Study of triaryl-based sulfamic acid derivatives as HPTPβ inhibitors

Article abstract of DOI:10.1016/j.bmc.2020.115777

A series of novel triaryl-based sulfamic acid analogs was designed, synthesized and evaluated as inhibitors of human protein tyrosine phosphatase beta (HPTPβ). A novel, easy and efficient synthetic method was developed for target compounds, and the activi

Full text of DOI:10.1016/j.bmc.2020.115777

Bioorg. Med. Chem. 28 (2020) 115777
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Study of triaryl-based sulfamic acid derivatives as HPTPβ inhibitors
,
Wenjuan Zhanga, Zhao Weib, Guozhi Huangc, Fei Xiea, Zhibing Zhenga *, Song Lia
a National Engineering Research Center for the Emergency Strategic Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
b Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical University, Xi’an 300071, China
c School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201203, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
A series of novel triaryl-based sulfamic acid analogs was designed, synthesized and evaluated as inhibitors of
human protein tyrosine phosphatase beta (HPTPβ). A novel, easy and efficient synthetic method was developed
for target compounds, and the activity determination results showed that most of compounds were good HPTPβ
inhibitors. Interestingly, the compounds G4 and G25 with simple structure not only showed potent inhibitory
activity on HPTPβ but also had good inhibitory selectivity over other PTPs (PTP1B, SHP2, LAR and TC-PTP). The
molecular docking simulation of compounds with the protein HPTPβ helped us understand the structure–activity
relationship and clarify some confusing assay results. This research provides references for further drug design of
HPTPβ and other PTPs inhibitors.
HPTPβ inhibitor
Drug design
Synthesis
Docking simulation
Triaryl-based derivatives
1. Introduction
located in vascular endothelial cells and plays a central role in vascular
stability. Angiopoietin 1 (Ang1) and angiopoietin 2 (Ang2) are the li-
Protein tyrosine phosphatases (PTPs) catalyze the removal of the
phosphate from the tyrosine residues of proteins, thus antagonizing the
functions of protein tyrosine kinases (PTKs).1 The level of protein
phosphorylation regulates by PTPs and PTKs plays an essential role in a
number of physiological and pathogenic processes in human body. The
alteration of PTP expression is related to numerous human diseases
including cancer, diabetes, autoimmune disorders, etc.2,3 Therefore,
PTPs have attracted considerable attention as the targets for disease
treatment, such as PTP1B (protein tyrosine phosphatase 1B), LAR
(leukocyte antigen related protein) for diabetes and obesity, SHP2 (SH2
domain-containing protein phosphatase), TC-PTP (T cell protein tyro-
sine phosphatase) for cancer, and HPTPβ (human protein tyrosine
phosphatase beta) for diabetic macular edema.
gands of Tie2. When Ang1 binds to Tie2, the signaling pathway and the
corresponding cascade response are triggered to stabilize the blood
vessels.8,9 Ang2 acts as a context-dependent Tie2 agonist or antagonist
that can inhibit the Ang1-Tie2 axis.10 Therefore, the HPTPβ-Tie2
signaling pathway is used to treat the diseases related to vascular
leakage, such as cancer and retinal and choroidal vascular diseases.11,12
The following difficulties are encountered in the process of devel-
opment of PTPs inhibitors. First, the key cysteine of the catalytic center
of PTPs results in obtaining compounds with undesirable physico-
chemical properties such as high oxidizing and alkylation abilities in the
high throughput screening.13 Second, the key cysteine has an extremely
low pKa (-5) compared with that of a general Cys in protein (ꢀ 8.5).14
The study found that the active-site residues such as histidine and
threonine could lower the pKa of Cys.15 The cysteine with low pKa is
deprotonated at physiological conditions, which acts as a nucleophilic
reagent to attack on pTyr. Therefore, the identified molecules generally
contain an electronegative group to match the electropositive environ-
ment of the catalytic center of PTPs, which results in the poor
bioavailability of the compounds. Third, PTPs share a common active-
site motif that is the sequence C(X)5R(S/T) (X can denote any amino
acid). Therefore, the obtained compounds have poor selectivity to other
PTPs by now. Despite these difficulties, many promising molecules and
probes have been found in the PTP family.3,16
HPTPβ is an endothelial cell-specific receptor tyrosine phosphatase
composed of an extracellular domain, a transmembrane region and a
cytoplasmic catalytic domain.4 Fachinger, et al. found that HPTPβ was a
negative regulator of Tie2 and specifically modulates the angiopoietin
(Ang)-tyrosine-protein kinase receptor 2 (Tie2) function.5,6 The Ang-Tie
signaling pathway has an important effect on regulating vascular
angiogenesis, remodeling, vascular permeability and stability. Tie,
including Tie1 and Tie2, is the receptor of Ang.Tie1 is regarded as an
orphan receptor without a ligand and negatively regulates the Tie2
activation by forming heterodimers with Tie2.7 Tie2 is predominantly
* Corresponding author.
E-mail address: zbzheng@bmi.ac.cn (Z. Zheng).
https://doi.org/10.1016/j.bmc.2020.115777
Received 11 July 2020; Received in revised form 14 September 2020; Accepted 15 September 2020
Available online 21 September 2020
0968-0896/© 2020 Elsevier Ltd. All rights reserved.

W. Zhang et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115777
The triaryl-based derivatives had been extensively studied by Affy-
against HPTPβ was evaluated in vitro using 6, 8-difluoro-4-methylumbel-
liferyl phosphate (DiFMUP) as a substrate. The compund 3 reported in
the literature was a competitive and kind of sulfamic acid inhibitor of
HPTPβ. Because its structure was similar to the novel sythesized com-
pounds, it was chosen as a postivie control in the biological evaluation.
The percentage of inhibition of each compound was assessed at a single
max Inc. as potent inhibitors of protein tyrosine phosphatase 1B
(PTP1B).17,18 Most of them belong to a series of efficient non-
hydrolyzable difluoromethylenephosphonic acid (DFMP) analogs.
However, the electronegative phosphonate group in compounds, DFMP,
leads to poor cell membrane permeability. Therefore, the DFMP struc-
tural moiety of compounds was replaced by potential bioisosteric or
other groups to explore the change in the activity.19,20 The HPTPβ in-
hibitors containing sulfamic acid group had been studied by Proctor and
Gamble (P&G)21 and Ontogen corporation22, and a series of amino-
sulfonic acid derivatives with good inhibitory effect on HPTPβ and good
selectivity to other PTPs has been reported.23 At the same time, our
previous studies also showed that phenylsulfamic acid was a good pTyr
mimetics.24 Therefore, we designed new inhibitors of HPTPβ through
hybridizing the drug inclusions and structural fragments of the two
compounds, which have a simple scaffold structure and are easy to
synthesize (Fig. 1).
concentration (10 μM). If the %inhibition of a compound was higher
than 65%, the compound was selected for the subsequent IC50 assay. All
results are shown in Table 1.
We investigated the effect of the R and Aryl groups on the activity of
the compounds. Compounds with diverse carboxylic acids at R position
showed slight differences in the inhibitory effect on HPTPβ when Aryl
was a phenyl. According to the previous report21, connection of (4-
(thiophen-2-yl)thiazol)-2-yl or (4-(phenyl-2-yl)thiazol)-2-yl groups
would improve activity. Therefore, new compounds were coupled with
them. However, the activity of G6-G9 and G10-G13 was lower than that
of G1-G4, respectively. It seems that (4-(thiophen-2-yl)thiazol)-2-yl or
(4-(phenyl-2-yl)thiazol)-2-yl at Aryl position was not favorable for
improving activity. However, compounds incorporated with sulfonyl
group could increase the activity (G16, G18, G19, G21 and G23)30 and
surprisingly by-product G25 with a hydrogen atom at R showed the
same activity to G16, which offered us the information that the sulfonyl
and the hydrogen atom was possibly favorable for increasing activity.
Four compounds (G4, G14, G16 and G25) with different structures
were chosen to evaluate their inhibition selectivity against other PTPs
targets (TC-PTP, PTP1B, SHP-2, and LAR). As shown in Table 2, the
secondary amine G25 demonstrated the highest selectivity (250-fold,
26-fold, 130-fold and 250-fold for HPTPβ versus PTP1B, SHP2, LAR, and
TC-PTP, respectively) in contrast to the other tertiary amines G4, G14
and G16, while compound G4 with a phenyl and N-BOC-piperidine-4-
carbonyl group showed higher selectivity than compounds G16 and
G14.
2. Results and discussions
2.1. Chemistry
The synthetic route of triaryl-based sulfamic acid derivatives was
outlined in Schemes 1–2. Compounds G1-G5 was synthesized via four
steps (Scheme 1). Commercially available 4-nitrobenzyl bromide reac-
ted with aniline through a substitution reaction to yield intermediate
2.25 Various carboxylic acids reacted with phosphorus pentachloride in
dry DCM, and then the intermediate 2 was added into the reaction
mixture to produce compounds 3.26 In the presence of a reducing agent,
the nitro group of compounds 3 was reduced to the amino group and
then the sulfonation reaction was conducted with the resulting amine 4
to obtain the target compounds.
Scheme 2 described the synthetic route for compounds G6-G25. The
route started with the condensation of an aryl amine and a carboxylic
acid in the presence of (Benzotriazol1yloxy)tris(dimethylamino)phos-
phonium hexafluophosphate (BOP) to produce compound 7.27 Com-
pound 8 were synthesized by electrophilic substitution of 4-nitrobenzyl-
bromide with compound 7 using potassium carbonate as a base and then
were converted to compounds 9 via reduction in the presence of
FeCl3⋅6H2O, charcoal and hydrazine hydrate. Sulfonation of compound
9 produced the target compounds. Sodium hydride as the strong base
was needed to yield compounds 7 in the reaction of an aryl amine with
sulfonyl chloride and then compounds 8 were synthesized in the pres-
ence of K2CO3 and 4-nitrobenzyl bromide.28 However, the nitro group of
8 must be reduced in the presence of Fe and ammonia chloride. The
synthetic method of compounds 10 was the same as that of compounds
5. All synthesized compounds were characterized by 1H NMR, 13C NMR
and mass spectrometry.
2.3. Docking simulations
To better understand why different types of compounds had variable
affinities to the protein and to guide further optimization of the com-
pounds, the molecular docking simulation was performed to study the
interaction between HPTPβ with the compounds G4, G14, G16 and G25.
The catalytic pocket of HPTPβ includes a P-loop, a WPD-loop, a pTyr-
loop, a Q-loop and an undefined loop (Fig. 2E).31 The P-loop
comprising Cys1904, Ser1905, Gly1907, Val1908, Gly1909 and
Arg1910 that produce a positive electrostatic potential to accommodate
the negatively charged group in inhibitors located in the bottom of the
catalytic pocket. The WPD-loop included Pro1869, Asp1870 and
His1871, and the Asp1870 showed acid/base-effect on binding and
catalyzing the substrate. The Asn1735 and Tyr 1733 of the pTyr-loop
showed the ability to recognize and bind compounds. Some residues
of the Q-loop and undefined loop are nonconservative, such as Gln1948
and Lys1811, when forming H-bond with them was beneficial for
increasing selectivity.
2.2. Biological evaluation
The docking results of chosen compounds were shown in Fig. 2. It
was discovered that the sulfamic acid group of synthesized compounds
could bind to the P-loop and WPD-loop like the reference ligand. The
other substitutions on the N atom interacted with the other loops. From
the docking results, the interaction mode of compounds G4, G14 and
G16 with the protein were similar in Fig. 2A, 2B, 2D and 2F. The Aryl
group was located in a gap between the Q-loop and pTyr-loop and
various R groups extended to the undefined loop and the pTyr-loop. In
Fig. 2B and Fig. 2D, the hydrogen bond interaction between (4-(phenyl-
2-yl)thiazol)-2-yl and Asn1735 that was conservative among PTPs, but
the H-bond interaction between the benzene ring of G4 and Asn1735
was lack in Fig. 2A, which might be the reason why the inhibitory
selectivity of G4 was better than that of G14 and G16. Additionally,
other interactions between G16 and protein such as Pi-Pi stacking
interaction of phenyl with Tyr1733 and Pi-sigma interaction of (4-
The inhibitory activity of the triaryl-based sulfamic acid derivatives
Figure 1. The design strategy of triaryl-based sulfamic acid derivatives, R
stands for acyl or sulfonyl groups, Aryl denotes an aromatic group.
2

W. Zhang et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115777
Scheme 1. Reagents and conditions: (a) Aryl amine, K2CO3, CH3CN, 85% yield; (b) carboxylic acid, PCl5, CH2Cl2, 30–50% yield; (c) FeCl3⋅6H2O, charcoal,
N2H4⋅H2O, EtOH, 75–95% yield; (d) Me3N⋅SO3, CH3CN, 30–70% yield.
Scheme 2. Reagents and conditions: (a) carboxylic acid, BOP, CH3CN or sulfonyl chloride, NaH, DCM; (b) 4-Nitrobenzyl-bromide, K2CO3, DMF; (c) FeCl3⋅6H2O,
charcoal, N2H4⋅H2O, EtOH or Fe, NH4Cl, EtOH:H2O; (d) Me3N⋅SO3, CH3CN.
(phenyl-2-yl)thiazol)-2-yl with Ile1736 results in G16 having better
activity than G4 and G14. In Fig. 2C, although the H-bond interaction
was also existed between N atom of G25 with the conservative Asn1735,
the two additional H-bond and Pi-Pi stacking interactions of (4-(phenyl-
2-yl)thiazol)-2-yl with special Gln1948 and His1871 were detected,
which may be the reson why G25 has higher activity and selectivity.
were purchased from Sinopharm Chemical Reagent Co. Ltd. and were of
the analytical grade.
4.1.1. The synthesis of key intermediates
4.1.1.1. N-(4-nitrobenzyl)aniline (2). The mixture of 4-nitrobenzyl
bromide (5.00 g, 23.1 mmol), aniline (2.15 g, 23.1 mmol), and K2CO3
(3.19 g, 23.1 mmol) was dissolved in acetonitrile (70.0 mL) and stirred
at room temperature (r.t). The reaction was stopped after the raw ma-
terials were completely consumed as indicated by TLC. The mixture was
filtered and evaporated under reduced pressure to dryness and then the
saturated ammonium chloride solution was added. The mixture was
filtered to obtain a yellow target product (4.50 g, 85.1%). M.P.:
67.4–69.6 ◦C; 1H NMR (400 MHz, CDCl3) δ 8.24 – 8.16 (m, 2H), 7.53 (d,
J = 8.8 Hz, 2H), 7.17 (dd, J = 8.6, 7.4 Hz, 2H), 6.78 – 6.71 (m, 1H), 6.58
(dd, J = 8.6, 1.0 Hz, 2H), 4.48 (s, 2H). ESI-MS m/z: 229.11 [M + H]+
3. Conclusion
In this paper, a sequence of new triaryl-based sulfamic acid de-
rivatives was designed, synthesized and evaluated in vitro against the
recombinant HPTPβ. The inhibitory potency against HPTPβ and inhib-
itory selectivity over other PTPs proteins of the compounds were
improved based on the ligand-based drug design, and it was proved that
sulfamic acid was a potential bioisoster of the DFMP moiety. Addition-
ally, the structure–activity relationship analysis suggested that the
hydrogen atom might be good for improving the activity and selectivity
of compounds when incorporated (4-(thiophen-2-yl)thiazol)-2-yl at Aryl
position. The phenyl and sulfonyl groups were favorable for improving
the selectivity and activity of compounds, respectively. Meanwhile, the
molecular docking study helped us understand the difference of inhib-
itory activity and selectivity among the compounds. These results ob-
tained in this study can provide a new direction for the further design of
HPTPβ inhibitors.
4.1.1.2. 2-phenylthiazol-4-amine hydrobromide (6–1). The mixture of 2-
bromoacetophenone (3.0 g, 15.1 mmol) and thiourea (1.4 g, 18.1 mmol)
was dissolved in ethanol (30.0 mL) and was heated to reflux. The re-
action was stopped after 2-bromoacetophenone was completely
consumed. The mixture was concentrated to nearly dry under reduced
pressure and then EA was added. The solution was filtered to yield a
white target product (3.58 g, 93.0%). These procedures were repeated
until no solid precipitation was detected. M.P.: 178.9–181.0 ◦C; 1H NMR
(400 MHz, DMSO‑d6) δ 7.70 (t, J = 1.7 Hz, 1H), 7.69 (t, J = 1.4 Hz, 1H),
7.49 – 7.43 (m, 2H), 7.43 – 7.38 (m, 1H), 7.23 (s, 1H). ESI-MS m/z:
177.04 [M + H]+
4. Materials and methods
4.1. Chemistry
The melting points of the compounds were determined by the
capillary tube method by using an RY-1G melting point instrument
(uncorrected temperature) purchased from Tianjin tianguang optical
instrument Co. Ltd. (China); 1H NMR spectrum was measured by an
electron JNM-ECA-400 nuclear magnetic resonance spectrometer
(Japan); ESI-MS mass spectrometry was performed by an API 3000 three
heavy four stage tandem mass spectrometer. Silica gel used in column
layer chromatography was purchased from Qingdao marine chemical
plant and a silica gel board was purchased from Yantai Chemical In-
dustry Research Institute. The routine solvents used in the experiments
4.1.1.3. 2-(thiophen-2-yl)thiazol-4-amine hydrobromide (6–2). To a so-
lution of 2-acetylthiophene (3.0 g, 24.8 mmol) in ether (70 mL), the
catalytic amounts of AlCl3 (0.13 g, 1.06 mmol) and bromine (1.9 mL,
37.2 mmol) were added in an ice-bath and the mixture was stirred
overnight at r.t. The mixture was filtered and the filtrate was washed
with saturated NaHCO3 solution; water and brine (3*20 mL) were added
stepwise. The organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Finally, thiourea (1.4 g, 18.1
mmol) reacted with the solution that was evaporated to dryness in a
rotary evaporator. The purification method of compound 6–2 was
3

W. Zhang et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115777
Table 1
Table 1 (continued)
Aryl
The inhibitory activity of newly synthesized compounds against HPTPβ.
R
IC50 (μM)
G25
3*
H
0.9950
0.3200
–
–
Aryl
R
IC50 (μM)
ND: The IC50 of compounds was not determined when the % inhibiton of was less
G1
1.684
than 65% at concentration of 10 μM, the corresponding %inhibition of G6, G10,
G11, G13 were 38.3%, 61.2%, 34.5%, 61.0%. *: A positive control was tested
and selected from the literature.29
G2
G3
1.715
3.419
Table 2
The inhibitory activities of selected compounds against a panel of PTPs.
G4
1.453
PTPs
G4
G14
G16
G25
3 *
HPTPβ (
μ
M)
1.453
122.7
24.68
111.6
101.9
2.976
22.19
19.59
42.29
32.83
0.9676
20.47
6.413
34.79
31.26
0.9950
>250.0
25.61
0.3200
15.70
55.33
76.41
20.11
PTP1B (
μ
M)
G5
G6
1.775
ND
SHP2 (
μ
M)
LAR (
μ
M)
129.8
TC-PTP(
μ
M)
>250.0
*
The positive control was tested and selected from the literature.29
G7
G8
6.397
3.459
consistent with that of compound 6–1 and a yellow solid was obtained
(4.84 g, 73.9%). M.P.: 123.1–125.0 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ
7.58 (dd, J = 5.1, 1.1 Hz, 1H), 7.46 (dd, J = 3.6, 1.2 Hz, 1H), 7.10 (dd, J
= 5.1, 3.7 Hz, 1H), 6.98 (s, 1H). ESI-MS m/z: 183.00 [M + H]+
G9
4.099
ND
4.1.2. General synthetic process of the target compounds (G1-G5)
To a solution of various aromatic acids (1.32 mmol) in DCM (15 mL),
PCl5 (0.33 g, 1.58 mmol) was added in an ice bath and stirred for an
uncertain time. N-(4-Nitrobenzyl)aniline (0.3 g, 1.32 mmol) was added
to the mixture in batches and stirred overnight at r.t. The reaction was
filtered and then quenched by the addition of TEA. The filtrate was
purified by column chromatography to give compounds 3 (30–50%).
To create compounds 4, FeCl3⋅6H2O (0.05 g, 0.2 mmol), charcoal
(0.14 g, 12.0 mmol) and hydrazine hydrate (12.0 mmol) were added to a
solution of compounds 3 (1.00 mmol) in ethanol (10 mL) at room
temperature and then the mixture was heated to reflux. After 4 h, the
reaction mixture was filtered through a Celite pad. The filtrate was
concentrated to give a crude product of compounds 4 (75–95%) as a
white solid, which was directly used in the next step without further
purification.
G10
G11
G12
ND
6.607
G13
G14
ND
2.976
G15
G16
G17
4.672
A solution of compounds 4 (1.00 mmol) in CH3CN was supplemented
with Me3N⋅SO3 (0.28 g, 2.0 mmol). The reaction solution was heated
and stirred overnight at 50–60 ◦C. Even though compounds 4 were not
completely consumed according to TLC, the reaction was stopped at that
point. A crude product was purified by column chromatography to give
the target compounds 5 (30–70%).
0.9676
2.066
G18
G19
G20
1.244
1.317
5.936
4.1.2.1. (S)-(4-((2-((methoxycarbonyl)amino)-N,3-diphenylpropana-
mido)methyl)phenyl)sulfamic acid(G1). White solid (0.31 g, 42.7%), m.
p.: 166.0–168.9 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.91 (s, 1H, NH),
7.55 (d, J = 2.6 Hz, 1H, Ar-H), 7.39 (dd, J = 15.2, 7.7 Hz, 2H, Ar-H),
7.34 (dd, J = 8.9, 2.5 Hz, 2H, Ar-H), 7.28 (d, J = 7.3 Hz, 2H, Ar-H),
6.93 (t, J = 6.8 Hz, 3H, Ar-H), 6.88 (d, J = 8.3 Hz, 2H, Ar-H), 4.74 (s,
2H, CH2), 4.60 (s, 2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ 166.33
(1C), 153.10 (1C), 143.50 (1C), 140.44 (1C), 130.12 (1C), 129.77 (2C),
128.79 (2C), 128.38 (2C), 126.71 (1C), 125.08 (2C), 122.68 (2C),
116.36 (2C), 115.46 (1C), 66.71 (1C), 52.42 (1C); ESI-MS m/z: 479.02
[Mꢀ H]-
G21
G22
1.414
1.806
G23
G24
1.071
1.745
4.1.2.2. (4-((2-(3-fluorophenyl)-N-phenylacetamido)methyl)phenyl)sulfa-
1
◦
mic acid (G2). White solid (80 mg, 14.8%), m.p.: 164.7–166.1 C; H
NMR (400 MHz, DMSO‑d6) δ 7.90 (s, 1H, NH), 7.40 – 7.27 (m, 4H, Ar-H),
4

W. Zhang et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115777
Figure 2. The compounds G4 (A), G14 (D), G16 (B) and G25 (C) interacted with HPTPβ. The 2E panel shows the composition of catalytic pocket. The 2F was the
superimposition map of docking poses of G4, G14, G16 and G25 (in yellow, blue, green, red, respectively).
7.11 (d, J = 7.3 Hz, 2H, Ar-H), 7.03 (dd, J = 9.4, 7.6 Hz, 1H, Ar-H), 6.92
(d, J = 8.5 Hz, 2H, Ar-H), 6.87 (t, J = 8.3 Hz, 4H, Ar-H), 4.73 (s, 2H,
CH2), 3.44 (s, 2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ 169.74 (1C),
163.64 (1C), 143.33 (1C), 142.43 (1C), 139.21 (1C), 130.45 (1C),
129.95 (2C), 129.08 (2C), 128.69 (2C), 128.35 (1C), 127.32 (1C),
125.85 (1C), 116.67 (1C), 116.37 (2C), 113.78 (1C), 52.33 (1C), 45.04
(1C); ESI-MS m/z: 413.05 [Mꢀ H]-
= 8.5 Hz, 2H, Ar-H), 6.85 (d, J = 8.5 Hz, 2H, Ar-H), 6.80 – 6.72 (m, 2H,
Ar-H), 4.83 (d, J = 14.5 Hz, 1H, CH), 4.60 (d, J = 14.5 Hz, 1H, CH), 4.16
(dd, J = 10.0, 3.9 Hz, 1H, CH), 3.47 (s, 3H, OCH3), 2.82 (dd, J = 13.4,
3.8 Hz, 1H, CH), 2.67 (dd, J = 13.4, 10.3 Hz, 1H, CH). 13C NMR (101
MHz, DMSO‑d6) δ 171.92 (1C), 157.01 (1C), 143.32 (1C), 141.70 (1C),
138.36 (1C), 129.83 (2C), 129.31 (2C), 128.59 (2C), 128.55 (2C),
126.96 (1C), 126.89 (2C), 116.34 (2C), 54.45 (1C), 52.61 (1C), 49.14
(1C), 37.14 (1C); ESI-MS m/z: 482.15 [Mꢀ H]-
4.1.2.3. (S)-(4-((2-((methoxycarbonyl)amino)-N,3-diphenylpropana-
mido)methyl)phenyl)sulfamic acid(G3). Light yellow solid (90 mg,
14.1%), m.p.: 118.9–120.2 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.88 (s,
1H, NH), 7.61 (d, J = 8.1 Hz, 1H, Ar-H), 7.38 (d, J = 7.4 Hz, 3H, Ar-H),
7.16 – 7.11 (m, 3H, Ar-H, NH), 7.09 (d, J = 7.9 Hz, 2H, Ar-H), 6.92 (d, J
4.1.2.4. (4-((1-(tert-butoxycarbonyl)-N-phenylpiperidine-4-carboxamido)
methyl)phenyl)sulfamic acid (G4). White solid (70 mg, 10.6%), m.p.:
174.1–176.2 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.43 – 7.30 (m, 4H, Ar-
H), 7.19 – 7.02 (m, 4H, Ar-H), 6.91 (t, J = 7.4 Hz, 2H, Ar-H), 6.82 (d, J =
5

W. Zhang et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115777
8.2 Hz, 1H, Ar-H), 6.68 (d, J = 8.0 Hz, 1H, Ar-H), 4.69 (s, 2H, CH2), 2.31
(d, J = 12.6 Hz, 4H, piperidin-H), 1.57 – 1.42 (m, 5H, piperidin-H), 1.37
(s, 9H, OC(CH3)3). 13C NMR (101 MHz, DMSO‑d6) δ 173.96 (1C), 154.21
(1C), 143.34 (1C), 142.35 (1C), 139.83 (1C), 133.11 (1C), 130.07 (2C),
129.59 (1C), 128.74 (1C), 128.62 (1C) 127.41 (1C), 116.39 (2C), 60.30
(1C), 52.22 (4C), 39.39 (1C), 28.69 (4C), 28.58 (3C); ESI-MS m/z:
488.18 [Mꢀ H]-
13C NMR (101 MHz, DMSO‑d6) δ 167.84 (1C), 152.86 (2C), 143.99 (1C),
134.60 (2C), 129.95 (1C), 129.29 (2C), 128.49 (2C), 128.44 (1C),
127.50 (2C), 126.25 (2C), 125.51 (1C), 122.73 (1C), 116.84 (2C),
115.40 (1C), 110.55 (1C), 67.10 (1C), 49.20 (1C); ESI-MS m/z: 562.01
[Mꢀ H]-
4.1.3.2. (4-((1-(tert-butoxycarbonyl)-N-(4-phenylthiazol-2-yl)piperidine-
4-carboxamido)methyl)phenyl) sulfamic acid (G7). White solid (0.11 g,
16.4%), m.p.: 105.6–108.2 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 8.91 (s,
1H, OH), 7.91 (dd, J = 6.3, 5.0 Hz, 3H, Ar-H), 7.71 (s, 1H, NH), 7.41 (t, J
= 7.6 Hz, 2H, thiazole-H, Ar-H), 7.30 (t, J = 7.3 Hz, 1H, Ar-H), 7.07 (d, J
= 8.6 Hz, 2H, Ar-H), 7.00 (d, J = 8.6 Hz, 2H, Ar-H), 5.56 (s, 2H, CH2),
3.93 (s, 2H, piperidin-H), 3.17 (d, J = 4.5 Hz, 2H, piperidin-H), 2.76 (s,
1H, piperidin-H), 1.62 (s, 2H, piperidin-H), 1.53 – 1.44 (m, 2H,
piperidin-H), 1.40 (s, 9H, OC(CH3)3). 13C NMR (101 MHz, DMSO‑d6) δ
175.43 (1C), 154.35 (1C), 143.70 (1C), 134.74 (2C), 129.25 (2C),
128.32 (2C), 127.30 (1C), 127.11 (2C), 126.17 (2C), 116.70 (2C),
110.51 (1C), 79.25 (1C), 50.29 (1C), 49.14 (2C), 30.95 (1C), 28.79 (2C),
28.60 (3C); ESI-MS m/z: 571.17 [Mꢀ H]-
4.1.2.5. (4-((2-(4-bromo-3-fluorophenyl)-N-phenylacetamido)methyl)
phenyl)sulfamic acid (G5). White solid (0.13 g, 15.1%), m.p.:
140.2–163.5 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 8.50 (s, 1H, OH), 7.92
(s, 1H, NH), 7.50 – 7.37 (m, 4H, Ar-H), 7.32 (t, J = 8.8 Hz, 1H, Ar-H),
7.19 (d, J = 7.4 Hz, 3H, Ar-H), 6.97 (d, J = 8.4 Hz, 2H, Ar-H), 6.91
(d, J = 8.3 Hz, 2H, Ar-H), 4.78 (s, 2H, CH2), 3.47 (s, 2H, CH2). 13C NMR
(101 MHz, DMSO‑d6) δ 169.72 (1C), 157.51 (1C, J = 244.4 Hz), 143.41
(1C), 142.31 (1C), 134.72 (1C), 134.66 (1C, J = 4.04 Hz), 131.14 (1C, J
= 7.07 Hz), 129.95 (2C), 129.11 (2C), 128.70 (2C), 128.36 (1C), 127.17
(1C), 116.70 (1C, J = 22.2 Hz), 116.33 (2C), 107.80 (1C, J = 21.2 Hz),
52.39 (1C), 46.03 (1C); ESI-MS m/z: 493.02 [Mꢀ H]-
4.1.3. General synthetic process of target compounds (G6-G25)
To a solution of compounds 6–1 (0.3 g, 1.17 mmol) or 6–2 (0.3 g,
1.14 mmol) in 15 mL of acetonitrile, BOP (1.04 g, 2.34 mmol; 1.01 g,
2.28 mmol, respectively), DIPEA (0.38 g mg, 2.92 mmol; 0.37 g, 2.85
mmol, respectively) and various aromatic acids (1.17 mmol; 1.14 mmol,
respectively) were added. The mixture was stirred at 70 ◦C until amine
was completely consumed according to TLC (8 h). The solution was
evaporated to dryness and 4% sodium hydroxide was added; the mixture
was extracted with EA and the extract was dried (Na2SO4). Concentrated
solution was directly used to obtain compounds 7 in the next reaction
step.
4.1.3.3. (S)-(4-((2-((methoxycarbonyl)amino)-3-phenyl-N-(4-phenyl-
thiazol-2-yl)propanamido)methyl)phenyl) sulfamic acid (G8). Yellow
solid (30 mg, 4.5%), m.p.: 147.8–151.2 ◦C; 1H NMR (400 MHz,
DMSO‑d6) δ 8.06 (d, J = 8.0 Hz, 1H, NH), 7.96 – 7.85 (m, 3H, Ar-H), 7.74
(s, 1H, thiazole-H), 7.42 (t, J = 7.6 Hz, 2H, Ar-H), 7.31 (t, J = 7.2 Hz, 1H,
Ar-H), 7.27 – 7.13 (m, 3H, Ar-H), 7.09 (d, J = 8.2 Hz, 2H, Ar-H), 7.02 (d,
J = 6.6 Hz, 4H, Ar-H), 5.69 (d, J = 16.1 Hz, 1H, CH), 5.40 (d, J = 16.3
Hz, 1H, CH), 4.86 (d, J = 7.6 Hz, 1H, CH), 3.50 (s, 3H, OCH3), 2.86 (d, J
= 6.2 Hz, 2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ 159.37 (1C),
157.25 (1C), 148.61 (1C), 143.74 (1C), 137.52 (1C), 134.67 (2C),
129.77 (2C), 129.27 (2C), 128.77 (2C), 128.38 (1C), 127.26 (2C),
127.03 (1C), 126.81 (1C), 126.21 (2C), 116.70 (2C), 110.73 (1C), 53.41
(1C), 52.29 (1C), 50.42 (1C), 37.34 (1C); ESI-MS m/z: 565.12 [Mꢀ H]-
To a solution of compounds 7 in 15 mL of DMF, K2CO3 (0.16 g, 1.17
mmol; 0.14 g, 1.14 mmol, respectively) and 4-nitrobenzyl bromide
(0.25 g mg, 1.17 mmol; 0.25 g, 1.14 mmol, respectively) were added in
an ice bath. The mixture was stirred overnight at r.t. A large volume of
water was added; the mixture was stirred and filtered to produce com-
pounds 8. The subsequent reduction of the nitro derivatives and sulfo-
nation of the amino derivatives were consistent with that of compound 4
and compound 5.
4.1.3.4. (4-((2-(3-fluorophenyl)-N-(4-phenylthiazol-2-yl)acetamido)
methyl)phenyl)sulfamic acid (G9). Light yellow solid (0.12 g, 20.0%), m.
p.: 153.2–154.6 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 9.32 (s, 1H, OH),
7.94 – 7.86 (m, 2H, Ar-H), 7.72 (s, 1H, NH), 7.37 (ddd, J = 17.6, 12.0,
7.4 Hz, 4H, thiazole-H, Ar-H), 7.11 (t, J = 8.3 Hz, 3H, Ar-H), 7.04 (t, J =
9.8 Hz, 3H, Ar-H), 6.57 (d, J = 8.4 Hz, 1H, Ar-H), 5.54 (d, J = 10.8 Hz,
2H, CH2), 4.11 (d, J = 4.7 Hz, 2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ
171.40 (1C), 162.54 (1C, J = 244.42 Hz), 148.48 (1C), 143.82 (1C),
137.67 (1C, J = 8.1 Hz), 134.73 (2C), 130.63 (1C, J = 8.6 Hz), 129.26
(2C), 128.34 (1C), 127.30 (2C), 126.53 (1C) (d, J = 3.03 Hz), 126.20
(2C), 117.30 (1C, J = 21.2 Hz), 116.78 (2C), 114.84 (1C), 114.19 (1C, J
= 21.2 Hz), 110.55 (1C), 50.51 (1C), 44.68 (1C); ESI-MS m/z: 496.08
[Mꢀ H]-
To a solution of compounds 6–1 (0.3 g, 1.17 mmol) or 6–2 (0.3 g,
1.14 mmol) in 15 mL of dry DCM, NaH (0.14 g, 5.85 mmol; 0.14 g, 5.70
mmol, respectively) and various sulfonyl chlorides (1.17 mmol; 1.14
mmol, respectively) were added in an ice bath and the mixture was
stirred overnight. Even though compounds 6 did not disappear
completely according to TLC, the reaction was stopped. The mixture was
filtered and purified by column chromatography to give compounds 7.
Compounds 7 were reacted with 4-nitrobenzyl bromide in the presence
of K2CO3 in DMF. The reaction solution was processed in a similar
manner to give compounds 8. The nitro group of compounds 8 was
reduced in the presence of Fe and NH4Cl in ethanol: water (5:1) system
to obtain compounds 9.
4.1.3.5. (4-((2-(2,4-dichlorophenoxy)-N-(4-(thiophen-2-yl)thiazol-2-yl)
acetamido)methyl)phenyl)sulfamic acid (G10). White solid (30 mg,
4.6%), m.p.: 130.2–133.4 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.94 (s,
1H, NH), 7.66 – 7.45 (m, 4H, Ar-H, thiazole-H, thiophen-H), 7.32 (d, J =
8.8 Hz, 1H, Ar-H), 7.16 (d, J = 7.4 Hz, 2H, Ar-H), 7.10 (s, 1H, Ar-H),
7.02 (d, J = 8.1 Hz, 2H, Ar-H), 6.87 (d, J = 8.6 Hz, 1H, thiophen-H),
5.38 (s, 2H, CH2), 5.34 (s, 2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ
167.82 (1C), 152.84 (1C), 144.09 (1C), 138.81 (2C), 129.96 (2C),
128.58 (1C), 128.50 (1C), 127.90 (2C), 126.28 (1C), 125.96 (1C),
125.52 (1C), 124.50 (1C), 122.73 (1C), 116.70 (1C), 115.43 (2C),
108.97 (1C), 67.13 (1C), 49.35 (1C); ESI-MS m/z: 567.96 [Mꢀ H]-
To prepare compounds 10, Me3N⋅SO3 (0.28 g, 2.0 mmol) was added
to a solution of compounds 9 (1.00 mmol) in CH3CN at r.t. The mixture
was stirred overnight at 50–60 ◦C. Compounds 9 were still detected in
the mixture according to TLC. However, the reaction was stopped and
purification by column chromatography produced the target compounds
10.
4.1.3.1. (4-((2-(2,4-dichlorophenoxy)-N-(4-phenylthiazol-2-yl)acet-
amido)methyl)phenyl)sulfamic acid (G6). Light yellow solid (50 mg,
7.6%), m.p.: 114.9–116.7 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 8.91 (s,
1H, OH), 8.02 – 7.89 (m, 3H, Ar-H), 7.77 (s, 1H, NH), 7.60 (d, J = 1.9 Hz,
1H, thiazole-H), 7.43 (t, J = 7.3 Hz, 2H, Ar-H), 7.31 (d, J = 6.0 Hz, 2H,
Ar-H), 7.14 (d, J = 8.2 Hz, 2H, Ar-H), 7.04 (d, J = 8.1 Hz, 2H, Ar-H),
6.86 (d, J = 8.8 Hz, 1H, Ar-H), 5.47 (s, 2H, CH2), 5.32 (s, 2H, CH2).
4.1.3.6. (4-((1-(tert-butoxycarbonyl)-N-(4-(thiophen-2-yl)thiazol-2-yl)
piperidine-4-carboxamido)methyl)pheny)sulfamic acid (G11). White solid
(60 mg, 13.0%), m.p.: 117.8–119.2 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ
7.92 (s, 1H, NH), 7.59 – 7.43 (m, 3H, thiazole-H, thiophen-H), 7.08 (dd,
J = 7.7, 2.4 Hz, 3H, Ar-H), 6.99 (d, J = 8.4 Hz, 2H, Ar-H, thiophen-H),
6

W. Zhang et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115777
5.48 (s, 2H, CH2), 3.92 (s, 2H, piperidin-H), 3.19 (s, 1H, piperidin-H),
2.76 (s, 2H, piperidin-H), 1.61 (s, 2H, piperidin-H), 1.46 (d, J = 11.3
Hz, 2H, piperidin-H), 1.40 (s, 9H, OC(CH3)3). 13C NMR (101 MHz,
DMSO‑d6) δ 175.43 (1C), 159.48 (1C), 154.35 (1C), 143.75 (1C), 138.92
(2C), 128.54 (1C), 127.47 (2C), 127.47 (1C), 126.14 (1C), 124.31 (1C),
116.59 (2C), 108.98 (1C), 79.26 (1C), 50.14 (1C), 43.42 (2C), 29.54
(1C), 28.75 (2C), 28.60 (3C); ESI-MS m/z: 577.12 [Mꢀ H]-
NMR (101 MHz, DMSO‑d6) δ 167.12 (1C), 159.69 (1C), 144.19 (1C),
143.18 (1C), 130.78 (3C), 129.65 (1C), 129.34 (2C), 129.05 (2C),
128.59 (2C), 121.22 (1C), 118.48 (2C), 116.88 (2C), 111.11 (2C), 56.04
(1C), 49.13 (1C); ESI-MS m/z: 530.05 [Mꢀ H]-
4.1.3.11. (4-(((4-methoxy-N-(4-phenylthiazol-2-yl)phenyl)sulfonamido)
methyl)phenyl)sulfamic acid (G17). Pink solid (20 mg, 3.2%), m.p.:
133.5–135.4 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.89 (s, 1H, NH), 7.72
(d, J = 8.9 Hz, 2H, Ar-H, thiazole-H), 7.50 (s, 2H, Ar-H), 7.49 (s, 2H, Ar-
H), 7.47 – 7.44 (m, 1H, Ar-H), 7.06 (d, J = 8.9 Hz, 2H, Ar-H), 6.99 (d, J
= 8.5 Hz, 2H, Ar-H), 6.90 (d, J = 8.6 Hz, 2H, Ar-H), 3.82 (s, 2H, CH2),
3.81 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO‑d6) δ 170.91 (1C),
162.43 (1C), 143.23 (1C), 134.74 (2C), 129.67 (1C), 129.36 (2C),
129.03 (2C), 128.58 (2C), 128.51 (1C), 128.44 (2C), 116.91 (2C),
115.96 (1C), 114.63 (3C), 56.12 (1C), 53.38 (1C); ESI-MS m/z: 530.03
[Mꢀ H]-
4.1.3.7. (S)-(4-((2-((methoxycarbonyl)amino)-3-phenyl-N-(4-(thiophen-
2-yl)thiazol-2-yl)propanamido)methyl) phenyl)sulfamic acid (G12).
White solid (30 mg, 4.6%), m.p.: 158.9–161.9 ◦C; 1H NMR (400 MHz,
DMSO‑d6) δ 8.07 (d, J = 7.4 Hz, 1H, NH), 7.91 (s, 1H, NH), 7.56 (s, 1H,
thiazole-H), 7.49 (dd, J = 10.5, 3.6 Hz, 2H, Ar-H thiophen-H), 7.23 (d, J
= 7.3 Hz, 2H, Ar-H), 7.18 (d, J = 6.3 Hz, 1H, Ar-H), 7.14 – 7.03 (m, 5H),
6.99 (d, J = 8.1 Hz, 2H, Ar-H, thiophen-H), 5.54 (t, J = 12.8 Hz, 1H, CH),
5.33 (d, J = 15.6 Hz, 1H, CH), 4.94 – 4.83 (m, 1H, CH), 3.50 (s, 3H,
OCH3), 2.87 (d, J = 6.0 Hz, 2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ
172.75 (1C), 157.25 (2C), 143.83 (1C), 138.92 (1C), 137.51 (2C),
129.77 (2C), 128.84 (2C), 128.54 (1C), 127.69 (4C), 127.06 (1C),
126.22 (1C), 124.39 (1C), 116.53 (2C), 109.14 (1C), 54.59 (1C), 50.39
(1C), 37.30 (1C); ESI-MS m/z: 571.08 [Mꢀ H]-
4.1.3.12. (4-(((3-fluoro-N-(4-phenylthiazol-2-yl)phenyl)sulfonamido)
methyl)phenyl)sulfamic acid (G18). White solid (30 mg, 4.9%), m.p.:
184.9–186.2 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.91 (s, 1H, NH), 7.63
(dt, J = 13.1, 7.9 Hz, 2H, Ar-H, thiazole-H), 7.57 – 7.42 (m, 8H, Ar-H),
7.00 (d, J = 8.4 Hz, 2H, Ar-H), 6.91 (d, J = 8.5 Hz, 2H, Ar-H), 3.85 (s,
2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ 167.24 (1C), 162.14 (1C, J =
249.47 Hz), 145.04 (1C, J = 6.3 Hz), 143.18 (2C), 132.02 (1C, J = 8.0
Hz), 129.76 (1C), 129.37 (2C), 129.09 (2C), 128.61 (2C), 128.51 (1C),
122.57 (1C, J = 2.9 Hz), 121.47 (1C), 119.75 (1C, J = 21.2 Hz), 116.93
(2C), 114.66 (1C), 113.26 (1C, J = 24.3 Hz), 44.65 (1C); ESI-MS m/z:
518.03 [Mꢀ H]-
4.1.3.8. (4-((2-(3-fluorophenyl)-N-(4-(thiophen-2-yl)thiazol-2-yl)acet-
amido)methyl)phenyl)sulfamic acid (G13). White solid (30 mg, 5.3%),
m.p.: 165.5–167.2 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.91 (s, 1H, NH),
7.53 (s, 1H, thiazole-H), 7.50 (dd, J = 3.5, 1.2 Hz, 1H, thiophen-H), 7.47
(dd, J = 5.0, 1.1 Hz, 1H, Ar-H), 7.36 (ddd, J = 8.9, 4.4, 2.9 Hz, 1H,
thiophen-H), 7.16 – 7.07 (m, 5H, Ar-H), 7.02 (dd, J = 12.3, 5.5 Hz, 3H,
Ar-H), 5.47 (s, 2H, CH2), 4.15 (s, 2H, CH2). 13C NMR (101 MHz,
DMSO‑d6) δ 171.39 (1C), 162.54 (1C, J = 243.0 Hz), 159.58 (1C),
143.90 (1C), 138.99 (2C), 137.64 (1C, J = 8.2 Hz), 130.63 (1C, J = 8.5
Hz), 128.54 (2C), 127.72 (2C), 126.55 (1C, J = 4.6 Hz), 126.16 (1C),
124.34 (1C), 117.32 (1C, J = 21.5 Hz), 116.65 (2C), 114.20 (1C, J =
20.8 Hz), 108.96 (1C) 50.53 (1C), 39.70 (1C); ESI-MS m/z: 502.03
[Mꢀ H]-
4.1.3.13. (4-(((3-chloro-N-(4-phenylthiazol-2-yl)phenyl)sulfonamido)
methyl)phenyl)sulfamic acid (G19). Yellow solid (30 mg, 4.8%), m.p.:
189.9–191.7 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.92 (s, 1H, NH), 7.76
(ddt, J = 5.4, 3.4, 1.7 Hz, 2H, Ar-H, thiazole-H), 7.68 (ddd, J = 8.0, 2.0,
1.2 Hz, 1H, Ar-H), 7.59 (t, J = 8.1 Hz, 2H, Ar-H), 7.54 – 7.44 (m, 5H, Ar-
H), 7.00 (d, J = 8.6 Hz, 2H, Ar-H), 6.92 (d, J = 8.6 Hz, 2H, Ar-H), 3.85 (s,
2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ 167.22 (1C), 144.79 (1C),
143.19 (1C), 134.09 (2C), 132.56 (1C), 131.77 (2C), 129.79 (1C),
129.38 (2C), 129.11 (2C), 128.62 (2C), 128.50 (1C), 125.84 (1C),
125.01 (1C), 116.94 (2C), 114.74 (1C), 49.14 (1C); ESI-MS m/z: 534.00
[Mꢀ H]-
4.1.3.9. (4-((2-chloro-N-(4-phenylthiazol-2-yl)nicotinamido)methyl)
phenyl)sulfamic acid (G14). Yellow solid (50 mg, 8.5%), 1H NMR (400
MHz, DMSO‑d6) δ 8.60 (d, J = 3.4 Hz, 1H, NH), 8.10 (d, J = 6.2 Hz, 1H,
pyridin-H), 8.00 – 7.90 (m, 3H, Ar-H, pyridin-H), 7.87 (s, 1H, thiazole-
H), 7.59 (dd, J = 7.1, 5.1 Hz, 1H, Ar-H), 7.44 (t, J = 7.5 Hz, 2H, Ar-H),
7.33 (t, J = 7.3 Hz, 1H, Ar-H), 6.89 (d, J = 8.2 Hz, 2H, Ar-H), 6.83 (d, J
= 8.5 Hz, 2H, Ar-H), 5.41 (d, J = 17.8 Hz, 1H, CH), 5.04 (d, J = 12.6 Hz,
1H, CH); 13C NMR (101 MHz, DMSO‑d6) δ 166.42 (1C), 158.60 (1C),
151.85 (1C), 148.90 (1C), 146.51 (1C), 143.81 (1C), 138.64 (1C),
134.52 (1C), 130.99 (1C), 129.33 (2C), 128.55 (1C), 127.61 (2C),
126.26 (2C), 123.82 (1C), 116.40 (2C), 111.10 (1C), 49.14 (1C). ESI-MS
m/z: 499.04 [Mꢀ H]- (4-((2-chloro-N-(4-phenylthiazol-2-yl)benzamido)
methyl)phenyl)sulfamic acid (G15)
4.1.3.14. (4-((2-chloro-N-(4-(thiophen-2-yl)thiazol-2-yl)benzamido)
methyl)phenyl)sulfamic acid (G20). White solid (50 mg, 8.6%), m.p.:
1
1
◦
145.8–148.3 C; H NMR (400 MHz, DMSO‑d6) δ H NMR (400 MHz,
DMSO‑d6) δ 7.91 (s, 1H, NH), 7.69 – 7.48 (m, 7H, Ar-H, thiazole-H,
thiophen-H), 7.13 – 7.08 (m, 1H, Ar-H, thiophen-H), 6.88 (s, 4H, Ar-H),
5.32 (d, J = 14.3 Hz, 1H, CH), 4.96 – 4.81 (m, 1H, CH); 13C NMR (101
MHz, DMSO‑d6) δ 167.74 (1C), 158.40 (1C), 143.81 (1C), 138.78 (1C),
134.29 (2C), 132.44 (1C), 130.30 (1C), 130.16 (1C), 129.46 (1C),
128.61 (1C), 128.25 (2C), 126.40 (2C), 125.81 (1C), 124.54 (1C),
116.13 (2C), 109.27 (1C), 52.08 (1C); ESI-MS m/z: 503.99 [Mꢀ H]-
Yellow solid (30 mg, 5.1%), m.p.: 180.1–181.3 ◦C; 1H NMR (400
MHz, DMSO‑d6) δ 7.89 (dd, J = 37.1, 12.1 Hz, 4H, NH, thiazole-H, Ar-
H), 7.61 (dd, J = 24.0, 7.1 Hz, 3H, Ar-H), 7.52 – 7.36 (m, 3H, Ar-H), 7.32
(t, J = 7.1 Hz, 1H, Ar-H), 6.87 (d, J = 7.6 Hz, 4H, Ar-H), 5.43 (d, J =
11.4 Hz, 1H, CH), 4.92 (d, J = 11.2 Hz, 1H, CH); 13C NMR (101 MHz,
DMSO‑d6) δ 167.83 (1C), 158.50 (1C), 148.83 (1C), 143.69 (1C), 134.57
(1C), 134.43 (1C), 132.37 (1C), 130.26 (1C), 130.09 (1C), 129.33 (2C),
128.50 (1C), 128.20 (1C), 127.70 (2C), 126.23 (2C), 126.12 (2C),
116.27 (2C), 110.89 (1C), 52.05 (1C). ESI-MS m/z: 498.04 [Mꢀ H]-
4.1.3.15. (4-(((3-methoxy-N-(4-(thiophen-2-yl)thiazol-2-yl)phenyl)sulfo-
namido)methyl)phenyl)sulfamic acid (G21). Pink solid (20 mg, 3.3%), m.
p.: 180.9–182.4 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.93 (s, 1H, NH),
7.70 (d, J = 4.9 Hz, 1H, thiazole-H), 7.46 (dd, J = 9.0, 6.5 Hz, 2H,
thiophen-H), 7.36 (d, J = 7.7 Hz, 1H, Ar-H), 7.28 – 7.23 (m, 1H, Ar-H),
7.20 – 7.12 (m, 2H, Ar-H), 7.01 (d, J = 8.5 Hz, 2H, Ar-H), 6.96 (d, J =
8.5 Hz, 2H, Ar-H, thiophen-H), 3.97 (s, 2H, CH2), 3.77 (s, 3H, OCH3). 13
C
4.1.3.10. (4-(((3-methoxy-N-(4-phenylthiazol-2-yl)phenyl)sulfonamido)
methyl)phenyl)sulfamic acid (G16). Yellow solid (20 mg, 3.2%), m.p.:
175.1–176.7 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.91 (s, 1H, NH), 7.68 –
7.42 (m, 8H, Ar-H, thiazole-H), 7.36 (d, J = 7.3 Hz, 1H, Ar-H), 7.26 (s,
1H, Ar-H), 7.15 (d, J = 8.2 Hz, 1H, Ar-H), 6.99 (d, J = 8.3 Hz, 2H, Ar-H),
NMR (101 MHz, DMSO‑d6) δ 166.43 (1C), 159.72 (1C), 144.03 (1C),
143.29 (1C), 131.49 (2C), 130.82 (1C), 128.71 (2C), 128.31 (1C),
128.21 (1C), 128.06 (1C), 121.68 (1C), 118.60 (1C), 118.48 (1C),
116.88 (2C), 114.66 (1C), 111.12 (1C), 56.05 (1C), 49.13 (1C); ESI-MS
m/z: 535.99 [Mꢀ H]-
6.91 (d, J = 7.9 Hz, 2H, Ar-H), 3.84 (s, 2H, CH2), 3.77 (s, 3H, OCH3). 13
C
7

W. Zhang et al.
Bioorganic & Medicinal Chemistry 28 (2020) 115777
4.1.3.16. (4-(((4-methoxy-N-(4-(thiophen-2-yl)thiazol-2-yl)phenyl)sulfo-
namido)methyl)phenyl)sulfamic acid (G22). Pain pink solid (30 mg,
4.9%), m.p.: 183.5–184.9 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.86 (s,
1H, NH), 7.70 (d, J = 8.6 Hz, 2H, thiazole-H, thiophen-H), 7.56 (d, J =
4.4 Hz, 1H, thiophen-H), 7.30 (s, 1H, Ar-H), 7.15 – 7.07 (m, 1H, Ar-H),
7.04 – 6.96 (m, 5H, Ar-H), 6.93 (d, J = 8.4 Hz, 2H, thiophen-H, Ar-H),
3.95 (s, 2H, CH2), 3.79 (s, 3H, OCH3). 13C NMR (101 MHz, DMSO‑d6) δ
166.32 (1C), 161.86 (1C), 142.96 (1C), 138.60 (1C), 136.05 (1C),
128.93 (1C), 128.53 (2C), 128.46 (1C), 128.09 (1C), 126.87 (2C),
126.29 (1C), 120.79 (1C), 116.86 (2C), 114.25 (2C), 107.19 (1C), 56.03
(1C), 32.19 (1C); ESI-MS m/z: 535.99 [Mꢀ H]-
4.2.2. Selectivity evaluation
The selectivity assays were performed using 2 µL of recombinant
PTPs: PTP1B (0.01 ng/ L), TC-PTP (0.002 ng/ L), SHP2 (0.008 ng/ L)
and LAR (0.002 ng/ L) and DiFMUP (20 M, 20 M, 10 M, 20 M and
10 M, respectively). Assays were performed as described above.
μ
μ
μ
μ
μ
μ
μ
μ
μ
4.2.3. Molecular docking
Molecular docking was carried out to predict the binding mode of
HPTPβ and compounds G4, G14, G16 and G25 by using the SYBYL
software. The docking results were analyzed by the DS software. The
structure of protein was retrieved from the Protein Data Bank (PDB ID:
2H02, www.rcsb.org). The energy-lowest conformation of a molecule
was explored before docking. Therefore, the molecules underwent initial
minimization and simulated annealing calculation; then, the obtained
conformations were docked to the protein. To prove reliability of opti-
mization and the docking methods, the ligand of the complex was
redocked into HPTPβ. The docking results showed that the redocked
ligand overlaps with the original ligand (similarity: 8.1). This protocol
was subsequently used for the selected compounds. The pose with the
highest value of C-score was selected from a series of docking poses and
was used for analysis and explanation of the activity differences between
the compounds.
4.1.3.17. (4-(((3-fluoro-N-(4-(thiophen-2-yl)thiazol-2-yl)phenyl)sulfona-
mido)methyl)phenyl)sulfamic acid (G23). Pink solid (30 mg, 5.0%), m.
p.: 178.9–181.1 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.93 (s, 1H, NH),
7.69 – 7.58 (m, 3H, thiazole-H, thiophen-H), 7.55 (d, J = 7.4 Hz, 1H, Ar-
H), 7.49 – 7.39 (m, 2H, Ar-H), 7.17 (d, J = 3.6 Hz, 1H, Ar-H), 7.01 (d, J
= 8.5 Hz, 2H, Ar-H), 6.96 (d, J = 7.7 Hz, 2H, Ar-H, thiophen-H), 3.98 (s,
2H, CH2). 13C NMR (101 MHz, DMSO‑d6) δ 166.64 (1C), 162.12 (1C, J =
248.0 Hz), 148.00 (1C), 145.32 (1C), 143.20 (2C), 131.93 (1C, J = 7.8
Hz), 129.53 (1C), 128.70 (2C), 128.20 (2C), 122.58 (1C, J = 3.0 Hz),
121.69 (1C), 119.56 (1C, J = 21.3 Hz), 116.91 (2C), 114.70 (1C), 113.29
(1C, J = 23.9 Hz), 49.14 (1C); ESI-MS m/z: 523.99 [Mꢀ H]-
5. Notes
4.1.3.18. (4-(((3-chloro-N-(4-(thiophen-2-yl)thiazol-2-yl)phenyl)sulfona-
mido)methyl)phenyl)sulfamic acid (G24). Pink solid (30 mg, 4.8%), m.
p.: 136.7–140.0 ◦C; 1H NMR (400 MHz, DMSO‑d6) δ 7.94 (s, 1H, NH),
7.79 – 7.73 (m, 2H, thiazole-H, thiophen-H), 7.71 – 7.64 (m, 2H,
thiophen-H, Ar-H), 7.58 (t, J = 8.2 Hz, 1H, Ar-H), 7.42 (d, J = 3.5 Hz,
1H, Ar-H), 7.16 (dd, J = 5.1, 3.7 Hz, 1H, Ar-H), 7.01 (t, J = 6.6 Hz, 2H,
Authors guarantee that there is no conflict of interest in the described
content of the article.
Declaration of Competing Interest
Ar-H), 6.96 (d, J = 8.7 Hz, 2H, Ar-H, thiophen-H), 3.98 (s, 2H, CH2). 13
C
The authors declared that there is no conflict of interest.
NMR (101 MHz, DMSO‑d6) δ 166.62 (1C), 147.94 (1C), 144.96 (1C),
143.21 (1C), 134.04 (1C), 132.46 (1C), 131.70 (1C), 129.54 (1C),
128.72 (2C), 128.21 (2C), 128.16 (1C), 125.89 (1C), 125.03 (1C),
121.78 (1C), 116.93 (2C), 114.75 (1C), 49.14 (1C); ESI-MS m/z: 539.95
[Mꢀ H]-
Acknowledgements
This work was supported by the Major New Drugs Innovation and
Development (grant numbers 2018ZX09J18102-002).
4.1.3.19. (4-(((4-(thiophen-2-yl)thiazol-2-yl)amino)methyl)phenyl)sulfa-
mic acid (G25). Yellow solid (30 mg, 7.1%), m.p.: 211.4–214.1 ◦C; 1H
NMR (400 MHz, DMSO‑d6) δ 8.12 (s, 1H, NH), 7.89 (s, 1H, thiazole-H),
7.40 (d, J = 5.1 Hz, 2H, thiophen-H), 7.07 (dd, J = 42.5, 8.1 Hz, 5H, Ar-
H, thiophen-H), 6.87 (s, 1H), 4.29 (d, J = 5.0 Hz, 2H). 13C NMR (101
MHz, DMSO‑d6) δ 168.94 (1C), 145.16 (1C), 143.35 (1C), 139.77 (1C),
128.83 (1C), 128.35 (2C), 128.27 (1C), 125.32 (1C), 123.43 (1C),
116.60 (2C), 99.86 (1C), 48.42 (1C); ESI-MS m/z: 366.01 [Mꢀ H]-
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