5-Aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety as potential PTP1B inhibitors

Article abstract of DOI:10.1016/j.bioorg.2020.104483

Two series of 5-aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, 5g was found to have the best PTP1B inhibitory potency (IC₅₀ = 2.66 ± 0.16 μM) and the best cell division cycle 25 homolog B (CDC25B) inhibitory potency (IC₅₀ = 0.25 ± 0.02 μM). Enzymatic data together with molecular modeling results demonstrated that the introduction of a sec-butyl group at the 2-position of the carboxyl group remarkably improved the PTP1B inhibitory activity.

Full text of DOI:10.1016/j.bioorg.2020.104483

Journal Pre-proofs
Short communication
5-Aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rho-
danine moiety as potential PTP1B inhibitors
Tianwei Niu, Peipei Wang, Cheng Li, Tong Dou, Huri Piao, Jia Li, Liangpeng
Sun
PII:
S0045-2068(20)31781-8
DOI:
https://doi.org/10.1016/j.bioorg.2020.104483
YBIOO 104483
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
2 July 2020
31 October 2020
16 November 2020
Please cite this article as: T. Niu, P. Wang, C. Li, T. Dou, H. Piao, J. Li, L. Sun, 5-Aryl-furan derivatives bearing
a phenylalanine- or isoleucine-derived rhodanine moiety as potential PTP1B inhibitors, Bioorganic Chemistry
(2020), doi: https://doi.org/10.1016/j.bioorg.2020.104483
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Elsevier Inc. All rights reserved.

5-Aryl-furan derivatives bearing a phenylalanine- or
isoleucine-derived rhodanine moiety as potential PTP1B inhibitors
Tianwei Niu a, e, 1, Peipei Wang b, 1, Cheng Li c, Tong Dou d, Huri Piao d,
Jia Li b, *, Liangpeng Sun a, d *
a College of Medicine, Yanbian University, Yanji 133000, China
b
National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Science, Chinese Academy of Sciences, Shanghai 201203, China
c Department of Pharmacy, Yanbian University Hospital, Yanji 133000, China
d College of Pharmacy, Yanbian University, Yanji 133000, China
e China-Japan Union Hospital of Jilin University, Changchun 130033, China
*
Corresponding author.
E-mail address: lpsun@ybu.edu.cn (L. Sun)
*
Co-corresponding author.
E-mail address: jli@simm.ac.cn (J. Li)
1 These authors contributed equally to this work.

Abstract
Two series of 5-aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived
rhodanine moiety were identified as competitive protein tyrosine phosphatase 1B
(PTP1B) inhibitors. Among the compounds studied, 5g was found to have the best
PTP1B inhibitory potency (IC50 = 2.66 ± 0.16 µM) and the best cell division cycle 25
homolog B (CDC25B) inhibitory potency (IC50 = 0.25 ± 0.02 µM). Enzymatic data
together with molecular modeling results demonstrated that the introduction of a
sec-butyl group at the 2-position of the carboxyl group remarkably improved the
PTP1B inhibitory activity.
Keywords: PTP1B inhibitor; Furan; Rhodanine; Phenylalanine; Isoleucine
Protein tyrosine phosphatase 1B (PTP1B), an intracellular protein tyrosine
phosphatase (PTP), is a key negative regulator in the insulin and leptin-signaling
pathway, which acts by dephosphorylating the insulin receptor (IR), insulin receptor
substrate-1 (IRS-1) and IRS-2, and JAK2, a kinase downstream of the leptin receptor
[1-4]. PTP1B-knockout mice exhibited phenotypes of increased insulin sensitivity,
improved glucose tolerance, and resistance to diet-induced obesity. PTP1B-deficient
mice had normal growth and longevity [5-6]. Previous studies have shown that the
overexpression of PTP1B is sufficient to drive tumorigenesis in mice [7-8]. Therefore,
PTP1B is widely recognized as an attractive target for the treatment of type II diabetes
mellitus, obesity, and cancer, and the development of small molecule inhibitors of
PTP1B has become a promising way to treat these diseases.
Following the elucidation of the basic structural requirements for PTP1B-substrate
and -inhibitor interactions, various PTP1B inhibitors with high activity have been
identified in the last decade. However, their assessment in clinical trials was restricted,
mainly because of two major drawbacks. First, the low cell permeability and
bioavailability of these compounds, because of the presence of highly negatively
charged residues that mimic the phosphate group in the IRS, has limited their
development as effective drugs [9-10]. Second, because of the structural homology

present throughout many PTP families, it is challenging to identify selective inhibitors
specific for each PTP [11-12]. Therefore, it is desirable to develop novel compounds
with new core scaffolds that not only inhibit PTP1B with sufficient efficacy, but
which also possess suitable pharmaceutical properties.
Rhodanine, 2-thioxo-1,3-thiazolidin-4-one, has emerged as an important
privileged structure in medicinal chemistry [13]. Molecules based on the rhodanine
core have received much attention because of their pharmacological properties,
including antibacterial [14-17], anticancer [18-19], antidiabetic [20],
anti-inflammatory [21], antiviral [22], and anti-HIV [23] activities. As reported
recently, rhodanine-3-acetic acid derivatives (1) have been identified as PTP1B
inhibitors, in which the rhodanine-3-acetic acid moiety can replicate the interactions
of the pTyr residue with the catalytic site of the enzyme (Fig. 1) [24]. In our previous
work, two series of 1,3-diaryl pyrazole derivatives containing rhodanine-3-alkanoic
acid groups (2 and 3) were identified as potent competitive PTP1B inhibitors [25].
Preliminary structure–activity relationships (SARs) revealed that the substituents at
positions 5 and N-3 of rhodanine play an important role in modulating PTP1B
inhibitory activity. Introducing a benzyl group at the 2-position of the carboxyl group
of compound 3 was shown to remarkably improve the PTP1B inhibitory activity and
selectivity toward other PTPs. Additionally, the 1,3-diaryl pyrazole group enhanced
the PTP1B inhibitory activity by extending into the hydrophobic sub-pocket near the
catalytic site and forming hydrophobic interactions with the protein. Thus, these
findings encouraged us to make additional structural modifications at positions 5 and
N-3 of rhodanine to obtain novel PTP1B inhibitors and further investigate the SARs.
As a part of our ongoing studies into the development of rhodanine PTP1B
inhibitors, based on the structure of compound 3, a series of compounds,
(S,Z)-2-(4-oxo-5-((5-substituted-phenylfuran-2-yl)methylene)-2-thioxothiazolidin-3-y
l)-3-phenylpropanoic acid (4), were designed by replacing the pyrazole ring with a
furan ring as a bioisosteric surrogate and simplification from a diaryl moiety to a
monoaryl
moiety.
Subsequently,
a
(2S)-3-methyl-2-((Z)-4-oxo-5-((5-substituted-phenylfuran-2-yl)methylene)-2-thioxoth

iazolidin-3-yl)pentanoic acid (5) series was also designed by the modification of the
phenylalanine moiety to an isoleucine (Fig. 2). All of the compounds showed
moderate to strong inhibitory activity against PTP1B. In the present work, we
developed two series of 5-aryl-furan derivatives bearing rhodanine moieties as novel
and potent inhibitors of PTP1B, and their mechanism of inhibition of PTP1B along
with their SARs were investigated.
Compounds 4 and 5 were synthesized as shown in Scheme 1. The synthesis
procedure and spectral data have been previously described [26].
All the compounds were evaluated for inhibitory activity against the PTP1B
enzyme, using p-nitrophenyl phosphate as a substrate and oleanolic acid as a positive
control [27]. As shown in Table 1, all of the compounds tested showed moderate to
strong PTP1B inhibitory activity against PTP1B with IC50 values ranging from 2.66 ±
0.16 to 20.84 ± 1.81 µM. Of these, 5g was the most potent with an IC50 value of 2.66
± 0.16 µM.
On the basis of the evaluation results, we analyzed preliminary SARs. As shown in
Table 1, all compounds 4a–l and 5a–l exhibited inhibitory activities against PTP1B
(IC50 = 3.02 ± 0.14 to 20.84 ± 1.81 µM and 2.66 ± 0.16 to 16.85 ± 3.49 µM,
respectively). Compared with compound 4h bearing a non-substituted phenyl ring, the
introduction of substituted phenyl rings, containing either electron-donating (4a–g) or
withdrawing (4j–l) groups, did not improve the activity of the compounds. In
compounds 4h (IC50 = 3.02 ± 0.14 µM) and 4i (IC50 = 14.48 ± 1.24 µM), the
introduction of a naphthalene ring instead of a phenyl ring resulted in a significant
decrease in inhibitory activity, as 4i was five-fold less potent than compound 4h. No
clear pattern was found for the SAR between the PTP1B inhibitory activity and the
position and physicochemical properties of the different substituents on the phenyl
ring. Similar trends were also observed for compounds in the 5 series. Interestingly,
except for 4b vs. 5b, 4j vs. 5j, and 4l vs. 5l, most of the isoleucine-derived rhodanine
(5) derivatives generally exhibited higher levels of inhibitory activity (1- to 5-fold)
compared with the corresponding phenylalanine-derived rhodanine derivatives (4).
These results indicated that introducing a sec-butyl group at the 2-position of the

carboxyl group might enhance inhibitory activity compared with introducing a benzyl
group. The sec-butyl group may not only form steric interactions with Phe182,
Leu195, and Gly220, but may also be conducive for the formation of stronger
hydrogen bond interactions between the isoleucine-derived rhodanine fragment and
Cys215, Ser216, Ala217, Ile219, and Gly220 of PTP1B, as suggested by the docking
study (Figure 3C). These findings demonstrated that it may be necessary to make
further structural modifications at the 2-position to optimize the binding potency in
the active site of the tyrosine phosphate binding pocket.
On the basis of the PTP1B enzyme inhibitory activity, compounds 4g, 4h, 5g, and
5h were selected to investigate their effect against other PTPs [27]. As shown in
Table 2, these compounds showed 1- to 2.5-fold greater selectivity for PTP1B than
for homogeneous T-cell protein tyrosine phosphatase, approximately 1–2-fold
selectivity for PTP1B over src homology phosphatase-1 (SHP-1), and approximately
2.5–7-fold selectivity for PTP1B over SHP-2. None of the compounds inhibited
leukocyte antigen-related phosphatase (LAR) activity at 20 µg/mL. Interestingly, the
compounds possessed 2- to 16-fold more potent inhibitory activity against CDC25B
than against PTP1B. CDC25B, a dual-specificity phosphatase, is an attractive
therapeutic antitumor target for potential small molecule intervention because of its
central role in controlling malignant cell proliferation by regulating cyclin dependent
kinases and because it is highly expressed in many human tumors [28]. Further
structural modification of these compounds may lead to the discovery of novel
inhibitory agents against the Cdc25 phosphatases.
To further understand the mechanisms of the rhodanine derivatives in the inhibition
of PTP1B, compound 5g was selected to evaluate the inhibitory kinetics [27]. As
shown in Fig. 3A, 5g demonstrated time-independent inhibition of PTP1B, which
showed that it was a fast-binding and specific inhibitor of PTP1B. As shown in Fig.
3B, the inhibition modality of 5g towards PTP1B exhibited the characteristics typical
of a competitive inhibitor, including increased Km values and unchanged Vmax values
following increases in the inhibitor concentration. The Lineweaver–Burk plot showed
straight lines that intersected with each other on the 1/v axis (Fig. 3C). These results

indicated that 5g binds to the catalytic pocket of PTP1B and behaves as a competitive
inhibitor. The Ki value was calculated to be 2.34 µM.
To investigate the binding mode of 4g and 5g with PTP1B, docking simulation
studies were carried out using MOE Dock in MOE v2014.0901 to predict the binding
affinity with PTP1B (PDB code: 2vey) [25]. The docking scores of 4g and 5g are
shown in Table 3 and were −7.23 kcal/mol and −7.33 kcal/mol, respectively, for
PTP1B. These computational results indicated that 4g and 5g can interact with PTP1B
and their binding ability with PTP1B was in the order 5g > 4g, which might explain
the difference in activity between compounds 4 and 5.
The binding mode of 4g with PTP1B is illustrated in Fig. 4A. The oxygen atom of
the hydroxyl group and the carbonyl of the carboxyl group, regarded as a hydrogen
bond donor and an acceptor, respectively, interact via hydrogen bonds with the side
chain of Asp181 and the backbone of Ala217 in the catalytic site of PTP1B,
respectively. The sulfur atom of the carbon-sulfur double bond of the thiazole ring,
regarded as a hydrogen bond acceptor, forms one hydrogen bond with the backbone
of Phe182 in PTP1B. The benzyl group at the 2-position of the carboxyl group
provides a good van der Waals interaction with Phe182 in PTP1B. The 5-aryl-furan
fragment interacts hydrophobically with the side chains of Phe182, Ile219, and
Gly259 in PTP1B.
The binding mode of 5g with PTP1B is illustrated in Fig. 4C. The oxygen atom of
the carbonyl of the carboxyl group, regarded as a hydrogen bond acceptor, forms
hydrogen bonds with the side chain of Cys215 and the backbone of Ser216 as well as
Ala217 in PTP1B. The oxygen atom of the hydroxyl of the carboxyl group, regarded
as a hydrogen bond acceptor, forms one hydrogen bond with the side chain of Ser216
in PTP1B. The sulfur atom of the carbon-sulfur double bond of the thiazole ring,
regarded as a hydrogen bond acceptor, interacts via hydrogen bonds with the
backbone of Ala217, Ile219, and Gly220 in PTP1B. Some van der Waals interactions
and hydrophobic interactions were also observed, including interactions between the
sec-butyl group at the 2-position of the carboxyl group and Phe182, Leu195, and
Gly220 and the 5-aryl-furan fragment and Phe182, Ile219, and Gly259 in PTP1B.

In conclusion, two series of 5-aryl-furan derivatives bearing
a
phenylalanine-derived rhodanine or isoleucine-derived rhodanine group were
identified as novel competitive PTP1B inhibitors. Compound 5g showed the best
PTP1B inhibitory potency (IC50 = 2.66 ± 0.16 µM) and the best CDC25B inhibitory
potency (IC50 = 0.25 ± 0.02 µM). Enzymatic data together with molecular modeling
results demonstrated that the introduction of a sec-butyl group at the 2-position of the
carboxyl group remarkably improved the PTP1B inhibitory activity. The results
obtained in this work demonstrate that isoleucine-derived rhodanine scaffolds might
represent a good starting point for developing more active inhibitors of PTP1B as well
as CDC25B.
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.
Acknowledgments
We wish to thank the National Natural Science Foundation of China (No.
81460524, 81660619 and 81773779). We thank Victoria Muir, PhD, from Liwen
Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a
draft of this manuscript.
References
1. J.C.H. Byon, A.B. Kusari, J. Kusari, Protein-tyrosine phosphatase-1B Acts as a Negative
Regulator of Insulin Signal Transduction, Mol. Cell Biochem. 182 (1998) 101-108.
2. S. Walchi, M.L. Curchod, R.P. Gobert, S. Arkinstall, R.H. Huijsduijnen, Identification of
Tyrosine Phosphatases That Dephosphorylate the Insulin Receptor. A Brute Force Approach
Based on "Substrate-Trapping" Mutants, J. Biol. Chem. 275 (2000) 9792-9796.
3. C. Ramachandran, B.P. Kennedy, Protein Tyrosine Phosphatase 1B: A Novel Target for Type
2 Diabetes and Obesity, Curr. Top Med. Chem. 3 (2003) 749-757.

4. W.S. Cook, R.H. Unger, Protein Tyrosine Phosphatase 1B: A Potential Leptin Resistance
Factor of Obesity, Developmental Cell 2 (2002) 385-387.
5. M. Elchebly, P. Payette, E. Michaliszyn, W. Cromlish, S. Collins, A.L. Loy, D. Normandin, A.
Cheng, J. Himms-Hagen, C.C. Chan, C. Ramachandran, M.J. Gresser, M.L. Tremblay, B.P.
Kennedy, Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein
Tyrosine phosphatase-1B Gene, Science 283 (1999) 1544-1548.
6. L.D. Klaman, O. Boss, O.D. Peroni, J.K. Kim, J.L. Martino, J.M. Zabolotny, N. Moghal, M.
Lubkin, Y.B. Kim, A.H. Sharpe, A. Stricker-Krongrad, G.I. Shulman, B.G. Neel, B.B. Kahn,
Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in
Protein-Tyrosine Phosphatase 1B-deficient Mice, Mol. Cell Biol. 20 (2000) 5479-5489.
7. W. Wang, Y. Cao, X. Zhou, B. Wei, Y. Zhang, X. Liu, PTP1B Promotes the Malignancy of
Ovarian Cancer Cells in a JNK-dependent Mechanism, Biochem. Biophys. Res. Commun. 503
(2018) 903-909.
8. H. Liu, Y. Wu, S. Zhu, W. Liang, Z. Wang, Y. Wang, T. Lv, Y. Yao, D. Yuan, Y. Song,
PTP1B Promotes Cell Proliferation and Metastasis Through Activating SRC and ERK1/2 in
Non-Small Cell Lung Cancer, Cancer Lett. 359 (2015) 218-225.
9. A.P. Combs, Recent Advances in the Discovery of Competitive Protein Tyrosine Phosphatase
1B Inhibitors for the Treatment of Diabetes, Obesity, and Cancer, J. Med. Chem. 53 (2010)
2333-2344.
10. A.J. Barr, Protein Tyrosine Phosphatases as Drug Targets: Strategies and Challenges of
Inhibitor Development, Future Med. Chem. 2 (2010) 1563-1576.
11. X.Q. Li, L.J. Wang, D.Y. Shi, The Design Strategy of Selective PTP1B Inhibitors Over
TCPTP, Bioorg. Med. Chem. 24 (2016) 3343-3352.
12. R.P. Nankar, M. Doble, Non-peptidyl Insulin Mimetics as a Potential Antidiabetic Agent,
Drug Discov. Today 18 (2013) 748-755.
13. D. Kaminskyy, A. Kryshchyshyn, R. Lesyk, Recent Developments With Rhodanine as a
Scaffold for Drug Discovery, Expert Opin. Drug Discov. 12 (2017) 1233-1252.
14. L. Slepikas, G. Chiriano, R. Perozzo, S. Tardy, A. Kranjc, O. Patthey-Vuadens, H.
Ouertatani-Sakouhi, S. Kicka, C.F. Harrison, T. Scrignari, K. Perron, H. Hilbi, T. Soldati, P.
Cosson, E. Tarasevicius, L. Scapozza, In Silico Driven Design and Synthesis of Rhodanine
Derivatives as Novel Antibacterials Targeting the Enoyl Reductase InhA, J. Med. Chem. 59
(2016) 10917-10928.
15. W. Sinko, Y. Wang, W. Zhu, Y. Zhang, F. Feixas, C.L. Cox, D.A. Mitchell, E. Oldfield, J.A.
McCammon, Undecaprenyl Diphosphate Synthase Inhibitors: Antibacterial Drug Leads, J.
Med. Chem. 57 (2014) 5693-5701.
16. C. Li, J.C. Liu, Y.R. Li, C. Gou, M.L. Zhang, H.Y. Liu, X.Z. Li, C.J. Zheng, H.R. Piao,
Synthesis and Antimicrobial Evaluation of 5-aryl-1,2,4-triazole-3-thione Derivatives
Containing a Rhodanine Moiety, Bioorg. Med. Chem. Lett. 25 (2015) 3052-3056.
17. M. Guo, C.J. Zheng, M.X. Song, Y. Wu, L.P. Sun, Y.J. Li, Y. Liu, H.R. Piao, Synthesis and
Biological Evaluation of Rhodanine Derivatives Bearing a Quinoline Moiety as Potent
Antimicrobial Agents, Bioorg. Med. Chem. Lett. 23 (2013) 4358-4361.
18. M. Azizmohammadi, M. Khoobi, A. Ramazani, S. Emami, A. Zarrin, O. Firuzi, R. Miri, A.
Shafiee, 2H-chromene Derivatives Bearing thiazolidine-2,4-dione, Rhodanine or Hydantoin
Moieties as Potential Anticancer Agents, Eur. J. Med. Chem. 59 (2013) 15-22.

19. Y. Sawaguchi, R. Yamazaki, Y. Nishiyama, T. Sasai, M. Mae, A. Abe, T. Yaegashi, H.
Nishiyama, T. Matsuzaki, Rational Design of a Potent Pan-Pim Kinases Inhibitor With a
Rhodanine-Benzoimidazole Structure, Anticancer Res. 37(2017) 4051-4057.
20. J. Choi, Y. Ko, H.S. Lee, Y.S. Park, Y. Yang, S. Yoon, Identification of (Beta-Carboxyethyl)-
Rhodanine Derivatives Exhibiting Peroxisome Proliferator-Activated Receptor Gamma
Activity, Eur. J. Med. Chem. 45 (2010) 193-202.
21. M.M.M. El-Miligy, A.A. Hazzaa, H. El-Messmary, R.A. Nassra, S.A.M. El-Hawash, New
Hybrid Molecules Combining Benzothiophene or Benzofuran With Rhodanine as Dual
COX-1/2 and 5-LOX Inhibitors: Synthesis, Biological Evaluation and Docking Study, Bioorg.
Chem. 72 (2017) 102-115.
22. C. Nitsche, V.N. Schreier, M.A. Behnam, A. Kumar, R. Bartenschlager, C.D. Klein,
Thiazolidinone-peptide Hybrids as Dengue Virus Protease Inhibitors With Antiviral Activity
in Cell Culture, J. Med. Chem. 56 (2013) 8389-8403.
23. R. Dayam, T. Sanchez, O. Clement, R. Shoemaker, S. Sei, N. Neamati, Beta-diketo Acid
Pharmacophore Hypothesis. 1. Discovery of a Novel Class of HIV-1 Integrase Inhibitors, J.
Med. Chem. 48 (2005) 111-120.
24. R. Maccari, A. Del Corso, P. Paoli, I. Adornato, G. Lori, F. Balestri, M. Cappiello, A. Naß, G.
Wolber, R. Ottanà, An Investigation on 4-thiazolidinone Derivatives as Dual Inhibitors of
Aldose Reductase and Protein Tyrosine Phosphatase 1B, in the Search for Potential Agents for
the Treatment of Type 2 Diabetes Mellitus and Its Complications, Bioorg. Med. Chem. Lett.
28 (2018) 3712-3720.
25. L.P. Sun, P.P. Wang, L.L. Xu, L.X. Gao, J. Li, H.R. Piao, Discovery of
1,3-diphenyl-1H-pyrazole Derivatives Containing rhodanine-3-alkanoic Acid Groups as
Potential PTP1B Inhibitors, Bioorg. Med. Chem. Lett. 29 (2019) 1187-1193.
26. J. Che, C.J. Zheng, M.X. Song, Y.J. Bi, Y. Liu, Y.J. Li, Y. Wu, L.P. Sun, H.R. Piao, Synthesis
and antibacterial evaluation of furan derivatives bearing a rhodanine moiety, Med. Chem.
Res. Med. Chem. Res. 23 (2014) 426–435.
27. L. Shi, H.P. Yu, Y.Y. Zhou, J.Q. Du, Q. Shen, J.Y. Li, J. Li, Discovery of a Novel
Competitive Inhibitor of PTP1B by High-Throughput Screening, Acta Pharmacol. Sin. 29
(2008) 278-284.
28. A.P. Ducruet, A. Vogt, P. Wipf, J.S. Lazo, Dual Specificity Protein Phosphatases: Therapeutic
Targets for Cancer and Alzheimer's Disease, Annu. Rev. Pharmacol. Toxicol. 45 (2005)
725-750.

HOOC
O
Ph
O
S
N
COOH
S
N
COOH
N
S
S
S
N
S
O
N
N
N
Ar
1
3
IC50 (PTP1B) = 1.81 ± 0.22 µM
2
IC50 (PTP1B) = 4.78 ± 0.27 µM
Fig. 1. Structures of known rhodanine PTP1B inhibitors and target compounds.

O
converted pyrazole
into furan ring
COOH
O
O
N
S
COOH
S
N
N
S
R
N
S
simplificated diaryl
to monoaryl moieties
4
3
converted phenylalanine
into isoleucine moiety
O
COOH
O
N
S
S
R
5
Fig. 2. The designed strategy for the title compounds.

Fig. 3. Characterization of 5g to PTP1B.
(A) Time-independent inhibition of PTP1B by 5g. (B) At various fixed concentrations of 5g the
initial velocity was determined with various concentrations of pNPP. (C) Typical competitive
inhibition of 5g shown by Lineweaver-Burk plot.

Fig. 4. The binding model of 4g and 5g with PTP1B. (A) The interaction model of 4g
with PTP1B. (B) The binding model of 4g on molecular surface of PTP1B. (C) The
interaction model of 5g with PTP1B. (D) The binding model of 5g on molecular
surface of PTP1B. The ligands are colored in yellow, and the surrounding residues in
the binding pockets are colored in green. The backbone of the receptor is depicted as
lightblue ribbon.

R
R
R
a
b
O
CHO
NH2
N2+Cl-
S
S
S
R'
N
N
R'
COOH
S
O
CH2C6H5
CH3
R'=
R
(4a-l)
O
O
c
(5a-l)
4-5
CHCH2CH3
a: 2-F; b: 2-Cl; c: 3-Cl; d: 4-Cl; e: 2,5-(Cl)2; f: 4-Br; g: 3-Cl, 4-F;
h: H; i: phenyl (3,4-fused); j: 2-CH3; k: 4-CH3; l: 4-OCF3
R=
Scheme 1 Regants and conditions: (a) NaNO2, HCl, 0 °C, 1 h; (b) furfural, CuCl2, acetone, 20
°C, 12 h; (c) Piperidine, AcOH, EtOH, 40-50 °C, 4 h.
Table 1
Inhibitory activity of compounds 4a-l and 5a-l against PTP1B
O
O
COOH
COOH
Ph
R
R
N
N
O
O
S
S
S
S
-l
a
4
-l
a
5
IC50 (μM) a
IC50 (μM)
Compound
R
Compound
R
4a
4b
4c
4d
4e
4f
2-F
2-Cl
3-Cl
4-Cl
16.62 ± 1.86
4.04 ± 0.19
4.77 ± 0.24
20.84 ± 1.81
17.94 ± 3.74
14.18 ± 1.04
4.78 ± 0.59
3.02 ± 0.14
5a
5b
5c
5d
5e
5f
2-F
2-Cl
3-Cl
4-Cl
3.41 ± 0.52
7.17 ± 1.17
4.47 ± 1.65
7.80 ± 0.62
6.10 ± 0.42
7.98 ± 1.08
2.66 ± 0.16
3.23 ± 0.41
2,5-Cl2
4-Br
2,5-Cl2
4-Br
4g
4h
3-Cl, 4-F
5g
5h
3-Cl, 4-F
H
H
Phenyl
Phenyl
4i
4j
14.48 ± 1.24
3.98 ± 0.48
5i
5j
6.73 ± 0.50
(3,4-fused)
2-CH3
(3,4-fused)
2-CH3
16.85 ± 3.49

4k
4l
4-CH3
13.11 ± 1.64
5.30 ± 0.83
3.26 ± 0.61
5k
5l
4-CH3
7.69 ± 2.08
8.79 ± 1.49
4-OCF3
4-OCF3
OA b
a The pNPP assay. IC50 values were determined by regression analyses and expressed as means ±
SD of three replications.
b Positive control: Oleanolic acid.

Table 2
Inhibitory activity of selected compounds against related PTPs
IC50 (μM) a
Compound
PTP1B
TCPTP
CDC25B
LAR
SHP-1
SHP-2
4g
4h
4.78 ± 0.59
3.02 ± 0.14
2.66 ± 0.16
3.23 ± 0.41
7.07 ± 0.03
3.08 ± 0.21
5.66 ± 0.11
8.14 ± 1.44
0.29 ± 0.07
0.20 ± 0.02
0.25 ± 0.02
0.69 ± 0.04
0.21 ± 0.01
NA b
NA
5.48 ± 0.28
4.73 ± 1.27
5.74 ± 0.28
2.73± 2.32
1.33 ± 0.04
31.26 ± 4.50
8.32 ± 1.98
14.09 ± 0.17
18.85 ± 3.45
3.46 ± 0.11
5g
NA
5h
NA
c
11.63 ± 1.97
Na3VO4
Oleanolic
acid c
3.27 ± 0.61
11.05 ± 0.57
a The pNPP assay. IC50 values were determined by regression analyses and expressed as means ±
SD of three replications.
b Not active at 20 μg/mL concentration.
c Positive control.

Table 3
The docking score of molecules binding with PTP1B
Ligands
4g
Receptor
PTP1B
PTP1B
Docking score (kcal/mol)
-7.23
-7.33
5g
5-Aryl-furan derivatives bearing a phenylalanine-derived or
isoleucine-derived rhodanine moiety as potential PTP1B inhibitors
Tianwei Niu a, e, 1, Peipei Wang b, 1, Cheng Li c, Tong Dou d, Huri Piao d,
Jia Li b, *, Liangpeng Sun a, d *
Two series of 5-aryl-furan derivatives bearing a phenylalanine-derived or
isoleucine-derived rhodanine moiety were identified as competitive protein tyrosine
phosphatase 1B (PTP1B) inhibitors.
O
O
Cl
COOH
Cl
COOH
O
O
N
N
S
F
F
S
S
S
5g
4g
IC50 (PTP1B) = 4.78 ± 0.59 
IC50 (PTP1B) = 2.66 ± 0.16 
M
M
IC50 (CDC25B) = 0.29 ± 0.07 
M
IC50 (CDC25B) = 0.25 ± 0.02 
M
Highlights
 Phenylalanine-derived or isoleucine-derived rhodanine groups were identified as
pTyr mimetics.

 The most potent compound 5g showed an IC50 value of 2.66 ± 0.16 µM against
PTP1B.
 The most potent compound 5g showed an IC50 value of 0.25 ± 0.02 µM against
CDC25B.
 Molecular docking studies supported the experimental observations.
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.