Identification, synthesis and photo-protection evaluation of arylthiazole derivatives as a novel series of sunscreens

Article abstract of DOI:10.3987/COM-13-12865

A novel series of arylthiazole derivatives have been designed, synthesized and evaluated in preventing keratinocytes cell (HaCaT) from UVB exposure induced cellar damage. The structure-activity relationship (SAR) was discussed. More importantly, compound 5a significantly protected the dorsal skin of BALB/c-nu mice against UVB-induced decrustation in vivo. The in vitro and in vivo data for these arylthiazole derivatives suggest further studies for their potential use as photo-protection agents as well as sunscreen candidates.

Full text of DOI:10.3987/COM-13-12865

HETEROCYCLES, Vol. 89, No. 2, 2014
453
HETEROCYCLES, Vol. 89, No. 2, 2014, pp. 453 - 464. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 17th October, 2013, Accepted, 9th January, 2014, Published online, 20th January, 2014
DOI: 10.3987/COM-13-12865
IDENTIFICATION,
SYNTHESIS
AND
PHOTO-PROTECTION
EVALUATION OF ARYLTHIAZOLE DERIVATIVES AS A NOVEL
SERIES OF SUNSCREENS
Guoliang Li,1,# Yundong He,1,# Wenbo Zhou,1 Peng Wang,1 Yong Zhang,1
Weiguang Tong,1 Haigang Wu,1 Mingyao Liu,1,2 Xiyun Ye,1* and Yihua
Chen1*
1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical
Sciences and School of Life Sciences, East China Normal University, Shanghai,
2
200241, China. Center for Cancer and Stem Cell Biology, Institute of
Biosciences and Technology, Texas A&M University Health Science Center,
Houston, 77030, USA. E-mail: yhchen@bio.ecnu.edu.cn, xyye@bio.ecnu.edu.cn
#These authors contributed equally to this work.
Abstract – A novel series of arylthiazole derivatives have been designed,
synthesized and evaluated in preventing keratinocytes cell (HaCaT) from UVB
exposure induced cellar damage. The structure-activity relationship (SAR) was
discussed. More importantly, compound 5a significantly protected the dorsal skin
of BALB/c-nu mice against UVB-induced decrustation in vivo. The in vitro and in
vivo data for these arylthiazole derivatives suggest further studies for their
potential use as photo-protection agents as well as sunscreen candidates.
Excessive exposure to ultraviolet radiation (UV) is believed to induce various skin diseases such as
sunburn, photo-aging and photo-immunosuppression.1-3 Moreover, skin oncology research has
demonstrated that acute or chronic UV exposure is responsible for photo-carcinogenesis as one of the key
factors in the process of skin cancer.4-6 Commercial sunscreens have been used since 1928 as one of the
most effective and prevalent methods of photo-protection, which have still played a major role in
decreasing UV radiation and skin cancer occurrence until today.7 Among UV light, UVB (290-320 nm) is
a predominant and most harmful component, which was regarded as main reasons for the most severe
damages.8, 9 As a result, more concern should be taken to develop sunscreen products capable of

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HETEROCYCLES, Vol. 89, No. 2, 2014
preventing UVB exposure. Up to date, FDA has approved a series of UVB organic sunscreen filters,
which include aminobenzoates, cinnamates, salicylates, octocrylene and ensulizole.10 However, several
striking weaknesses such as photoallergic reaction or estrogen-like side effects restrict the popularity of
these sunscreens.11 In addition, a limited number of sunscreen products can’t meet our growing demand.
Thus discovering and developing more effective and safer sunscreens that minimize damage from UVB
radiation is still a crucial goal of our research.
In this study, a series of arylthiazole derivatives were identified as a novel class of sunscreens for their
potent protective activity against UVB-induced damage. By screening our chemical library with high
structural diversity which was derived from ChemBridge company as well as set up in our laboratory, we
found compound 1 (Figure 1), an arylthiazole derivative exerted commendable ability to protect
keratinocytes cell from UVB-induced damage. Arylthiazole derivatives were reported to show various
biological activities such as antitumor,12 anti-tubercular,13 anti-virulence,14 accelerating neuronal
differentiation.15 But whether these arylthiazole compounds showed the function of reversing or blocking
UVB-induced damage or not still remained unclear. Therefore, a series of novel arylthiazole derivatives
based on compound 1 were designed, synthesized and their activity were assessed for their
photo-protection effects. The most potent compound 5a was validated through cell viability assay in vitro
and skin damage experiment in vivo. Compound 5a effectively protected UVB-induced skin damage of
nude mice, suggesting it was a novel potential photo-protection agent or a promising sunscreen candidate.
arylthiazole modification
amide modification
N
N
S
linker modification
O
N
ethyl modification
Figure 1. The chemical structure of compound 1 and possible modification strategies
Synthesis of 2-(4-pyridinyl)thiazole derivatives (4a−d, 5a−d, 6a−c, 8, 9a−c). Compounds 4a−d, 5a−d,
6a−c, 8 and 9a−c were prepared using the methods outlined in Scheme 1. Compounds 2a−d16 were
hydrolyzed to corresponding acids 3a−d, compound 3b was further coupled with arylamines in the
presence of EDC.HCl and HOBt to provide compounds 4a−d. Coupling of acid 3b with a variety of
amino acid esters gave compounds 5a−d, while 6a−c were afforded based on 3a and 3c−d coupled with
glycine ethyl ester hydrochloride. In addition, compound 2b can also be reduced under lithium aluminium

HETEROCYCLES, Vol. 89, No. 2, 2014
455
hydride to give compound 7 in a high yield, which was then reacted with methyl bromoacetate in the
presence of sodium hydride at ambient temperature to generate intermediate 8, which was hydrolyzed and
then coupled with various amines to afford compounds 9a−c.
O
O
NHR3
OH
N
O
O
N
O
N
S
S
d
a, b
c
S
N
N
N
R
Et
Et
9a: R3 = Ph
7
: R = Et
8
9b: R3 = Bn
9c
3
N
O
O
: R = Ph-Et
R2
S
O
HN
O
n
N
R1
N
HN
N
OH
N
S
R
S
2a
: R = H
O
S
or
O
2b: R = Et
2c: R = n-Pr
2d
a
b
N
N
N
: R = n-Bu
R
5a: n = 1, R2 = OEt, R = Et
5b: n = 2, R2 = OMe, R = Et
5c: n = 3, R2 = OEt, R = Et
R
4a: R1 = Ph
3a
: R = H
3b: R = Et
4b: R1 = 4-Br-Ph
4c: R1 = 3-MeO-Ph
3c: R = n-Pr
3d
2
5d
6a
: R = n-Bu
: n = 5, R = OEt, R = Et
1
2
4d
: R = 2-MeO-Ph
: n = 1, R = OEt, R = H
6b: n = 1, R2 = OEt, R = n-Pr
6c: n = 1, R2 = OEt, R = n-Bu
Scheme 1. Reagents and conditions: (a) LiOH·H2O, MeOH, H2O; (b) amines, EDC·HCl, HOBt,
anhydrous DMF; (c) LiAlH4, Et2O; (d) NaH (60%), methyl 2-bromoacetate, anhydrous DMF.
Synthesis of 2-phenylthiazole derivatives (11a−f). To synthesize compounds 11a−f, a series of
commercial or prepared substituted thiobenzamides were selected to react with ethyl
2-bromo-3-oxobutanoate to afford corresponding esters,16 which were then hydrolyzed by lithium
hydroxide monohydrate to obtain compound 10a−f, then coupled with glycine ethyl ester hydrochloride
under EDC·HCl and HOBt conditions to give target compounds 11a−f in a satisfactory yield.
O
R2 NH2
O
R2
N
OH
R2
N
HN
O
S
a,b
S
c
O
S
R1
R3
R1
R3
R1
R3
10a-f
10a: R1 = R2 = R3 = H
11a-f
11a: R1 = R2 = R3 = H
1
2
3
1
2
3
10b
10c
10d
: R = CF3, R = R = H
11b
11c
11d
: R = CF3, R = R = H
1
2
3
1
2
3
: R = MeO, R = R = H
: R = MeO, R = R = H
1
2
3
1
2
3
: R = Cl, R = R = H
: R = Cl, R = R = H
10e: R1 = R2 = H, R3 = Cl
10f: R1 = H, R2 = R3 = Cl
11e: R1 = R2 = H, R3 = Cl
11f: R1 = H, R2 = R3 = Cl
Scheme 2. Reagents and conditions: (a) 2-bromo-3-oxobutanoate, anhydrous EtOH, reflux, 2 h; (b)
LiOH·H2O, MeOH, H2O; (c) EDC·HCl, HOBt, anhydrous DMF.

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Synthesis of compound 13a-c. Intermediates 12a−c were prepared using standard palladium-catalyzed
cross-coupling reaction followed by oxidation with selenium dioxide.17,18 Compounds 12a−c were
subsequently coupled with glycine ethyl ester hydrochloride to give target compounds 13a−c, as shown in
Scheme 3.
R
O
R
Y
R
O
CO2H
X
Y
a
b
c
N
X
Y
H
CHO
O
CHO
Y
X
X
R
Br
12a: X = O, Y = C, R = H
12b: X = S, Y = C, R = H
13a: X = O, Y = C, R = H
13b: X = S, Y = C, R = H
12c
13c
: X = O, Y = N, R = Me
: X = O, Y = N, R = Me
Scheme 3. Reagents and conditions: (a) PhB(OH)2, Pd(PPh3)4, Na2CO3; (b) SeO2, THF, reflux; (c)
EDC·HCl, HOBt, anhydrous DMF.
Synthesis of compound 15 and 17. Compounds 15 and 17 were afforded through intermediates 1419 and
16,20 which were hydrolyzed, and then coupled with glycine ethyl ester hydrochloride to give compounds
15 and 17.
O
O
O
NH
O
O
a,b
N O
N O
14
15
O
O
O
O
O
NH
N
a, b
N
S
S
N
N
16
17
Scheme 4. (a) LiOH·H2O, MeOH, H2O; (b) EDC·HCl, HOBt, anhydrous DMF.
Structure-activity relationship of arylthiazole derivatives
To investigate the photo-protection activities of these arylthiazole derivatives, polydatin15 and BP-3

HETEROCYCLES, Vol. 89, No. 2, 2014
457
(2-hydroxy-4-methoxy-benzophenone)16 which showed photo-protection and sunscreen activities were
selected as positive controls. For demonstration of structure-activity relationships, a series of compounds
containing arylthiazole skeleton derived from compound 1 were evaluated for their photo-protective
effects against 30 mJ/cm2 of UVB exposure which was appropriate to induce about 50% HaCaT cell death.
The strategic modification was shown in Figure 1. Firstly, piperidinyl group of compound 1 was replaced
by alkyl or alkenyl amines with the retention of 2-(2-ethylpyrdinyl)thiazole scaffold. Unfortunately the
result indicated that protective effects of these compounds were significantly lost (data not shown).
Secondly, substitutive anilines with different electron-donating or electron-withdrawing properties were
selected to afford compounds 4a-d based on coupling with the 2-(2-ethylpyrdinyl)thiazole scaffold of the
hit compound 1. Examination of the assay result, compound 4c with introduction of 3-methoxyphenyl
group showed mild protection against UVB exposure as compound 1, though the protection effect was
weaker than positive controls polydatin and BP-3 (Figure 3). These results suggested that more diverse
substitution would be explored to increase activities. Subsequently a variety of chainlike amino acid
esters with different length were chosen to couple with 2-(2-ethylpyrdinyl)thiazole carboxylic acid 3b
because amino acid ligands usually contributed to potent protection against UVB induced damage.17
Interestingly, the length of chain between amino and terminal carboxyl group of amino acid demonstrated
extremely influences toward protective activity. When n = 1, compound 5a provided best protective effect
among them (5a−d) and superior to positive controls polydatin and BP-3 in the same concentration, while
the potency was decreased when increasing chain length (5a >5b >5c >5d). Thus compound 5a was
chosen for subsequent optimizations (Figures 1, 2).
O
R1
N
OR3
N
HN
O
R2
N
N
N
S
S
S
O
O
N
N
N
1
4
5
O
O
O
O
OR3
NHR5
OR3
O
HN
O
R8
N
O
N
N
HN
O
Y
HN
S
S
X
S
O
N
N
R7
R9
R6
R4
13
11
6
9
Figure 2. Representative derivatives based on hit compound 1 optimization

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Figure 3. The screening results of target compounds via cell viability assay: control group was without
UVB and others with UVB irradiation (30 mJ/cm2), polydatin and BP-3 were used as positive controls.
The following chemical modifications of compound 5a were divided into four parts. As listed in Figure 2
and Figure 3, the first part was that the substitution in pyridinyl group, alkyl substitutions (6b−c) in this
position as well as hydrogen atom (6a) were explored, which showed that a suitable small alkyl group
was crucial for maintaining the activity. For example, when the position was not substituted (6a), the
activity was decreased compared to 5a, while if the substitution was a large group such as butyl group
(6c), it showed toxicity against the HaCat cell instead of protection. Our interest was then turned over
other parts of compound 5a. Next, when the linker amide of 5a was investigated for changing to ether 8
with similar length, the activity was not increased, and replacement of ester with amide moiety in the
terminal of compound 8 was also proven to decrease the activities of those compounds (9a−c). Further
pyridinyl group was substituted by other biomimetic aryl groups such as substituted phenyl ring (11a−f),
which resulted in the discovery of 11a with almost equal activity to compound 5a, while other substituted
phenyl ring either with electron-donating or electron-withdrawing groups showed no increase in activity.
These results suggested that pyridinyl group was not the necessary moiety, and other aromatic groups
might lead to the bioactive compounds. Thus pyridinylthiazole group was further replaced by other
heteroaromatic groups such as phenylfuran (13a), phenylthiophene (13b), phenyloxazole (13c),
phenylisoxazole (15) and phenylthiazole (17). The result showed these changes were tolerant, since most
of them showed good photo-protection against UVB exposure except 13a, which showed severe
cytotoxicity against HaCaT cell (Figure 3). In conclusion, the introduction of amino acid moiety to the
arylthiazole skeleton and the existence of amide other than ether as a linker group were necessary for

HETEROCYCLES, Vol. 89, No. 2, 2014
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retaining photo-protection activities of these compounds. Replacement of thiazole with oxazole moiety
that possessed similar electron configuration was tolerant, whose activity was in line with compound 5a.
With good potency against UVB induced damage, compounds 5a, 11a, 15 and 17 were selected for
comprehensive comparison. Among these candidates, compound 5a was found to show lower
cytotoxicity, better photo-protection effect against UV radiation, and more favourable physical characters
especially water solubility, and was subsequently chosen for further evaluation in vitro and in vivo.
In order to detect the toxicity of compound 5a against HaCaT cell, a viability test experiment was carried
out and the result suggested that inferior to 500 μM, compound 5a had very weak effects on the viability
of HaCaT cell, and the viability of HaCaT cell was maintained more than 75% (Figure 4A). Irradiation
with 30 mJ/cm2 of UVB resulted in half of cell death compared with the non-irradiated group while
treatment with compound 5a reduced HaCaT cell death induced by UVB-irradiation in a dose-dependent
manner and the proportions of cell death were 35.0 ± 7.0%, 23.7 ± 6.2% and 8.1 ± 6.8% at 25, 50, 100
μM of 5a, respectively, compared with the non-irradiated group. Those results showed that the
photo-protection activity of compound 5a was directly correlated with its treatment dose suggesting its
potential use as a sunscreen (Figure 4B). Furthermore, more cell death was observed after UVB
irradiation compared with the non-irradiated groups and compound 5a dose-dependently reduced HaCaT
cell death by photograph (Figure 4C). To further investigate the mechanisms of compound 5a, the free
radical scavenging capacity and UV absorption spectra of compound 5a were assessed. We found that
compound 5a did not have radical scavenging activity but potently absorbed the UVB radiation at
wavelength 200-400 nm (Figure S2 and Figure S3). Moreover, we compared the photo-protective effect
of compound 5a with a widely known UV absorber BP-3 (2-hydroxy-4-methoxy-benzophenone).16 As
shown in Figure S1C, both 5a and BP-3 have the photo-protective effect on HaCaT cells and there is no
significant difference between them at the indicated concentrations. Taken together, our results indicated
that 5a is an effective sunscreen candidate.

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Figure 4. (A) Cell viability was assessed after treatment with various concentrations (0 μM, 10 μM, 100
μM, 500 μM, 1000 μM) of compound 5a for 24 h. (B) Compound 5a protected HaCaT cells from
UVB-induced cell death in dose-dependent manner. (C) Pictures of UVB-irradiated HaCaT cells which
were pretreated with or without indicated concentrations of compound 5a were taken at 10 h.
Compound 5a protects BALB/c-nu mice against UVB-induced desquamation and epidermis
thickness
Compound 5a was next investigated its protective effect from UVB induced skin damages in BALB/c-nu
mice. For in vivo studies, the ointment containing 5a (1.0 mM) was applied on the right side of
BALB/c-nu mice dorsal skin once every 12 h while the left side as a control was treated with ointment
without compound 5a. One hour later, the animals were irradiated with Bio-Sun system at wavelength
312 nm for UVB (360 mJ/cm2) irradiation once a day for 7 days. The results were listed in Figure 5A and
Figure 5B. Figure 5A clearly demonstrated that 360 mJ/cm2 UVB irradiation resulted in severe
desquamation whereas treatment with 1.0 mM 5a attenuated those skin damages induced by UVB
irradiation. As shown in Figure 5B, the epidermis thickness of nude mice dorsal skin was incrassate after
UVB exposure and the average thickness of epidermis of UVB-irradiated mice was 86.8 ± 8.4 μm which
was decreased to 37.5 ± 3.7 μm after treatment with 1.0 mM 5a twice a day. Altogether, these data
suggested that compound 5a effectively protect against UVB-induced skin damage in vivo.

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461
Figure 5. (A) BALB/c-nu mice skin were treated with only ointment on left dorsal skin and ointment
containing 10 mg/mL compound 5a on right dorsal skin, and were exposed to UVB. After 7 days,
animals’ images were shot. (B) The normal and UVB irradiated mice skin which was coated with or
without compound 5a were stained with hematoxylin-eosin and beside was a statistic panel.
CONCLUSION
In this study, a novel class of arylthiazole derivatives were designed and synthesized and then their effect
on UVB-induced cellular damage were evaluated by measuring cell viability. The relationship between
their structure and photo-protection activity was concluded. The photo-protection activity of potent
compound 5a was studied at BALB/c-nu mice model. Both in vivo and in vitro experiments suggested
that compound 5a had an excellent photo-protective activity on UVB-induced damage. Further studies to
identify the detail mechanism of photo-protective activity of compound 5a are in process.
EXPERIMENTAL
All of the reagent and solvents used in synthesis experiments were purchased from Sigma-Aldrich and
TCI Co. Ltd, and when necessary, were purified and dried by standard methods before use.
1
The H NMR Spectra were recorded with a Bruker Avance 300 MHz spectrometer instruments, using
TMS as an internal standard. Chemical shifts are expressed in parts per million (ppm). Mass spectra were

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HETEROCYCLES, Vol. 89, No. 2, 2014
obtained in ESI mode via Shimadzu LCMS spectrometer. TLC and preparative thin-layer
chromatography were performed on silica gel GF/UV 254, and the chromatography were performed on
silica gel ( 200-300 mesh) visualized under UV light at 254 nm and 365 nm. Unless otherwise a special
note, the progress of reaction was detected by TLC and protected under nitrogen. High-resolution mass
data of 5a, 8, 11a, 13c, 15 and 17 were obtained on a Micromass Q-Tof UltimaTM spectrometer.
N-(Ethoxycarbonylmethyl)-2-(2-ethyl-4-pyridinyl)-4-methyl-5-thiazolecarboxamide (5a). The title
compound was prepared according to 4a except using glycine ethyl ester hydrochloride instead of aniline.
1
Yield: 44%: H NMR (300 MHz, CDCl3):  8.62 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 5.1 Hz,
1H), 6.71 (br s, 1H), 3.73–3.68 (m, 5H), 2.90 (q, J = 7.2 Hz, 2H), 2.75 (s, 3H), 2.70 (t, J = 5.7 Hz, 2H),
1.35 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3):  169.90, 165.42, 165.11, 161.56, 156.92, 150.39,
140.11, 127.22, 118.88, 118.06, 62.15, 42.17, 31.62, 17.67, 14.35, 13.98. ESI-HRMS Calculated for
[C16H19N3O3S + H]+: 334.1225, found: 334.1227.
Methyl 2-((2-(2-ethyl-4-pyridinyl)-4-methyl-5-thiazolyl)methoxy)acetate (8). To a solution of
compound 7 (1.22 g, 5.2 mmol) in 10 mL of DMF was added sodium hydride (60%, 312 mg, 7.8 mmol)
at 0 C with stirring for 10 min, then methyl 2-bromoacetate (0.73 mL, 7.8 mmol) was added in at the
same temperature. The resultant mixture was sirring at room temperature for 2 h. The reaction was
quenched with ice water and extracted with EtOAc. The organic layer was washed with water and brine
in twice and then dried with anhydrous Na2SO4. After concentrated by a rotary evaporator, the products
was purified by silica gel column chromatography (petroleum ether/EtOAc = 1/1) to give compound 8
(908 mg, 57% yield). 1H NMR (300 MHz, CDCl3):  8.58 (d, J = 5.1 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J =
5.1 Hz, 1H), 4.81 (s, 2H), 4.16 (s, 2H), 3.79 (s, 3H), 2.88 (q, J = 7.2 Hz, 2H), 2.49 (s, 3H), 1.35 (t, J = 7.2
Hz, 3H). ESI-HRMS Calculated for [C15H18N2O3S + H ]+: 307.1116, found: 307.1096.
N-(Ethoxycarbonylmethyl)-2-phenyl-4-methyl-5-thiazolecarboxamide (11a). The title compound was
1
prepared according to 5a except using compound 10a instead of 3b. Yield 63%: H NMR (300 MHz,
CDCl3):  7.94–7.92 (m, 2H), 7.46–7.44 (m, 3H), 6.39 (br s, 1H), 4.27 (q, J = 6.9 Hz, 2H), 4.21 (d, J =
13
4.8 Hz, 2H), 2.77 (s, 3H), 1.32 (t, J = 6.9 Hz, 3H). C NMR (125 MHz, CDCl3):  170.01, 167.98,
161.99, 156.82, 133.08, 131.09, 129.28, 127.00, 125.44, 62.08, 42.15, 17.74, 14.37. ESI-HRMS
Calculated for [C15H16N2O3S + Na]+: 327.0779, found: 327.0777.
N-(Ethoxycarbonylmethyl)-2-phenyl-4-methyl-5-oxazolecarboxamide (13c). The title compound was
1
prepared according to 5a except using compound 12c instead of 3b. Yield 63%: H NMR (300 MHz,
CDCl3):  8.08–8.05 (m, 2H), 7.49–7.47 (m, 3 H), 6.81 (br s, 1H), 4.28 (q, J = 6.9 Hz, 2H), 4.22 (d, J =
13
4.8 Hz, 2H), 2.56 (s, 3H), 1.32 (t, J = 6.9 Hz, 3H). C NMR (125 MHz, CDCl3):  170.02, 160.66,
158.49, 144.92, 138.87, 131.60, 129.15, 127.17, 126.60, 62.02, 41.12, 14.38, 13.31. ESI-HRMS

HETEROCYCLES, Vol. 89, No. 2, 2014
463
Calculated for [C15H16N2O4 + Na]+: 311.1008, found: 311.1003.
N-(Ethoxycarbonylmethyl)-3-phenyl-5-methyl-4-isooxazolecarboxamide (15). The title compound
was prepared according to 5a except using 5-methyl-3-phenyl-4-isoxazolecarboxylic acid instead of 3b.
Yield 44%: 1H NMR (300 MHz, CDCl3):  7.66–7.63 (m, 2H), 7.54–7.52 (m, 3H), 5.95 (br s, 1H), 4.16
(q, J = 7.2 Hz, 2H), 4.03 (d, J = 5.4 Hz, 2H), 2.74 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz,
CDCl3):  174.78, 169.41, 161.81, 160.47, 130.72, 129.39, 129.30, 128.16, 110.70, 61.76, 41.52, 14.32,
13.28. ESI-HRMS Calculated for [C15H16N2O4 + Na]+: 311.1008, found: 311.0997.
N-(Ethoxycarbonylmethyl)-2-phenyl-4-thiazolecarboxamide (17). The title compound was prepared
according to 5a except using 2-(2-ethyl-4-pyridinyl) thiazole-4-carboxylic acid instead of 3b. Yield 27%:
1H NMR (300 MHz, CDCl3):  9.04 (br s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.80 (d, J = 15.3 Hz,), 7.73–7.68
(m, 1H), 7.61–7.56 (m, 2H), 7.05 (d, J = 15.3 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 4.00 (d, J = 2.0 Hz, 2H),
13
3.33 (s, 2H), 1.21 (t, J = 7.2 Hz, 3H). C NMR (125 MHz, CDCl3):  169.88, 166.14, 165.17, 161.01,
150.93, 150.45, 140.00, 124.98, 118.92, 118.04, 61.89, 41.52, 31.68, 14.39, 14.07. ESI-HRMS Calculated
for [C15H17N3O3S + H]+: 320.1069, found: 320.1072.
ACKNOWLEDGEMENTS
This work was supported by the grants from National Basic Research Program of China (2012CB910404),
National Major Scientific and Technological Special Project for "Significant New Drugs Development"
(2013ZX09507001), National Natural Science Foundation of China (81202407), The Science and
Technology Commission of Shanghai Municipality (11DZ2260300), Research Fund for the Doctoral
Program of Higher Education of China (20120076120029) and the Fundamental Research Funds for the
Central Universities (78210048).
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