1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological evaluation

Article abstract of DOI:10.1016/j.bmcl.2019.04.049

Glycogen synthase kinase 3 (GSK-3)has become known for its multifactorial involvement in the pathogenesis of Alzheimer's disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3β, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC₅₀ = 0.086 ± 0.023 μM)and halomethylketone-substituted benzimidazolylurea 9b (IC₅₀ = 0.13 ± 0.060 μM)displayed high GSK-3β inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC₅₀ = 0.072 ± 0.043)in our assay. The results suggest further investigation of 2b and 9b as potential covalent inhibitors of GSK-3β, since a targeted interaction might provide improved kinase-selectivity.

Full text of DOI:10.1016/j.bmcl.2019.04.049

Accepted Manuscript
1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase
kinase 3 inhibitors: Synthesis and biological evaluation
Jana Venter, Concepción Perez, Willem A.L. van Otterlo, Ana Martínez,
Margaret A.L. Blackie
PII:
S0960-894X(19)30281-1
https://doi.org/10.1016/j.bmcl.2019.04.049
BMCL 26416
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
26 March 2019
25 April 2019
27 April 2019
Please cite this article as: Venter, J., Perez, C., van Otterlo, W.A.L., Martínez, A., Blackie, M.A.L., 1-Aryl-3-(4-
methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological
evaluation, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.04.049
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Bioorganic & Medicinal Chemistry Letters
1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase
kinase 3 inhibitors: Synthesis and biological evaluation
Jana Ventera, Concepción Perezb, Willem A. L. van Otterloa, Ana Martínezc, Margaret A. L. Blackiea
aDepartment of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch 7602, South Africa
bInstituto de Quimica Medica-CSIC, Juan de la Cierva 6, 28003 Madrid, Spain
cCentro de Investigaciones Biológicas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Glycogen synthase kinase 3 (GSK-3) has become known for its multifactorial involvement in
the pathogenesis of Alzheimer’s disease. In this study, a benzothiazole- and benzimidazole set of
1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent
inhibitors of GSK-3β, through the incorporation of an electrophilic warhead onto their ring
scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC50 = 0.086 ± 0.023 µM) and
halomethylketone-substituted benzimidazolylurea 9b (IC50 = 0.13 ± 0.060 µM) displayed high
GSK-3β inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC50= 0.072 ±
0.043) in our assay. The results suggest further investigation of 2b and 9b as potential covalent
inhibitors of GSK-3β, since a targeted interaction might provide improved kinase-selectivity.
Keywords:
Glycogen synthase kinase 3
Alzheimer’s disease
Targeted covalent inhibitor
Cysteine 199
2019 Elsevier Ltd. All rights reserved.
Ureas
As the most prevalent form of dementia, Alzheimer’s disease
(AD) is defined as a progressive neurodegenerative disease with
clinical symptoms of memory loss and cognitive decline, which
is characterised at the molecular level by deposits of intracellular
neurofibrillary tangles (NFTs) and extracellular β-amyloid (Aβ)
plaques in the brain.1 The global impact of dementia was
analysed by Alzheimer’s Disease International in the World
Alzheimer Report of 2015, which stated that the number of
dementia cases would increase from 46.8 million to 74.7 million
by 2030.2 There is currently no cure for AD, and thus far only
palliative drugs have successfully reached the market.3
nerve cells. Tau hyperphosphorylation thus destabilises
association, which result in microtubule degeneration and the
aggregation of tau proteins to form NFTs.11,12 Recent years in
GSK-3β inhibitor development were focused on preclinical
efforts to address issues involving toxicity and selectivity.13
AD drug discovery is challenging since the risk factors and
molecular mechanisms of AD development are multifactorial and
not fully understood.4,5 The development of disease-modifying
therapeutics (DMTs), which can intervene in primary molecular
mechanisms of AD to prevent or delay the onset/progression of
the disease, is priority.6 Glycogen synthase kinase 3 (GSK-3) is a
promising CNS drug target, since dysregulated GSK-3 activity
plays a central role in AD development and provides a link
between Aβ plaques, NFTs, inflammatory responses and reduced
cholinergic transmission.7,8
Figure 1. GSK-3β inhibitors, AR-A014418 (1, AstraZeneca14) and
its non-toxic benzothiazole derivative (2a, Lo Monte et al.15)
Protein kinases display high sequence conservation in the
ATP binding site, therefore kinase inhibitors should display high
kinase-selectivity.7 In 2003, AstraZeneca reported the potent
activity (IC50 = 104 nm) and high selectivity of the novel GSK-3
inhibitor, AR-A014418 (1).14 This reversible ATP-competitor did
not significantly inhibit CDK-2, CDK-5, or the rest of the 26
protein kinases which were assayed. In subsequent work, Lo
Monte et al. showed that when the thiazole ring of AR-A014418
was replaced with a pyridine or benzothiazole ring structure, the
toxicity of the compound diminished in a zebrafish embryo
phenotype assay.15 Their benzothiazole derivative 2a had a GSK-
3 inhibition potency comparative to AR-A014418 (1).
Mammalian GSK-3 exists in two homologous isoforms,
known as GSK-3α (51 kDa) and GSK-3β (47 kDa), which share
98% amino acid sequence similarity in their catalytic domain.9
GSK-3β has been identified as a key kinase responsible for
abnormal tau hyperphosphorylation in AD.10 Tau proteins are
microtubule-associated proteins (MAP) which associate to
tubulin in order to stabilise cytoskeletal microtubules in CNS

Martínez and co-workers were the first to describe irreversible
GSK-3β inhibitors, which covalently target Cys199, as a strategy
to improve selectivity and to obtain high potency.16 The ATP
binding pocket of GSK-3 uniquely contains a Cys199 residue,
which is not conserved in structurally-related kinases.16 Martínez
and co-workers successfully switched reversible GSK-3β
inhibitors into irreversible GSK-3β inhibitors, by using an
electrophilic moiety which can target Cys199.17 Recently this
hypothesis has been confirmed by X-ray crystallography.18
Figure 2. The urea functionality of 9a formed two hydrogen
bonds with hinge residue Val135, and weaker aromatic hydrogen
bonds with Tyr134 and Asp133. The Cα atom of the HMK
moiety was situated 4.5 Å from the sulfur atom of Cys199.
Compound 9b docked similarly, but the imidazole moiety
allowed for one additional hydrogen bond with the hinge region,
as well as an intramolecular hydrogen bond with the urea
carbonyl oxygen.
The synthesis of the benzothiazole 4 and benzimidazole 5
Our aim was to transform the non-toxic, selective, reversible
GSK-3β inhibitor 2a into a Cys199-targeted covalent inhibitor.
Different electrophilic warheads would be explored and
incorporated onto the ring structure, with the potential to form a
covalent bond with Cys199 in the GSK-3 ATP pocket. Thus, a
small library of 1-aryl-3-(4-methoxybenzyl)ureas was designed
and synthesised, in which the aryl scaffold structure was either a
benzothiazole or a benzimidazole ring. The biological activities
heterocycles are depicted in Scheme 1. Cyano-substituted
benzothiazole 4a was synthesised via
a
thiocyanated
intermediate, using a modified conventional procedure.19 The
stoichiometric control in the reaction was improved, by use of an
organic ammonium tribromide as bromine source.20 Thus, 4-
aminobenzonitrile (3a) was thiocyanated with KSCN in glacial
acetic acid, utilising phenyltrimethylammonium tribromide
(PhNMe3Br3)
as
the
oxidant.
The
4-amino-3-
thiocyanatobenzonitrile intermediate was isolated and cyclised
with NaH in THF under reflux to yield 4a. A better cyclisation
yield was obtained in basic conditions, than in previously
described acidic conditions.
9a
The 2-aminobenzothiazoles 4b-d were synthesised in one-pot
reactions in good to acceptable yields, since these reactions
proceeded with fewer by-products and displayed spontaneous
cyclisation alongside the thiocyanation step. Thus, the substituted
anilines 3b-d were treated with KSCN/ PhNMe3Br3 in glacial
acetic acid, and after 5 h of stirring at r.t., the crude mixture was
heated under reflux for 10 min to form the cyclised product.
The 2-aminobenzimidazoles 5a-c were synthesised in
accordance to published methods.21–24 The first three steps (ii –
iv) entailed acylation of the free amine, nitration ortho of the
protected amine and deprotection. We found mixed acid nitration
with equal volumes of 65% HNO3 and conc H2SO4 (1:1 v/v) to
be very convenient. Subsequently, the nitro group was reduced
with H2, Pd/C and the diamine cyclised with CNBr. The diamine
precursor of nitro-substituted benzimidazole 5d was purchased
and cyclised.
9b
of the compounds were also tested.
Molecular modelling studies with the proposed covalent
inhibitors were performed using the Maestro Schrödinger Drug
Figure 2. Binding interactions of HMK ligands 9a and 9b
with the GSK-3β ATP binding pocket. Dashed lines:
yellow—hydrogen bond, cyan—aromatic hydrogen bond,
purple—Cys199 target distance
Discovery Suite and the X-ray crystallographic structure of AR-
A014418 (1) in complex with GSK-3β (PDB ID: 1Q5K). The
proposed covalent inhibitors docked similarly to 1 along the
hinge region. The reversible docking modes of the
halomethylketone (HMK) inhibitors 9a and 9b are displayed in
Scheme 1. (i) 4a: 1. KSCN, glacial AcOH, PhNMe3Br3, 5 °C – rt,
5 h, 75%; 2. NaH, THF, reflux, 2 h, 85%. 4b-d: 1. KSCN, glacial
AcOH, PhNMe3Br3, 10 °C – r.t., 5 h, then reflux, 10 min, 54 –
81%. (ii) Ac2O, DCM, 83 – 97%. (iii) 5a: KNO3, conc. H2SO4,
−15 to −10 °C, 3.5 h, 69%. 5b-c: 65% HNO3/ conc. H2SO4 (1:1
v/v), 0 °C, 1 h, 69%, 90%. (iv) 1 M H2SO4, reflux, 2 h, 82 – 96%.
(v) H2, 10% Pd/C, EtOAc/MeOH, r.t., 90 – 99%. (vi) BrCN,
MeOH, H2O, CH3CN, r.t., 18 h, 87% – quant.

Scheme 2. (vii) 1. 4 M HCl in dioxane, DCM, r.t., 10 min; 2. CDI, DMF, 0 °C, 7 min, quant. yield. (viii) NaH, DMF, r.t., 22 h, 2a: 99%, 2b:
49%, 8a: 82%, 8b: 75%, 10a: 74%, 10b: 61%, 14a: quant., 14b: 57%. (ix) 9a: PhNMe3Br3, THF, 30 °C, 64 h, 35%. 9b: 1. TMSOTf, DCM,
DIPEA, 0 – 30 °C, 20 h; 2. NBS, THF, NaHCO3, −78 °C, 1.5 h, 48% (over 2 steps). (x) MeO(Me)NH·HCl, i-PrMgBr, THF, −20 °C to
–5 °C, 1 h, 11a: 81%, 11b: 78%. (xi) 1. vinylmagnesium bromide, THF, −20 °C to 15 °C, 20 h; 2. 1 M aq. NaHSO4, 0 °C, 12a: 26%, 12b:
11%. (xii) 1. ethynylmagnesium bromide, THF, −20 °C to 15 °C, 20 h; 2. 1 M aq. NaHSO4, 0 °C, 13a: 76%, 13b: 15%. (xiii) H2, 10% Pd/C,
DMF, MeOH, 60 °C, 4.5 h, 14a: 40%, 14b: 85%. (xiv) acryloyl chloride, THF, DMF, NEt3, 0 °C – r.t., 1.25 h, 16a: 54%, 16b: 40%.
As depicted in Scheme 2, the prepared heterocycles 4a–d, 5a–
d were next subjected to 4-methoxybenzylamine (6) through a
CDI-mediated coupling to form unsymmetrical disubstituted
ureas. The well-developed coupling methods of Batey and co-
workers,25,26 were extrapolated into this study to synthesise novel
compounds 2b, 8a–b, 10a–b, 14b, and to improve the literature
yields15 of 2a and 14a which were 70% and 26%, respectively, to
99% and a quantitative yield.
corresponding Weinreb amides in good yields.
A
MeO(Me)NH·HCl/i-PrMgBr system, inspired by the general
Weinreb preparation methods of Williams and co-workers,29 was
utilised. Unfortunately, the subsequent Grignard reactions
proceeded in generally low yields, but provided enough material
for further reactions.
Acrylamides 16a-b were synthesised in low to moderate
yields by catalytic hydrogenation of their 6-nitro precursors (14a-
b), and subsequent treatment of the free amines with acryloyl
chloride in THF and DMF.
To prevent symmetrical urea formation in the first step of
Scheme 2 (vii), the ammonium hydrochloride salt of 6 was
generated in situ using 4 M HCl in dioxane in DCM, whereafter
it was reacted with CDI for a shortened time of 7 min to yield the
electrophile, N-(4-methoxybenzyl) carbamoylimidazole (7) in a
quantitative yield.25 Compound 7 was reacted with the 6-
substituted 2-aminobenzothiazoles (4a–d) in a NaH/DMF system
over 22 h at r.t. to afford the 1-(6-substituted benzothiazol-2-yl)-
3-(4-methoxybenzyl)ureas (2a, 8a, 10a, 14a) in high to
quantitative yields. The similar synthesis of the 1-(6-substituted
benzimidazol-2-yl)-3-(4-methoxybenzyl)ureas (2b, 8b, 10b, 14b)
proved more challenging, with moderate yields proposedly due to
tautomeric effects in the benzimidazole ring moiety and thus the
weaker nucleophilic nature of the 2-aminobenzimidazoles (5a-d).
Compound 2a and newly synthesised compounds 2b, 8a-8b,
9a-b, 12a-b, 13a-b, 16a-b, were evaluated for GSK-3β inhibitory
activity using a luminescent assay (see Table 1). Potent GSK-3β
inhibitor AR-A014418 (1, synthesised according to known
procedure25) was used as reference standard.
The benzimidazole-derived compounds (Q = NH) were
generally better inhibitors than their benzothiazole equivalents
(Q= S), supposedly due to their ability to form one additional
hydrogen bond with the hinge region of the GSK-3β ATP pocket.
The most potent inhibitor in the library was 1-(6-cyano-1H-
benzo[d]imidazol-2-yl)-3-(4-methoxybenzyl)urea (2b) with an
IC50 value of 0.086 ± 0.023 μM, which compared well to the
reference inhibitor (1), which displayed an IC50 value of 0.072 ±
0.043 μM in our assay. The inhibitory ability of its benzothiazole
equivalent, 2a, is known in the literature.15
The ureas were further modified in position 6 of the benzazole
portion of the scaffolds, to incorporate the respective
electrophilic warheads. Compound 8a was α-brominated with
PhNMe3Br3 in THF, at 30 °C over 64 h, to afford HMK 9a with a
yield of 35%. To obtain regioselectivity and controlled α-
monobromination, 8b was brominated via its silyl enol ether
intermediate.27,28 The crude enol ether intermediate was treated
with NBS at −78 °C to yield HMK 9b in a 48% overall yield.
The benzimidazole-derived HMK, 9b, displayed satisfactory
inhibitory activity with an IC50 value of 0.13 ± 0.060 µM. The
HMK inhibitors 9a and 9b were more potent than their
corresponding acetyl-derivatives, 8a and 8b, confirming the
structure-activity influence of the halomethylketone moiety to
increase inhibitory activity. Furthermore, the biological activities
of the vinyl and ethynyl ketones (12a-b, 13a-b) were low,
Vinyl and ethynyl ketones 12a-b, 13a-b were prepared from
their ester precursors (10a-b) by converting the esters into their

whereas the acrylamides (16a-b) displayed insignificant
biological activity (Figure 3). This is most clearly observed in the
inhibition.
values obtained for the acrylamides 16a and 16b.
Table 1. The GSK-3β inhibitory activity (IC50) and results of
An initial GSK-3β time-dependent study, performed according
to the methods of Martínez and co-workers,17 suggested that
active compounds, nitrile 2b and HMK 9b, react in an
irreversible fashion. Berteotti et al have shown that such an
interaction is theoretically possible.30 As seen in Figure 4,
inhibitors 2b and 9b displayed increased inhibition percentage,
when the inhibitor was pre-incubated with the enzyme for a
longer time. These findings potentially support a covalent
interaction between the incorporated electrophilic warhead and
Cys199 in the GSK-3β ATP pocket. However, more extensive
studies are necessary to ascertain a Cys199-targeted covalent
interaction, and to confirm whether this interaction is irreversible
reversible docking studies of compounds produced in Scheme
2.
Substituent
Compd
IC50 (µM)
XP
Dist from
dock-ing
Gscore
reactive atom
to Cys 199
(kcal/mo
l)
(Å)
Nitrile
Acetyl
HMK
2a
0.11 ± 0.040
2.26 ± 0.41
0.77 ± 0.037
4.05 ± 0.39
-7.561
n.d.a
4.01
n.d.
8a
9a
-7.305
-7.305
4.45
5.53
Vinyl
12a
2b
ketone
0.1 μM
Ethynyl
ketone
13a
4.21 ± 0.33
>10
-7.206
-7.562
5.16
0.05 μM
Acrylamide
Nitrile
16a
2b
5.08
3.95
n.d.
0.086 ± 0.023 -9.089
Acetyl
8b
0.26 ± 0.030
0.13 ± 0.060
1.82 ± 0.22
n.d.
HMK
9b
-8.859
-9.338
4.73
3.84
Vinyl
ketone
12b
9b
Ethynyl
ketone
13b
2.47 ± 0.32
-8.596
5.15
0.2 μM
Acrylamide
Reference
16b
1
>10
-9.180
5.20
n.a.
0.072 ± 0.043 -7.005
0.05 μM
an.d. – not determined; b n.a. not applicable
The IC50 values were compared with the molecular modelling
studies. Both reversible and irreversible modes were examined.
There was no difference in the trend shown between the two
modes, so only the reversible modes are reported here, because
the distance from the reactive atom to the sulfur atom of the
cysteine was determined under the same conditions. The acetyl
derivatives were only included later in the study as they had to be
made on the route to the bromomethylketone derivatives.
on the biological timescale.
In this study, two sets of 1-aryl-3-(4-methoxybenzyl)ureas
were transformed into proposed Cys199-targeted covalent
inhibitors, by incorporation of an electrophilic warhead onto their
ring scaffolds. The compounds were designed by way of
modelling, synthesised and biologically evaluated. No clear
correlation was observed between the modelled interaction and
the biological inhibition observed. High GSK-3β inhibitory
activity was measured for inhibitors 2b and 9b. The potential
covalent interaction of these inhibitors with Cys199, a unique
residue in the GSK-3 ATP binding pocket, may potentially
provide enhanced kinase-selectivity which is highly desirable in
GSK-3 kinase inhibitors.
10
8
6
IC50
(µM)
4
2
Acknowledgments
0
-10.00
-9.00
Docking Score (kcal/mol)
B E N Z O T H I A Z O L E S B E N Z I M I D A Z O L E S
-8.00
-7.00
-6.00
This research was financially supported by the National
Research Foundation (Innovation Master’s Scholarship 2017 –
2018), Stellenbosch University and MINECO (grant no.
SAF2016-76693-R). We acknowledge the Central Analytical
Facilities (CAF) at Stellenbosch University for assisting with
Figure 3. Docking score (reversible binding) and biological activity
(IC50)
Figure 4. Time-dependent GSK-3β inhibition studies with
inhibitors 2b and 9b, respectively.
NMR, MS and UPLC-MS data.
Neither the docking score, nor the distance from the reactive
atom to Cys 199 was shown to correlate well with the observed

Supplementary Material
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found online at doi:
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Graphical Abstract
1-Aryl-3-(4-methoxybenzyl)ureas as
potentially irreversible glycogen synthase
kinase 3 inhibitors: Synthesis and biological
evaluation
Leave this area blank for abstract info.
Jana Venter, Concepción Perez, Willem A. L. van Otterlo, Ana Martínez, Margaret A. L. Blackie