2-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action

Article abstract of DOI:10.1021/jm8004306

SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic

Full text of DOI:10.1021/jm8004306

J. Med. Chem. 2008, 51, 5221–5228
5221
2-Thiazolylimino/Heteroarylimino-5-arylidene-4-thiazolidinones as New Agents with SHP-2
Inhibitory Action
A. Geronikaki,*,† P. Eleftheriou,† P. Vicini,‡ I. Alam,§ A. Dixit,§ and A. K. Saxena§
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle UniVersity, Thessaloniki 54124, Greece, Dipartimento Farmaceutico,
UniVersity of Parma, Parma 43100, Italy, and Medicinal Chemistry DiVision, Central Drug Research Institute, Chattar Manzil Palace,
Lucknow-226 001, India
ReceiVed February 25, 2008
SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling
by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene
account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2
mutations leading to continuously active enzyme were found in more than 50% of Noonan syndrome patients
and are considered to be responsible for the high tendency of these patients to juvenile leukemias and other
cancer types. Recently SHP-2 became a new drug target, but till now little has been done in this field. In
the present study, 17 2-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones divided into three series
of derivatives bearing thiazole-, benzo[d]thiazole-, and benzo[d]isothizole rings were tested for SHP-2
inhibitory activity. Most of the compounds were good SHP-2 inhibitors. Benzo[d]thiazole derivatives exhibited
the best inhibitory action. Docking studies revealed that hydrophobic interactions and hydrogen bond formation
stabilize enzyme-inhibitor complex.
Introduction
46% of the mutations observed in NS and relative disorders
and 91% of the mutations present in hematologic disorders are
located at the N-SH2 domain.1
SHP-2 is a nonmembranic protein tyrosine phosphatase that
mediates cell signaling by growth factors and cytokines acting
via the RAS/MAP kinase pathway.1 The enzyme is normally
inactive because N-SH2 domain blocks the active site. It is
activated when its SH2 domains are connected to other tyrosine
phosphorylated proteins.2 Mutations of somatic or germline
origin in the PTPN11 gene,3–5 encoding the enzyme, were found
in many cases of leukemia and myeloblastic disorders as well
as in Noonan syndrome, which is characterized by high tendency
to juvenile myelomonocytic leukemia (JMMLa). Although
JMML6 is the most common hematologic disorder in which
PTPN11 mutations were observed, cases of acute lymphoblastic
leukemia (ALL), acute myeloid leukemia (AML), chronic
myelomonocytic leukemia (CMML), and myelodysplastic syn-
dromes (MDS)7 with PTPN11 mutations are mentioned.3
Moreover, PTPN11 mutations were observed in patients suf-
fering from Leopard syndrome (LS),8,9 which is phenotypically
related to Noonan syndrome (NS).
Noonan syndrome is a genetic disorder that causes abnormal
development of multiple parts of the body, low stature,
congenital heart diseases, especially pulmonary valve stenosis,
and other disorders.10 Moreover, NS patients often suffer from
inflammations.11
PTPN11 mutations leading to continuously active SHP-2 were
found in more than 50% of Noonan syndrome patients and are
considered to be responsible for the high tendency of these
patients to juvenile leukemias and other types of cancer. The
Noonan syndrome affects 1 in 1000-2500 children,12 while
leukemia accounts for 2% of adult cancers and 1/3 of childhood
cancers.13 Since SHP-2 overactivation, due to PTPN11 gene
mutations, seems to be the cause of a great portion of these
incidents, regulation of enzyme activity would prevent disease
development in many patients. Specific SHP-2 inhibitors could
be used for the treatment of individuals bearing these mutations.
PTPN11 gene was first connected to Noonan syndrome4 and
leukemia7 incidences in 2001 and 2003, respectively. Thus,
SHP-2 became a drug target only the past few years, and little
has been done in this field till now. A number of SHP-2
inhibitors have been found accidentally during researchers’
efforts to discover PTP1B or other tyrosine phosphatase
inhibitors.14–16 In 2006, No¨ren-Mu¨ller and co-workers, following
biological oriented synthesis, designed and synthesized a number
of furanodictin A derivatives with SHP-2 inhibitory action,17
while Chen and co-workers discovered a novel potent SHP-2
inhibitor, 8-hydroxy-7-(2-(6-sulfonaphthalen-2-yl)hydrazinyl)quin-
oline-5-sulfonic acid (NSC-87877).18 In the experimental condi-
tions used by No¨ren-Mu¨ller and co-workers, the best furanod-
ictin A derivative 2a, (2S,3aR,6S,6aR)-N-(cyclohexylmethyl)-
6-(5-((R)-3-(pyrrolidin-1-ylmethyl)phenyl)-1H-tetrazol-1-
yl)hexahydrofuro[3,2-b]furan-2-amine (Figure 1), exhibited an
IC50 value of 2.47 µM using p-nitrophenyl phosphate as
substrate. NSC-87877 inhibitor, evaluated using 20 µM 6,8-
difluoro-4-methylumbellferyl phosphate as substrate, exhibited
a much lower IC50 value: 0.318 µM. NSC-87877 is the most
potent SHP-2 inhibitor known till now, although a straight
comparison with furanodictin A derivatives cannot be done,
since different experimental conditions were used. The com-
pound, bearing a naphthalene 1-sulfonate and a 8-hydrox-
yquinoline 5-sulfonate group connected via a -NdN- bridge,
was considered to be stabilized in the active center cleft via
hydrogen bond interactions between sulfonate groups and
Arg465, Lys280, and Asn281.
* To whom correspondence should be addressed. Phone: 00302310997616.
Fax: 00302310997612. E-mail: geronik@pharm.auth.gr.
†
Aristotle University.
University of Parma.
Central Drug Research Institute.
‡
§
a Abbreviations: MAP, mitogen activated protein; PTPN 11, protein
tyrosine phosphatase nonreceptor type 11; JMML, juvenile myelomonocytic
leukemia; ALL, acute lymphoblastic leukemia; CMML, chronic my-
elomonocytic leukemia; MDS, myelodysplastic syndrome; LS, Leopard
syndrome; NS, Noonan syndrome.
10.1021/jm8004306 CCC: $40.75
2008 American Chemical Society
Published on Web 08/15/2008

5222 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Geronikaki et al.
Scheme 1. Synthesis of the Compoundsa
Figure 1. Structures of the SHP-2 inhibitors furanodictin A derivative
2a and compound NSC-87877.
a Reagents and conditions: (a) ClCOCH2Cl, N,N-DMF, room temp, 2 h;
(b) NH4SCN, EtOH, reflux, 1-3 h; (c) RC6H4CHO, MeCOOH, MeCOONa,
reflux 2-4 h.
mechanism suggested for the formation of all synthesized
compounds is described in our previous publications.28,33
All the new compounds were characterized by mp, elemental
analyses, and spectroscopic data (1H NMR, MS, and IR). The
substitution position in the cyclocondensation step and the
tautomeric structure of the 2-imino-5-arylidene-4-thiazolidinones
were determined through the analysis of IR and 1H NMR
spectral data.28,33 Benzo[d]thiazole and benzo[d]isothiazole
derivatives show, in the 1H NMR spectra, a NH proton at
12.00-12.87 ppm which is in accordance with a lactam proton
and not with an imine proton (expected around 9.70 ppm). This
observation accounts for the ring closure, as already discussed
in our previous papers.22 The feature of a γ-lactam heterocycle,
in the solid state, is also supported by the IR spectral data (NH
group band at 3100 cm-1 and a strong band at about 1690-1714
cm-1) for the majority of the compounds. Compound 16 is an
exception because it shows an absorption band around 3234
cm-1, typical of a secondary amine.
Evaluation of SHP-2 Inhibition. All thiazolidin-4-one
derivatives synthesized were tested for SHP-2 inhibitory action
using human recombinant GST-fusion SHP-2 (Table 1). Ac-
cording to the results obtained, most of the tested compounds
exhibited good inhibitory activity. It was found that the most
active compound is 4-methoxy-substituted thiazole derivative
3, as well as its benzothiazolyl-analogue 11 (Ki ) 11.7 µM). In
the series of thiazole derivatives, two subgroups are observed:
compounds 3, 2, 8, and 6, with Ki values varying between 11.7
and 54.5 µM, and compounds 1, 4, 5, and 7, which are
practically inactive, with Ki values varying between 388.0 and
1088.2 µM. As gathered by the results, the presence of a
methoxy substituent strongly favors inhibitory action. Replace-
ment of the methoxy group at the 4-position of the phenyl ring
(3) with a hydroxy group (1) resulted in loss of activity (Ki )
388.0 µM). Moreover, addition of a methoxy group at the
3-position of the 4-hydroxy derivative led to compound 2 with
increased inhibitory activity (Ki ) 25.6 µM). The 2-Cl and 4-Cl
derivatives also showed considerable inhibitory action (Ki values
of 32.3 and 54.5 µM, respectively). In contrast, the 3-Cl
derivative exhibited the lowest inhibition (Ki ) 1088.2 µM),
pointing out the importance of the position of the substituent
in this case. The nitro derivatives of this series, 4 and 5, are
also practically inactive (Ki values of 473.6 and 547.5 µM,
Figure 2. Structures of tested compounds.
During the past decade, many thiazole and thiazolidinone
derivatives have been tested for protein phosphatase inhibitory
action. Because of their structural resemblance to the natural
peptide substrates of the enzymes, many derivatives of these
series have been found to effectively inhibit protein phos-
phatases, mainly PTP1B.19–27
Taking into account previous knowledge in this field, we
synthesized and tested a series of 2-thiazolylimino/heteroarylimi-
no-5-arylidene-4-thiazolidinone derivatives for SHP-2 inhibitory
activity. According to the heteroarylimino group, the compounds
can be divided into three series bearing thiazole-, benzo[d]thia-
zole-, and benzo[d]isothiazole moieties. In order to analyze the
mode of binding of different derivatives, docking studies for
selected compounds were performed.
Results and Discussion
Chemistry. The compounds described in this paper (Figure
2) were synthesized by a three-step reaction protocol reported
earlier by us.28
Appropriate thiazol-2-chloroacetamides or benzo[d]thiazol-2-
yl/benzo[d]isothiazole chloracetamides were synthesized starting
from 2-aminothiazoles/2-aminobenzothiazoles/aminobenzothia-
zoles/3-aminobenzo[d]isothiazoles as described in ref 29.
The first step of the synthetic procedure was carried out by
reaction of appropriate amines with chloroacetyl chloride in
DMF at room temperature for 2 h or by heating in dry benzene
for 3 h.29,30
2-Chloro-N-(thiazole/benzo[d]thiazol-2-yl/benzo[d]isothiazol-
3-yl)acetamides efficiently reacted with ammonium thiocyanate
in refluxing ethanol to produce 2-(thiazol-2-ylimino)thiazolidin-
4-ones or 2-(heteroarylimino)thiazolidin-4-ones.28,31,32
The final compounds were obtained by refluxing the previous
products with commercially available aromatic aldehydes and
anhydrous sodium acetate in glacial acetic acid (Scheme 1). The

4-Thiazolidinones with SHP-2 Inhibitory Action
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5223
Table 1. SHP-2 Inhibitory Action of Synthesized Compounds
compd
ring
thiazole
thiazole
thiazole
thiazole
thiazole
thiazole
thiazole
thiazole
R
R1
Kia (µM)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
4-OH
388.0
25.6
11.7
473.6
547.5
54.5
1088.2
32.3
3-OCH3, 4-OH
4-OCH3
4-NO2
3-NO2
4-Cl
3-Cl
2-Cl
9
thiazole
thiazole
4-phenyl
4-adamantanyl
H
H
3-OCH3, 4-OH
3-OCH3, 4-OH
4-OCH3
3,5-OCH3, 4-OH
3,5-OCH3, 4-OH
4-NO2
3-NO2
4-OCH3
3-OCH3, 4-OH
103.2
12.3
11.7
18.1
12.9
16.2
28.7
22.8
90.8
10
11
12
13
14
15
16
17
benzothiazole
benzothiazole
benzothiazole
benzothiazole
benzothiazole
benzisothiazole
benzisothiazole
6-NO2
H
H
H
H
compd
furanodictin A derivative 2a
a Ki values were the mean of two experiments. SD did not exceed 10% of the mean value. b IC50 value of furanodictin A was taken from the literature.17
IC50 (µM)
2.47b
respectively). Comparison of compound 10 (Ki ) 12.3 µM) with
compound 2 (Ki ) 25.6 µM) showed that addition of the bulky,
hydrophobic adamantanyl group at the 4 position of the thiazolyl
ring (10) significantly increased inhibition. Interestingly, addition
of a phenyl substituent at the same position (9, Ki ) 103.2 µM)
did not favor inhibitory action. Among compounds of ben-
zo[d]thiazole series, 4-methoxy derivative 11 is the most active
one, with activity equal to that of the thiazolyl analogue (3).
Generally, the benzo[d]thiazolyl derivatives exhibited equal or
better inhibitory action than thiazole derivatives, as shown by
comparing compound 11 (Ki ) 11.7 µM) to compound 3 (Ki )
11.7 µM), compound 14 (Ki ) 16.2 µM) to compound 4 (Ki )
474.0 µM), and compound 15 (Ki ) 28.7 µM) to compound 5
(Ki ) 548.0 µM). Comparison of the 6-nitrobenzo[d]thiazolyl
derivative 13 (Ki ) 12.9 µM) with its benzo[d]thiazolyl
analogue 12 (Ki ) 18.1 µM) showed that the presence of the
nitro group in the benzo[d]thiazolyl moiety further enhanced
inhibitory activity. Among compounds of the benzo[d]isothia-
zolyl series, the 4-methoxy derivative 16 (Ki ) 22.8 µM) caused
stronger SHP-2 inactivation than the 3-methoxy-4-hydroxy
derivative 17 (Ki ) 90.9 µM). This is in accordance with its
thiazolyl analogues, indicating the propitious addition of the
methoxy group. In general, the benzo[d]isothiazoles tested were
found to be less active compared to the thiazole analogues.
In order to analyze the mode of binding of different de-
rivatives, docking studies for selected compounds were performed.
Docking. Docking analysis revealed that hydrogen bond (HB)
formation and hydrophobic interactions are the most important
factors affecting inhibitory action of compounds of the thiazole
series. In general, compounds of the most active group (3, 2, 8,
6) form more hydrogen bonds than compounds of the practically
inactive group (1, 4, 5, 7). Moreover, hydrophobic interactions
are involved in the binding of the most active compounds.
All compounds of the active group of the thiazole series are
oriented in the active center of the enzyme in a way that places
the phenyl ring into the pocket consisting of the amino acids
Lys366, Arg362, Glu361, Val360, Ser365, Tyr62, and Ser460.
Compound 3, exhibiting the highest activity, forms four
hydrogen bonds (Figure 3a). Hydrogen-bond interaction is
observed between oxygen of the methoxy group at the 4-position
of the phenyl ring and hydrogen of the NH group of the side
chain of the amino acid Lys366 (distance 2.55 Å). Hydrogen
of the NH group that connects the thiazole and thiazolidinone
rings of the ligand forms a hydrogen bond with oxygen of the
carbonyl group of amino acid Arg278 (distance 2.37 Å).
Hydrogen of the OH group of the amino acid Tyr62 showed
hydrogen-bond interaction with oxygen of the carbonyl group
of the thiazolidinone ring (distance 2.84 Å), while the backbone
NH group of the amino acid Lys280 formed a hydrogen bond
with N of the thiazole ring (distance 2.58 Å). Moreover,
hydrophobic interactions between the phenyl ring, the methyl
group of the methoxy substituent, and the four-carbon chain of
Lys 364 may occur.
The presence of the methoxy group at the 3-position and of
an OH group at the 4-position of the phenyl ring in compound
2 causes a change in orientation of the compound in the active
site of the enzyme (Figure 3b). Hydrogen of the NH group
between the thiazole and thiazolidinone rings still forms a
hydrogen bond with the oxygen of the carbonyl group of amino
acid Arg278 (distance 1.83 Å), while the carbonyl group of the
thiazolidinone ring fails to interact with the HO group of Tyr62.
This carbonyl group now forms a hydrogen bond with oxygen
of the methoxy group at the 3-position of the phenyl ring
(distance 2.49 Å). A third hydrogen bond is formed between
hydrogen of the OH group at the 4-position of the phenyl ring
and oxygen of the carbonyl group of the backbone peptide bond
of amino acid Glu361 (distance 2.49 Å). Hydrophobic interac-
tions between the methyl group of methoxy substituent and the
four-carbon chain of Lys 364 may be involved in complex
stabilization. The lower number of hydrogen bonds in the case
of compound 2 explains its higher Ki value compared to the
most active derivative 3.
The three hydrogen bonds observed in the 4-Cl derivative,
compound 6 (Figure 3c), are formed between the NH group
that connects the thiazole and thiazolidinone rings and the
oxygen of the carbonyl group of Arg278 (distance 1.27 Å), the
oxygen of the carbonyl group of the thiazolidinone ring, and
the OH group of Tyr62 (distance 3.11 Å) and between the N

5224 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Geronikaki et al.
Figure 3. (a) Docking of compound 3, (b) docking of compound 2, (c) docking of compound 6, and (d) docking of compound 7 in the active site
of human SHP-2. Green lines represent H-bonding.
Figure 4. (a) Docking of compound 5 and (b) docking of compound 15 in the active site of human SHP-2. Green lines represent H-bonding.
atom of the thiazole ring and the backbone NH group of Lys280
(distance 2.42 Å). Orientation of the phenyl ring does not favor
any hydrophobic interaction. The number of hydrogen bonds
and the lack of hydrophobic interactions are probably respon-
sible for the lower activity of this compound compared to the
most active compounds of this series (3 and 2).
The presence of the Cl substituent at the 3-position of the
phenyl ring, compound 7, forces it to be placed in the opposite
orientation in the active site compared to compounds 6 and 8,
where Cl substituent is in positions 4 and 2, respectively.
Docking results showed that the phenyl ring with 3-Cl sub-
stituent is placed in the cavity comprising amino acids Glu69,
Lys70, Lys280, and Asn281, while the thiazole and thiazolidi-
none rings are in the vicinity of the amino acids Tyr62, Arg278,
Tyr279, Lys364, Lys366, and Ser460 (Figure 3d). The only
hydrogen bond observed in this orientation is formed between
hydrogen of the OH group of Tyr62 and N of the thiazole ring
(distance 2.71 Å). Moreover, no hydrophobic interactions are
favored. These results explain the huge decrease in activity of
the 3-Cl derivative (7) compared to 4-/2-Cl derivatives.
The same upside-down orientation is observed in all com-
pounds of the inactive group of the thiazole series bearing a
nitro substituent at the 4 or 3 position of the phenyl ring
(compounds 4 and 5, respectively) or a OH group at the
4-position (compound 1). A low number of hydrogen bonds
and lack of hydrophobic interactions are observed in all cases.
It is interesting to mention that this orientation is also observed
in the benzo[d]thiazole derivatives that exhibit significant
activities compared to their thiazole analogues. The number of
hydrogen bonds and the hydrophobic interactions of ben-
zo[d]thiazole moiety are probably responsible for better activity
in this case.
Docking of the 3-nitrothiazole derivative, compound 5,
showed that one oxygen atom of the NO2 group forms a
hydrogen bond with the NH group of the side chain of Lys 280
(distance 1.64 Å), while the other oxygen atom interacts with
the hydrogen of the backbone NH of Lys70 (distance 2.38Å)
(Figure 4a). Docking of the benzo[d]thiazolyl analogue 15
revealed that oxygen atoms of the NO2 group also form
hydrogen bonds with the side chain NH of Lys 280 and the

4-Thiazolidinones with SHP-2 Inhibitory Action
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5225
Figure 5. (a) Docking of compound 12 and (b) docking of compound 13 in the active site of human SHP-2. Green lines represent H-bonding.
Figure 6. (a) Docking of compound 9 and (b) docking of compound 10 in the active site of human SHP-2. Green lines represent H-bonding.
backbone NH of Lys 70 (distances 1.94 and 1.62 Å, respec-
tively). However, a minor rearrangement due to the presence
of the benzo[d]thiazole results in an extra hydrogen bond
formation between the NH group that connects the thiazole and
thiazolidinone rings and the backbone carbonyl group of Ser365
(distance 2.70) (Figure 4b). Docking studies of the thiazole and
benzo[d]thiazole 4-nitro derivatives (compounds 4 and 14,
respectively) revealed that both oxygen atoms of the NO2 group
form hydrogen bonds with the NH group of the side chain of
Lys280 (distances of 1.99 and 2.44 Å in compound 4 and of
1.58 and 2.54 Å in compound 14). Hydrophobic interactions
between the benzo[d]thiazole ring system and the four-carbon
chain of Lys364 favor complex stabilization in this case.
The positive influence of the nitro group at the 6-nitroben-
zo[d]thiazole derivative 13 is well explained by docking analysis
of compounds 12 and 13 (Figure 5). The presence of the nitro
group forces the compound to an orientation that allows
formation of an extra hydrogen bond compared to the ben-
zo[d]thiazolyl analogue 12. Docking of compound 12 showed
that the 3,5-OCH3-4-OH substituted phenyl ring is oriented in
the pocket consisting of Glu69, Lys70, Asn277, Arg278, Tyr279,
and Lys280, while the benzo[d]thiazole and thiazolidinone
moieties are in the vicinity of Tyr62, Glu361, Arg362, Tyr279,
Lys364, Ser365, Lys366, and Ser460. Hydrogen bond interac-
tions are observed between the 4-OH and 5-OCH3 groups of
the phenyl ring and the backbone NH of Lys280 (distances of
1.81 and 2.34 Å, respectively) and between the OH group of
Tyr62 and nitrogen of the benzo[d]thiazole moiety (distance
2.51 Å) (Figure 5a). Docking of compound 13 revealed that
the 3,5-OCH3-4-OH substituted phenyl ring is placed in the
pocket consisting of Tyr62, Glu69, Lys70, Arg278, Tyr279, and
Lys280 while the 6-NO2 benzo[d]thiazole group is in proximity
to amino acids Tyr62, Glu361, Arg362, Lys364, Ser365,
Lys366, and Ser460. The 4-OH and 5-OCH3 groups show HB
interactions with a backbone NH of Lys280 (distances of 2.19
and 2.29 Å, respectively), while the OH group of the amino
acid Tyr62 interacts with the nitrogen of the thiazole ring of
the 4-nitrobenzo[d]thiazole moiety (distance 2.72 Å). An extra
hydrogen bond is formed between hydrogen of the NH
connecting the benzo[d]thiazole and thiazolidinone moieties and
oxygen of the carbonyl group of the amino acid Ser365 (distance
2.34 Å) (Figure 5b).
Docking of the 4-phenyl/adamantanyl-thiazole derivatives 9
and 10 revealed a general orientation similar to the compounds
of the benzo[d]thiazole series. However, a minor difference in
orientation due to the presence of the bulky adamantanyl group
results in formation of two more hydrogen bonds compared to
the 4-phenylthiazolyl analogue where only one hydrogen bond
is formed (Figure 6). This explains well the difference in
inhibitory activities of these compounds. More precisely,
docking of 4-phenylthiazole derivative 9 showed that the
3-OCH3-4-OH substituted phenyl ring is placed in the pocket
consisting of Gly68, Glu69, Lys70, and Lys280, whereas the
thiazole and thiazolidinone rings are in proximity to the amino
acids Tyr62, Tyr279, Lys364, Ser365, Lys366, and Ser460.
Hydrogen bond interaction is observed between oxygen of the
4-OH substituent of the phenyl ring of the compound and
nitrogen of the side chain NH group of Lys280 (distance 2.65
Å). Docking of 4-adamantanylthiazole derivative 10 showed that
the substituted phenyl ring is located in the pocket consisting
of Glu69, Lys70, Arg278, Tyr279, and Lys280, while thiazole
and thiazolidinone rings and the 4-adamantanyl group are placed
in the cavity of Gln57, Thr59, Asp61, Tyr62, Asp64, Lys70,
Tyr279, Glu361, Arg362, Lys364, Ser365, and Lys366. The
4-OH group of the phenyl ring forms a hydrogen bond with
the NH group of the side chain of Lys280 (distance 1.74Å).
Moreover, hydrogen bonds are observed between oxygen of the
3-OCH3 group of the phenyl ring and hydrogen of the backbone
NH of Lys70 (distance 2.19 Å) and between OH group of Tyr62
and nitrogen of the thiazole ring (distance 2.16 Å).

5226 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17
Geronikaki et al.
5-(4-methoxy-benzylidene)-2-(benzo[d]thiazol-2-ylimino)thia-
zolidin-4-one exhibited the best inhibitory action with Ki ) 11.7
µM. In general, benzo[d]thiazole derivatives showed equal/better
inhibitory activity than their thiazole analogues. Docking results
explain inhibitory action well. In all cases, stable complex
formation was favored by the placement of a hydrophobic group
in the vicinity of amino acids Tyr62, Glu361, Arg362, Lys364,
Ser365, Lys366, and Ser460. Hydrogen bond formation and
hydrophobic interactions are involved in stabilization.
Unfortunately, a direct comparison of the activity of the best
compounds of these series with NSC-87877, the most potent
SHP-2 inhibitor known till now (IC50 ) 0.318 µM) is not
possible because of the use of different methods of SHP-2
activity evaluation (different substrate and substrate concentra-
tion).
Figure 7. Docking of compound 17 in the active site of human SHP-
2. Green lines represent H-bonding.
Toxicity of some of our compounds has been tested during
a previous investigation, and results were very encouraging.34
Since investigation on SHP-2 inhibitors targets the development
of potent drugs for the chronic treatment of individuals bearing
PTPN11 mutations, low or no toxicity of the compounds is
essential. Furthermore, anti-inflammatory activity of some of
the compounds was observed.34 Because Noonan syndrome
patients often suffer from chronic inflammations, which may
be the reason for the deafness observed in some individuals,
compounds of this series may possess an extra beneficial
property. Of course, more experiments have to be done for the
determination of selectivity of the compounds. Moreover, new
derivatives with improved properties could be designed taking
into account all previous results.
Upside-down orientation is observed in benzo[d]isothiazole
derivatives, as well, resulting in a low number of hydrogen
bonds and reduced activity of the compounds. Docking
studies of compound 17 (Figure 7), the benzo[d]isothiazole
analogue of the thiazole derivative 2, showed that the phenyl
ring with the 3-OCH3 and 4-OH substituents is placed in the
cavity comprising Glu69, Lys70, Phe71, Arg278, Tyr279,
Lys280, and Asn281, while the thiazole and thiazolidinone
rings are in proximity to amino acids Tyr62, Arg278, Tyr279,
Glu361, Arg362, Lys364, Ser365, Lys366, and Ser460.
Hydrogen bond interaction has been observed between the
oxygen of the methoxy group of the phenyl ring and the
backbone NH of Lys70 (distance 2.11 Å), while the oxygen
of the OH group of the ligand interacts with the hydrogen of
the NH of side chain of Lys280 (distance 1.97Å). This
orientation does not strongly favor hydrophobic interactions.
The low number of hydrogen bonds and lack of strong
hydrophobic interaction explains the lower activity of
compound 17 compared to its thiazole analogue (2).
In all cases, stable complex formation was favored by the
placement of a hydrophobic group in the vicinity of amino acids
Tyr62, Glu361, Arg362, Lys364, Ser365, Lys366, and Ser460.
Hydrogen bond interactions between the compounds and
aminoacids of the enzyme further justify the complex stabiliza-
tion explaining differences in activity. Lys 280, Tyr62, and Arg
278 are the amino acids mainly involved in this process. Lys280
is implicated in hydrogen bond formation of most of the active
derivatives (8 out of 11). It interacts with the substituents of
the phenyl ring of benzo[d]thiazoles with the exception of
benzo[d]thiazolyl derivative 11, where it forms a hydrogen bond
with the carbonyl group of the thiazolidinone ring. In compounds
of the thiazole series, HB formation between Lys280 and the
thiazolyl ring was observed. Tyr62 is also involved in hydrogen
bond interactions with the thiazole or thiazolidinone ring of
many active compounds (7 out of 11), while the NH group
connecting the thiazole and thiazolidinone rings interacts with
Arg278. Lys 280, involved in stabilization of most complexes,
was one of the tree amino acids referred to interact with inhib-
itor NSC-87877, according to the literature.18
Experimental Section
Materials. Synthetic starting material, reagents, and solvents
were purchased from Aldrich or Fluka. All the solvents were reagent
grade and dried prior to use. Melting points were determined with
a Boetius apparatus and are uncorrected. Elemental analysis was
performed in the analytical laboratory of Dipartimento Farmaceu-
tico, Universita` di Parma, on a ThermoQuest (Italia) FlashEA 1112
elemental analyzer, for C, H, N, and S. The found values for C, H,
N, S were always (0.4% of the theoretical ones. IR spectra were
taken as KBr pellets on a Jasco FT-IR 300E spectrophotometer
(Jasco Ltd., Tokyo, Japan) or on Perkin-Elmer spectrophotometer,
and the reported wavenumbers are given in cm-1. 1H NMR spectra,
in DMSO-d6 solutions, were recorded on a Bruker AC 300
instrument at 298 K. Chemical shifts are reported as δ (ppm) relative
to TMS as internal standard. Mass spectra were recorded on a VG-
250 spectrometer (VG Laboratories., Tritech England) at 70 eV.
The progress of the reactions was monitored by thin layer
chromatography using F254 silica gel precoated sheets (Merck,
Darmstadt, Germany). Human recombinant GST-fusion SHP-2 was
purchased by Calbiochem.
Chemistry. Synthesis of 4-adamantyl-2-aminothiazole. To a
solution of 1-adamantyl bromomethyl ketone, I (257 mg, 1 mmol),
in 5 mL of isopropanol, a suspension of thiourea (152 mg, 2 mmol)
in 10 mL of isopropanol was added. The mixture was stirred for
half an hour. After this time the resulting solution was poured into
a solution of sodium carbonate, and the precipitate formed was
filtered and dried to give, after recrystallization from ethyl acetate,
220 mg (94%) of pure product, II. Mp 215-215.5 °C. IR(KBr): ν
) 3050 cm-1 (N-H), 1650 cm-1 (CdO).
Conclusions
Chloracetylchloride of 4-adamantyl-2-aminothiazole, chlor-
acetamidothiazoles/benzothiazoles/benzoisothiazoles were pre-
pared as previously described.30
General Procedure for Synthesis of 4-Adamantyl-2-thiazolylimino-
5-arylidene-4-thiazolidinones. A well-stirred solution of 0.8 g of
2-(thiazol-2-ylimino)thiazolidin-4-one (4 mmol) in 35 mL of acetic
acid was buffered with sodium acetate (8 mmol) and added to the
appropriate arylaldehyde (6 mmol). The solution was refluxed for
As a result of our research, a number of new SHP-2 inhibitors
have been found and a new class of inhibitors have emerged.
The tested compounds are the first thiazole/thiazolidinone
derivatives found to have SHP-2 inhibitory action. Eleven out
of seventeen compounds have Ki values lower than 54.5 µM,
whereas four of them have Ki values lower than 12.9 µM. 5-(4-
Methoxybenzylidene)-2-(thiazol-2-ylimino)thiazolidin-4-one and

4-Thiazolidinones with SHP-2 Inhibitory Action
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 17 5227
4 h and then poured into ice-cold water. The precipitate was filtered
and washed with water, and the resulting crude product was purified
by recrystallization from dioxane.
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