Synthesis, Structure-Activity Relationship and Docking Studies of Substituted Aryl Thiazolyl Phenylsulfonamides as Potential Protein Tyrosine Phosphatase1B Inhibitors

Full text of DOI:10.1002/cmdc.201200197

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DOI: 10.1002/cmdc.201200197
Synthesis, Structure–Activity Relationship and Docking Studies of
Substituted Aryl Thiazolyl Phenylsulfonamides as Potential Protein Tyrosine
Phosphatase 1B Inhibitors
Kanika Varshney,[a] Swati Gupta,[a] Neha Rahuja,[b] Arun K. Rawat,[b] Nagendra Singh,[a] Akhilesh K. Tamarkar,[b]
Arvind K. Srivastava,[b] and Anil K. Saxena*[a]
Type 2 diabetes mellitus (T2DM) is a growing chronic diseases
both in developed and developing countries. It is a metabolic
disorder characterized by insulin resistance and hyperglycemia.
If left untreated, the hyperglycemia and associated dyslipide-
mia lead to long-term problems such as retinopathy, nephrop-
athy and neuropathy.[1] Though a large number of antidiabetic
agents are available for the treatment of diabetes, the number
of individuals with diabetes worldwide has increased from
30 million in 1985 to at least 180 million people in 2000, and
this number is likely to double by 2030 according to a recent
World Health Organization (WHO) report.[2] As such, there are
increasing research efforts to identify novel targets and new
chemical entities (NCEs) to combat this problem.
fonylaminobenzothiazoles (for structures, see Figure S6 in the
Supporting Information).[21]
Most of the inhibitors containing multiple charged phos-
phate mimicking components cannot be developed into effec-
tive drugs because of their low cell permeability and bioavaila-
bility. In view of the above and considering the present PTP1B
inhibitors with different scaffolds, a series of 28 aryl thiazolyl
phenylsulfonamides was synthesized and screened for PTP1B
inhibitory activity (Table 1). The design of these molecules was
based on the observation that the sulfonyl moiety in different
scaffolds, such as aryl trifluoromethyl sulfone and aryl trifluoro-
methyl sulfonamide pTyr mimetics[19] and arylsulfamic acid,[20]
interacts with the catalytic A site (Ile221, Ala217, Gln262), the
non-catalytic B site (Arg254, Arg24, Tyr20), and the C site
(Arg47, Asp48, Phe182). In addition, sulfonamides are known
to function as good hydrogen acceptors in biological systems.
Using a fragment-based approach, compounds containing
a sulfonyl moiety were designed, synthesized and evaluated
for their in vitro PTP1B inhibitory and in vivo antidiabetic (STZ
model) activities. Since the synthesized compounds show
promising PTP1B inhibitory activity, docking simulations of se-
lected compounds were also performed to analyze the poten-
tial binding mode of these compounds. The results of these
studies are presented herein.
Protein tyrosine phosphatase 1B (PTP1B) is a typical member
of protein tyrosine phosphatase superfamily, and its inhibition
results both in increased insulin sensitivity and resistance to
obesity, with no abnormalities in growth or fertility or other
pathogenetic effects.[3,4] Hence, PTP1B is considered to be an
excellent target for the treatment of type 2 diabetes and obesi-
ty.[5] Efforts are being made to discover orally active and selec-
tive PTP1B inhibitors that could be useful for probing signal
transduction pathways as well as for the treatment of diabetes
and obesity.[6]
Several active PTP1B inhibitors reported in recent years in-
clude difluoromethylene phosphonate (DFMP) pTyr mimetics,[7]
arylketone DFMP,[8] benzotriazole DFMP,[9] naphthyl DFMP,[10] di-
carboxylic acid-containing O-malonyltyrosine (OMT)[11] and o-
carboxy-(O-carboxymethyl)tyrosine peptide,[12] benzoic acid de-
rivatives,[13] hydroxypropionic acid pTyr mimetics,[14] dicarboxyl-
ic acid-containing thiophene scaffolds,[15] thiadiazolidinedione
(TDZ) and thiazolidinediones scaffolds,[16] unsaturated isothia-
zolidin-3(2H)-one 1,1-dioxide and saturated isothiazolidin-3-one
1,1-dioxide (IZD) pTyr mimetics,[17] sulfonamidebenzimid-
azoles,[18] aryl trifluoromethyl sulfones, aryl trifluoromethyl sul-
fonamide pTyr mimetics,[19] aryl sulfamic acids,[20] and 2-arylsul-
The compounds were synthesized from the cyclized inter-
mediates according to a literature procedure.[22] Substituted
(R1) aniline, on reaction with benzoyl isothiocyanate in dry ben-
zene, results in the formation of phenylcarbamothioyl benza-
mides 1, which upon alkaline hydrolysis give corresponding
thioureas 2. Condensation of the phenylthiourea with 2-bro-
moethylamine in the presence of hydrogen bromide affords
4,5-dihydrothiazol-2-amines 3, which on reaction with substi-
tuted (R2) benzene sulfonyl chlorides give the desired com-
pounds 4–6 (Scheme 1). The synthesis of compound 6a from
N-(2-(trifluoromethyl))-4, 5-dihydrothiazol-2-amine (3c) is given
in the Experimental Section; details of all intermediate and
final compounds are given in the Supporting Information.
In order to fully explore the structure–activity relationships
associated with the PTP1B inhibitors, we sought to probe hy-
drophobic, steric and electronic requirements by efficiently
and systematically installing R1 and R2 substituents on the core
aryl thiazolyl phenylsulfonamide scaffold. A series of 28 substi-
tuted aryl thiazolyl phenylsulfonamides was synthesized and
evaluated against PTP1B using a colorimetric, non-radioactive
PTP1B assay (Table 1). Among these, the most active com-
pound 6a with a 2-trifluoromethyl group at R1 and a 4-me-
thoxyphenyl group at R2 showed good in vitro inhibitory activi-
[a] K. Varshney, S. Gupta, N. Singh, Dr. A. K. Saxena
Division of Medicinal and Process Chemistry
Council of Scientific and Industrial Research (CSIR)
Central Drug Research Institute (CDRI)
Chattar Manzil Palace, M G Marg, Lucknow, Uttar Pardesh 226001 (India)
E-mail: anilsak@gmail.com
[b] N. Rahuja, A. K. Rawat, Dr. A. K. Tamarkar, Dr. A. K. Srivastava
Division of Biochemistry, CSIR–CDRI
Lucknow, Uttar Pardesh 226001 (India)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201200197.
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ty with 73% inhibition at 10 mm (IC50 =1.08 mm). Replacement
of the 2-trifluoromethyl group with a 4-fluoro group at R1 re-
sulted in compound 4h, with slight decreased activity (IC50 =
2.96 mm). Insertion of a 2,5-dimethoxy group at R1 with a 4-me-
thoxyphenyl group at R2 (compound 5b) leads to a further de-
crease in activity, with compound 5b exhibiting ony 48.5% in-
hibition of PTP1B in vitro. Among analogues 6 with a 2-trifluor-
omethyl group at R1, compounds with a 2,5-dichlorophenyl
(6d), a 4-fluorophenyl (6 f) and a 4-methylphenyl (6h) group
at R2 position showed 50% inhibition against PTP1B at 10 mm.
However, replacement of the 2-trifluoromethyl group at R1
Table 1. Evaluation of compounds 4–6 in vitro for PTP1B enzyme inhibi-
tory and in vivo for anti-hyperglycemic activity in the STZ rat model.
Compd R1
R2
Inhibition IC50 Blood glucose level
[%][a]
[mm]
[% decrease][b]
0–5 h
0–24 h
4a
4b
4c
4d
4e
4 f
4g
4h
4i
5a
5b
5c
5d
5e
5 f
5g
5h
5i
4-F
1-naphthyl
2,5-di-Cl-Ph
4-NO2-Ph
2,4,6-tri-iPr-Ph
2-naphthyl
2-CF3-Ph
C4H4S
4-CH3O-Ph
4-F-Ph
7.6
2.9
66.3
56.9
51.3
3.9
–
–
–
–
–
–
4-F
4-F
4-F
4-F
4-F
4-F
4-F
4-F
1.7
9.09 11.1
9.65 13.0
–
–
20.6**
18.8*
6.4
11.4
–
9.2
14.5
–
–
48.2
59.5
43.2
39.1
48.5
12.4
59.9
52.8
72.2
46.4
55.5
46.7
43.2
69.0
73.6
38.8
31.5
50.2
49.7
50.0
44.6
50.8
60.0
–
17.3*
with
a 2,5-dimethoxy group gave compounds 5, which
2.96 12.2
showed good PTP1B inhibitory activity (Table 1). Among these
the compound, 5k with 4-fluorophenyl ring at the R2 position
showed almost 69% inhibition against PTP1B (IC50 =1.46 mm).
Assessment of these compounds indicated that derivatives
with an ortho substituent at the R2 position show potent inhib-
ition. In order to support this hypothesis, compounds substi-
tuted at the R2 position with a 2-thiophene (5d), 2,4,6-iso-pro-
pylphenyl (5e), 2-nitrophenyl (5 f), 2-naphthyl (5h) or a 2,5-di-
chlorophenyl (5j) group were synthesized and evaluated. Inter-
estingly, most of these compounds showed more than 50%
PTP1B inhibition at 10 mm, and compound 5 f was the second
most active derivative of the series with 72.2% inhibition
(IC50 =1.25 mm). Replacement of the 2,5-dimethoxy group at R1
in these compounds by a 4-fluoro group leads to compounds
4a–i with decreased activity, with the exception of compounds
4c and 4h, which showed 66.3% and 59.48% PTP1B inhibition,
respectively, compared with 2,5-dimethoxy analogues 5g and
5b with 46.41% and 48.5% inhibition, respectively. All the
other analogues (4a, 4b, 4d–i), along with derivatives 5c and
6b, exhibited decreased inhibitory activities.
Earlier we reported the successful use of docking studies to
understand the structure–activity relationships and elucidate
the essential structural requirements for molecules acting on
the same receptor/enzyme.[23] In the present work, we evaluat-
ed the 28 substituted aryl thiazolyl phenylsulfonamides by
docking the compounds in the PTP1B binding site using the
GLIDE 5.6 module of the Schrodinger software package.[24] All
the ligands were prepared with the LigPrep 2.3 application
using an OPLS 2005 force field. The PTP1B protein used was
the crystal structure of the PTP1B catalytic domain taken from
the protein data bank (PDB: 2ZMM[25]). The protein structure
was prepared with the protein preparation wizard available in
the Schrodinger software package and used for grid genera-
tion (active site of the protein). Compounds 4–6 were docked
into the prepared grid using the automated flexible-ligand
docking in the extra precision (XP) mode.
–
–
–
–
–
–
2,5-di-OMe 1-naphthyl
2,5-di-OMe 4-CH3O-Ph
2,5-di-OMe 3-CF3-Ph
2,5-di-OMe C4H4S
2,5-di-OMe 2,4,6-tri-iPr-Ph
2,5-di-OMe 2-NO2-Ph
2,5-di-OMe 4-NO2-Ph
2,5-di-OMe 2-naphthyl
2,5-di-OMe Ph
–
19.4**
–
18.0*
–
11.7
7.8
17.5*
–
11.7
–
–
3.99 13.4
7.26 8.6
1.25 19.1**
–
–
6.59 13.0
–
–
1.46 19.3**
1.08 15.5
–
–
–
–
5j
2,5-di-OMe 2,5-di-Cl-Ph
2,5-di-OMe 4-F-Ph
5k
6a
6b
6c
6d
6e
6 f
6g
6h
20.3**
15.4
–
2-CF3
2-CF3
2-CF3
2-CF3
2-CF3
2-CF3
2-CF3
2-CF3
4-CH3O-Ph
2-CF3-Ph
4-NO2-Ph
2,5-di-Cl-Ph
2,4,6-tri-iPr-Ph
4-F-Ph
–
–
–
9.93 18.3*
14.7
8.7
20.5**
–
21.0**
–
–
10.1
–
4.72 16.3*
9.5
–
10.1
20.7**
–
2-naphthyl
4-CH3-Ph
Suramin[c]
Metformin[c]
–
20.9**
21.3**
[a] Compounds were evaluated for PTP1B inhibition at 10 mm using a col-
orimetric, non-radioactive PTP1B drug discovery kit (BML-AK 822, Enzo
Life Sciences, USA). Compounds 5c, 5j and 6g showed no change in
maximum inhibition up to 10 mm. For 5c, maximum inhibition was ob-
served at 1.0 mm (13%); for 5j, maximum inhibition was observed at
0.3 mm (44%); for 6g, maximum inhibition was observed at 1.0 mm (46%).
[b] Animals were dosed at 100 mgkgꢀ1. Values are the mean ꢁSEM (n=
6): * p <0.05; ** p <0.01. [c] Suramin and metformin were used as refer-
ence compounds in the enzymatic assay and in vivo model, respectively.
From the docking results, the formation of hydrogen bonds
and hydrophobic interactions with the active site are predicted
to be the most crucial factors affecting the inhibitory potency
of these compounds. The predicted binding pose of the most
active compound (6a) suggest that the observed improved
potency arises due to the extensive hydrophobic interactions
predicted to be formed with the side chains of Tyr46, Phe182,
Ala217, Ile219, Gln262 and Val49 (Figure 1a–c). The p–p inter-
action predicted to form between the 4-methoxy phenyl ring
Scheme 1. Reagents and conditions: a) C6H5CONCS, anhyd benzene, RT, 2 h;
b) 10 % aq NaOH, 908C, 20 min; c) Br(CH2)NH2·HBr, EtOH, H2O, reflux, o/n;
d) R2SO2Cl, Et3N, anhyd acetone, RT, 12 h. Overall yield: 25–90%
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Figure 1. a) Analysis of the predicted binding pose of compound 6a with PTP1B; b) Schematic two-dimensional plot of the predicted binding interactions be-
tween 6a and PTP1B; c) Predicted conformation of compound 6a in the binding site cavity of PTP1B; d) Analysis of the predicted binding pose of compound
4a with PTP1B; e) Schematic two-dimensional plot of the predicted binding interactions between 4a and PTP1B; f) Predicted conformation of compound 4a
in the binding site cavity of PTP1B. The crystal structure of the PTP1B catalytic domain (residues 1–299), available from the RCSB Protein Data Bank (PDB:
2ZMM),[25] was used to evaluate the binding of both compounds in the active site of PTP1B.
of 6a and Phe182, and the predicted water-molecule (325 and
acid residues Ser216, Arg221, Gly220 with the oxygen atom of
600)-mediated hydrogen-bond interactions involving amino
the 4-methoxyphenyl group of 6a anchor the compound in
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the active site. Furthermore, the trifluoromethylphen-
yl moiety of 6a is predicted to occupy the hydropho-
bic cleft formed by residues Asp48 and Val49 result-
ing its improved activity. Docking of two analogues
of 6a in which the 2-trifluomethylphenyl moiety is
replaced by a 4-fluorophenyl (4h) or a 2,5-dimethox-
yphenyl (5b) moiety can also help explain the re-
spective activities of these compound; a comparison
of the docking results for compounds 4h, 5b and 6a
is shown in Figure S5 in the Supporting Information.
The ligand binding analysis of one of the least
active analogues (4a) predicts hydrophobic interac-
tions between the phenyl thiazolyl moiety and resi-
dues Phe182 and Ile219, and between the naphthyl
moiety and Val49; however, the anchoring interac-
tions predicted to be formed between the active ana-
logues and the binding site of PTP1B are not ob-
served in the docking results of compound 4a, ex-
plaining its decreased activity (Figure 1d–f). The
amino acid residues close to the active site (Arg47
and Asp48) have been found to impart selectivity to-
wards PTP1B over most other PTPs,[26,27] which is due
to the Asp!Asn at position 48 in other PTPs. Asp48
is close to the active site and plays an important role
in positioning the ligand for binding in the active
site, as judged by B-factors in the published PTP1B
structures.[28–30]
Compounds that exhibited potent in vitro inhibi-
tion of PTP1B (>48% at 10 mm; Table 1) were next
evaluated in
a streptozotocin-induced (STZ) rat
Figure 2. Antihyperglycemic activity of test compounds (100 mgkgꢀ1) in low-dosed
model of diabetes. Of the 16 compounds evaluated,
derivatives 4c, 4g, 5b, 5 f, 5k, 6a, 6d, 6 f and 6h
caused significant lowering of blood glucose over
both five hours and a 24 hour period (Table 1 and
Figure 2). The most active compound (6 f) showed
comparable activity to the reference antidiabetic
!
~
*
^
streptozotocin-induced diabetic rats: a) compounds 4c ( ), 5b ( ), 5k ( ), 6d ( ), and
~
!
&
^
^
*
6 f ( ); b) compounds 5 f ( ), 4h ( ), 6h ( ), and 6a ( ). Vehicle control ( ) is given in
both panels. Statistical analysis was made by Dunnet test (Prism software 3).
drug, metformin, at the same dose. The other active com-
pound, 4c, also showed similar efficacy (20.6% decrease at
5 h) to metformin (20.9% decrease at 5 h). However, com-
pound 4c was slightly less active (18.8% decrease) after 24
hours as compared with metformin (21.3% decrease).
velopment of novel PTP1B inhibitors with promising selectivity
and improved pharmacological properties. Among the 16 com-
pounds exhibiting greater than 48% inhibition against PTP1B
in vitro, nine analogues showed good in vivo activity in the
STZ rat model of diabetes, and compounds 6 f and 4c showed
comparable in vivo activity to metformin.
In summary, a series of aryl thiazolyl phenylsulfonamides
was designed, synthesized and evaluated against PTP1B.
Among the 28 synthesized compound, 16 exhibited greater
than 48% inhibition of PTP1B in vitro. Docking studies were
performed on the most (6a) and one of the least (4a) active
compounds to gain insight into the predicted interactions with
the binding site. Compound 6a is suggested to form good in-
teractions with the active site amino acid residues Gln262 and
Ala217, as well as with C-site amino acid residues Asp48 and
Phe182. In contrast, the docking results for inactive compound
4a lack interactions with Tyr46, Ala217, Gln262 and Val49,
and the water-mediated hydrogen bond, which were predicted
to be formed with the active analogue. Interestingly, the most
active compound is suggested to interact with Asp48, a residue
specific to PTP1B, indicating potential selectivity for PTP1B
over other PTPs. These studies could prove useful for the de-
Experimental Section
Chemistry
N-(4,5-Dihydrothiazol-2-yl)-4-methoxy-N-(2-(trifluoromethyl)-
phenyl) benzenesulfonamide (6a): A solution of N-(2-(trifluoro-
methyl))-4, 5-dihydrothiazol-2-amine (3c) (2.46 g, 0.01 mol) in dry
acetone was treated with Et3N (2.08 mL, 0.015 mol) and 4-methoxy
benzenesulfonyl chloride (2.05 g, 0.01 mol) under dry conditions
and stirred at RT for 12 h. The volatiles were removed in vacuo,
water (100 mL) was added to the organic residue, and the mixture
was extracted with EtOAc (3ꢁ25 mL). The combined organic ex-
tracts were dried (Na2SO4), filtered and concentrated to give crude
6a. Precipitation from EtOAc/hexane provided pure compound 6a
1
(2.27 g, 53%): H NMR (CDCl3, 200 MHz): d=3.21 (t, J=6.6 Hz, 2H),
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Waddleton, P. Payette, C. Ramachandran, B. P. Kennedy, G. Scapin,
3.88 (s, 3H), 4.25 (t, J=6.6 Hz, 2H), 6.84 (d, J=7.6 Hz, 1H), 6.96 (d,
J=2.0 Hz, 2H), 7.13 (t, J=7.8 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.55
(d, J=7.8 Hz, 1H), 7.98 (d, J=2.2 Hz, 2H); IR (KBr): n˜ =680, 761,
1165, 1320, 1644, 2365 cmꢀ1; MS (ESI+): m/z (%): 417 [M+H]+
(100); HRMS (ESI+): m/z [M+H]+ calcd for C17H16F3N2O3S2:
417.05544, found: 417.05096.
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Acknowledgements
This work was supported by grants from the Indian Ministry of
Health (K.V.), the Indian Council of Medical Research (S.G.), and
the Indian Council of Scientific and Industrial Research (N.S., N.R.,
and A.K.R.). The authors thank the Sophisticated Analytical Instru-
ments Facility of Central Drug Research Institute (CDRI) for pro-
viding analytical data, and Mr. Zahid Ali and Mr. A. S. Kushwaha
for technical assistance. The CDRI communication number allot-
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Keywords: molecular modeling
tyrosine phosphatase 1B · sulfonamides · type 2 diabetes
mellitus
· drug design · protein
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