Novel 2,4,5-trisubstituted oxazole derivatives: Synthesis and antiproliferative activity

Article abstract of DOI:10.1016/j.ejmech.2009.04.019

Microwave irradiation promotes the rapid O,N-acylation-cyclodehydration cascade reaction of oximes and acid chloride. Twenty novel 2,4,5-trisubstituted oxazole derivatives containing heterocycle moiety were synthesized and evaluated for their antiproliferative activity. The twenty compounds are all first reported and their structures were established by elemental analysis, ¹H NMR and ¹³C NMR spectra. The bioassay tests showed that compounds 2-(2-(2-fluorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-ylthio)benzo[d]thiazole (6af), 2-(2-(pyridin-3-yl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-ylthio)pyrimidine (6bg) and 2-(2-(2-fluorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-ylthio)-5-methyl-1,3,4-thiadiazole (6cf) displayed good antiproliferative activity in vitro, which were comparable to the positive control (5-fluorouracil).

Full text of DOI:10.1016/j.ejmech.2009.04.019

European Journal of Medicinal Chemistry 44 (2009) 3930–3935
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel 2,4,5-trisubstituted oxazole derivatives: Synthesis
and antiproliferative activity
,
,b,
*
Xin-Hua Liu a b, Peng-Cheng Lva, Jia-Yu Xue a, Bao-An Song c, Hai-Liang Zhu a
a State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China
b Key Laboratory of Anhui Educational Department, Anhui University of Technology, Maanshan 243002, PR China
c Key Laboratory of Green Pesticide and Agriculture Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave irradiation promotes the rapid O,N-acylation–cyclodehydration cascade reaction of oximes
and acid chloride. Twenty novel 2,4,5-trisubstituted oxazole derivatives containing heterocycle moiety
were synthesized and evaluated for their antiproliferative activity. The twenty compounds are all first
reported and their structures were established by elemental analysis, 1H NMR and 13C NMR spectra. The
bioassay tests showed that compounds 2-(2-(2-fluorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-ylth-
io)benzo[d]thiazole (6af), 2-(2-(pyridin-3-yl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-ylthio)pyrimidine (6bg)
and 2-(2-(2-fluorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-ylthio)-5-methyl-1,3,4-thiadiazole (6cf) dis-
played good antiproliferative activity in vitro, which were comparable to the positive control
(5-fluorouracil).
Received 14 June 2007
Received in revised form
7 April 2009
Accepted 8 April 2009
Available online 17 April 2009
Keywords:
Oxazole
Synthesis
Ó 2009 Elsevier Masson SAS. All rights reserved.
Antiproliferative activity
Structure–activity relationship
1. Introduction
antiproliferative activity. We began with a leading natural
compound pyrogallol, followed by etheration, acylation, bromina-
tion, and etherification, then 2-substituted 1-(2,3,4-trimethox-
Oxazoles are one of the key building elements of natural prod-
ucts. Among the numerous heterocyclic moieties of biological and
pharmacological interest, the oxazole ring is endowed with various
activities [1], such as hypoglycemic [2], analgesic [3], anti-inflam-
matory [4], and antibacterial [5] activities. It is reported that new
yphenyl)ethanone
was
condensed
with
hydroxylamine
hydrochloride, eventually, through microwave irradiation over the
oxime and acyl chloride, the target compounds were obtained.
When we structurally modified an oxazole with diverse substitutes
some of which actually had appeared in drugs and medicine, it was
reasonable to believe that our new compounds would hold better
bioactivity. Through the comparison of their activity, more struc-
ture–activity relationship (SAR) could be reflected.
In this paper, a series of 2,4,5-trisubstituted oxazole derivatives
containing heterocyclic moiety were designed and synthesized. The
structures of the compounds were verified by 1H NMR, 13C NMR
and elemental analysis. Preliminary bioassays indicated that
compounds 6af, 6bg and 6cf displayed good antiproliferative
activity in vitro, which were comparable to the positive control
(5-fluorouracil).
D
2-isoxazoline derivatives can be as
b-adrenergic receptor antag-
onists [2]. A series of new carbapenems containing isoxazole
moiety showed potent antibacterial activities [5]. Besides, Srivas-
tava et al. reported that on evaluation of HIV-inhibitory activity of
5-(2,2-dibromoacetyl)-3-phenylisoxazole [6]. In this case, oxazole
derivatives have raised considerable attention to medicinal
research, and a large number of investigations on their synthesis
and biological activities have been reported during the last ten
years [7–10]. However, little attention has been paid to the
synthesis of 2,4,5-trisubstituted oxazole bearing another hetero-
cyclic moieties. Previous research showed that compounds con-
taining trimethoxyphenyl and benzothiazol moieties had moderate
antiproliferative activity [11–14].
2. Results and discussion
In view of that, a series of pyrogallol derivatives which have the
oxazole moiety were synthesized in order to improve the
2.1. Chemistry
The synthetic route leading to 6 was based on the following
sequence of reactions, as shown in Scheme 1. 1,2,3-trimethox-
ybenzene (1) was prepared from pyrogallol etheration [15],
* Corresponding author. State Key Laboratory of Pharmaceutical Biotechnology,
Nanjing University, Nanjing 210093, PR China. Tel./fax: þ86 25 8359 2672.
E-mail address: zhuhl@nju.edu.cn (H.-L. Zhu).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.04.019

X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 3930–3935
3931
OMe
OH
OMe
MeO
OMe
OMe
HO
OH
MeO
OMe
MeO
I
II
2
1
O
OMe
MeO
OMe
O
OMe
IV
III
R1
Br
S
S
4
3
O
OMe
OMe
MeO
OMe
MeO
OMe
V
VI
R1
R1
S
O
6
5
N
N
OH
R2
N
N
Me
Me
S
Me
N
R =
1
N
N
NN
S
(b)
(a)
(c)
R =
2
CF3
F
Cl
N
(g)
(i)
(e)
(f)
(h)
Scheme 1. Route for synthesis of oxazole. Reagents and conditions: I) Me2SO4, NaOH, 0 ꢀC–r.t., 3–4 h, 82%; II) (CH3CO)2O, PPA, 80%; III) Br2, benzene, 25–60 ꢀC, 20–40 min, 78%; IV)
R1–SH, Et3N, 2–4 h, 74%; V) NH2OH$HCl, CH3OH, pyridine, reflux, 5 h, 70%; VI) N-methylmorpholine, DMF, irradiation, 100 ꢀC, 10 min, then, 5 ꢀC, 10 h.
substituted acetophenone (2) was prepared from trimethox-
ybenzene and acetic anhydride via Friedel–Crafts acetylation
reaction [16], while compound 3 was synthesized by bromination
of substituted acetophenone (2). The ethanone 4a was prepared by
alkylation of thioles [17,18]. The reaction of compound 4 with
hydroxylamine was carried out in methanol catalyzed by pyridine
to produce compound 5, and the reaction was completed within 5 h
at refluxing temperature [19,20]. Using the literature method for
converting oxime to oxazole under microwave irradiation at
various temperatures in pyridine/toluene (5.6:1) actually did not
lead to formation of oxazoles [21]. Then catalytic N-methyl-
morpholine in DMF was added to attempt to facilitate acyl trans-
ferring processes. In addition to a much faster conversion, the
major advantage of microwave irradiation was a considerable
increased yield [22]. Control reactions with oxime 5 and acid
chloride under a range of thermal and optimized microwave
conditions are shown in Table 1.
proliferate in presence of tested material for 48 h, and the results
were reported in terms of IC50 values (Table 2). From the IC50
values, it is obvious that compounds 6af, 6bg and 6cf exhibited
the strongest inhibitory activity against the two assayed cell lines
with some of their IC50s much lower than the positive control,
while compounds 6ag, 6ai, 6bi, 6ce, 6cg, 6ch, 6de, 6df, 6dh and
6di demonstrated less potent cytotoxicity, and the others’ inhi-
bition was much weaker. From the molecular structures of 6af and
6cf, it can be clearly figured out that they have an identical
substitute group R2, which may be crucial. Based on the above
facts, it can be concluded that the fluorophenyl group has an
important effect on the antiproliferative activity. In addition, it
was noted that both 6af and 6cf held S-containing groups,
comparing them to 6bf and 6df without an S-containing group, it
was found that the former two showed clearly higher inhibitory
activity than the latter ones. By comparing the average IC50 values
Table 1
Microwave promoted oxazole formation reaction.
2.2. Biological activity
Entry
Solvent (v/v)
Conditions
120 ꢀC, 18 h
Additive 6ae (Yield/%)
It is reported that oxazoles showed antiproliferative activity
against many cancer cells, especially PC-3 (human prostate cancer)
and A431 (human epidermoid carcinoma) [23–25]. In view of that,
in order to search for new antiproliferative agents, all the twenty
compounds were evaluated for their antiproliferative activity
against the above two cell lines. The cells were allowed to
1
2
3
4
5
Pyridine/toluene (5.6:1)
Pyridine/toluene (5.6:1)
DMF
DMF
DMF
–
–
m
m
m
m
W, 100 ꢀC, 30 min
W, 120 ꢀC, 15 min
W, 140 ꢀC, 30 min
W, 100 ꢀC, 10 min
NMMa
NMMa
NMMa
NMMa
–
37.2
22.3
62.5
a
5 mol % of NMM was used.

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X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 3930–3935
Table 2
3.3. Spectral properties of intermediate compounds 3, 4a–d and 5a–d
3.3.1. 2-Bromo-1-(2,3,4-trimethoxyphenyl)ethanone (3)
Antiproliferative activity of the synthesized compounds against PC-3 and A431cell
lines.
1H NMR (400 MHz, CDCl3)
d
: 3.75–3.84 (3s, 9H), 4.69 (s, 2H),
Compound
IC50
PC-3
0.036
(
m
M)
Compound
IC50
PC-3
0.022
0.0035
0.032
0.024
0.042
0.023
0.020
0.035
0.018
0.020
(mM)
6.52–7.38 (m, 2H); 13C NMR (100 MHz, CDCl3)
d: 31.5, 56.2, 56.5,
A431
A431
56.6, 108.3, 114.2, 122.6, 138.9, 153.0, 155.2, 192.3. ESI-MS: 289.1
(C11H14BrO4, [M þ H]þ). Anal. Calcd for C11H13BrO4: C 45.70, H 4.53;
Found C 45.71, H 4.51.
6ae
6af
6ag
6ah
6ai
6be
6bf
6bg
0.047
0.0031
0.026
0.032
0.042
0.059
0.038
0.0076
0.109
0.032
0.018
6ce
6cf
6cg
6ch
6ci
6de
6df
6dg
6dh
6di
0.025
0.0026
0.022
0.041
0.038
0.028
0.020
0.081
0.021
0.023
0.0030
0.023
0.039
0.025
0.066
0.051
0.0047
0.047
0.023
0.016
3.3.2. 2-(Benzo[d]thiazol-2-ylthio)-1-(2,3,4-trimethoxyphenyl)
ethanone (4a)
1H NMR (400 MHz, CDCl3)
d
: 3.73–3.81 (3s, 9H), 4.59 (s, 2H),
6.48–8.41 (m, 6H); 13C NMR (100 MHz, CDCl3)
d: 39.4, 56.5, 56.7,
6bh
6bi
56.8, 108.1, 114.4, 121.2, 121.4, 122.9, 126.1, 127.0, 134.6, 139.6, 151.5,
153.0, 156.0, 165.3, 195.0. ESI-MS: 376.1 (C18H18NO4S2, [M þ H]þ).
Anal. Calcd for C18H17NO4S2: C 57.58, H 4.56; Found C 57.59, H 4.54.
5-Fluorouracila
The data represented the mean of three experiments in triplicate.
The IC50 value was defined as the concentration at which 50% survival of cells was
observed. The results are listed in the table.
a
3.3.3. 2-(Pyrimidin-2-ylthio)-1-(2,3,4-trimethoxyphenyl)ethanone (4b)
Used as a positive control.
1H NMR (400 MHz, CDCl3)
d: 3.75–3.80 (3s, 9H), 4.28 (s, 2H),
6.48–7.32 (m, 3H), 8.79 (d, J ¼ 5.1 Hz, 2H); 13C NMR (100 MHz,
of four groups of synthetic compounds (6ae–6ai, 6be–6bi, 6ce–6ci
and 6de–6di), it was found that the third group (6ce–6ci)
exhibited the highest inhibition, indicating that thiadiazole may
play an important role in antiproliferative activities against the
two cancer cells.
CDCl3) d: 40.2, 56.3, 56.5, 56.6, 108.4, 114.2, 117.5, 123.7, 140.0, 152.0,
155.9, 158.1, 172.8, 195.2. ESI-MS: 321.1 (C15H17N2O4S2, [M þ H]þ).
Anal. Calcd for C15H16N2O4S2: C 56.24, H 5.03; Found C 56.26, H
5.05.
3.3.4. 2-(5-Methyl-1,3,4-thiadiazol-2-ylthio)-1-(2,3,4-
trimethoxyphenyl)ethanone (4c)
3. Experimental section
1H NMR (400 MHz, CDCl3)
d
: 2.32 (s, 3H), 3.73–3.79 (3s, 9H),
4.26 (s, 2H), 6.51–7.32 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
: 17.1,
3.1. General
38.9, 56.5, 56.6, 56.7, 108.3, 114.0, 123.3, 140.3, 152.1, 155.9, 165.0,
167.9, 194.7. ESI-MS: 341.1 (C14H17N2O4S2, [M þ H]þ). Anal. Calcd for
C14H16N2O4S2: C 49.40, H 4.74; Found C 49.42, H 4.73.
Melting points (uncorrected) were determined on an XT4 MP
apparatus (Taike Corp., Beijing, China). ESI mass spectra were
obtained on a Mariner System 5304 mass spectrometer, and 1H
NMR spectra were recorded on a Bruker PX500 or DPX300 spec-
trometer at 25 ꢀC with TMS and solvent signals allotted as internal
standards. The 13C NMR spectra were recorded on a Varian
INOVA400 (100 MHz) pulse Fourier-transform NMR spectrometer.
Chemical shifts were reported in ppm (d). Elemental analysis was
performed by a Vario-III CHN analyzer. The reagents were all
analytical reagents or chemically pure.
3.3.5. 2-(4,5-Dimethylpyrimidin-2-ylthio)-1-(2,3,4-
trimethoxyphenyl)ethanone (4d)
1H NMR (400 MHz, CDCl3)
d
: 2.37–2.41 (2s, 6H), 3.73–3.78 (3s,
9H), 4.24 (s, 2H), 6.48–7.32 (m, 2H), 8.51 (s, 1H); 13C NMR (100 MHz,
CDCl3) : 17.4, 17.5, 39.3, 56.4, 56.6, 56.7, 108.0, 114.2, 123.7, 12.9,
d
140.0, 152.1, 155.7, 158.2, 163.9, 169.9, 194.9. ESI-MS: 349.1
(C17H21N2O4S, [M þ H]þ). Anal. Calcd for C17H20N2O4S: C 58.60, H
5.79; Found C 58.62, H 5.78.
3.2. General procedure for the synthesis of compounds 1, 2, 3, 4, 5
3.3.6. (Z)-2-(Benzo[d]thiazol-2-ylthio)-1-(2,3,4-
trimethoxyphenyl)ethanone oxime (5a)
1,2,3-trimethoxybenzene (1) was prepared from pyrogallol.
Treating pyrogallol (1.26 g, 10 mmol) with dimethyl sulfate yielded
compound 1 (1.34 g, 82%). Treating 1,2,3-trimethoxybenzene (1)
(1.68 g, 10 mmol) with acetic anhydride via Friedel–Crafts acetyla-
tion reaction gave substituted acetophenone (2) (1.78 g, 80%).
Compound 3 was synthesized by bromination of substituted ace-
tophenone (2) with a yield of 78%, and compound 4a was prepared
by alkylation of thioles with a yield of 74%. Treating compound 4a
with hydroxylamine in methanol catalyzed by pyridine produced
compound 5a, and the reaction was completed within 5 h at
refluxing temperature with a yield of 70%. Similarly, 4b–4d were
prepared according to the same method as 4a, and 5b–5d were
prepared following the same method as 5a.
Derivatives 5a–d were obtained from the oxime formation
reaction as a mixture of E and Z isomers, E/Z ratios depended on the
reaction conditions and substituents. As in the Z isomers hetero-
cyclic moieties and hydroxy group are situated on one side relative
to the imino bond of oxime, the formation of the intramolecular
hydrogen bond occurred, that led to the appearance of the shift
corresponding to the signal of hydrogen from N–OH group at
around 10.8 ppm.
1H NMR (400 MHz, CDCl3)
d
: 3.73–3.79 (3s, 9H), 4.76 (s, 2H),
6.68–8.42 (m, 6H), 10.92 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
: 36.2,
56.5, 56.6, 56.8, 108.4, 110.9, 122.8, 123.0, 123.9, 125.8, 126.1, 136.2,
140.5, 151.7, 154.1, 154.6, 164.9, 165.3. ESI-MS: 391.1 (C18H19N2O4S2,
[M þ H]þ). Anal. Calcd for C18H18N2O4S2: C 55.37, H 4.65; Found C
55.39, H 4.64.
3.3.7. (Z)-2-(Pyrimidin-2-ylthio)-1-(2,3,4-trimethoxyphenyl)
ethanone oxime (5b)
1H NMR (400 MHz, CDCl3)
d: 3.78–3.80 (3s, 9H), 4.39 (s, 2H),
6.57–7.39 (m, 3H), 8.82 (d, J ¼ 5.1 Hz, 2H), 10.85 (s, 1H); 13C NMR
(100 MHz, CDCl3) d: 36.3, 56.4, 56.5, 56.7, 108.2, 111.1, 117.2, 124.3,
140.4, 152.4, 153.9, 157.8, 165.6, 172.8. ESI-MS: 336.1 (C15H18N3O4S,
[M þ H]þ). Anal. Calcd for C15H17N3O4S: C 53.72, H 5.11; Found C
53.74, H 5.13.
3.3.8. (Z)-2-(5-Methyl-1,3,4-thiadiazol-2-ylthio)-1-(2,3,4-
trimethoxyphenyl)ethanone oxime (5c)
1H NMR (400 MHz, CDCl3)
d
: 2.38 (s, 3H), 3.77–3.79 (3s, 9H),
4.41 (s, 2H), 6.61–7.39 (m, 2H), 10.88 (s, 1H); 13C NMR (100 MHz,
CDCl3) : 17.3, 36.6, 56.5, 56.6, 56.7, 108.5, 110.9, 124.2, 140.5, 152.5,
d

X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 3930–3935
3933
153.8, 165.0, 165.7, 168.2. ESI-MS: 356.1 (C14H18N3O4S2, [M þ H]þ).
132.7,135.4,136.9,138.4,139.8,149.5,150.9,153.6,159.2,167.2. ESI-MS:
511.0 (C25H20ClN2O4S2, [M þ H]þ). Anal. Calcd for C25H19ClN2O4S2: C
58.76, H 3.75, N 5.48; Found: C 58.51, H 3.89, N 5.40.
Anal. Calcd for C14H17N3O4S2: C 47.31, H 4.82; Found C 47.32, H 4.80.
3.3.9. (Z)-2-(4,5-Dimethylpyrimidin-2-ylthio)-1-(2,3,4-
trimethoxyphenyl)ethanone oxime (5d)
3.4.5. 2-(2-Phenyl-4-(2,3,4-trimethoxyphenyl)oxazol-5-ylthio)
benzo[d]thiazole (6ai)
1H NMR (400 MHz, CDCl3)
d
: 2.67–2.70 (2s, 6H), 3.73–3.77
(3s, 9H), 4.69 (s, 2H), 6.61–7.41 (m, 2H), 8.68 (s, 1H), 10.86 (s, 1H);
13C NMR (100 MHz, CDCl3)
: 17.2, 17.4, 36.4, 56.5, 56.7, 56.8, 108.2,
Colorless crystals, yield 58.9%. Mp: 140–141 ꢀC, 1H NMR
d
(400 MHz, CDCl3)
d
: 3.77–3.92 (3s, 9H), 6.30 (d, J ¼ 8.8 Hz, 1H), 6.87
110.9, 124.1, 124.3, 140.3, 151.9, 154.2, 157.8, 164.1, 165.2, 170.1. ESI-
MS: 364.1 (C17H22N3O4S, [M þ H]þ). Anal. Calcd for C17H21N3O4S: C
56.18, H 5.82; Found C 56.16, H 5.81.
(d, J ¼ 8.8 Hz,1H), 7.20–7.45 (m, 5H), 7.52 (m, 2H), 8.15 (d, J ¼ 8.2 Hz,
1H), 8.28 (d, J ¼ 8.2 Hz,1H); 13C NMR (100 MHz, CDCl3)
d: 56.2, 56.4,
56.5, 108.2, 112.5, 121.7, 121.8, 121.9, 125.3, 125.6, 125.9, 126.2, 127.8,
128.9, 129.7, 135.4, 138.3, 139.8, 149.4, 150.6, 153.8, 159.3, 167.0. ESI-
MS: 477.9 (C25H21N2O4S2, [M þ H]þ). Anal. Calcd for C25H20N2O4S2:
C 63.01, H 4.23, N 5.88; Found: C 62.79, H 4.55, N 6.20.
3.4. General procedure for the synthesis of compound 6
3.4.1. 2-(2-(4-(Trifluoromethyl)phenyl)-4-(2,3,4-trimethoxyphenyl)
oxazol-5-ylthio)benzo[d]thiazole (6ae)
3.4.6. 2-(2-(4-(Trifluoromethyl)phenyl)-4-(2,3,4-
To a solution of oxime 5a (2 mmol) and N-methylmorpholine
(0.010 mmol) in DMF (30 mL) at 1–5 ꢀC was added dropwise
4-trifluoromethylbenzoyl chloride (2.5 mmol). The reaction
mixture was heated in the microwave for 10 min at 100 ꢀC and
poured into water (50 mL), then the solution was maintained at
5 ꢀC for 10 h. The product was collected by filtration, and the crude
residue was purified by chromatography on SiO2 (acetone/petro-
leum, 3:1) to give 6ae (0.68 g, 62.5%) as a colorless solid. Mp:
171–172 ꢀC. Other title compounds were prepared according to the
trimethoxyphenyl)oxazol-5-ylthio)pyrimidine (6be)
Colorless crystals, yield 63.1%. Mp: 91–92 ꢀC, 1H NMR (400 MHz,
CDCl3)
J ¼ 8.8 Hz, 1H), 7.18 (m, 1H), 7.44–7.56 (m, 4H), 8.69 (d, J ¼ 5.1 Hz,
2H); 13C NMR (100 MHz, CDCl3)
: 56.2, 56.3, 56.5, 108.3, 112.5,
d
: 3.76–3.92 (3s, 9H), 6.30 (d, J ¼ 8.8 Hz, 1H), 6.90 (d,
d
118.9, 121.9, 124.4, 125.7, 126.1, 127.9, 129.7, 131.2, 138.5, 139.9, 149.4,
151.0, 157.9, 159.4, 172.2. ESI-MS: 490.1 (C23H19F3N3O4S, [M þ H]þ).
Anal. Calcd for C23H18F3N3O4S: C 56.44, H 3.71, N 8.58; Found: C
56.77, H 3.80, N 8.41.
same method. 1H NMR (400 MHz, CDCl3)
d: 3.78–3.95 (3s, 9H), 6.34
(d, J ¼ 8.8 Hz,1H), 6.90 (d, J ¼ 8.8 Hz,1H), 7.39–7.50 (m, 4H), 7.58 (m,
3.4.7. 2-(2-(2-Fluorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)pyrimidine (6bf)
2H), 8.16 (d, J ¼ 8.2 Hz, 1H), 8.24 (d, J ¼ 8.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3)
d: 56.1, 56.3, 56.4, 108.2, 112.2, 121.5, 121.7, 121.9,
Colorless crystals, yield 56.9%. Mp: 87–88 ꢀC, 1H NMR (400 MHz,
124.2, 125.5, 125.7, 125.8, 125.9, 127.8, 129.8, 131.3, 135.3, 138.3,
139.8, 149.5, 150.6, 153.5, 159.0, 167.6. ESI-MS: 545.1
(C26H20F3N2O4S2, [M þ H]þ). Anal. Calcd for C26H19F3N2O4S2: C
57.34, H 3.52, N 5.14; Found: C 57.61, H 3.81, N 4.92.
CDCl3)
d
: 3.75–3.89 (3s, 9H), 6.30 (d, J ¼ 8.8 Hz, 1H), 6.86 (d,
J ¼ 8.8 Hz, 1H), 7.00–7.48 (m, 5H), 8.66 (d, J ¼ 5.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d: 56.2, 56.5, 56.6, 108.2, 112.4, 116.2, 119.2, 122.1,
123.7, 125.2, 125.6, 129.4, 130.6, 138.5, 139.8, 149.4, 150.9, 157.9,
158.4, 159.5, 172.1. ESI-MS: 440.1 (C22H19FN3O4S, [M þ H]þ). Anal.
Calcd for C22H18FN3O4S: C 60.13, H 4.13, N 9.56; Found: C 60.22, H
3.91, N 9.79.
3.4.2. 2-(2-(2-Fluorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)benzo[d]thiazole (6af)
Colorless crystals, yield 66.3%. Mp: 153–154 ꢀC, 1H NMR
(400 MHz, CDCl3)
d
: 3.75–3.96 (3s, 9H), 6.32 (d, J ¼ 8.8 Hz, 1H), 6.88
3.4.8. 2-(2-(Pyridin-3-yl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)pyrimidine (6bg)
(d, J ¼ 8.8 Hz,1H), 7.00–7.48 (m, 4H), 7.58 (m, 2H), 8.11 (d, J ¼ 8.2 Hz,
1H), 8.26 (d, J ¼ 8.2 Hz,1H); 13C NMR (100 MHz, CDCl3)
d: 56.3, 56.4,
Colorless crystals, yield 59.2%. Mp: 115–116 ꢀC, 1H NMR
56.5, 108.2, 112.4, 116.3, 121.6, 121.8, 122.1, 123.7, 125.0, 125.4, 125.6,
126.1, 129.4, 130.2, 135.3, 138.4, 139.7, 149.5, 150.9, 153.8, 155.5,
159.6, 167.9. ESI-MS: 495.1 (C25H20FN2O4S2, [M þ H]þ). Anal. Calcd
for C25H19FN2O4S2: C 60.71, H 3.87, N 5.66; Found C 60.88, H 3.61, N
5.91.
(400 MHz, CDCl3)
d
: 3.79–3.88 (3s, 9H), 6.33 (d, J ¼ 8.8 Hz, 1H), 6.88
(d, J ¼ 8.8 Hz, 1H), 7.12 (m, 1H), 7.48 (q, 1H), 7.97 (d, J ¼ 7.7 Hz, 1H),
8.47 (d, J ¼ 6.1 Hz, 1H), 8.68 (d, J ¼ 5.2 Hz, 2H), 8.89 (s, 1H); 13C NMR
(100 MHz, CDCl3) d: 56.2, 56.3, 56.6, 108.3, 112.6, 118.9, 122.0, 124.2,
124.8, 125.6, 134.0, 138.7, 140.2, 148.4, 149.3, 149.5, 151.1, 158.0,
159.6, 172.0. ESI-MS: 423.1 (C21H19N4O4S, [M þ H]þ). Anal. Calcd for
C21H18N4O4S: C 59.70, H 4.29, N 13.26; Found: C 60.01, H 4.04, N
13.55.
3.4.3. 2-(2-(Pyridin-3-yl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)benzo[d]thiazole (6ag)
Colorless crystals, yield 61.0%. Mp: 197–198 ꢀC, 1H NMR
(400 MHz, CDCl3)
d
: 3.75–3.94 (3s, 9H), 6.30 (d, J ¼ 8.8 Hz, 1H), 6.8
3.4.9. 2-(2-(2-Chlorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)pyrimidine (6bh)
(d, J ¼ 8.8 Hz, 1H), 7.48–7.59 (m, 3H), 7.93 (d, J ¼ 7.9 Hz, 1H), 8.16 (d,
J ¼ 8.2 Hz, 1H), 8.31 (d, J ¼ 8.2 Hz, 1H), 8.60 (d, J ¼ 6.1 Hz, 1H), 8.84
Colorless crystals, yield 57.1%. Mp: 100–101 ꢀC, 1H NMR
(s, 1H); 13C NMR (100 MHz, CDCl3)
d: 56.3, 56.4, 56.6, 108.3, 112.5,
(400 MHz, CDCl3)
d
: 3.75–3.89 (3s, 9H), 6.35 (d, J ¼ 8.8, 1H), 6.90 (d,
121.6, 121.8, 121.9, 124.2, 124.8, 125.5, 125.6, 126.3, 134.5, 135.5,
138.4, 139.6, 148.2, 149.5, 149.6, 150.9, 153.4, 159.5, 167.1. ESI-MS:
478.1 (C24H20N3O4S2, [M þ H]þ). Anal. Calcd for C24H19N3O4S2: C
60.36, H 4.01, N 8.80; Found: C 60.11, H 3.64, N 8.46.
J ¼ 8.8, 1H), 7.12 (m, 1H), 7.18–7.46 (m, 4H), 8.71 (d, J ¼ 5.2, 2H); 13C
NMR (100 MHz, CDCl3) d: 56.2, 56.4, 56.6, 108.5, 112.4, 119.2, 122.1,
125.7, 127.9, 129.3, 129.8, 130.4, 132.8, 137.3, 138.4, 140.2, 149.4,
151.0, 158.1, 159.3, 172.2. ESI-MS: 456.1 (C22H19ClN3O4S, [M þ H]þ).
Anal. Calcd for C22H18ClN3O4S: C 57.96, H 3.98, N 9.22; Found: C
58.05, H 4.17, N 9.01.
3.4.4. 2-(2-(2-Chlorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)benzo[d]thiazole (6ah)
Colorless crystals, yield 64.2%. Mp: 180–181 ꢀC, 1H NMR (400 MHz,
3.4.10. 2-(2-Phenyl-4-(2,3,4-trimethoxyphenyl)oxazol-5-ylthio)
pyrimidine (6bi)
CDCl3)
d
: 3.75–3.89 (3s, 9H), 6.26 (d, J ¼ 8.8 Hz, 1H), 6.86 (d, J ¼ 8.8 Hz,
1H), 7.18–7.45 (m, 4H), 7.59 (m, 2H), 8.10 (d, J ¼ 8.2 Hz, 1H), 8.25 (d,
Colorless crystals, yield 69.2%. Mp: 89–91 ꢀC, 1H NMR (400 MHz,
J ¼ 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d: 56.2, 56.3, 56.6, 108.2,
CDCl3)
d
: 3.79–3.94 (3s, 9H), 6.29 (d, J ¼ 8.8 Hz, 1H), 6.88 (d,
112.4, 121.9, 122.2, 122.4, 125.4, 125.7, 126.2, 127.7, 128.9, 129.6, 130.5,
J ¼ 8.8 Hz, 1H), 7.10 (m, 1H), 7.18–7.46 (m, 5H), 8.75 (d, J ¼ 5.2 Hz,

3934
X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 3930–3935
2H); 13C NMR (100 MHz, CDCl3)
d
: 56.0, 56.4, 56.5, 108.3, 112.5,
(d, J ¼ 8.8 Hz, 1H), 6.91 (d, J ¼ 8.8 Hz, 1H), 7.46–7.56 (m, 4H), 8.31
(s, 1H); 13C NMR (100 MHz, CDCl3)
: 17.9, 18.1, 56.1, 56.3, 56.4,
108.3, 112.5, 122.1, 124.6, 125.7, 126.0, 126.2, 127.2, 129.9, 131.5,
138.4, 140.0, 149.8, 150.2, 157.6, 159.8, 164.4, 169.9. ESI-MS: 518.1
(C25H23F3N3O4S, [M þ H]þ). Anal. Calcd for C25H22F3N3O4S: C 58.02,
H 4.28, N 8.12; Found: C 58.24, H 4.41, N 8.01.
119.0, 122.0, 125.6, 126.5, 127.8, 129.1, 129.6, 138.7, 140.4, 149.5,
151.3, 158.2, 159.4, 171.7. ESI-MS: 422.1 (C22H20N3O4S, [M þ H]þ).
Anal. Calcd for C22H19N3O4S: C, 62.69; H, 4.54; N, 9.97; Found: C,
62.77; H, 4.19; N, 10.12.
d
3.4.11. 2-Methyl-5-(2-(4-(trifluoromethyl)phenyl)-4-(2,3,4-
trimethoxyphenyl)oxazol-5-ylthio)-1,3,4-thiadiazole (6ce)
Colorless crystals, yield 70.5%. Mp: 168–169 ꢀC, 1H NMR
3.4.17. 2-(2-(2-Fluorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)-4,5-dimethylpyrimidine (6df)
(400 MHz, CDCl3)
d
: 2.26 (s, 3H), 3.70–3.87 (3s, 9H), 6.38 (d,
Colorless crystals, yield 56.0%. Mp: 116–117 ꢀC, 1H NMR
J ¼ 8.8 Hz, 1H), 6.97 (d, J ¼ 8.8 Hz, 1H), 7.32–7.58 (m, 4H); 13C NMR
(400 MHz, CDCl3)
(d, J ¼ 8.8 Hz, 1H), 6.93 (d, J ¼ 8.8 Hz, 1H), 7.05–7.50 (m, 4H), 8.36
(s, 1H); 13C NMR (100 MHz, CDCl3)
: 17.9, 18.0, 56.2, 56.3, 56.5,
d: 2.31–2.36 (2s, 6H), 3.75–3.91 (3S, 9H), 6.30
(100 MHz, CDCl3) d: 16.9, 56.4, 56.5, 56.6, 108.0, 112.1, 122.2, 124.0,
125.5, 127.4, 128.1, 129.7, 131.3, 137.7, 140.2, 149.1, 151.4, 159.0, 161.5,
167.8. ESI-MS: 510.1 (C22H19F3N3O4S2, [M þ H]þ). Anal. Calcd for
C22H18F3N3O4S2: C 51.86, H 3.56, N 8.25; Found: C 52.07, H 3.44, N
8.11.
d
108.4, 112.6, 116.7, 121.9, 123.8, 124.6, 125.3, 126.5, 129.6, 131.0,
138.7, 140.2, 149.5, 150.9, 157.9, 159.0, 159.4, 164.8, 169.9. ESI-MS:
468.1 (C24H23FN3O4S, [M þ H]þ). Anal. Calcd for C24H22FN3O4S: C
61.66, H 4.74, N 8.99; Found: C 61.47, H 5.02, N 9.21.
3.4.12. 2-(2-(2-Fluorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)-5-methyl-1,3,4-thiadiazole (6cf)
3.4.18. 4,5-Dimethyl-2-(2-(pyridin-3-yl)-4-(2,3,4-
Colorless crystals, yield 71.3%. Mp: 154–155 ꢀC, 1H NMR
trimethoxyphenyl)oxazol-5-ylthio)pyrimidine (6dg)
(400 MHz, CDCl3)
d: 2.32 (s, 3H), 3.73–3.88 (3s, 9H), 6.34 (d,
Colorless crystals, yield 54.1%. Mp: 158–159 ꢀC, 1H NMR
J ¼ 8.8 Hz, 1H), 6.90 (d, J ¼ 8.8 Hz, 1H), 7.01–7.50 (m, 4H); 13C NMR
(400 MHz, CDCl3) d: 2.34–2.40 (2s, 6H), 3.77–3.90 (3s, 9H), 6.33
(100 MHz, CDCl3)
d
: 16.3, 56.2, 56.5, 56.6, 108.3, 112.5, 116.7, 121.9,
(d, J ¼ 8.8 Hz, 1H), 6.92 (d, J ¼ 8.8 Hz, 1H), 7.40 (q, 1H), 7.92
123.8, 125.2, 125.1, 128.7, 129.9, 138.3, 140.0, 149.4, 151.0, 158.0,
159.8, 161.7, 166.9. ESI-MS: 460.1 (C21H19FN3O4S2, [M þ H]þ). Anal.
Calcd for C21H18FN3O4S2: C 54.89, H 3.95, N 9.14; Found: C 55.08, H
3.74, N 8.89.
(d, J ¼ 7.7 Hz, 1H), 8.26 (s, 1H), 8.61 (d, J ¼ 6.1 Hz, 1H), 8.89 (s, 1H);
13C NMR (100 MHz, CDCl3)
d: 17.6, 17.7, 56.2, 56.3, 56.4, 108.1, 112.4,
122.1, 123.9, 124.4, 125.6, 126.3, 134.7, 138.4, 140.0, 148.3, 150.0,
150.2, 157.6, 159.0, 159.5, 164.4, 169.5. ESI-MS: 451.1 (C23H23N4O4S,
[M þ H]þ). Anal. Calcd for C23H22N4O4S: C 61.32, H 4.92, N 12.44;
Found: C 61.41, H 5.09, N 12.17.
3.4.13. 3-(5-(5-Methyl-1,3,4-thiadiazol-2-ylthio)-4-(2,3,4-
trimethoxyphenyl)oxazol-2-yl)pyridine (6cg)
Colorless crystals, yield 77.8%. Mp: 189–190 ꢀC, 1H NMR
3.4.19. 2-(2-(2-Chlorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)-4,5-dimethylpyrimidine (6dh)
(400 MHz, CDCl3)
d: 2.33 (s, 3H), 3.77–3.89 (3s, 9H), 6.32 (d,
J ¼ 8.8 Hz, 1H), 6.90 (d, J ¼ 8.8 Hz, 1H), 7.38 (q, 1H), 8.01 (d,
Colorless crystals, yield 61.1%. Mp: 136–137 ꢀC, 1H NMR
J ¼ 7.7 Hz, 1H), 8.51 (d, J ¼ 6.2 Hz, 1H), 8.89 (s, 1H); 13C NMR
(400 MHz, CDCl3)
(d, J ¼ 8.8 Hz, 1H), 6.90 (d, J ¼ 8.8 Hz, 1H), 7.18–7.47 (m, 4H), 8.26
(s, 1H); 13C NMR (100 MHz, CDCl3)
: 17.8, 18.0, 56.2, 56.3, 56.5,
d: 2.30–2.36 (2s, 6H), 3.75–3.9 (3s, 9H), 6.28
(100 MHz, CDCl3) d: 16.4, 56.2, 56.3, 56.4, 108.4, 112.2, 122.0, 124.3,
124.5, 125.8, 134.3, 138.7, 140.1, 148.5, 149.4, 149.5, 150.6, 159.5,
161.4, 167.5. ESI-MS: 443.1 (C20H19N4O4S2, [M þ H]þ). Anal. Calcd
for C20H18N4O4S2: C 54.28, H 4.10, N 12.66; Found: C 54.55, H 4.36,
N 12.30.
d
108.3, 112.3, 121.9, 125.7, 126.6, 127.8, 129.3, 129.8, 130.7, 132.8,
136.8, 138.3, 140.1, 149.6, 150.6, 158.1, 159.4, 164.2, 169.6. ESI-MS:
484.1 (C24H23ClN3O4S, [M þ H]þ). Anal. Calcd for C24H22ClN3O4S: C
59.56, H 4.58, N 8.68; Found: C 59.69, H 4.30, N 9.02.
3.4.14. 2-(2-(2-Chlorophenyl)-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)-5-methyl-1,3,4-thiadiazole (6ch)
3.4.20. 4,5-Dimethyl-2-(2-phenyl-4-(2,3,4-
Colorless crystals, yield 70.8%. Mp: 178–179 ꢀC, 1H NMR
trimethoxyphenyl)oxazol-5-ylthio)pyrimidine (6di)
(400 MHz, CDCl3)
d: 2.38 (s, 3H), 3.75–3.87 (3s, 9H), 6.35 (d,
Colorless crystals (yield 51.7%). Mp: 96–97 ꢀC, 1H NMR
J ¼ 8.8 Hz, 1H), 6.89 (d, J ¼ 8.8 Hz, 1H), 7.14–7.48 (m, 4H); 13C NMR
(400 MHz, CDCl3)
J ¼ 8.8 Hz, 1H), 6.92 (d, J ¼ 8.8 Hz, 1H), 7.26–7.49 (m, 5H), 8.30 (s,
1H); 13C NMR (100 MHz, CDCl3)
: 17.9, 18.0, 56.4, 56.5, 56.6, 108.3,
d: 2.33–2.40 (2s, 6H), 3.77–3.91 (3s, 9H), 6.24 (d,
(100 MHz, CDCl3) d: 16.7, 56.2, 56.3, 56.5, 108.5, 112.5, 121.7, 125.6,
127.2, 129.2, 129.8, 130.3, 132.5, 137.2, 138.7, 139.1, 149.0, 150.9,
159.8, 161.2, 166.9. ESI-MS: 476.0 (C21H19ClN3O4S2, [M þ H]þ). Anal.
Calcd for C21H18ClN3O4S2: C 52.99, H 3.81, N 8.83; Found: C 52.81, H
4.10, N 9.07.
d
112.2, 122.0, 125.7, 126.3, 126.4, 127.9, 129.1, 129.7, 138.4, 140.0,
149.4, 151.1, 158.2, 159.6, 164.4, 169.8. ESI-MS: 450.1 (C24H24N3O4S,
[M þ H]þ). Anal. Calcd for C24H23N3O4S: C 64.13, H 5.16, N 9.35;
Found: C 64.01, H 5.44, N 9.64.
3.4.15. 2-Methyl-5-(2-phenyl-4-(2,3,4-trimethoxyphenyl)oxazol-5-
ylthio)-1,3,4-thiadiazole (6ci)
3.5. Antiproliferative assay
Colorless crystals, yield 68.7%. Mp: 144–145 ꢀC, 1H NMR
(400 MHz, CDCl3)
d
: 2.34 (s, 3H), 3.79–3.88 (3s, 9H), 6.32 (d, J ¼ 8.8,
The method for cytotoxicity evaluation was described elsewhere
[26,27] with some modifications. Briefly, target tumor cells were
grown to log phase in RPMI 1640 medium supplemented with 10%
fetal bovine serum. After diluting to 3 ꢁ104 cells mlꢂ1 with the
1H), 6.88 (d, J ¼ 8.8 Hz, 1H), 7.28–7.55 (m, 5H); 13C NMR (100 MHz,
CDCl3) d: 16.8, 56.4, 56.5, 56.7, 108.0, 112.1, 121.9, 125.8, 126.8, 128.0,
129.2, 130.0, 138.8, 140.2, 149.5, 151.1, 159.6, 161.5, 167.4. ESI-MS:
442.1 (C21H20N3O4S2, [M þ H]þ). Anal. Calcd for C21H19N3O4S2: C
57.13, H 4.34, N 9.52; Found: C 57.00, H 4.59, N 9.19.
complete medium, 100 mL of the obtained cell suspension was
added to each well of 96-well culture plates. The subsequent incu-
bation was permitted at 37 ꢀC, 5% CO2 atmosphere for 24 h before
the cytotoxicity assessment. Tested samples at pre-set concentra-
tions were added to 6 wells with 5-fluorouracil co-assayed as
3.4.16. 4,5-Dimethyl-2-(2-(4-(trifluoromethyl)phenyl)-4-(2,3,4-
trimethoxyphenyl)oxazol-5-ylthio)pyrimidine (6de)
Colorless crystals, yield 52.5%. Mp: 131–132 ꢀC, 1H NMR
a positive reference. After 48-h exposure period, 25 mL of PBS con-
(400 MHz, CDCl3)
d
: 2.32–2.39 (2s, 6H), 3.77–3.90 (3s, 9H), 6.26
taining 2.5 mg mlꢂ1 of MTT (¼3-(4,5-dimethylthiazol-2-yl)-2,

X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 3930–3935
3935
[11] M. Sriram, J.J. Hall, N.C. Grohmann, T.E. Strecker, T. Wootton, A. Franken,
M.L. Trawick, K.G. Pinney, Bioorg. Med. Chem. 16 (2008) 8161–8171.
[12] R. Romagnoli, P.G. Baraldi, T. Sarkar, M.D. Carrion, O. Cruz-Lopez, C.L. Cara,
M. Tolomeo, S. Grimaudo, A.D. Cristina, M.R. Pipitone, J. Balzarini, R. Gambari,
L. Ilaria, R. Saletti, A. Brancale, E. Hamel, Bioorg. Med. Chem. 16 (2008) 8419–
8426.
[13] K. Odlo, J. Hentzen, J.F. dit Chabert, S. Ducki, Osman A.B.S.M. Gani, I. Sylte,
M. Skrede, V.A. Flørenes, T.V. Hansen, Bioorg. Med. Chem. 16 (2008) 4829–
4838.
[14] N. Xue, X.C. Yang, R. Wu, J. Chen, Q.J. He, B. Yang, X.Y. Lu, Y.Z. Hu, Bioorg. Med.
Chem. 16 (2008) 2550–2557.
[15] P.C. Lv, Z.P. Xiao, R.Q. Fang, H.Q. Li, H.L. Zhu, Eur. J. Med. Chem. 44 (2009) 1779–
1787.
5-diphenyltetrazolium bromide) was added to each well. And 4 h
later the medium was replaced by 150 L DMSO to solubilize the
m
purple formazan crystals produced. The absorbance at 570 nm of
each well was measured on an ELISA plate reader. The data repre-
sented the mean of three experiments in triplicate. The IC50 value
was defined as the concentration at which 50% survival of cells was
observed. The results are listed in Table 2.
Acknowledgements
[16] X.F. Huang, B.F. Ruan, X.T. Wang, C. Xu, H.M. Ge, H.L. Zhu, R.X. Tan, Eur. J. Med.
Chem. 42 (2007) 263.
[17] S. Yang, B.A. Song, H. Zhang, D.Y. Hu, L.-H. Jin, G. Liu, J. Heterocycl. Chem. 41
(2004) 617–619.
[18] G.F. Xu, B.A. Song, P.S. Bhadury, S. Yang, P.Q. Zhang, L.H. Jin, W. Xue, D.Y. Hu,
P. Lu, Bioorg. Med. Chem. 15 (2007) 3768–3774.
The work was co-financed by the grant (Project 070416274X)
from Anhui Natural Science Foundation, Anhui Province, China and
the key research projects of University Natural Science, Anhui
Province (KJ2009A011Z).
[19] H. Liu, Z.B. Gao, Z.Y. Yao, S.X. Zheng, Y. Li, W.L. Zhu, X.J. Tan, X.M. Luo, J.H. Shen,
K.X. Chen, G.Y. Hu, H.L. Jiang, J. Med. Chem. 50 (2007) 83–93.
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Heterocycl. Chem. 43 (2006) 867–871.
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