Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors

Article abstract of DOI:10.1016/j.bmcl.2019.03.023

Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC₅₀ = 0.67 ± 0.09 μM) and the best selectivity (9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy simultaneously at both the catalytic site and the adjacent pTyr binding site. These results provide novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Full text of DOI:10.1016/j.bmcl.2019.03.023

Accepted Manuscript
Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-al-
kanoic acid groups as potential PTP1B inhibitors
Liangpeng Sun, Peipei Wang, Lili Xu, Lixin Gao, Jia Li, Huri Piao
PII:
S0960-894X(19)30163-5
https://doi.org/10.1016/j.bmcl.2019.03.023
BMCL 26337
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
16 December 2018
14 March 2019
19 March 2019
Please cite this article as: Sun, L., Wang, P., Xu, L., Gao, L., Li, J., Piao, H., Discovery of 1,3-diphenyl-1H-pyrazole
derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors, Bioorganic & Medicinal
Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.03.023
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Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing
rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors
a, 1
b, 1
c
b
b,*
c,*
Liangpeng Sun , Peipei Wang , Lili Xu , Lixin Gao , Jia Li , Huri Piao
a
b
College of Medicine, Yanbian University, Yanji, 133000, PR China
National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Science, Chinese Academy of Sciences, Shanghai 201203, China
c
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of
Education, Yanbian University College of Pharmacy, Yanji, 133000, PR China
*
Corresponding author. Tel: + 86 433 2436149
E-mail address: piaohr@ybu.edu.cn (H. -R. Piao)
*
Co-corresponding author. Tel/Fax: + 86 21 50800721
E-mail address: jli@simm.ac.cn (J. Li)
1
These authors contributed equally to this work.

Abstract
Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic
acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B)
inhibitors. Among the compounds studied, IIIv was found to have the best in vitro
inhibition activity against PTP1B (IC50 = 0.67 ± 0.09 µM) and the best selectivity
(
9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular
docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy
simultaneously at both the catalytic site and the adjacent pTyr binding site. These
results provide novel lead compounds for the design of inhibitors of PTP1B as well as
other PTPs.
Keywords: PTP1B inhibitor; 1,3-Diphenyl-1H-pyrazole; Rhodanine-3-alkanoic acid
Protein tyrosine phosphatases (PTPs) play an important regulatory role in the
1
intracellular phosphorylation state of proteins. Unregulated PTP activity is
responsible for several human diseases including cancer, diabetes, obesity and
2
-4
dysfunction of the immune system. Among the PTPs, protein tyrosine phosphatase
B (PTP1B) activates c-Src in human breast cancer and also downregulates insulin
signaling by dephosphorylating the insulin receptor (IR), insulin receptor substrate-1
1
5
–6
(IRS-1) and insulin receptor substrate-2 (IRS-2).
Additionally, PTP1B is a negative
regulator in the leptin signaling pathway and dephosphorylates JAK2, a kinase
7-8
downstream of the leptin receptor.
PTP1B knockout mice exhibit phenotypes of
increased insulin sensitivity, improved glucose tolerance and resistance to
9–10
diet-induced obesity.
Therefore, PTP1B could be a useful target for the treatment
of type 2 diabetes mellitus, obesity and cancer, and small molecule inhibitors of
PTP1B may be promising drug candidates for treating these diseases.
In recent years, following the elucidation of the basic structural requirements for
PTP1B-substrate and -inhibitor interactions, a large variety of potent PTP1B
inhibitors have been identified through high-throughput screening, structure-based
and fragment-based drug design. The low cell permeability and bioavailability of

these compounds have limited their development as effective drugs because of the
presence of highly negatively charged residues (including
difluoromethylphosphonates, carboxymethylsalicyclic acids and oxalylaminobenzoic
11-12
acids) that mimic the phosphate group in IRS.
Additionally, because of the
structural homology present throughout many PTP families, it is challenging to
identify selective inhibitors specific to each PTP. Hence, it is imperative to identify
novel compounds with new core scaffolds that inhibit PTP1B with sufficient efficacy
and desirable pharmaceutical properties.
Figure 1. Structures of known PTP1B inhibitors (I and II) and rhodanine-3-alkanoic acid
derivatives (III and IV).
13
Because of the electrostatic properties of the PTP1B enzyme active site, it has
proven difficult to develop effective uncharged pTyr mimetics. Replacing the
phosphate group of pTyr with bioisosteric monoanionic groups, such as carboxylates,
1
4-15
is considered a valid method to obtain inhibitors with low polarity.
Indeed,
several carboxylic acids with good PTP1B inhibitory profiles and cellular activity or
1
6-22
oral bioavailability have been reported.
compound I was identified as inhibitors of PTP1B, in which a 4-[(2,
-dioxothiazolidin-3-yl)methyl]benzoic acid moiety could act as a monoanionic
For example, as shown in Figure 1,
4
pTyr-mimetic group and replicate the interactions of pTyr with the catalytic site of the
enzyme and the 5-arylidene moiety could bind the surrounding lipophilic amino acid
2
1
residues, including the PTP1B secondary noncatalytic binding pocket. Subsequent
studies showed that compound II, where a 2-phenylimino moiety was introduced into
the 4-thiazolidinone ring, could further enhance the affinity between the inhibitor and

enzyme by means of favorable interactions with active site residues and the
2
2
surrounding loops. Moreover, these compounds were capable to induce the insulin
metabolic pathway in mouse C2C12 skeletal muscle cells by remarkably stimulating
1
8
both IRβ phosphorylation and 2-deoxyglucose cellular uptake.
In our previous work, a large variety of rhodanine-3-alkanoic acid derivatives (e.g.
23-26
III and IV) were synthesized and identified as potential antibacterial agents.
The
structures of 4-[(2, 4-dioxothiazolidin-3-yl)methyl]benzoic acid (V) and
rhodanine-3-acetic acid (VII) are based on similar scaffolds. According to the strategy
of pharmacophore-oriented scaffold hopping, we assumed by extension that
rhodanine-3-acetic acid derivatives might possess inhibition activity against PTP1B.
Inspired
by
the
fragment
VI,
we
assumed
that
a
(
R)-2-(4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropanoic acid group (VIII) might
offer a possible alternative skeleton which could bind simultaneously in both the
catalytic site and the adjacent pTyr binding site, and improve not only the binding
affinity but also the opportunity for selectivity over other PTPs (Figure 2).
Figure 2. Design strategies of the novel pTyr mimetic based pharmacophore-oriented
scaffold hopping.
To expand the range of available pharmacophores from which new PTP1B
inhibitors can be developed, compounds III and IV were selected and tested against
PTP1B. Interestingly, most of the tested compounds showed good PTP1B inhibitory
activity at 20 µg/mL and dose-dependently inhibited PTP1B with IC50 values in the
micromolar range as expected. In the present work, we report a class of rhodanine

compounds as novel and potent inhibitors of PTP1B. Additionally, the mechanism of
inhibition of PTP1B by these compounds along with their structure–activity
relationships (SARs) were probed, which provides insights for further optimization of
lead compounds of this class and generation of a pharmacophore model.
Compounds III and IV were synthesized according to Scheme 1. The synthetic
procedures to generate compounds III and IV along with their spectral data were
2
5-26
previously described by our laboratory.
Scheme 1. Regants and conditions: (a) carbon disulfide, NaOH, 25 °C, 16 h; (b) sodium
chloroacetate, 25 °C, 3 h; (c) 6M HCl, reflux, 16 h. (d) phenylhydrazine, acetic acid, NaOH,
CH
3
CH
2
OH, reflux, 1h; (e) (i) N, N-dimethylformamide, POCl
3
, 0-5 °C, 0.5 h; (ii) N,
N-dimethylformamide, 50 °C; (f) piperidine, acetic acid, CH
3
CH OH, 40-50 °C, 4 h.
2
The inhibitory activities of all the compounds against PTP1B were measured using
p-nitrophenyl phosphate (pNPP) as a substrate, and the results are summarized in
Tables 1 and 2. The known PTP1B inhibitor oleanolic acid (IC50 = 1.62 ± 0.13 µM)
17, 27
was used as the positive control.
As shown in Tables 1 and 2, 27 out of 36
compounds tested showed good PTP1B inhibitory activity at 20 µg/mL and
dose-dependently inhibited PTP1B with IC50 values ranging from 0.67 ± 0.09 to 24.56
±
1.21 µM. Of these, IIIv was the most potent with an IC50 value of 0.67 ± 0.09 µM,
about 2.5-fold better than that of the positive control.
The following SARs were obtained by analyzing the activities of compounds III
and IV. As shown in Table 1, among compounds IIIa–p containing
rhodanine-3-acetic acid, seven compounds (e.g. IIId, IIIg, IIIh, IIIi, IIIk, IIIm and
IIIn) exhibited inhibitory activities against PTP1B (IC50 = 4.78 ± 0.27 ~ 24.56 ± 1.21

µM). These results indicated that the PTP1B inhibitory activity was significantly
influenced by the position and nature of the substituent on the phenyl ring. The impact
of the substituent position on the benzene ring on the efficacy was not predictable.
Compared with compounds IIIj and IIIm, the compound with the phenyl ring
substituent (IIIj) showed no activity at 20 µg/mL, but interestingly, the compound
with the naphthalene ring (IIIm) had dramatically improved PTP1B inhibitory
activity with an IC50 value of 4.78 ± 0.27 µM. This is consistent with earlier studies in
which lipophilic moieties stabilized the enzyme–compound complex via hydrophobic
interactions with the active site and surrounding subpockets, a common feature of
1
8-22
PTP1B–inhibitor complexes.
This concept is also supported by our docking
simulations as described below (Figure 5B). To investigate the effects of the
substituents on the nitrogen atom of the rhodanine on the PTP1B inhibitory activity,
the acetic acid moiety was changed to various fatty acids with different carbon chain
lengths while simultaneously fixing the substituents on the phenyl ring, such as 2,
4
-chlorine or 4-chlorine. Interestingly, the results for the 2-thioxo-4-thiazolidinone
N-alkanoic acids derivatives (IIIq–x) showed that increasing the length of the carbon
chain resulted in a significant increase of inhibitory activity, in particular, compound
IIIv was found to have the best inhibitory activity against PTP1B (IC50 = 0.67 ± 0.09
µM). This result suggests that the carbon chain length between the COOH group and
2
-thioxo-4-thiazolidinone ring plays a crucial role in determining the inhibitor binding
affinity. In this regard, more derivatives possessing different rhodanine-3-fatty acids
need to be designed and synthesized to establish the optimum length required for the
best inhibitory potency, and this work is currently in progress in our laboratory.
Table 1
Inhibitory activity of compounds IIIa-x against PTP1B.

2
a
2
Compound
R
n
1
IC50 (μM)
Compound
R
n
1
IC50 (μM)
Phenyl
b
IIIa
2-F
NA
IIIm
4.78 ± 0.27
(
3,4-fused)
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
4-F
2-Cl
3-Cl
4-Cl
2,4-Cl
3-Br
4-Br
1
1
1
1
1
1
1
1
1
1
1
NA
NA
IIIn
IIIo
IIIp
IIIq
IIIr
IIIs
IIIt
2-OCH
3-OCH
4-OCH
4-Cl
3
3
3
1
1
1
2
2
3
3
4
4
5
5
24.56 ± 1.21
NA
13.23 ± 2.68
NA
NA
6.58 ± 1.76
7.93 ± 0.42
2.27 ± 0.35
3.66 ± 0.38
2.20 ± 0.36
0.67 ± 0.09
1.85 ± 0.60
1.35 ± 0.27
2
NA
2,4-Cl
4-Cl
2
12.14 ± 1.64
14.22 ± 0.30
9.24 ± 0.60
NA
2,4-Cl
4-Cl
2
4-NO
2
IIIu
IIIv
IIIw
IIIx
IIIj
IIIk
IIIl
H
2,4-Cl
4-Cl
2
2
4-CH
3
14.68 ± 3.08
NA
2,4-(CH
3
)
2
2,4-Cl
c
Oleanolic acid
1.62 ± 0.13
a
The pNPP assay. IC50 values were determined by regression analyses and expressed as means ±
SD of three replications.
Not active at 20 μg/mL concentration.
Positive control.
b
c
As shown in Table 2, phenylalanine-derived rhodanine derivatives (IVa–l)
generally exhibited higher levels of inhibitory activity compared with the
corresponding rhodanine-3-acetic acid compounds (IIIc, IIIe–k and IIIm–p). As
expected, introducing a benzyl group at the 2-position of the carboxyl group
remarkably affected the activity, which might be attributed to the ability of the phenyl
ring to form steric interactions with Phe182, Met258, Leu260 and Gln262 as
suggested by the docking study (Figure 5D). On the basis of these observations, we
inferred that introduction of different substituents at the 2-position of the carboxyl
group might influence the PTP1B inhibitory activity. Thus it was necessary to make
further structural modifications at the 2-position to optimize the binding potency in
the tyrosine phosphate binding pocket of the active site. The compounds with
electron-withdrawing groups on the phenyl ring (IVa–f) showed better activity than
compounds IVi–l containing electron-donating groups. These results indicated that
electron-withdrawing groups contributed more to the inhibitory activity of PTP1B
than electron-donating groups. Interestingly, compound IVg containing the

naphthalene group (IC50 = 1.81 ± 0.22 µM) dramatically improved the enzyme
inhibitory activity as IVg was 3.5-fold more potent than compound IVh (IC50 = 6.37
±
0.52 µM). A similar trend was also observed for compounds identified as part of the
III numerical series.
Table 2
Inhibitory activity of compounds IVa-l against PTP1B.
2
a
2
Compound
R
IC50 (μM)
Compound
R
IC50 (μM)
Phenyl
3,4-fused)
H
IVa
2-Cl
4.89 ± 0.47
IVg
1.81 ± 0.22
(
IVb
IVc
IVd
IVe
IVf
4-Cl
2,4-Cl
3-Br
2.10 ± 0.34
3.56 ± 0.20
2.76 ± 0.55
4.42 ± 0.91
3.57 ± 0.41
1.62 ± 0.13
IVh
IVi
IVj
IVk
IVl
6.37 ± 0.52
2.05 ± 0.21
6.30 ± 1.46
4.95 ± 0.42
7.09 ± 0.81
2
4-CH
3
2-OCH
3-OCH
4-OCH
3
3
3
4-Br
4-NO
2
b
Oleanolic acid
a
The pNPP assay. IC50 values were determined by regression analyses and expressed as means ±
SD of three replications.
Positive control.
b
A number of representative compounds (e.g. IIIm, IIIr, IIIt, IIIv, IIIx, IVc and
1
7,
IVg) were investigated for their selectivity toward other PTPs by the same method,
2
7
including TCPTP, cell division cycle 25 homolog B (CDC25B), leukocyte
antigen-related phosphatase (LAR), src homology phosphatase-1 (SHP-1) and src
homology phosphatase-2 (SHP-2). As shown in Table 3, these compounds showed 2-
to 9-fold greater selectivity for PTP1B than for TCPTP. None of the compounds
inhibited LAR activity at 20 µg/mL. We concluded that these compounds possessed
about 3- to 42-fold selectivity for PTP1B over CDC25B. The compounds had no
visible activities toward SHP-1 and SHP-2 (except for IIIm and IVc).

Table 3
Inhibitory activity of selected compounds against related PTPs.
a
IC50 （μM）
Compound
PTP1B
TCPTP
CDC25B
LAR
SHP-1
SHP-2
b
IIIm
IIIr
IIIt
4.78 ± 0.27 7.91 ± 0.93 11.30 ± 0.65
7.93 ± 0.42 14.05 ± 1.64 17.10 ± 1.01
3.66 ± 0.38 9.18 ± 1.35 13.81 ± 0.32
0.67 ± 0.09 5.77 ± 0.35 28.15 ± 3.00
1.35 ± 0.27 5.63 ± 0.47 10.90 ± 0.49
3.56 ± 0.20 12.66 ± 1.67 13.72 ± 2.92
NA
24.45 ± 1.10 20.91 ± 1.42
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
IIIv
IIIx
IVc
IVg
16.81 ± 1.01 16.67 ± 1.06
NA NA
1.81 ± 0.22 4.61 ± 0.42
6.12 ± 0.92
c
d
Na
3
VO
4
—
—
2.08 ± 0.16 15.14 ± 0.23 26.14 ± 1.65 24.05 ± 0.95
c
Oleanolic acid
1.62 ± 0.13 4.89 ± 0.63
—
—
—
—
a
The pNPP assay. IC50 values were determined by regression analyses and expressed as means ±
SD of three replications.
Not active at 20 μg/mL concentration.
Positive control.
b
c
d
Not tested.
A kinetic study was performed to investigate the inhibitory mechanism of
2
7
compounds IIIv and IVg.
As shown in Figure 3A and 4A, IIIv and IVg
demonstrated a time-independent inhibition of PTP1B, which showed IIIv and IVg
were fast-binding inhibitors of PTP1B. The time-independent inhibition of IIIv and
IVg towards PTP1B may also exclude that IIIv and IVg were nonspecific inhibitors,
because nonspecific inhibitors always show time-dependent behavior and steep
2
8
inhibition curve. As shown in Figure 3B and 4B, the inhibition modality of IIIv and
IVg toward PTP1B exhibited characteristics typical of a competitive inhibitor,
including increased K
m
values and unchanged Vmax values following increases in
inhibitor concentration. The Lineweaver-Burk plot also indicated that IIIv and IVg
were competitive inhibitors of PTP1B as shown by the intersection of the best fit lines
on the y-axis (Figure 3C and 4C). These results indicate that IIIv and IVg bind to the
catalytic pocket of PTP1B and behave as competitors to the physiological substrate.
i
The K values were calculated as 0.31 µM and 0.70 µM, respectively.

Figure 3. Characterization of IIIv to PTP1B.
A) Time-independent inhibition of PTP1B by IIIv. (B) At various fixed concentrations of IIIv
(
the initial velocity was determined with various concentrations of pNPP. (C) Typical competitive
inhibition of IIIv shown by Lineweaver-Burk plot.
Figure 4. Characterization of IVg to PTP1B.
(A) Time-independent inhibition of PTP1B by IVg. (B) At various fixed concentrations of IVg
the initial velocity was determined with various concentrations of pNPP. (C) Typical competitive
inhibition of IVg shown by Lineweaver-Burk plot.

To understand the inhibitory activities of IIIm, IIIv and IVg against PTP1B, we
subjected them to molecular docking analysis using MOE Dock in MOE v2014.0901
2
9
30
and predicted their binding affinity with PTP1B (PDB code: 2vey). The binding
modes of three compounds revealed by docking studies are illustrated in Figure 5.
These results indicated that their interaction modes were similar to those of
2
1-22
compounds I and II,
in which the rhodanine-3-alkanoic acid moieties were
situated in the catalytic site of PTP1B and the 1,3-diaryl pyrazole group extended into
the hydrophobic subpocket near the catalytic site.
As shown in Figure 5B, the carbonyl and hydroxyl moieties of the carboxyl group
in IIIm, regarded as the hydrogen bond acceptor and donor, respectively, form
hydrogen bonds with the backbone of Gly220 and side chain of Cys215 in the
catalytic site of PTP1B, respectively. The naphthalene ring showed good van der
Waals interactions with Met258, Gln262 and Asp48 in PTP1B, indicating it might
contribute to the improved activities of this compound compared with IIIj.
Additionally, the terminal benzene ring provided good van der Waals interactions with
Tyr46 and Phe182 in PTP1B.
As shown in Figure 5D, the oxygen atom of the carboxyl group in IVg, regarded as
the hydrogen bond donor, forms one hydrogen bond with the sidechain of Cys215 in
PTP1B. The sulfur atom of the carbon-sulfur double bond of the thiazole ring,
regarded as the hydrogen bond acceptor, forms one hydrogen bond with the sidechain
of Phe182 in PTP1B. Some van der Waals interactions were also observed, including
interactions of the naphthalene ring with Asp48, Arg47 and Met258 and interactions
of the terminal benzene ring with Tyr46 and Arg45. The benzyl group of the adjacent
carboxyl group provides good van der Waals interactions with Phe182, Met258,
Leu260 and Gln262 in PTP1B, which might explain the activity difference between
compounds IV and IIIa–p.
As shown in Figure 5F, the pyrazole of IIIv forms a H-π conjugation with the
sidechain of Gln262 in PTP1B. The sulfur atom of the thiazole and carbon atom of the
adjacent vinyl moiety, regarded as a hydrogen bond acceptor, forms two hydrogen
bonds with the sidechain of Asp48 in PTP1B. The carbonyl and hydroxyl moieties of

the carboxyl group, regarded as the hydrogen bond acceptor and donor, forms three
hydrogen bonds with the backbone of Ser216 and sidechains of Arg221 and Cys215
in PTP1B. Some van der Waals interactions were also observed, such as interactions
between the terminal benzene ring and Gly259 and Arg24, the sulfur atom of the
carbon-sulfur double bond of the thiazole ring and Met258, and the sulfur atom of the
thiazole ring and Asp48.

Figure 5. The binding model of IIIm, IIIv and IVg with PTP1B. (A) The binding
model of IIIm on molecular surface of PTP1B. (B) The interaction model of IIIm
with PTP1B. (C) The binding model of IVg on molecular surface of PTP1B. (D) The
interaction model of IVg with PTP1B. (E) The binding model of IIIv on molecular
surface of PTP1B. (F) The interaction model of IIIv with PTP1B. The ligands are
colored in yellow, and the surrounding residues in the binding pockets are colored in
cyan. The backbone of the receptor is depicted as light blue ribbon.
The Asp48 residue provided the specificity of PTP1B for phosphotyrosine over
phosphoserine or phosphothreonine and the Gly220 residue of PTP1B was important
3
1
in modulating the activities according to previous studies.
Taken together, the
docking simulation studies indicate that IIIm interacts with Gly220 and Cys215 of
PTP1B through hydrogen bonds, IVg interacts with Cys215 and Phe182 of PTP1B
through hydrogen bonds, and IIIv interacts with Asp48, Gln262, Ser216, Arg221 and
Cys215 of PTP1B through hydrogen bonds and H-π conjugation. The different
binding models between ligands and PTP1B result in different binding abilities. The
docking scores of IIIm, IIIv and IVg are shown in Table 4, which are -7.3611
kcal/mol, -8.2432 kcal/mol and -7.3841 kcal/mol for PTP1B, respectively. The
computational results indicate that IIIm, IIIv and IVg all interact with PTP1B and the
binding ability with PTP1B is in the order IIIv > IVg > IIIm.
Table 4
The docking score of molecules binding with PTP1B.
Ligands
IIIm
IIIv
Receptor
PTP1B
PTP1B
PTP1B
Docking score (kcal/mol)
-7.3611
-8.2432
IVg
-7.3841
In summary, two series of 1,3-diaryl pyrazole derivatives containing
rhodanine-3-alkanoic acid groups were identified as novel competitive PTP1B
inhibitors with IC50 values in the micromolar range. Compound IIIv showed the best
PTP1B inhibitory potency (IC50 = 0.67 ± 0.09 µM) and the best selectivity (9-fold)
between PTP1B and TCPTP. This preliminary SAR study highlighted that the carbon
chain length of the alkanoic acid and introduction of a benzyl group at the 2-position

of the carboxyl group remarkably improved the PTP1B inhibitory activity and
selectivity toward other PTPs. Molecular docking studies of three compounds (IIIm,
IIIv and IVg) indicated that the rhodanine-3-alkanoic acid moieties were situated in
the catalytic site of PTP1B and the 1,3-diaryl pyrazole group extended into the
hydrophobic subpocket near the catalytic site, which indicated a possible binding
mode and provided insights for further optimization of the scaffold. The design and
synthesis of new potential PTP1B inhibitors based on the available biological data and
SAR analysis are currently ongoing in our research group.
Acknowledgments
We wish to thank the National Natural Science Foundation of China (No. 81460524
and 81773779) and the Education Department of Jilin Province Scientific Research
Fund Project (2015-50) for financial support. We thank Renee Mosi, PhD, from
Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English
text of a draft of this manuscript.
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Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A2R7, 2014.09.
3
0. The 2D structures of the molecules were drawn in ChemBioDraw 2014 and converted to 3D in
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Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing
rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors
a, 1
b, 1
c
b
b,*
c,*
Liangpeng Sun , Peipei Wang , Lili Xu , Lixin Gao , Jia Li , Huri Piao
Two series of the 1,3-diphenyl-1H-pyrazole derivatives containing
rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine
phosphatase 1B (PTP1B) inhibitors.

Highlights


Rhodanine-3-alkanoic acid groups were identified as pTyr mimetics.
The most potent compound IIIv showed an IC50 value of 0.67 ± 0.09 µM against
PTP1B.


The compound IIIv showed the best selectivity (9-fold) between PTP1B and
TCPTP.
Molecular docking studies supported the experimental observations.