δ = 7.4 - 7.9 ppm) as expected in Z-form, relative to the slightly shielded protons of the
E-form (δ = 6.2 - 6.3 ppm), thus indicating that all the derivatives were obtained exclusively
in Z-form. This deshielding of the arylidene proton is caused by the anisotropic effect exerted
by the nearby carbonyl group of various 2,4-thiazolidinedione derivatives in Z-isomer.
Moreover, Z-isomer is thermodynamically more stable because of intramolecular hydrogen
bond that can be formed between the hydrogen bond of =CH and oxygen atom of carbonyl
group in TZD26. Further, a broad singlet due NH proton appeared in the range of δ 11.38 -

12.59 for compounds 10a-f whereas, protons of methylene group (-N-CH2) in case of
compounds 11a-f were resonated as a singlet at δ 4.95 - 4.99 ppm. All other protons were
13
observed at expected regions. In C NMR, signals due to two carbonyl carbons of TZD ring
(C2=O and C4=O) were appeared at δ 166.57 - 168.04 and 165.37 – 167.79 respectively. All
the compounds showed prominent signals at δ 139.03 - 139.82 and 150.28 - 155.37 due to
arylidene carbon (-CH=) and C-3 of pyrazolyl ring. Further, compounds 11a-f also showed
characteristic signal in the range of δ 44.46 - 44.63 due to carbon of CH2 group attached to N-
3 of TZD ring. Finally, the assigned structures of various compounds were confirmed by their
mass spectra where characteristic [M+1]+ peak was observed. All compounds gave
satisfactory elemental analysis.
The synthesized compounds (10a-f and 11a-f) were subjected to in vitro PL inhibitory
assay using two methods (A and B using p-nitrophenyl butyrate (PNPB) and tributyrin as
substrates, respectively). The assay procedure for method A was performed using the
protocol standardized in our laboratory27, while method B (a pH indicator based assay) was
implemented from the literature28 with relevant modifications17,18 (see Supplementary data
for detailed assay procedures).
Table 1
PL inhibitory activity of the synthesized compounds using method A (IC50) and B (Xi50).
Compound
Activity
IC50 (µM)*
Compound
Activity
IC50 (µM)*
Xi50*
Xi50*
18.81 ± 0.21
15.12 ± 0.83
13.05 ± 2.81
12.90 ± 0.89
10.30 ± 1.27
17.32 ± 0.48
0.99 ± 0.1117
65.1 ± 2.98
27.18 ± 1.15
24.36 ± 2.61
25.39 ± 2.24
19.30 ± 2.75
39.47 ± 2.96
3.72 ± 0.21
12.46 ± 2.92
9.87 ± 1.03
9.40 ± 0.88
5.42 ± 0.43
4.81 ± 0.82
8.44 ± 0.32
21.76 ± 2.11
19.34 ± 2.70
18.12 ± 2.33
12.99 ± 0.96
10.01 ± 1.16
18.69 ± 1.57
10a
10b
11a
11b
11c
11d
11e
11f
10c
10d
10e
10f
Orlistat
*All experiments were performed in triplicate and the results were expressed as Mean ± S.E.M.
Table 1 represents the PL inhibitory activity of the synthesized compounds, 10a-f and
11a-f. Compound 11e exhibited the most potent PL inhibitory activity (IC50 = 4.81 µM, Xi50
= 10.01), comparable to that of orlistat (IC50 = 0.99 µM, Xi50 = 3.72), followed by 11d (IC50
= 5.42 µM, Xi50 = 12.99). Analogues 11f, 11c and 11b exhibited potential activity (8–10
µM). However, analogues 10a-f and 11a exhibited moderate PL inhibitory activity (> 10
µM). Enzyme kinetic study was performed for 11e using the optimized protocol27, to
understand its nature of inhibition. The protocol was performed at three concentration levels

of the inhibitor, and a double reciprocal Lineweaver-Burk plot was acquired. As represented
in Fig. 2 and Table 2, the km values increased with inhibitor concentration, indicating a
reversible competitive inhibition similar to that of orlistat17. Further, compound 11e exhibited
an inhibition constant (Ki) value of 14.4 μM (calculated from Dixon plot).
Table 2
Vmax and Km values calculated from Lineweaver-Burk plot at different concentrations of 11e [I].
[I] (μM)
Vmax (μM.min-1)
Km (μM)
69.32
0.0545
0
2.5
5
0.0565
125.15
145.37
165.11
0.0557
0.0566
10
140
120
100
80
60
High inhibitor concentration
Mediuminhibitor concentration
Low inhibitor concentration
No inhibitor
40
20
0
-0.02
-0.01
0
0.01
0.02
0.03
0.04
0.05
1/[S]
Fig. 2. Lineweaver-Burk plot of 11e representing reversible competitive inhibition.
A preliminary structure-activity relationship of the compounds 10a-f and 11a-f with
reference to their PL inhibitory activity has been analysed (Fig. 3). Significant variation in the
PL inhibitory activity was observed with reference to the introduction of p-nitrobenzyl
substitution on the ring nitrogen of TZD, wherein the activity was significantly potent with
the tested analogues (11a-f) over their unsubstituted counterparts (10a-f). Moreover, nature
of the substitution at para position of the 3-phenyl ring (-R1) played an important role in the
PL inhibition. The PL inhibitory activity did not vary significantly with the substitution of
electron donating groups, as observed with 11c (-OCH3), 11b (-CH3) and 11a (-H). However,

the presence of an electron withdrawing group resulted in potent PL inhibitory activity (as
seen with 11e (-Cl),11d (-F) and 11f (-NO2)). Compound 11f exhibited lower inhibitory
activity in comparison to 11d and 11e. This might be due to the comparatively higher
electron withdrawing potential of the nitro group which resulted in an electron pull, thus
reducing the hydrophobicity of the diaryl pyrazole moiety. The fact can be further confirmed
with the partition coefficient values of the analogues, 11d-f, wherein the PL inhibitory
potential was in correlation to their respective ClogP values (6.31 for 11f, 6.68 for 11d and
7.04 for 11e).
Fig. 3. Preliminary SAR for pyrazolyl thiazolidinediones10a-f and 11a-f depicting the PL inhibitory
potency (IC50 or Xi50) vs. substitution.
Compounds 10a-f and 11a-f were docked into the active site of the human PL to
understand their interactions with the active site amino acids. Molegro Virtual Docker (v 6.0)
was used to perform the docking, and the validated grid parameters were opted from our
previous studies17,27. The MolDock scores and the interactions exhibited by the analogues
10a-f and 11a-f are summarized in Table 3. The major H-bond interactions included with that
of Gly 76, Phe 77, His 151, Ser 152 and Arg 256. Further, the diaryl substituted pyrazole
moiety played an important role in maintaining π-π stacking interactions with the amino acids
of the lid domain (Phe 77 and Phe 215), along with Tyr 114. Additionally, the p-nitrobenzyl
substituted analogues (11a-f) exhibited a π-cation interaction with Arg 256, which was not
observed with their unsubstituted counterparts (10a-f). Previously, Lowe et al. reported that
the open lid conformation of human PL is attained through formation of salt bridge between
Arg 256-Asp 257 and Tyr 267-Lys 26829. Further, Birari et. al. suggested the role of Arg 256
interaction for potential PL inhibitory activity30. This fact can be correlated to the potent
activity exhibited by the nitrobenzyl substituted thiazolidinediones (11a-f) over their
counterparts (10a-f). Further, in an attempt to understand the probable role of the diamide
linkage in covalent interaction with Ser 152 of the active site, the binding pose of 11e was
superimposed with that of orlistat (Fig. 4c). The reactive carbonyl groups of both the

molecules existed equidistance from Ser 152 with minor deviation. Molecular docking results
are in accordance to the PL inhibitory activity exhibited by the analogues, 10a-f and 11a-f.
Further, the binding pose analysis has validated the rationale for designing the pyrazolyl
thiazolidinediones as PL inhibitors.

Fig. 4. (a) Binding pose of 11e in the active site of PL; (b) 2D interaction diagram of 11e; (c) Overlay diagram
of 11e (White) over orlistat (Brown) representing the distances of reactive carbonyl carbon from Ser 152.
In order to understand the binding mode and interactions in a dynamic environment, a
10 ns molecular dynamics (MD) simulation was performed for the 11e – PL complex. The
simulation parameters used for the study were earlier optimized17,27. Analogue 11e exhibited
a stable binding conformation throughout the MD run, as confirmed through the ligand
RMSD (Fig. 5). 11e exhibited a maximum RMSD of 3 Å in the active site of PL, as observed
at 3rd ns. The interactions of 11e with the active site of the PL through the 10 ns MD run are
summarized in Table 4. The initial π-cation interaction of p-nitrobenzyl group with Arg 256
vanished with the initiation of MD. However, compound 11e maintained stable π-π
interactions with the amino acids of the lid domain. Further, H-bond interactions with Ser 152
and Arg 256 were prominent through the run, with an exception at 7th and 8th ns.

Table 4: Summary of interactions exhibited by 11e through the 10 ns MD run.
Time frame (ns)
H-bond
Pi-Pi
Pi-cation
0
1
2
3
4
5
6
7
8
9
10
Phe 77, Ser 152
Ser 152, Arg 256
Arg 256
Arg 256
Ser 152, Arg 256
Arg 256
Arg 256
-
Phe 77, Tyr 114, His 263
Phe 77, Tyr 114
Arg 256
-
-
-
-
-
-
-
-
-
-
Phe 77, Tyr 114
Phe 77, Tyr 114, Phe 215
Phe 77, Tyr 114, Phe 215
Phe 77, Tyr 114, Phe 215
Phe 77, Tyr 114, Phe 215
Phe 77, Tyr 114, Phe 215
Phe 77, Tyr 114, Phe 215
Phe 77
-
Ser 152
Ser 152
Phe 77, Tyr 114
Fig. 5. Ligand RMSD of compound 11e acquired through the 10 ns MD run.
To summarize, the present study involved design, synthesis, characterization, in vitro
evaluation and molecular modelling studies of novel diaryl pyrazolyl thiazolidinedione
analogues as potent PL inhibitors. Two assay protocols were performed to validate the
potential of the analogues. 11e exhibited potent PL inhibitory activity (IC50 = 4.81 µM and
Xi50 = 10.01) comparable to that of orlistat (IC50 = 0.99 µM and Xi50 = 3.72). Further, enzyme
kinetics established a reversible competitive nature of PL inhibition by 11e. Molecular
docking study of the synthesized analogues was in accordance to the in vitro results and
validated the pharmacophoric design. MD simulation of 11e, resulted in a stable binding
conformation of 11e (RMSD ≤ 3 Å). To conclude, the present study identified diaryl

substituted pyrazolyl thiazolidinediones as a novel class of potent PL inhibitors. Further
studies would pave the way for the analogues as potential anti-obesity agents.
Acknowledgements
The authors acknowledge Birla Institute of Technology and Science, Pilani (BITS Pilani),
Pilani Campus, Pilani, Rajasthan (India) and Rajendra Institute of Technology & Science,
Sirsa, Haryana (India) for providing necessary laboratory facilities. Mr. S. N. C. Sridhar
sincerely acknowledges the award of fellowship by BITS Pilani. The authors further extended
their sincere thanks to Director, CIL-Guru Jambheshwar University, Hisar, Haryana (India)
for providing spectral data.
A. Supplementary Data
All experimental procedures for synthesis, full characterization of compounds and pancreatic
lipase inhibition assay protocols.
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Highlights
 A series of novel diaryl substituted pyrazolyl thiazolidinediones were synthesized
 Pancreatic lipase inhibition assay was performed using two methods
 Compound 11e exhibited potent and reversible competitive inhibition (IC50 = 4.81
µM)
 Molecular dynamics of 11e indicated its stable binding conformation (RMSD ≈ 3 Å)