Design and synthesis of conformationally constraint Dyrk1A inhibitors by creating an intramolecular H-bond involving a benzothiazole core

Article abstract of DOI:10.1039/c8md00142a

We present the development of conformationally pre-organised Dyrk1A inhibitors based on the hydroxybenzothiazole urea scaffold. The modifications introduced to the discovered hit (AHS-211) proved the crucial role of the urea linker to preserve the bioacti

Full text of DOI:10.1039/c8md00142a

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Design and synthesis of conformationally constraint Dyrk1A
inhibitors by creating an intramolecular H-bond involving
Received 00th January 20xx,
Accepted 00th January 20xx
a benzothiazole core
*
Mohamed Salah,a§ Mohammad Abdel-Halimb§ and Matthias Engel a†
DOI: 10.1039/x0xx00000x
www.rsc.org/
We present the development of conformationally pre-organised
Dyrk1A inhibitors based on the hydroxybenzothiazole urea
scaffold. The modifications introduced to the discovered hit (AHS
-
211) proved the crucial role of the urea linker to preserve the
bioactive conformation and led to the development of compound
b5 as a promising selective Dyrk1a inhibitor.
Introduction
Dyrk1A (the dual-specificity tyrosine phosphorylation-
regulated kinase 1A) is a serine/threonine protein kinase that
belongs to the DYRK family. The other members in the family
are Dyrk1B, Dyrk2, Dyrk3, and Dyrk4. Together with the cyclin-
dependent kinases (CDKs), mitogen-activated protein kinases
(MAP kinases), glycogen synthase kinases (GSK) and Ccd2-like
kinases (CLKs), they compose CMGC super family of kinases. 1, 2
DYRK1A gene is allocated in the Down Syndrome (DS) critical
region of chromosome21. The cognitive impairments and
neurofibrillary degeneration seen in DS as well as in
Alzheimer’s disease (AD) have been found to be associated
with DYRK1A overexpression.3-5 Additionally, DYRK1A was
reported to be implicated in numerous biological processes
such as T cell regulation,6 cell cycle regulation and cell
Figure 1. Previously published benzothiazole- and benzothiophene-based Dyrk1A/Clk1
inhibitors (INDY, TG003, A and B) and new benzothiazole urea derivatives (C and AHS-
211).
Results and discussion
Compound design. The benzothiazole scaffold was known to be
a promising building block for the development of Dyrk1A
inhibitors since the discovery of the Dyrk1A/Clk1 inhibitors
TG003 and INDY (Figure 1).11,
12
The binding mode of the
benzothiazole core to the ATP pocket of Dyr1A was
determined by X-ray crystallography for INDY;12 further Dyrk1A
co-crystal structures were reported later for acetylated 2-
aminobenzothiazole fragments (Figure 1, Structure
INDY and our previously reported benzothiophene
Clk1/Dyrk1A inhibitor14 (Figure 1, compound
) contained a
B
).13 Both
7
differentiation,6, stabilization of cytoskeleton,8 and brain
A
neurodevelopment.9 Drug discovery efforts aim at the
development of selective Dyrk1A inhibitors, in particular in
light of the putative tumor suppressor activity of the
homologous Dyrk2 isoform.10
hydroxyl group which is important to maintain potency against
Dyrk1A. We thought of expanding the hydroxybenzothiazole
scaffold to get potent and selective Dyrk1A inhibitors. To this
end, we exploited the benzothiazole ring nitrogen to design
and synthesize new derivatives which are rigidized via an
internal H-bond, avoiding the need to synthesize polycyclic
aromatic systems which may have toxicological issues. We
envisaged extending the benzothiazole fragment with a urea
linker to achieve the desired pseudo 6-membered ring
structure between the benzothiazole nitrogen (as HBA) and
In this communication we present 6-hydroxybenzothiazol-2-yl
urea as a promising new scaffold for DYRK1A inhibition that
allows pre-organisation of the biologically active conformation.
We report some modifications for the scaffold exploration as
well as scaffold expansion using an in-house discovered hit
(AHS-211, Figure 1) as a starting compound.
the distant urea NH (as HBD) as shown in structure
C Figure 1.
§ Both authors contributed equally to this work.
Using ab initio calculations, it was corroborated that the
suggested benzothiazole urea scaffold showed the proposed
pseudo-ring formation in the most stable conformer
(conformer c1, Figure 2). In contrast, a considerably higher
energy content was calculated for the also coplanar rotamer
aPharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3,
D-66123 Saarbrücken, Germany.
bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy and
Biotechnology, German University in Cairo, Cairo 11835, Egypt
†Correspondence:Dr. Matthias Engel. Phone: +49 681 302 70312. Fax: +49
681 302 70308. E-mail: ma.engel@mx.uni-saarland.de. Website:
http://www.pharmmedchem.de.
*Electronic Supplementary Information (ESI) available. See DOI:
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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c2 (ΔE= 59 kJ/mol, Figure 2), probably attributable to the lack derivatives starting from the ester a2 which was hydrolysed to
of the energetically favourable H-bond as well as to the the respective carboxylic acid a8 under alkaline conditions
unfavourable polar repulsion between the endocyclic nitrogen followed by amide coupling with benzyl amine or 1-
and the urea oxygen (cf. c2, Figure 2).
methylpiperazine using HBTU as coupling agent. Finally, the
methyl ether dealkylation was performed using BBr3 in
dichloromethane (Scheme 5).
c2
c1
Figure 2. Lowest energy conformer (c1) and the higher energy linear conformer (c2) of
the benzothiazole urea scaffold, exemplified by hit compound AHS-211, as calculated
by the B3LYP density functional method. Shown are the fully coplanar conformers with
a mesh displaying the electrostatic potential on an isoelectronic density surface (0.025
e/a3). The intramolecular H-bond that stabilizes a pseudo 6-membered ring in c1 is
indicated by the overlapping electron density in the center. The calculated energy
difference between the conformers is 59 kJ/mol.
Scheme 2. Synthesis of urea derivatives via carbamates. Reagents and conditions: (i)
Dioxane, pyridine, RT, 1hr (ii) 1.5 equiv amine derivative, dioxane, overnight, reflux.
Searching in our in-house library for possible hits that may
overlap with the designed target urea derivatives revealed the
previously published compound AHS-211 as a good candidate.
AHS-211 (compound 23 in ref 15) was previously published as
an inactive compound against 17β-hydroxysteroid dehydro-
genase type 1 (17βHSD1).15 Testing AHS-211 against Dyrk1A
greatly supported our design concept as it inhibited the
recombined enzyme with an IC50 of 0.134 µM. AHS-211 also
inhibited Dyrk1B with an IC50 of 0.37 µM, yielding a selectivity
factor of 2.7 for Dyrk1A (Table 2). Furthermore, AHS-211
showed 64.7% inhibition when screened against Dyrk2 at 5 µM
concentration (Table2).
Scheme 3. Synthesis of benzothiazoleamide. Reagents and conditions: (i) Acetone,
Na2CO3, ice cooling then RT, 1 hr.
Scheme 4. Synthesis of the benzamide derivatives. Reagents and conditions: (i) Aq.
KOH, THF, RT, 14hr (ii) 4 equiv amine derivative, 1.5 equiv HBTU, TEA, RT, overnight.
Scheme 1. Synthesis of urea derivatives via isocyanates. Reagents and conditions: (i)
DMF, RT, overnight.
Chemistry. The synthesis of the designed urea derivatives was
performed mainly thorough the reaction of the aryl amine
derivatives with phenylisocyanates in DMF at room
temperature (Scheme 1), or alternatively through the reaction
of 2-amino-6-methoxy benzothiazole with phenylchloro-
formate in the presence of pyridine as a base and dioxane as
solvent to give the carbamate compound a4 which is itself was
isolated as the oxygen isostere of urea or further reacted in
situ with amine derivatives in refluxing dioxane to give the
urea compounds (a5 and a6) as shown in Scheme 2. Acylation
of 2-amino-6-methoxybenzothiazole was done in acetone in
presence of K2CO3 to yield the methylene isostere of urea
(Scheme 3). Scheme 4 shows the preparation of the amide
Scheme 5. Ether dealkylation. Reagents and conditions: (i) 15 equiv BBr3, CH2Cl2, -78 oC
then room temperature, 20h.
Cpd#
b1
R3
X
R4
H
H
H
-NH-
-O-
b2
H
b3
3-OCH3
4-
-CH2-
-NH-
3-OH
4-
b4
C
NH
C
NH
O
O
b5
4-
-NH-
4-
C
N
N
C
N
N
O
O
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Biological evaluation. Table 1 shows the screening results of In contrast, the deletion of the 3-hydroxyl (at the phenyl ring)
the synthesized methoxy precursors against both Dyrk1A and in AHS-211 almost did not influence the activity, as observed
Dyrk1B while Table 2 shows the screening results for the with compound b1 (IC50= 0.163 µM against Dyrk1A). Of note,
phenolic analogues against Dyrk1A, Dyrk1B and Dyrk2. As can the latter change reduced the potency against Dyrk1B,
be seen, the 6-methoxy precursors showed a huge reduction increasing the selectivity factor to 4.3 toward Dyrk1B, and also
of potency when compared to their 6-hydroxy analogues, reduced the off-target activity against Dyrk2 when compared
indicating that the 6-hydroxyl (born at the benzothiazole) in with the hit AHS-211 (Table 2).
AHS-211 has a crucial share in binding to Dyrk1A as HBD Compounds b2-b3 were prepared to prove the importance of
function; in fact, none of the 6-methoxy derivatives exhibited the urea linker in maintaining the biologically active
more than 31% inhibition at 2 µM of the tested compounds conformer; in these compounds, the –NH– assumed to act as
(Table 1). Likewise, compound a3, in which the 6-hydroxy- HBD and help the pseudo ring formation was replaced by the
benzothiazole moiety was replaced by 5-pyridylthiadiazole, did isosteric –O– and –CH2–, respectively. Compound b2 gave no
not show significant activity. In this analogue, the internal H- inhibition for Dyrk1A and Dyrk1B at 0.5 µM while its urea
bond is expected to be conserved and the pyridine nitrogen analogue b1 showed more than 80% inhibition at the same
lies in a similar distance from the urea linker as the 6-methoxy concentration (Table 2). Since the carbamate-derivative b2
oxygen, thus enabling
a similar potential role as HBA; was least likely to adopt a coplanar conformation similar to c1
nevertheless, the lack of the HBD impeded the success of this (Figure 2) because of the electronic repulsion between the
modification.
oxygen and the ring nitrogen, the complete loss of inhibitory
activity supported our hypothesis that the biological activity
was associated with a c1–like molecule shape. In further
accordance, the more neutral electrostatic potential of the
methylene bridge in b3 led to a partial recovery of the
inhibitory potency, but failed to reach the potency of AHS-211
due to the lack of the conformation-stabilizing H-bond. Of
interest, compound b3 showed its highest inhibitory potency
against Dyrk2 (IC50 ≈ 5 µM, [ATP] = 100 µM), probably due to
the additional presence of the m-hydroxy function at the
phenyl, which also enhanced the Dyrk2 inhibitory activity of
AHS-211 (Table 2).
Table 1. Inhibition of Dyrk1A and Dyrk1B by the methoxy
precursors and compound a3.
Dyrk1A
%
inhibition
at 0.5 µMa
Dyrk1B
%
inhibition
at 0.5 µMa
Having proven the crucial role of the urea motif, we envisaged
some substantial modifications of compound b1 to improve
potency and selectivity for Dyrk1A; further attempts aimed at
optimization of the drug-like properties, such as water
solubility and LogP. To achieve this, two main types of
modifications were planned: the first one was to replace the
phenyl ring in b1 with an alkyl chain linked to a basic alicyclic
amine like morpholine and N-methyl piperazine. This is
represented by the 6-methoxy precursors a5 and a6,
respectively. Unfortunately, the unsuccessful O-demethylation
of both compounds hampered testing the effect of such a
modification. However, the inhibition noted for these two
precursors at 0.5 µM did not indicate a potential advantage
over the other modifications presented in Table 1. The second
approach was to extend compound b1 through amide
derivatives arising from the phenyl ring. Two amide derivatives
offering diverse possible interactions with the binding site
were prepared: the benzyl amide b4 and the methyl piperazine
amide b5. Although the extension with the 4-benzyl amide in
compound b4 enhanced the potency toward Dyrk1A (IC50=
0.063 µM) by more than 2-fold compared with b1 and AHS-
211, it did not show any improvement in selectivity over
Dyrk1B (Table 2). On the other hand, compound b5 was almost
similar to AHS-211 in potency against Dyrk1A, yet, it showed
more than 15 fold selectivity for Dyrk1A over Dyrk1B.
Importantly, both b4 and b5 displayed superior selectivity for
Dyrk1A over Dyrk2 when compared with AHS-211.
Cpd#
a1
X
Y
-NH-
8
0
a3
a4
a5
a6
-NH-
-O-
19.6
13.3
13.8
20.3
12
0
-NH-
-NH-
0
0
a7
a8
-CH2-
-NH-
21.2
25.5
25
0
a9
-NH-
30.5
0
N
N
C
O
a10
-NH-
28.1
0
aValues are mean values of at least two independent experiments each were done in
duplicates; standard deviation <10%. The ATP concentration in the assay was 15 µM.
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Table 2. Inhibition of Dyrk1A, Dyrk1B and Dyrk2 by the phenolic analogues.
HO
S
O
Ar
N
N
X
H
Dyrk1A
Dyrk1B
Dyrk2
Selectivity
Factorc
%
Cpd#
X
Ar
% inhibition
at 0.5 µMa,b
% inhibition
at 0.5 µMa,b
IC50µMa,b
IC50µMa,b
inhibition
at 5 µMa,d
b1
b2
b3
-NH-
-O-
80.8
0
0.163
ND
43.6
0
0.710
ND
4.3
40.4
18.6
50.1
-
-
-CH2-
37.8
89.8
ND
0
ND
b4
b5
-NH-
-NH-
0.063
69
0.130
2.1
38.1
99.1
74.4
0.095
0.134
21
1.513
0.370
16
34.5
64.7
AHS-211 -NH-
54.6
2.8
aValues are mean values of at least two independent experiments each were done in duplicates; standard deviation <10%; bthe assay was carried out at ATP conc. of 15 µM;
cSelectivity factor: IC50 (Dyrk1B) / IC50 (Dyrk1A); d the assay was carried out at ATP conc. of 100 µM
As compound b5 was more selective over Dyrk1B, it was Additionally, b5 displayed good selectivity for Dyrk1A over
selected for an extended selectivity profiling against all kinases Clk1, one of the most common off targets of many reported
that were frequently reported as being co-inhibited by Dyrk1A inhibitors, with a selectivity factor >7 (IC50 of b5 against
previously published Dyrk1A inhibitor classes (Table 3).16-18 Clk1 = 730 nM, [ATP] = 15 µM).
This profiling revealed that our combination of modifications Because of its marked selectivity and good potency, we aimed
led to a significant increase in selectivity compared with the at analyzing the metabolic stability of b5 against human
previously published benzothiazole-based Dyrk1A inhibitors hepatic CYP enzymes. Compared to testosterone, which was
such as INDY, which strongly inhibited, among other kinases, included as a reference known to be rapidly metabolized, b5
Dyrk2, PIM1 and CK1δ.12
showed a promising stability (half-life >60 min, Table 4). It is
worth mentioning that at 60 min incubation time, 88% of the
initial compound concentration could be still detected.
Table 4. Metabolic stability of compounds 4b and 5b against
human CYP enzymes
Table 3. Selectivity profile of b5 vs. the related kinasesa
.
%
%
Kinase
inhibition
at 5 µM
2±1
Kinase
inhibition
at 5 µM
1±1
Cpd.
Half-life [min]a
CDK5/p25
CLK1
Haspin
PIM1
b4
b5
33
>60
9.6
72±0.5
9±2
29±2.5
5±0.5
45±3
Testosteroneb
CK1δ
SRPK1
aIncubation with pooled human liver S9 fraction at 37ºC; samples taken at 0, 15,
30, 60 min, determination of the parent compound by MS. bReference
compound with low metabolic stability.
HIPK1 (Myak)
NTRK2 (TRKB)
Dyrk1A
50±0.5
13±1
MLCK (MLCK2)
STK17A (DRAK1)
39±0
85±0.5
aValues are mean values of at least two duplicates; testing was done at an ATP
These data were encouraging, suggesting that b5 might also be
applicable in in vivo models. As it was expected, compound b4
exhibited lower, yet, appreciable stability toward hepatic CYP
concentration of 100 µM.
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enzymes with a metabolic half-life of 33 min which is mostly homologous Dyrk2 isoform and even showed a remarkable 15
attributed to the presence of the unsubstituted benzyl group fold selectivity over the most closely related isoform Dyrk1B.
(Table 4).
In addition, the activity toward the atypical kinase haspin that
Next we aimed at identifying the putative binding mode of b5 was strongly inhibited by most of the previously reported
to Dyrk1A in order to explain its high potency and selectivity. Dyrk1A inhibitors was completely abolished with b5. Together
To this end, we employed molecular docking to Dyrk1A with the favorable balance of lipophilic/hydrophilic functions,
coordinates derived from a co-crystal structure with a 5- further testing of b5 as a potential agent for the treatment of
hydroxy benzothiazole fragment (PDB code: 5A3X). Thus, we Dyrk1A-related neuropathological disorders can be envisaged.
anticipated that any realistic docking pose should exhibit a
significant overlap with the original co-crystallized fragment;
A
this was the case with the docking pose showing the highest
F170
score (depicted in Figure 3). Another criterion for plausibility
V173
was that b5 was binding in the H-bond–stabilized low energy
conformation, which was in full agreement with the observed
structure-activity relationships and the ab initio calculations.
The docking model predicts several classical and non-classical
H-bonds contributing to the binding affinity inside the ATP
pocket (Figure 3A). Of note, because of the shifted position,
the 6-hydroxy function was only acting as an HBD, thus
explaining the loss of potency seen with the methoxy
precursors.
F238
K188
V306
L241
D287
Noteworthy, Rothweiler et al. had identified an alternative
binding mode, inverted by 180°, with a 5-methoxybenzo-
thiazole fragment in the ATP binding pocket of Dyrk1A.13 Using
the corresponding crystal structure coordinates (PDB: 5A4E)
we also evaluated the possibility of an inverted binding mode
B
F238
K188
for our best compound b5
. Indeed, we found that
theoretically, binding of b5 might also occur in a flipped
orientation, with the hydroxyl then forming an H-bond with
Asp307 (Figure S1, Supporting Information). However, we
considered this inverted pose to be less likely, because it did
not well explain the drop of potency observed with the
methoxy precursor a10 (28% inhibition at 0.5 µM, Table 1).
With a10, the H-bond interaction in the hypothetical flipped
mode simply switched from Asp307 to Lys188, now with the
methoxy oxygen as acceptor (not shown). Thus, the binding
pose shown in Figure S1, although it cannot be totally ruled
out, would predict a comparable potency for b5 and a10, in
contrast to our experimental results.
Figure 3: Predicted binding mode of b5 in the ATP binding pocket of Dyrk1A.
Compound b5 was docked to the Dyrk1A coordinates derived from the co-crystal
structure with 2-acetamido-5-hydroxy benzothiazole (PDB code: 5A3X) using MOE. The
pose with the highest score is depicted, showing binding of b5 (yellow) in the lowest
energy conformation of the scaffold (cf. c1, Figure 2). A. Inside the pocket, the ligand is
anchored via two crucial H-bonds involving the backbone carbonyl of the hinge region
residue Leu241, and the conserved Lys188 as a donor. Several CH-π and an NH-π
An important structural feature enhancing the selectivity over
Dyrk1B was the amide-linked N-methyl piperazine extension,
which was predicted to engage in an ionic interaction with
Asp287 in our model. Although this residue is conserved in interaction (with Phe238) additionally enhance the affinity. At the border of the pocket,
the protonated piperazine amine is predicted to form a salt bridge with Asp287. H-
Dyrk1B, it could be speculated that its position is slightly
bonds and ionic bonds are indicated by blue lines and H-π bonds by brown lines. B. Top
shifted in the Dyrk1B 3D structure, thus causing a less efficient
ionic interaction. Such a shift in the spatial position of the
corresponding Asp257 can be observed in the X-ray structures
of the homologous Dyrk2 (data not shown), however, it cannot
be verified with Dyrk1B due to the lack of a published 3D
structure.
view on the ATP binding pocket visualized by a transparent surface. The ligand is bound
as in A; through the central pseudo 6-membered ring, ideal shape complementarity to
the pocket is achieved.
Experimental section
Chemistry: Solvents and reagents were obtained from
commercial suppliers and used as received. A Bruker DRX 500
spectrometer was used to obtain 1H NMR and 13C NMR
spectra, in some cases Bruker Fourier 300 was used. The
chemical shifts are referenced to the residual protonated
solvent signals. At least 95% purity in all the tested compounds
Conclusion
Our design concept of attaching
a urea linker to the
benzothiazole core, followed by a scaffold expansion, led to a
new class of potent and selective Dyrk1A inhibitors. Of note,
the best compound, b5, did not appreciably inhibit the
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was obtained by means of HPLC coupled with mass
spectrometry. Mass spectra (HPLC-ESI-MS) were obtained
for synthesis of urea derivatives (method A) by the reaction of
2-amino-6-methoxybenzothiazole and phenylisocynate. White
o
1
using
a TSQ quantum (Thermo Electron Corporation)
solid; yield: 78%; mp 201-202 C; H NMR (500 MHz, DMSO) δ
10.64 (s, 1H), 9.12 (s, 1H), 7.55 (t, J = 9.2 Hz, 1H), 7.54 – 7.44
(m, 3H), 7.39 – 7.25 (m, 2H), 7.08 – 7.01 (m, 1H), 6.98 (dd, J =
8.8, 2.6 Hz, 1H), 3.80 (s, 3H); 13C NMR (126 MHz, DMSO) δ
157.32, 155.67, 151.73, 142.83,138.47, 132.48, 128.91, 122.88,
120.15, 118.75, 114.36, 104.92, 55.58; MS (ESI): m/z = 300.14
(M+H)+.
instrument prepared with a triple quadrupole mass detector
(Thermo Finnigan) and an ESI source. All samples were
inserted using an autosampler (Surveyor, Thermo Finnigan) by
an injection volume of 10 μL. The MS detection was
determined using a source CID of 10 V and carried out at a
spray voltage of 4.2 kV, a nitrogen sheath gas pressure of 4.0 X
105 Pa, a capillary temperature of 400 oC , a capillary voltage of
35 V and an auxiliary gas pressure of 1.0 X 105 Pa. The
stationary phase used was a RP C18 NUCLEODUR 100-3 (125 X
Ethyl 4-(3-(6-methoxybenzo[d]thiazol-2-yl)ureido)benzoate
(
a2). The title compound was prepared according to the
3
mm) column (Macherey-Nagel). The solvent system
general procedure for synthesis of urea derivatives (method A)
by the reaction of 2-amino-6-methoxybenzothiazole and 4-
(ethoxycarbonyl)phenylisocyanate. White solid; yield: 73%; mp
290-291 oC; 1H NMR (500 MHz, DMSO) δ 10.73 (s, 1H), 9.51 (s,
1H), 8.02 – 7.87 (m, 2H), 7.76 – 7.62 (m, 2H), 7.66 (d, J = 8.5 Hz,
2H), 6.99 (dd, J = 8.8, 2.6 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.80
(s, 3H), 1.31 (t, J = 7.1 Hz, 3H); MS (ESI): m/z = 372.02 (M+H)+.
consisted of water containing 0.1% TFA (A) and 0.1% TFA in
acetonitrile (B). HPLC-Method: flow rate 400 μL/min. The
percentage of B started at an initial of 5%, was increased up to
100% during 16 min, kept at 100% for 2 min, and flushed back
to 5% in 2 min. High resolution precise mass spectra were
recorded on Thermo Fisher Scientific (TF, Dreieich, Germany)
Q Exactive Focus system equipped with heated electrospray
ionization (HESI)-II source and Xcalibur software (version
4.0.27.19). Before analysis external mass calibration was done
according to the manufacturer’s recommendations. The
1-Phenyl-3-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)urea
(a3).
The title compound was prepared according to the general
procedure for synthesis of urea derivatives (method A) by the
reaction of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine and
samples were dissolved and diluted in methanol in
a
o
1
concentration of 3 μM and directly injected into the Q Exactive
Focus using the integrated syringe pump. All the data analyses
were done in positive ion mode using voltage scans and the
data collected in continuous mode. Melting points were
determined using a Mettler FP1 melting point apparatus and
are uncorrected.
phenylisocynate. White solid; yield: 88%; mp 153-154.5 C; H
NMR (500 MHz, DMSO) δ 11.34 (s, 1H), 9.11 (s, 1H), 8.72 (dd, J
= 4.4, 1.7 Hz, 2H), 7.88 (dd, J = 4.5, 1.7 Hz, 2H), 7.51 (d, J = 7.6
Hz, 2H), 7.42 – 7.25 (m, 2H), 7.16 – 6.98 (m, 1H); 13C NMR (126
MHz, DMSO) δ 161.25, 158.83, 151.37, 150.68, 138.21, 137.19,
128.94, 123.19, 120.53, 118.90; MS (ESI): m/z = 297.80 (M+H)
+
General procedure for synthesis of urea derivatives
.
Method A: A solution of the aryl amine (2 mmol) and the
respective isocyanate derivative (2.4 mmol) in DMF (10 mL)
was left to stir at room temperature for 3h. The product was
precipitated by adding a 50 mL of ice/water mixture then
purified with column chromatography.
1-(6-Methoxybenzo[d]thiazol-2-yl)-3-(2-
morpholinoethyl)urea (a5). The title compound was prepared
according to the general procedure for synthesis of urea
derivatives (method B) using 4-(2-aminoethyl)morpholine.
Beige solid; yield: 68%; mp 179-181 oC; H NMR (500 MHz,
1
Method B: To a solution of 6-methoxy-2-aminobenzothiazole
(0.36 gm, 2 mmol) in dioxane (6 mL) containing pyridine (179
µL, 2.22 mmol) phenyl chloroformate (0.25 mL, 2 mmol) was
added dropwise at room temperature. After 10 min, the
carbamate derivative a4 precipitated, then the corresponding
amine derivative (2 mmol) was added and the reaction mixture
was heated to 100°C for 5h. After cooling to room
temperature, the reaction mixture was diluted with ethyl
acetate and washed with water. The combined organic layers
were dried over anhydrous MgSO4 and concentrated under
reduced pressure. The residue was purified with column
chromatography to give the desired compounds. Compound
a4 was isolated by filtration in case of the carbamate is needed
as a product to be tested or for further demethylation.
DMSO) δ 10.64 (s, 1H), 7.52 – 7.48 (m, 1H), 7.47 (d, J = 2.6 Hz,
1H), 6.94 (dd, J = 8.8, 2.6 Hz, 1H), 6.77 (s, 1H), 3.78 (s, 3H), 3.64
– 3.54 (m, 4H), 3.28 (dd, J = 11.8, 6.1 Hz, 2H), 2.46 – 2.34 (m,
6H); 13C NMR (126 MHz, DMSO) δ 157.87, 155.46, 153.77,
143.22, 132.56, 120.12, 114.07, 104.80, 66.17, 57.27, 55.55,
53.11, 36.15; MS (ESI): m/z = 337.04 (M+H)+.
1-(6-Methoxybenzo[d]thiazol-2-yl)-3-(3-(4-methylpiperazin-1-
yl)propyl)urea
according to the general procedure for synthesis of urea
derivatives (method B) using 1-(3-aminopropyl)-4-
(a6). The title compound was prepared
o
1
methylpiperazine. White solid; yield: 61%; mp 192-194 C; H
NMR (500 MHz, DMSO) δ 10.76 (s, 1H), 7.47 (dd, J = 15.2, 5.7
Hz, 2H), 7.12 (s, 1H), 6.94 (dd, J = 8.8, 2.6 Hz, 1H), 3.78 (s, 3H),
3.42 – 3.31 (m, 4H), 3.17 (dd, J = 12.6, 6.5 Hz, 2H), 2.48 – 2.39
(m, 4H), 2.34 (dd, J = 17.2, 10.0 Hz, 2H), 2.25 (s, 3H), 1.66 –
1.56 (m, 2H); 13C NMR (126 MHz, DMSO) δ 157.78, 155.41,
150.70, 143.22, 132.59, 120.05, 114.01, 104.78, 62.59, 55.55,
54.89, 54.10, 52.01, 44.99, 26.44; MS (ESI): m/z = 363.99
(M+H)+.
Phenyl (6-methoxybenzo[d]thiazol-2-yl)carbamate (a4). The
carabmate derivative was isolated by filtration as mentioned
above. White solid; yield: 88%; mp >300 oC; 1H NMR (500 MHz,
DMSO) δ 9.34 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 2.6
Hz, 1H), 7.49 – 7.43 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.35 – 7.25
(m, 2H), 7.02 (td, J = 8.7, 2.6 Hz, 1H), 3.80 (s, 3H); MS (ESI):
m/z= 301.12 (M+H)+.
N-(6-Methoxy-benzothiazol-2-yl)-2-(3-methoxy-phenyl)-
acetamide (a7). 3-methoxyphenylacetyl chloride (0.18 g, 1
1-(6-Methoxybenzo[d]thiazol-2-yl)-3-phenylurea (a1).The title
mmol) was added gradually to a stirred solution of 6-methoxy-
2-aminobenzothiazole (0.16 g, 1 mmol) and Na2CO3 (0.16 g, 1.5
compound was prepared according to the general procedure
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COMMUNICATION
mmol) in acetone (20 mL) under ice cooling. The mixture was 3H), 3.48 (s, 4H), 2.35 (s, 4H), 2.22 (s, 3H); 13C NMR (126 MHz,
stirred at room temperature under a nitrogen atmosphere for DMSO) δ 168.74, 157.74, 155.71, 152.27, 141.75, 139.85,
2h then added to 100 mL of water/ice mixture, the solid 132.25, 129.78, 128.19, 119.84, 118.11, 114.41, 104.98, 55.58,
obtained was separated by filtration followed by column 54.41, 45.70, 45.43; MS (ESI): m/z = 426.03 (M+H)+.
chromatogrpahy purification to give the title compound as a General procedure for ether dealkylation. 1 M BBr3 solution in
1
white solid; yield : 82%; mp 151-152 °C; H NMR (500 MHz, CH2Cl2 (15 equiv) was added dropwise via syringe under
DMSO) δ 12.44 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 2.5 nitrogen to a stirred solution of the methyl ether derivative
Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.02 (dd, J = 8.8, 2.6 Hz, 1H), (1 equiv) in CH2Cl2 at -78 °C. Then the reaction was maintained
6.92 (dd, J = 9.4, 4.9 Hz, 2H), 6.84 (dd, J = 7.9, 2.2 Hz, 1H), 3.79 at -78 °C for 1 hour, after that allowed to reach room
(s, 3H), 3.77 (s, 2H), 3.75 (s, 3H); 13C NMR (126 MHz, DMSO) δ temperature and stirred for an additional 20h. The mixture
169.72, 159.24, 156.11, 155.83, 142.57, 136.13, 132.71, was cooled to 0 °C and H2O was carefully added (15-25 mL).
129.42, 121.47, 121.10, 115.11, 114.89, 112.23, 104.68, 55.57, The product was then repeatedly extracted with EtOAc and the
54.97, 41.83; MS (ESI): m/z = 329.19 (M+H)+.
organic layers were dried over anhydrous Na2SO4. Upon
4-(3-(6-Methoxybenzo[d]thiazol-2-yl)ureido)benzoic acid
(
a8). solvent removal the residue was purified by column
The compound was prepared by alkaline ester hydrolysis of chromatography.
compound a2 where 2M aqueous potassium hydroxide 1-(6-hydroxybenzo[d]thiazol-2-yl)-3-phenylurea (b1).The title
solution (10 mL) was added to a stirred solution of a2 (1mmol) compound was prepared by demethylation of compound a1
in THF (50 ml). After stirring at room temperature for 14h the according to the general procedure for ether dealkylation. Off-
1
solvent was evaporated under reduced pressure. The residue white solid; yield: 83%; mp 260-262 °C; H NMR (500 MHz,
was diluted with water (20 mL) and the solution was acidified CDCl3) δ 10.57 (s, 1H), 9.44 (s, 1H), 9.12 (s, 1H), 7.54 – 7.40 (m,
using 2M HCl. The product was extracted with ethylacetate (3 3H), 7.33 (t, J = 7.9 Hz, 2H), 7.23 (d, J = 2.2 Hz, 1H), 7.03 (dd, J =
x 15 ml). The organic layers were combined and dried over 17.6, 10.3 Hz, 1H), 6.84 (dd, J = 8.7, 2.4 Hz, 1H); MS (ESI): m/z =
MgSO4 followed by evaporation of solvent under reduced 286.08 (M+H)+ HRMS m/z = 286.0627 (calculated = 286.0645).
;
pressure to give the crude product that was used directly for Phenyl (6-hydroxybenzo[d]thiazol-2-yl)carbamate (b2). The
the next steps without further purification. White solid; yield: title compound was prepared by demethylation of compound
1
93%; mp 284-286 °C; ); H NMR (300 MHz, DMSO) δ 11.10 (s, a4 according to the general procedure for ether dealkylation.
1
1H), 10.41 (s, 1H), 7.93 (t, J = 6.0 Hz, 2H), 7.67 (d, J = 8.8 Hz, White solid; yield: 68%, mp 119-120 °C; H NMR (300 MHz,
2H), 7.59 (d, J = 8.8 Hz, 1H), 7.52 (t, J = 4.0 Hz, 1H), 6.99 (dd, J = DMSO) δ 12.36 (s, 1H), 9.52 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H),
8.8, 2.6 Hz, 1H), 3.81 (s, 3H); MS (ESI): m/z = 343.95 (M+H)+.
7.45 (dt, J = 10.6, 2.2 Hz, 2H), 7.35 – 7.24 (m, 4H), 6.88 (dd, J =
General procedure for amide synthesis. The appropriate 8.7, 2.5 Hz, 1H); MS (ESI): m/z = 286.98 (M+H)+; HRMS m/z =
amine (4 equiv) was added dropwise to the solution of the 287.0466 (calculated = 287.0485).
benzoic acid derivative (a8) (0.34g, 1 mmol), HBTU (0.57 g, 1.5 N-(6-Hydroxybenzo[d]thiazol-2-yl)-2-(3-
mmol) and TEA (0.5 mL) in DCM (20 mL). The reaction mixture hydroxyphenyl)acetamide
(b3). The title compound was
was stirred at room temperature overnight. The solvent was prepared by demethylation of compound a7 according to the
evaporated under reduced pressure. The residue was general procedure for ether dealkylation. Beige powder; yield:
1
partitioned between 50 mL of ethyl acetate and 20 mL of 70 %; mp 227-228 °C; H NMR (500 MHz, DMSO) δ 12.36 (s,
water, and the aqueous layer was extracted with 20 mL of 1H), 9.52 (s, 1H), 9.37 (s, 1H), 7.54 (dd, J = 8.5, 5.9 Hz, 1H), 7.26
ethyl acetate (over 3 times). The combined organic extracts (q, J = 2.5 Hz, 1H), 7.09 (dt, J = 25.2, 12.8 Hz, 1H), 6.92 – 6.81
were dried over anhydrous MgSO4, the solvent was removed (m, 1H), 6.81 – 6.71 (m, 2H), 6.65 (ddd, J = 8.1, 2.3, 1.1 Hz, 1H),
under reduced pressure, and the product was purified by 3.68 (s, 2H); 13C NMR (126 MHz, DMSO) δ 169.68, 157.32,
column chromatography to give the descried amide derivative. 154.93, 154.15, 141.53, 136.04, 132.70, 129.34, 121.07,
N-benzyl-4-(3-(6-methoxybenzo[d]thiazol-2-
yl)ureido)benzamide
a9). The title compound was prepared 301.15 (M+H)+ HRMS m/z = 301.0622 (calculated = 301.0641).
according to the general procedure for amide synthesis using N-Benzyl-4-(3-(6-hydroxybenzo[d]thiazol-2-
119.80, 116.03, 115.19, 113.81, 106.45, 41.85; MS (ESI): m/z =
(
;
1
benzylamine. White solid; yield : 64%; mp 284-286 °C; H NMR yl)ureido)benzamide (b4). The title compound was prepared
(300 MHz, DMSO) δ 10.76 (s, 1H), 9.39 (s, 1H), 8.94 (t, J = 5.9 by demethylation of compound a9 according to the general
Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.67 – 7.50 (m, 4H), 7.36 – 7.30 procedure for ether dealkylation. Light brown solid; yield: 73%;
(m, 4H), 7.25 (dq, J = 6.0, 4.1 Hz, 1H), 7.00 (dd, J = 8.8, 2.6 Hz, mp 200-201 °C; 1H NMR (500 MHz, DMSO) δ 10.75 (s, 1H), 9.47
1H), 4.49 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H); MS (ESI): m/z= 433.04 (s, 1H), 9.42 (s, 1H), 8.95 (t, J = 6.0 Hz, 1H), 7.89 (d, J = 8.8 Hz,
(M+H)+.
2H), 7.60 (d, J = 8.6 Hz, 2H), 7.53 – 7.40 (m, 1H), 7.36 – 7.28 (m,
4H), 7.28 – 7.19 (m, 2H), 6.85 (dd, J = 8.7, 2.5 Hz, 1H), 4.48 (d, J
1-(6-methoxybenzo[d]thiazol-2-yl)-3-(4-(4-methylpiperazine-
1-carbonyl)phenyl)urea
(
a10). The title compound was = 6.0 Hz, 2H);13C NMR (126 MHz, DMSO) δ 165.60, 154.88,
prepared according to the general procedure for amide 154.21, 147.81, 140.37, 139.82, 131.12, 128.30, 128.23,
synthesis using N-methylpiperazine. White solid; yield : 72%; 127.17, 126.66, 122.55, 117.72, 115.32, 114.81, 112.70,
mp 284-286 °C; 1H NMR (500 MHz, DMSO) δ 10.83 (s, 1H), 9.41 106.70, 42.53; MS (ESI): m/z = 418.97 (M+H)+ HRMS m/z =
;
(s, 1H), 7.57 (ddd, J = 11.9, 6.6, 3.6 Hz, 3H), 7.52 (d, J = 2.6 Hz, 419.1149 (calculated = 419.1172).
1H), 7.41 – 7.33 (m, 2H), 6.99 (dd, J = 8.8, 2.6 Hz, 1H), 3.79 (s,
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COMMUNICATION
MedChemComm
D. Dombkowski, A. K. Bhan, R. Roychoudhuri, N. P. Restifo
and J. J. O'Shea, Elife, 2015, 4.
1-(6-Hydroxybenzo[d]thiazol-2-yl)-3-(4-(4-methylpiperazine-
1-carbonyl)phenyl)urea
(b5). The title compound was
7.
8.
9.
U. Soppa, J. Schumacher, T. Pasqualon, W. Becker, O. V.
Florencio and F. J. Tejedor, Cell Cycle, 2014, 13, 2084-
2100.
K. M. Ori-McKenney, T. Li, S. Meltzer, L. Y. Jan, R. J.
McKenney, R. D. Vale, H. H. Huang, A. P. Wiita and Y. N.
Jan, Neuron, 2016, 90, 551-563.
prepared by demethylation of compound a10 according to the
general procedure for ether dealkylation. White solid; yield:
48%; mp 153-155 °C; 1H NMR (300 MHz, DMSO) δ 10.80 (s,
1H), 9.46 (s, 1H), 9.39 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.46 (d, J
= 8.6 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 2.3 Hz, 1H),
6.84 (dd, J = 8.6, 2.4 Hz, 1H), 3.51 (s, 4H), 2.36 (s, 4H), 2.22 (s,
F. J. Tejedor and B. Hammerle, FEBS J., 2011, 278, 223-
235.
3H); MS (ESI): m/z = 412.03 (M+H)+ HRMS m/z = 412.1415
;
(calculated = 412.1438).
10.
11.
W. Becker, Cell Cycle, 2012, 11, 3389-3394.
M. Muraki, B. Ohkawara, T. Hosoya, H. Onogi, J. Koizumi,
T. Koizumi, K. Sumi, J.-i. Yomoda, M. V. Murray, H. Kimura,
K. Furuichi, H. Shibuya, A. R. Krainer, M. Suzuki and M.
Hagiwara, J. Biol. Chem. , 2004, 279, 24246-24254.
Y. Ogawa, Y. Nonaka, T. Goto, E. Ohnishi, T. Hiramatsu, I.
Kii, M. Yoshida, T. Ikura, H. Onogi, H. Shibuya, T. Hosoya,
N. Ito and M. Hagiwara, Nat. Commun., 2010, 1, 86.
U. Rothweiler, W. Stensen, B. r. O. Brandsdal, J. Isaksson,
F. A. Leeson, R. A. Engh and J. S. M. e. Svendsen, J. Med.
Chem., 2016, 59, 9814-9824.
C. Schmitt, P. Miralinaghi, M. Mariano, R. W. Hartmann
and M. Engel, ACS Med. Chem. Lett., 2014, 5, 963-967.
A. Spadaro, M. Negri, S. Marchais-Oberwinkler, E. Bey and
M. Frotscher, PLOS ONE, 2012, 7, e29252.
T. Tahtouh, J. M. Elkins, P. Filippakopoulos, M.
Soundararajan, G. Burgy, E. Durieu, C. Cochet, R. S.
Schmid, D. C. Lo, F. Delhommel, A. E. Oberholzer, L. H.
Pearl, F. Carreaux, J.-P. Bazureau, S. Knapp and L. Meijer,
J. Med. Chem., 2012, 55, 9312-9330.
Biological assays. Protein Kinase Assays were done exactly as
described before,14 except that the ATP concentration were
varied as indicated in the legends. Metabolic stability assay is
described in the Supporting Information.
12.
13.
Molecular modeling. Ab initio calculations of the equilibrium
conformer of AHS-211 and energy levels were carried out as
previously described.19 Molecular docking simulations of the
b5 binding to human Dyrk1A (extracted from PDB entries 5A3X
or 5A4E, respectively) were performed as previously
described.20
14.
15.
16.
Conflicts of interest
The authors declare no competing interest.
17.
18.
J. Bain, H. McLauchlan, M. Elliott and P. Cohen, Biochem.
J., 2003, 371, 199-204.
G. D. Cuny, M. Robin, N. P. Ulyanova, D. Patnaik, V. Pique,
G. Casano, J.-F. Liu, X. Lin, J. Xian, M. A. Glicksman, R. L.
Stein and J. M. G. Higgins, Bioorg. Med. Chem. Lett., 2010,
20, 3491-3494.
P. Miralinaghi, C. Schmitt, R. W. Hartmann, M. Frotscher
and M. Engel, ChemMedChem, 2014, 9, 2294-2308.
A. K. ElHady, M. Abdel-Halim, A. H. Abadi and M. Engel, J.
Med. Chem., 2017, 60, 5377-5391.
Acknowledgment
The support by the Deutsche Forschungsgemeinschaft (DFG)
(EN381/2-3) to ME is greatly acknowledged. We thank Mariam
G. Tahoun (Helmholtz Institute for Pharmaceutical Research
Saarland) for carrying out the metabolic stability studies.
19.
20.
Notes and references
1.
2.
W. Becker and W. Sippl, FEBS J., 2011, 278, 246-256.
W. Becker, Y. Weber, K. Wetzel, K. Eirmbter, F. J. Tejedor
and H.-G. Joost, J. Biol. Chem., 1998, 273, 25893-25902.
J. Wegiel, K. Dowjat, W. Kaczmarski, I. Kuchna, K. Nowicki,
J. Frackowiak, B. Mazur Kolecka, J. Wegiel, W. P.
Silverman, B. Reisberg, M. deLeon, T. Wisniewski, C.-X.
Gong, F. Liu, T. Adayev, M.-C. Chen-Hwang and Y.-W.
Hwang, Acta Neuropathol. , 2008, 116, 391-407.
3.
4.
5.
F. Liu, Z. Liang, J. Wegiel, Y.-W. Hwang, K. Iqbal, I.
Grundke-Iqbal, N. Ramakrishna and C.-X. Gong, FASEB J.,
2008, 22, 3224-3233.
R. Kimura, K. Kamino, M. Yamamoto, A. Nuripa, T. Kida, H.
Kazui, R. Hashimoto, T. Tanaka, T. Kudo, H. Yamagata, Y.
Tabara, T. Miki, H. Akatsu, K. Kosaka, E. Funakoshi, K.
Nishitomi, G. Sakaguchi, A. Kato, H. Hattori, T. Uema and
M. Takeda, Hum. Mol. Genet. , 2007, 16, 15-23.
6.
B. Khor, K. L. Conway, R. J. Xavier, J. D. Gagnon, L. N.
Aldrich, T. B. Sundberg, M. Schirmer, A. F. Shamji, S. L.
Schreiber, G. Goel, M. I. Roche, B. D. Medoff, K. Tran, P. H.
Tan, S. Y. Shaw, A. M. Paterson, A. H. Sharpe, S. Mordecai,
8 | MedChemComm., 2018, 00, 1-3
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DOI: 10.1039/C8MD00142A
hydroxyl
inspired by
INDY
HO
H
R
O
N
N
pseudo 6-membered
ring structure
S
N
H
O
N
HO
H
OH
H
N
N
optimisation
N
HO
N
N
S
O
N
H
S
O
N
H
AHS-211
b5
Discovered hit (in-house liberary)
Dyrk1A IC50 = 95 nM
Dyrk1B IC50 = 1513 nM
Dyrk1A IC50 = 134 nM
Dyrk1B IC50 = 370 nM