Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration in tau-driven models of Alzheimer's disease

Article abstract of DOI:10.1016/j.ejps.2011.05.014

A novel series of 2-aminothiazoles with strong protection in an Alzheimer's disease (AD) model comprising tau-induced neuronal toxicity is disclosed. These derivatives can be synthesized in one-pot and a small SAR of the substitution within these series afforded several compounds that counteracted tau-induced cell toxicity at nanomolar concentrations. These congeners therefore have strong potential as possible treatment for Alzheimer's disease and other related tauopathies.

Full text of DOI:10.1016/j.ejps.2011.05.014

European Journal of Pharmaceutical Sciences 43 (2011) 386–392
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences
journal homepage: www.elsevier.com/locate/ejps
Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration
in tau-driven models of Alzheimer’s disease
Irene Lagoja a,1, Christophe Pannecouque b,1, Gerard Griffioen c, Stefaan Wera c,
Veronica Maria Rojasdelaparra c, Arthur Van Aerschot a,
⇑
a Laboratory for Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
b Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
c N.V. reMYND, Gaston Geenslaan 1, B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 2-aminothiazoles with strong protection in an Alzheimer’s disease (AD) model compris-
ing tau-induced neuronal toxicity is disclosed. These derivatives can be synthesized in one-pot and a
small SAR of the substitution within these series afforded several compounds that counteracted tau-
induced cell toxicity at nanomolar concentrations. These congeners therefore have strong potential as
possible treatment for Alzheimer’s disease and other related tauopathies.
Received 29 March 2011
Accepted 27 May 2011
Available online 2 June 2011
Keywords:
Ó 2011 Elsevier B.V. All rights reserved.
2-Aminothiazole
Hantzsch synthesis
Tauopathies
Alzheimer’s disease
Neuronal toxicity
Neurofibrillary tangles
1. Introduction
with b-secretase inhibitors (Citron, 2004; Dominguez et al., 2001)
or
c-secretase modulators (Garofalo, 2008; Serneels et al., 2009;
In view of the continuously rising life expectancy of mankind,
increasing numbers of patients with neurodegenerative diseases
are expected particularly in the western world. This has triggered
major research both at universities and in the pharmaceutical
industry, with efforts centered on delineating the underlying dis-
ease mechanisms as well as on the development of new therapeu-
tic treatments.
Weggen et al., 2001)] or aiming at increased Ab clearance using
antibodies (Gilman et al., 2005). However, where a large reduction
in Ab levels clearly can be attained, there seems to be a lack of sig-
nificant clinical effects, which has led some researchers to put the
amyloid cascade hypothesis into question (van Marum, 2009). Oth-
ers however argue the scientific basis for the hypothesis to remain
quite compelling (Aisen, 2009).
Generation of proteinaceous aggregates is a predominant path-
ological process in many common neurodegenerative diseases. In
AD, accumulation of b-amyloid plaques (Ab) (Suh and Checler,
2002) and neurofibrillary tangles comprising tau (Ballatore et al.,
2007) are major pathological hallmarks. Although the underlying
mechanisms of brain degeneration and cognitive impairment have
not been uncovered, it is nevertheless clear that the formation of
these aggregates is a noxious event responsible for neuronal de-
mise and ultimately death. Most therapeutic efforts have concen-
trated so far on modulation of Ab levels. Different strategies
hereto are available, with among others the use of anti-aggregation
molecules (Aisen et al., 2006), inhibitors of the processing of the
amyloid precursor protein leading to reduced Ab formation [either
Another self-aggregating protein involved in neurodegenerative
disorders is tau (Buee et al., 2000). Tau is an intracellular protein
with the ability to bind and consequently stabilize and define
microtubule structure and function. Apart from its physiological
function tau also plays a direct role in numerous neurodegenera-
tive disorders collectively known as ‘‘tauopathies’’ with the most
notable examples AD and Pick’s disease. Tauopathies are character-
ized by insoluble aggregates or polymers of tau which are formed
by self-polymerization of tau monomers. An important aspect of
tau-misfolding and subsequent aggregation is its inherent cytotox-
icity reducing cellular integrity or even triggering cell death. In
case of neurodegenerative diseases loss of affected neurons leads
to cognitive and/or motoric dysfunctioning. A direct role of tau in
disease onset has been established unequivocally by the elucida-
tion of familial mutations in tau which appear to be responsible
for a very early and sometimes aggressive form of tauopathy (Lee
et al., 2001). Such mutations lead to changes in the amino acid
⇑
Corresponding author. Tel.: +32 016 33 73 88; fax: +32 016 33 73 40.
E-mail address: arthur.vanaerschot@rega.kuleuven.be (A. Van Aerschot).
1
These authors contributed equally to this work.
0928-0987/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejps.2011.05.014

I. Lagoja et al. / European Journal of Pharmaceutical Sciences 43 (2011) 386–392
387
sequence of tau (e.g. P301L or R406W) promoting toxic aggrega-
2.4. General procedure for the preparation of thiazoles (3)
tion and thereby provoke loss of cellular integrity.
Treatments aimed to suppress cytotoxic tau pathology are pres-
ently not available. Thus there is a medical need for designing new
drugs for therapeutic treatments that target the underlying molec-
ular mechanism of tau related pathologies and toxicity such as in
AD. The present manuscript will highlight a short SAR study on a
series of 2-aminothiazoles, which proved to be endowed with a
remarkable potency in counteracting tau-induced cytotoxicity in
a human neuronal cell line model. In light of some recent publica-
tions wherein analogous but different structures based on the
same 2-aminothiazole scaffold were described as interesting ther-
apeutic leads for prion diseases (Gallardo-Godoy et al., 2011;
Ghaemmaghami et al., 2010) we felt it appropriate to communi-
cate our preliminary results on inhibition of tau-induced neuronal
toxicity.
A solution of the halocarbonyl compound 4 (3 mmol) and potas-
sium thiocyanate (0.44 g, 4.5 mmol) in methanol (10 ml) was stir-
red at ambient temperature for 30 min. Subsequently the
respective amine 5 was added drop wise (solution in 5 ml MeOH)
and the reaction mixture was heated under reflux overnight. After
reducing the volatiles to approximate 1 ml and cooling to ambient
temperature the precipitate was filtered off and washed with
water. Recrystallization from either ethanol/water (4:1) or ace-
tone/water (5:1) afforded the crystalline products 3. The purity
of the products was verified by TLC (ethyl acetate/petrol ether
1:3). In case the product did not crystallize from the reaction mix-
ture, the volatiles were removed. The obtained solid was treated
with water (5 ml) to remove inorganic impurities and extracted
with ethyl acetate. After drying the organic layer over Na2SO4
and removal of the solvent the desired products either crystallized
or could be obtained by flash-column chromatography (silica,
n-hexane/ethyl acetate 3:1) as a powder. Alternatively this modi-
fied Hantzsch synthesis can be carried out under microwave as-
sisted conditions, heating the mixture under reflux at 100 W/
80 °C for 60 min. Workup was carried out as described above.
2. Materials and methods
2.1. General
NMR spectra were recorded on a Bruker AM-300 spectrometer
(1H 300.12 MHz, 13C 75.47 MHz). All NH protons were assigned
by exchange with D2O. In case of AA’BB’ systems determination
of J is based on the assumption of an AB quartet (Becker, 1969).
Mass spectrometry was carried out on a Finnigan LC Duo spec-
trometer (FAB+, FAB-). The reactions were monitored by thin-layer
chromatography (TLC) analysis using silica gel plates (Kieselgel 60
2.4.1. 5-Methyl-N,4-diphenylthiazol-2-amine (3a)
Yield 85%; 1H NMR (DMSO-d6): d 2.43 (3H, s, 5-CH3), 6.89 (1H, t,
J = 7.3 Hz, 4-H NPh), 7.26–7.36 (3H, m, 2,4,6-H 4-Ph), 7.46 (2H, (t),
J ꢀ 7.5 Hz, 3,5-H 4-Ph), 7.64–7.68 (4H, m, 2,3,5,6H NPh), 10.06 (1H,
s, br, ex, NH); 13C NMR (DMSO-d6): d 117.3, 145.3, 159.4 (5, 4, 2C
thiazole); R1: 127.5, 128.4, 128.7, 135.1 (4C, 2,6C, 3,5C, 1C); R2:
12.4; R3: 117.3, 120.8, 129.4, 141.1 (2,6C, 3,5C, 4C, 1C); MS m/z
267 [M+H]+.
F
254, E. Merck). Compounds were visualized by UV irradiation. Col-
umn chromatography was performed on Silica Gel 60 M (0.040–
0.063 mm, E. Merck). Nomenclature of the obtained compounds
follows the rules of IUPAC and was checked with Autonome
(ACD-Chem-Sketch).
2.4.2. 5-Isopropyl-N,4-diphenylthiazol-2-amine (3b)
Yield 87%; 1H NMR (DMSO-d6): d 1.26, 1.27 (6H, d, J = 6.6 Hz,
2xCH3), 2.50 (1H, m, 5-CH), 6.91 (1H, t, J = 7.3 Hz, 4-H NPh), 7.28
(2H, (t), J ꢀ 7.6 Hz, 3,5H 4-Ph), 7.35 (1H, t, J = 7.3 Hz, 4-H 4Ph),
7.49 (2H, (t), J ꢀ 7.4 Hz, 3,5-H NPh), 7.58 (2H, d, J = 8.1 Hz, 2,6-H
4-Ph), 7.64 (2H, d, J = 8.1 Hz, 2,6-H NPh), 10.08 (1H, s, br, ex,
NH); 13C NMR (DMSO-d6): d 117.2, 144.5, 160.1 (5, 4, 2C thiazole);
R1: 127.7, 128.7, 129.4, 136.0 (4, 2,6, 3,5, 1C); R2: 26.0 (2xCH3), 27.4
(CH); R3: 117.2, 121.3, 131.0, 141.8 (2,6, 3,5, 4, 1C); MS m/z 295
[M+H]+.
2.2. Syntheses of precursor ketones from nitriles – general procedure
In a 2-neck flask equipped with a reflux condenser and a drop-
ping funnel, a suspension of magnesium (2.83 g, 0.12 mol) and al-
kyl bromide (0.12 mol) in dry ether were stirred under nitrogen
atmosphere. After addition of a crystal of iodine the reaction
started. After the reaction was completed a solution of the nitrile
(0.1 mol) in dry ether (15 ml) was added drop wise. Following
heating under reflux for 6 h the mixture was quenched with 6 N
H2SO4 ice (100 ml). To complete the hydrolysis of the ketimine,
the mixture was warmed and afterwards extracted with ether.
After removing the solvent, the resulting ketones were used with-
out further purification.
2.4.3. 4-(4-Fluorophenyl)-5-methyl-N-phenylthiazol-2-amine (3c)
Yield 82%; 1H NMR (DMSO-d6): d 2.40 (3H, s, 5-CH3), 6.91 (1H, t,
J = 7.3 Hz, 4-H NPh), 7.24–7.31 (4H, m, 2,6-H 4-Ar, 2,6H NPh), 7.64–
7.72 (4H, m, 3,5-H 4-Ar, 3,5-H NPh), 10.10 (1H, s, br, ex, NH); 13C
NMR (DMSO-d6): d 116.7, 144.6, 159.7 (5, 4, 2C thiazole); R1:
115.5, 115.8; 130.3, 130.4; 132.1, 132.15; 160.0, 163.2 (3,5, 2,6,
1, 4); R2: 12.4; R3: 117.1, 121.4, 130.3, 141.7 (2,6, 4, 3,5, 1C); MS
m/z 285 [M+H]+.
Example: Isobutylphenylketone (Evans and Gordon, 1938):
Yield: quant; 1H NMR (CDCl3): 0.97, 1.00 (6H, 2s, 2xCH3), 2.29
(1H, m, CH), 2.80 (2H, d, J = 6.6 Hz, CH2), 7.43–7.63 (3H, m,
3,4,5H Ar), 7.93 (2H (d), 2,6H Ar).
2.4.4. 4-(4-Chlorophenyl)-5-methyl-N-phenylthiazol-2-amine (3d)
Yield 86%; 1H NMR (DMSO-d6): d 2.46 (3H, s, 5-CH3), 6.92(1H, t,
J = 7.3 Hz, 4-H NPh), 7.30 (2H, (t), J ꢀ 7.3 Hz, 3,5-H NPh), 7.49 (2H,
d, J = 8.1 Hz, 2,6-H NPh), 7.62, 7.65; 7.68, 7.71 (4H, AA0BB0,
J ꢀ 8.5 Hz, 4-Ar), 10.07 (1H, s, br, ex, NH); 13C NMR (DMSO-d6): d
117.6, 144.5, 159.8 (5, 4, 2C thiazole); R1: 128.8, 130.1, 132.1,
134.4, (3,5, 2,6, 1, 4); R2: 12.4; R3: 117.1, 121.5, 129.4, 141.7,
(2,6, 4, 3,5, 1C); MS m/z 301 [M+H]+.
2.3. Syntheses of a-haloketones (4) – general procedure
To an ice-cooled solution of the corresponding ketone
(0.04 mol) in diethyl ether, bromine (0.04 mol, 2 ml) was added
dropwise. The almost colorless solution was stirred at room tem-
perature for another 20 min. After addition of aqueous NaHCO3-
solution (100 ml) the organic layer was separated and dried over
Na2SO4. Following removal of the solvent, the haloketones could
be used without further purification.
2.4.5. 4-(4-Chlorophenyl)-5-methyl-N-(naphtalen-1-yl)thiazol-2-
amine (3e)
Example:
a-Bromoisobutylphenylketone (Boswell et al., 1996)
(4b): Yield: quant; 1H NMR (CDCl3): 1.05, 1.23 (6H, 2d, J = 6.6 Hz,
2xCH3), 2.47 (1H, m, CH), 5.01 (1H, d, J = 8.4 Hz, CHC@O), 7.41–
7.66 (5H, m, Ar).
Yield 82%; 1H NMR (DMSO-d6): d 2.42 (3H, s, 5-CH3), 7.49–7.70,
7.92, 8.22–8.31 (11H, m, H Ar), 9.98 (1H, s, br, ex, NH); 13C NMR
(DMSO-d6): d 118.1, 144.3, 161.8 (5, 4, 2C thiazole); R1: 128.8,

388
I. Lagoja et al. / European Journal of Pharmaceutical Sciences 43 (2011) 386–392
130.1, 134.4, 134.5 (3,5, 2,6, 1, 4C); R2: 12.5; R3: 116.4, 122.6,
123.3, 126.0, 126.2, 126.5, 126.5, 128.7, 132.0, 132.2 (2, 4, 8, 7,
8a, 6, 3, 5, 4a, 1C); MS m/z 351 [M+H]+.
129.5, 133.6, 133.7, 133.9, 134.2 (5, 6,3, 2, 4, 1C); R2: 11.9; R3:
114.8, 120.3, 131.4, 143.0 (3,5, 2,6, 1, 4C); MS m/z 350 [M+H]+.
2.4.13. N-(3,5-Dimethylphenyl)-4,5-dimethylthiazol-2-amine (3m)
Yield 63%; 1H NMR (DMSO-d6): d 2.24, 2.27 (2x3H, 2xs, 4-CH3,
5-CH3), 6.73 (1H, s, 4-H NAr), 6.98 (2H, s, 2,6-H, NAr), 9.00 (1H, s,
br, ex, NH); 13C NMR (DMSO-d6): d 113.6, 142.3, 162.5 (5, 4, 2C thi-
azole); R1: 14.5; R2: 11.0; R3: 21.4 (2xCH3), 116.2, 124.4, 139.0,
141.0 (4, 3,5, 2,6, 1C); MS m/z 233 [M+H]+.
2.4.6. 4-(2,4-Dichlorophenyl)-5-methyl-N-(naphtalen-1-yl)thiazol-2-
amine (3f)
Yield 88%; 1H NMR (DMSO-d6): d 2.15 (3H, s, 5-CH3), 7.41–7.55
(6H, m, H-Ar), 7.60 (1H, s, 3-H 4Ar), 7.71, 7.89, 8.32 (3H, NAr),
10.01 (1H, s, br, ex, NH); 13C NMR (DMSO-d6): d 199.9, 142.9,
162.2 (5, 4, 2C thiazole); R1: 127.7, 129.6, 133.7, 134.3, 134.4,
137.1 (5, 6, 3, 2, 4, 1C); R2: 11.9; R3: 116.1, 122.6, 123.1, 125.9,
126.0, 126.5, 126.6, 128.7, 133.6, 133.8 (2, 4, 8, 7, 8a, 6, 3, 5, 4a,
1C); MS m/z 385 [M+H]+.
2.4.14. N-(3,5-Dimethylphenyl)-5-methyl-4-phenylthiazol-2-amine
(3n)
Yield 86%; 1H NMR (DMSO-d6): d 2.24 (6H, s, 2xCH3), 2.42 (5-
CH3), 6.58 (1H, s, 4-H NAr), 7.24 (2H, s, 2,6H NAr), 7.33 (1H, t,
J = 7.3 Hz, 4-H 4-Ph), 7.46 (2H, (t), J ꢀ 7.4 Hz, 3,5-H 4-Ph), 7.66
(2H, d, J = 7.5 Hz, 2,6-H, 4-Ph), 9.89 (1H, s, br, ex, NH); 13C NMR
(DMSO-d6): d 116.6, 145.7, 159.8 (5, 4, 2C thiazole); R1: 127.5,
128.4, 128.8, 135.7 (4, 2,6, 3,5, 1C); R2: 12.4; R3: 21.7 (2xCH3),
115.0, 123.1, 138.3, 141.7 (4, 3,5, 2,6, 1C); MS m/z 295 [M+H]+.
2.4.7. 4-(4-Bromophenyl)-N-(3-chlorophenyl)-5-methylthiazol-2-
amine (3g)
Yield 73%; 1H NMR (DMSO-d6): d 2.27 (3H, s, 5-CH3), 6.97 (1H, d,
J = 7.5 Hz, 6-H NAr), 7.31 (1H, t, J = 7.9 Hz, 5-H NAr), 7.64–7.99 (6H,
m, H-Ar), 10.35 (1H, s, br, ex, NH); 13C NMR (DMSO-d6): d 118.3,
144.5, 160.7 (5, 4, 2C thiazole); R1: 119.7, 130.4, 131.6, 132.7 (4,
3,5, 2,6, 1C); R2: 12.4; R3: 116.7, 119.7, 129.4, 131.0, 131.2, 132.6
(6, 2, 4, 5, 3,1C); MS m/z 379 [M+H]+.
2.4.15. N-(3,5-Dimethylphenyl)-5-isopropyl-4-phenylthiazol-2-amine
(3o)
Yield 89%; 1H NMR (DMSO-d6): d 1.25, 1.27 (6H, d, J = 6.6 Hz,
2xCH3), 2.22 (6H, s, 2xCH3Ar), 2.50 (1H, m, 5-CH), 6.57 (s, 4-H
NAr), 7.22 (2H, s, 2,6-H, NAr), 7.34 (1H, t, J = 7.3 Hz, 4-H 4Ph),
7.46 (2H, (t), J ꢀ 7.5 Hz, 2,6-H 4Ph), 7.55 (2H, d, J = 7.5 Hz, 2,6-H
4Ph), 9.22 (1H, s, br, ex, NH); 13C NMR (DMSO-d6): d 118.0,
144.3, 160.2 (5, 4, 2C thiazole); R1: 127.7, 128.7, 128.8, 136.1 (4,
2,6, 3,5, 1C); R2: 26.02 (2xCH3), 27.4 (CH); R3: 21.7 (2xCH3),
115.1, 123.2, 138.3, 141.7 (4, 3,5, 2,6, 1C); MS m/z 323 [M+H]+.
2.4.8. 4-(4-Chlorophenyl)-N-(3-chlorophenyl)-5-methylthiazol-2-
amine (3h)
Yield 72%; 1H NMR (DMSO-d6): d 2.43, (3H, s, 5-CH3), 6.94 (1H,
d, J = 7.5 Hz, 6-H NAr), 7.31 (1H, t, J = 7.95 Hz, 5-H NAr), 7.50, 7.53,
7.67, 7.70 (4H, AA0BB0, J = 8.2 Hz, 4-Ar), 7.87 (1H, s, 2-H NAr), 8.07
(1H, d, J = 8.7 Hz, 4-H NAr), 10.04 (1H, s, br, ex, NH); 13C NMR
(DMSO-d6): d 118.5, 143.0, 159.3 (5, 4, 2C thiazole); R1: 128.9,
130.1, 133.7, 134.3, (3,5, 2,6, 1, 4C), R2: 12.3, R3: 116.4, 120.9,
129.5, 131.0, 131.3, 132.2 (6, 2, 4, 5, 3, 1C); MS m/z 335 [M+H]+.
2.4.16. 4-(3-Bromophenyl)-N-(3,5-dimethylphenyl)-5-methylthiazol-
2-amine (3p)
2.4.9. N1-(4-(3-Bromophenyl)-5-methylthiazol-2-yl)benzene-1,4-
diamine (3i)
Yield 82%; 1H NMR (DMSO-d6): d 2.24 (6H, s, 2xCH3Ar), 2.43
(3H, s, 5-CH3), 6.59 (1H, s, 4-H NAr), 7.24 (2H, s, 2,6-H NAr), 7.44
(1H, (t), J ꢀ 7.7 Hz, 5-H 4Ar), 7.52 (1H, d, J = 7.7 Hz, 4-H 4Ar), 7.68
(1H, d, J = 7.5 Hz, 6-H 4Ar), 7.86 (1H, s, 2-H 4Ar), 9.97 (1H, s, br,
ex, NH); 13C NMR (DMSO-d6): d 118.1, 143.7, 159.9 (5, 4, 2C thia-
zole); R1: 122.2, 127.0, 130.2, 130.9, 131.0, 137.9 (3, 6, 4, 5, 2,
1C); R2: 12.4; R3: 21.7 (2xCH3), 115.1, 123.3, 138.4, 141.6 (4, 3,5,
2,6, 1C); MS m/z 373 [M+H]+.
Yield 76%; 1H NMR (DMSO-d6): d 2.49 (3H, s, 5-CH3), 4.20 (2H, s,
br, ex, NH2), 7.40 (1H, (t) J ꢀ 7.8 Hz, 5-H 4Ar), 7.51 (1H, d, J = 7.9 Hz,
6-H 4Ar), 7.58 (4H, m, NAr), 7.65 (1H, d, J = 7.7 Hz, 4-H 4Ar), 7.80
(1H, s, 2-H 4Ar), 10.03 (1H, s, br, ex, NH); 13C NMR (DMSO-d6): d
122.1, 137.9, 160.2 (5, 4, 2C thiazole), R1: 120.1, 127.3, 130.2,
130.8, 131.0, 135.8 (3, 6, 4, 2, 5, 1C); R2: 12.4; R3: 117.7, 118.2,
135.8, 143.0 (3,5, 2,6, 1, 4C); MS m/z 360 [M+H]+.
2.4.17. 4-(4-Chlorophenyl)-N-(3,5-dimethylphenyl)-5-methylthiazol-
2-amine (3q)
2.4.10. N1-(4-(4-Chlorophenyl)-5-methylthiazol-2-yl)benzene-1,4-
diamine (3j)
Yield 87%; 1H NMR (DMSO-d6): d 2.23 (6H, s, 2 CH3Ar), 2.41 (3H,
s, 5-CH3), 6.57 (1H, s, 4-H NAr), 7.23 (2H, s, 2,6-H NAr), 7.49, 7.51;
7.67, 7.69 (4H, AA0BB0, J = 7.5 Hz, 4-Ar), 9.94 (1H, s, br, ex, NH); 13C
NMR (DMSO-d6): d 117.3, 144.4, 159.9 (5, 4, 2C thiazole); R1: 128.8,
130.0, 132.0, 134.5 (4, 3,5, 2,6, 1C); R2: 12.4; R3: 21.7 (2xCH3),
115.0, 123.2, 138.3, 141.6 (4, 3,5, 2,6, 1C); MS m/z 329 [M+H]+.
Yield 72%; 1H NMR (DMSO-d6): d 2.38 (3H, s, 5-CH3), 4.13 (2H, s,
br, ex, NH2), 7.47, 7.65 (4H, AA0BB0, J = 7 Hz 4Ar), 7.57 (4H, m, NAr),
10.02 (1H, s, br, ex, NH); 13C NMR (DMSO-d6): d 118.3, 144.0, 159.9
(5, 4, 2C thiazole), R1: 128.6, 129.8, 131.6, 134.2 (3,5, 2,6, 1, 4C); R2:
12.0; R3: 117.8, 117.9, 135.6, 144.0 (3,5, 2,6, 1, 4C); MS m/z 316
[M+H]+.
2.4.18. 4-(4-Bromophenyl)-N-(3,5-dimethylphenyl)-5-methylthiazol-
2-amine (3r)
2.4.11. N1-(4-(4-Bromophenyl)-5-methylthiazol-2-yl)benzene-1,4-
diamine (3k)
Yield 81%; 1H NMR (DMSO-d6): d 2.23 (6H, s, 2xCH3Ar), 2.41
(3H, s, 5-CH3), 6.57 (1H, s, 4-H, NAr), 7.23 (2H, s, 2,6-H NAr), 7.62
(4H, AA0BB0, 4-Ar), 9.96 (1H, s, br, ex, NH); 13C NMR (DMSO-d6): d
117.4, 144.6, 159.9 (5, 4, 2C thiazole); R1: 120.6, 130.3, 131.7,
134.8, (4, 3,5, 2,6, 1C); R2: 12.4; R3: 21.7 (2xCH3), 115.0, 123.2,
138.3, 141.6 (4, 3,5, 2,6, 1C); MS m/z 373 [M+H]+.
Yield 69%; 1H NMR (DMSO-d6): d 2.40 (3H, s, 5-CH3), 7.57 (2H, s,
br, ex, NH2), 7.63 (4H, m, H Ar), 9.97 (1H, s, br, ex, NH); 13C NMR
(DMSO-d6): d 120.5, 144.5, 160.3 (5, 4, 2C thiazole), R1: 126.3,
130.4, 131.7, 134.4 (4, 3,5, 2,6, 1C); R2: 12.5; R3: 116.9, 118.2,
135.8, 143.0 (3,5, 2,6, 1, 4C); MS m/z 360 [M+H]+.
2.4.12. N1-(4-(2,4-Dichlorophenyl)-5-methylthiazol-2-yl)benzene-
1,4-diamine (3l)
2.4.19. 4-(4-Fluorophenyl)-N-(3,5-dimethylphenyl)-5-methylthiazol-
2-amine (3s)
Yield 74%; 1H NMR (DMSO-d6): d 22.09 (3H, s, 5-CH3), 4.85 (2H,
s, br, ex, NH2), 6.53, 7.19 (4H, AA0BB0, J = 8.5 Hz, NAr), 7.46 (2H, (s),
5,6H 4-Ar), 7.70 (1H, s, 3-H 4-Ar), 9.49 (1H, s, br, ex, NH); 13C NMR
(DMSO-d6): d 117.5, 144.3, 162.3 (5, 4, 2C thiazole); R1: 127.7,
Yield 74%; 1H NMR (DMSO-d6): d 2.23 (6H, s, 2xCH3Ar), 2.40
(3H, s, 5-CH3), 6.57 (1H, s, 4-H NAr), 7.23 (2H, s, 2,6-H NAr), 7.27,
7.69 (4H, AA‘BB‘4-Ar), 9.94 (1H, s, br, ex, NH); 13C NMR (DMSO-
d6): d 116.4, 144.6, 159.8 (5, 4, 2C thiazole), R1: 115.5, 115.8;

I. Lagoja et al. / European Journal of Pharmaceutical Sciences 43 (2011) 386–392
389
130.3, 130.4; 132.2; 160.2, 163.3 (3,5, 2,6, 1, 4C); R2: 12.4; R3: 21.7
(2xCH3), 115.0, 123.2, 138.3, 141.7 (4, 3,5, 2,6, 1C); MS m/z 313
[M+H]+.
lowed-up by an in-house study uncovering the 2-aminothiazole
scaffold 3 as a new lead for tau-induced cytotoxicity. This general
scaffold has three variables, the thiazole 4- and 5-substituents R1
and R2, and the amine moiety R3, with overall geometry resembling
the NAIM core.
The thiazoles were assembled according to a slightly modified
version of the Hantzsch thiazole synthesis (Hantzsch, 1890; Han-
tzsch and Weber, 1887; Schantl and Lagoja, 1998). Herein, the con-
2.4.20. 4-(2,4-Dichlorophenyl)-N-(3,5-dimethylphenyl)-5-
methylthiazol-2-amine (3t)
Yield 82%; 1H NMR (DMSO-d6): d 2.15 (3H, s, 5-CH3), 2.20 (6H, s,
2xCH3Ar), 6.56 (1H, s, 4-H NAr), 7.17 (2H, s, 2,6-H NAr), 7.49 (2H,
5,6-H 4-Ar), 7.73 (1H, s, 3-H 4Ar), 9.92 (1H, s, br, ex, NH); 13C
NMR (DMSO-d6): d 119.3, 143.0, 160.4 (5, 4, 2C thiazole); R1:
127.7, 129.7, 133.5, 133.6, 133.8, 134.3 (5, 6, 3, 2, 4, 1C); R2:
11.9; R3: 21.7 (2xCH3), 115.0, 123.2, 138.3, 141.5 (4, 3,5, 2,6, 1C);
MS m/z 363 [M+H]+.
densation of one eq of
a-halo ketones 4 with potassium
thiocyanate (1.2 eq) and an (hetero)aromatic or aliphatic amine
derivative 5 in refluxing methanol yielded the corresponding N-
aminothiazole derivatives 3a–v in good to excellent yield. By use
of microwave assisted synthesis the reaction time could signifi-
cantly be decreased as worked out for some analogs (1.5 h com-
pared to 10 h), without affecting the yield. The reaction is
suitable for aromatic, heteroaromatic or aliphatic substituted halo-
carbonyl aldehydes and ketones, and aromatic, heteroaromatic or
aliphatic amines. A possible synthetic pathway is lined out in
Scheme 1. The required (halo)ketones if commercially not avail-
able, could be obtained from the respective nitriles via Grignard
2.4.21. N-Benzyl-5-methyl-4-phenylthiazol-2-amine (3u)
Yield 65%; 1H NMR (DMSO-d6): d 2.33 (3H, s, 5-CH3), 4.43 (2H, d,
J = 5.9 Hz, CH2Bn), 7.22–7.561 (10H, m, 4-Ph, Bn), 7.85 (1H, t, ex,
J = 5.9 Hz, NH); 13C NMR (DMSO-d6): d 114.9, 145.5, 164.9 (5, 4,
2C thiazole); R1: 127.3, 128.6, 128.7, 136.0 (4, 2,6, 3,5, 1C); R2:
12.6; R3: 47.9 (CH2), 127.2, 127.9, 128.4, 139.9 (4, 2,6, 3,5, 1C);
MS m/z 281 [M+H]+.
reaction followed by a-bromination.
3.2. Cytoprotective activity in a neuronal cell line model of tau-
induced toxicity
2.4.22. 4-(3-Bromophenyl)-5-methyl-N-(4-methylpyridin-2-
yl)thiazol-2-amine (3v)
Yield 48%; 1H NMR (DMSO-d6): d 2.50 (3H, s, 5-CH3), 2.56 (3H, s,
Specific clinical mutations predispose tau for toxic aggregation.
To recapitulate this process a tau expression plasmid was con-
structed by sub-cloning the cDNA of human TAU-P301L (encoding
for tau with proline 301 substituted by a leucine residue) into a
mammalian expression vector, which subsequently was transfec-
ted to human neuroblastoma cells. The expression of TAU-P301L
in M17-TAU-P301L cells was found to confer increased toxicity rel-
ative to control cells not over-expressing wild type tau (data not
shown). In degenerated or dead cells intracellular LDH leaks out
into the extracellular environment due to a loss of plasma-mem-
brane integrity. This principle was used to determine tau related
cytotoxicity by quantifying the level of leaked LDH into the growth
medium. The M17-TAU-P301L cell line therefore made it possible
to assess the ability of novel compounds (when brought in contact
with the cells) to counteract tau cytotoxicity since such com-
pounds are expected to inhibit tau-instigated LDH leakage. In this
way the neuroprotective potential of the aminothiazoles as de-
scribed above was evaluated (Table 1).
Ar-CH3), 7.43–7.85 (8H, m, aromatic-H), 10.2 (1H, s, br, ex, NH); 13
C
NMR (DMSO-d6): d 118.0, 145.5, 158.8 (5, 4, 2C thiazole); R1: 131.0,
132.0, 132.1, 140.8 (4, 3,5, 2,6, 1C); R2: 12.6; R3: 22.7 (CH3), 118.0,
122.1, 132.1, 148.0, 148.4 (6, 4, 5, 1, 3C); MS m/z 360 [M+H]+.
2.5. Use of tau expressing cells as a model of neuronal degradation
Sub-cloning the cDNA of human TAU-P301L into mammalian
expression vector pcDNA3.1 resulted in plasmid pcDNA3.1-TAU-
P301L. Plasmids pcDNA3.1 and pcDNA3.1-TAU-P301L were trans-
fected to human neuroblastoma cells (BE-M17; ATCC No. CRL-
2267) and independent clonal lines with the plasmids stably inte-
grated into the genome were selected. These resulted in cell lines
named M17-3.1 and M17-TAU-P301L (transfected with pcDNA3.1
and pcDNA3.1-TAU-P301L, respectively). Expression of the TAU-
P301L genes in the cell lines was confirmed by Western analysis.
Tau induced cytotoxicity was determined as follows: from
appropriate precultures of M17-3.1 and M17-TAU-P301L, cells
As can be seen in Table 1, several compounds with nanomolar
activity were uncovered. Although the number of compounds is
still too small for complete SAR conclusions, some interesting
trends can already be deduced. The starting compound 3a with
unsubstituted phenyl rings already inhibited the tau-induced tox-
icity at 53 ng/ml or approximately 180 nM concentrations. In
search of the key variables, substitution of the aromatic R1-phenyl
for a methyl moiety reduced the potency 5-fold (compare 3n with
3m). On the other hand, introduction of the larger isopropyl moiety
at the 5-position while keeping the 4-phenyl ring, afforded con-
flicting results. The 10-fold reduction in potency for 3b versus 3a
is in sharp contrast with the results for N-3,5-dimethylphenyl
substituted aminothiazoles, with 3o displaying the strongest
inhibitory activity within this series with a 5-fold reduction com-
pared to 3n.
were differentiated for 7 days with 2.5 lM retinoic acid in the pres-
ence of the tested compounds. Hereto, stock solutions of the test
compounds were prepared in DMSO and the appropriate amount
was added to the respective wells. The same amount of DMSO
was used throughout all experiments. LDH activity was deter-
mined using Promega Cytotox 96 non-radioactive cytotoxicity as-
say, (Cat. G1780) according the supplier’s instructions. The
potency of the compounds under study for protection versus neu-
ronal insult, could be determined by evaluating these substances at
different concentrations ranging from non-effective (thus at a rel-
atively low concentration) to an effective concentration for their
ability to reduce LDH activity of retinoic acid incubated M17-
TAU-P301L cells. These measurements were used to calculate the
respective EC50 values.
In general, para-halogenation of the phenyl ring R1 increased
the potency (3c and d versus 3a, and 3q–s versus 3n), but meta-
bromination likewise does (compare 3p with 3n and notice the
analogous activity for 3i, 3j and 3k). Introducing a p-methoxy-phe-
nyl substituent at R1 however annihilated the activity, regardless
the nature of R2 and R3 (not shown). Considerable improvement
3. Results and discussion
3.1. Synthesis of the 2-aminothiazole congeners
The cytoprotective effect of a series of N-aminoimidazole
(NAIM) compounds (highlighted by compounds 1 and 2, Fig. 1)
has been documented before (Stevens et al., 2007), and was fol-
of activity is noticed with the more bulky
and h) and even more pronounced with a p-amino-phenyl (3i–l)
a
-naphtyl at R3 (3g

390
I. Lagoja et al. / European Journal of Pharmaceutical Sciences 43 (2011) 386–392
Fig. 1. Chemical structures of the cytoprotective N-aminoimidazole lead compounds 1 and 2 and general new thiazole scaffold 3a–v under study with 3j and 3o as prototype
examples.
or a 3,5-dimethylphenyl (3m–t) moiety, culminating as mentioned
in 3o with an IC50 of 4 ng/ml or 14 nM. However, the lipophilicity
as calculated average for different programs is further increased,
and might hamper future in vivo applications. Nevertheless, while
all compounds are endowed with a high log P value, this does not
seem to prevent the in vitro activity in this cellular system. Lipo-
philicity by itself proved not to be a prime determinant for the
inhibitory properties within this series as can be deduced from Ta-
ble 1. The strong lipophilicity is reflected as well in the high Rf-val-
ues for the system n-hexane: ethyl acetate 3:1, which for all
compounds are found in the range of 0.86–0.88.
Furthermore, although the orientation of the meta-methyl is
preserved in 3v, the introduction of the more polar pyridine ring
at R3 almost annihilated the inhibitory potency in comparison with
3p. Likewise introducing an extra methylene spacer using an N-
benzyl moiety as in 3u afforded a considerable loss in activity.
3.3. Comparison with related aminothiazole scaffolds for modulation
of proteinopathies
Generation of proteinaceous aggregates either by misprocessing
or misfolding cause serious cellular toxicity leading to neurodegen-
erative diseases. In our study we focused on counteracting the
cytotoxicity as provoked by formation of tau neurofibrillary tan-
gles, one of the hallmarks of AD, using compounds based on a 2-
aminothiazole scaffold. Remarkably, some very recent communica-
tions by Prusiner and Renslo likewise report on the use of 2-amino-
thiazoles as novel lead compounds with antiprion properties
(Gallardo-Godoy et al., 2011; Ghaemmaghami et al., 2010). Either
formation of the misfolded endogenous prion protein into a b-
sheet-rich form (PrPSc) leading to oligomeric deposits or their
clearance seem to be influenced by the 2-aminothiazole scaffold,
leading to lowered toxicity. The structures for the most active com-
pound within their series (6a) and for the one evaluated for bio-
availability in mice (6b) are shown in Fig. 2.
While prion diseases and AD both can be classified belonging to
proteinopathies, the latter is very different from the former. Both
proteins PrPSc and tau eventually end up as b-sheet fibrils, which
are structurally similar, but it has not been proven that full blown
aggregates are the primary toxic conformation for the tau related
toxicity. Hence, where for antiprion properties one primarily
screens for reduction in the PrPSc load, here the specific cytotoxic-
ity elicited by tau aggregation is determined by evaluating the
plasma membrane integrity.
Scheme 1. Plausible reaction mechanism for synthesis of the aminothiazole
scaffold.
Table 1
Substitution pattern, calculated log P data and inhibitory activity of the aminothiaz-
oles 3.
b
Compound
R1
R2
R3
log Pa
IC50
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Me
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
4.75
5.55
4.92
5.36
6.46
7.05
6.09
5.97
4.59
4.45
4.59
5.05
4.14
5.52
6.30
6.26
6.13
6.25
5.68
6.72
4.61
5.24
53
582
46
32
7
51
1750
220
9
7
8
11
90
20
4
4-F-Ph
4-Cl-Ph
4-Cl-Ph
2,4-DiCl-Ph
4-Br-Ph
4-Cl-Ph
3-Br-Ph
4-Cl-Ph
4-Br-Ph
2,4-DiCl-Ph
Me
a
a
-Naphtyl
-Naphtyl
3-Cl-Ph
3-Cl-Ph
4-NH2-Ph
4-NH2-Ph
4-NH2-Ph
4-NH2-Ph
3,5-DiMe-Ph
3,5-DiMe-Ph
3,5-DiMe-Ph
3,5-DiMe-Ph
3,5-DiMe-Ph
3,5-DiMe-Ph
3,5-DiMe-Ph
3,5-DiMe-Ph
Bn
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
Ph
Ph
3-Br-Ph
4-Cl-Ph
4-Br-Ph
4-F-Ph
2,4-DiCl-Ph
Ph
9
6
12
16
10
300
1250
As already described by Ghaemmaghami et al., the aminothia-
zole scaffold exhibits very diverse pharmacology and can be found
in many therapeutic classes with at first glance only slight struc-
tural changes. Clearly also some differences can be found between
our set of compounds and the one of the University of California
(UCal). Structurally, the most obvious one is that UCal’s most active
3u
3v
3-Br-Ph
4-Me-2-pyridinyl
a
The average log P values are given as calculated by a variety of programs on the
ALOGPS 2.1 program website (VCCLAB, 2005).
b
In ng/ml.

I. Lagoja et al. / European Journal of Pharmaceutical Sciences 43 (2011) 386–392
391
Fig. 2. Resembling known compounds: representative structures for the antiprion aminothiazole derivatives (6a and b) with annotation of the aromatic ring system A, B and
C, and for the anti-b-amyloid compounds (6c) with their reported activity in nM.
derivative (6a) has an acyl moiety on the amino group, whereas all
the derivatives we tested have a secondary amine. Further, while
all compounds from UCal lack a substituent on position 5 of the
thiazole ring (excluding the tricyclic derivatives), all our congeners
carry a 5-methyl or 5-isopropyl moiety. Where coplanar arrange-
ment of the aromatic A- and B-ring (respectively the 4-aryl and
the thiazole ring, as shown in 6a) is believed to be important for
antiprion activity as shown in the UCal papers, one can argue
therefore that analogs comprising a 5-alkyl substituent prohibiting
this coplanarity, will be hampered in their antiprion activity. Yet,
most active congeners in the 5-H series display low micromolar
or submicromolar activity, with only the most active compound
having a potency of 81 nM. In contrast, within the 5-alkyl series
several congeners were uncovered being endowed with sub-
50 nM activity in reducing tau instigated toxicity. It is therefore
plausible that the mechanism or target by which the compounds
act will be different.
4. Conclusion
A cellular assay was developed for evaluation of tau-instigated
neuronal toxicity by sub-cloning and transfecting the cDNA of a
clinically relevant mutated tau into a human neuroblastoma cell-
line. The lead compound 5-methyl-N,4-diphenylthiazol-2-amine
(3a) was found to counteract tau-induced cell toxicity at submi-
cromolar concentration. Hence, a straightforward one-pot modifi-
cation of the Hantzsch thiazole synthetic scheme was used to
obtain a 2-aminothiazole scaffold with 3 variables. Several congen-
ers were found which strongly counteracted tau-induced cell tox-
icity culminating in 3o with an IC50 of 14 nM. A clear structural
distinction on several points was made with some resembling 2-
aminothiazole derivatives endowed with antiprion properties.
The here uncovered thiazole derivatives therefore seem to have
strong potential as possible treatment for Alzheimer’s disease
and other related tauopathies.
This is further illustrated with the lack of activity in our series
when introducing a pyridine ring on the amine, where all antiprion
compounds carry either a pyridine or quinoline ring as the C-moi-
ety. In addition, where ortho substitution on the A ring is not tol-
erated for antiprion activity, we do not observe this intolerance,
with a strong anti-tau toxicity found for compounds 3l and 3t
(sub-50 nM), and to a lower extent for 3f, all having a 2,4-dichloro-
phenyl moiety at the 4-position of the thiazole scaffold. Some pat-
ent reports filed by Neurogenetic Pharmaceuticals likewise claim
reduction in b-amyloid levels using a 2-aminothiazole scaffold as
the central part of a series of compounds comprising several aro-
matic rings as exemplified by structure 6c (Neurogenetic Pharma-
ceuticals, 2004, 2010). Most of the hundreds of analogs reported
herein likewise are devoid of a 5-alkyl substituent, and show in
general only micromolar activities. These structures therefore have
more resemblance to the UCal derivatives. Overall, we can con-
clude that we have uncovered a new scaffold based on the amino-
thiazole ring system, providing strong inhibition of neuronal
toxicity induced by tau self-polymerization via a new as yet
unidentified mechanism.
Acknowledgments
reMYND received support for this work by the Institute for the
Promotion of Innovation by Science and Technology in Flanders
(IWT). Irene M. Lagoja was holder of a postdoctoral research fel-
lowship of the Research Foundation-Flanders (FWO-Vlaanderen).
We are indebted to Jef Rozenski for MS analyses and to Chantal
Biernaux for assistance in editing the manuscript.
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