Synthesis of new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing γ-butenolide moiety and preliminary evaluation of in vitro anticancer activity

Article abstract of DOI:10.1016/j.ejmech.2009.03.023

A new series of chiral 1,3,4-thiadiazoles derivatives possessing γ-substituted butenolide moiety were synthesized and evaluated for in vitro anticancer properties. All the compounds showed good anticancer activities against Hela cell lines. Of all the studied compounds, compound 9e exhibited the best inhibitory activity with an IC₅₀ of 0.9 μM. After being treated with 0.1 μg/mL compound 9e for 24 h, the growth inhibition rate of Hela cell lines was 59.2%.

Full text of DOI:10.1016/j.ejmech.2009.03.023

European Journal of Medicinal Chemistry 44 (2009) 3340–3344
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis of new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing
-butenolide moiety and preliminary evaluation of in vitro anticancer activity
g
,
b
c,
**
Meng-Xue Wei a, Lei Feng a, Xue-Qiang Li a , Xue-Zhang Zhou , Zhi-Hui Shao
*
a Key Laboratory of Energy Sources and Chemical Engineering, Development Center of Natural Products and Medication and School of Chemistry and Chemical Engineering,
Ningxia University, Yinchuan 750021, China
b Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Science, Ningxia University, Yinchuan 750021, China
c Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, Yunnan University, Kunming 650091, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of chiral 1,3,4-thiadiazoles derivatives possessing
g-substituted butenolide moiety were
Received 4 December 2008
Received in revised form
19 February 2009
Accepted 19 March 2009
Available online 27 March 2009
synthesized and evaluated for in vitro anticancer properties. All the compounds showed good anticancer
activities against Hela cell lines. Of all the studied compounds, compound 9e exhibited the best inhib-
itory activity with an IC50 of 0.9
m
M. After being treated with 0.1
m
g/mL compound 9e for 24 h, the growth
inhibition rate of Hela cell lines was 59.2%.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
1,3,4-Thiadiazoles
Butenolide
X-ray crystallography
Hela cells
Growth inhibitory
1. Introduction
knowledge, the synthesis and anticancer activities of these
compounds have not been reported so far.
The identification of new compounds for the treatment of
cancer is an important undertaking in pharmaceutical research.
1,3,4-Thiadiazole derivatives have received much attention due to
their versatile biological properties [1–13]. In particular, a few
differently substituted 1,3,4-thiadiazoles have been found to
2. Results and discussion
2.1. Chemistry
exhibit anticancer activities [14–18]. Besides, g-substituted bute-
The enantiomerically pure
g-substituted butenolides 4 were
nolide moiety represents a biological important entity that is
present in natural products such as dysidiolide [19], andirolactone
[20] and vallapin [21]. Dysidiolide and its derivatives have been
found to possess varying anticancer properties [22–24].
In view of these above mentioned facts and an attempt to ach-
ieve new compounds with better anticancer properties, we
designed and synthesized a new series of hybrid 1,3,4-thiadiazoles
prepared by the procedure shown in Scheme 1 [25,26]. Muco-
bromic acid 2 was easily accessible by the treatment of furfural 1
with Br2/H2O. The enantiomerically pure g-substituted butenolides
4 were obtained via acetalization of mucobromic acid 2 by
employing (ꢀ)-menthol and (þ)-borneol as a chiral auxiliary,
respectively and followed by resolution of the resulting
diastereomers.
derivatives possessing g-substituted butenolide moiety (Fig. 1) to
The 5-substituted-2-mercapto-1,3,4-thiadiazoles
8
were
evaluate their in vitro anticancer properties. To the best of our
prepared as previously described (Scheme 2) [27]. The aroyl
hydrazides 6 were obtained by reaction of the esters 5 with
hydrazine in EtOH. Treatment of the hydrazides 6 with CS2 under
a basic condition (KOH/EtOH) gave the corresponding potassium
aroyl dithiocarbazates 7. Compounds 7 were then cyclized with
cold concentrated sulfuric acid to provide the corresponding
5-substituted-2-mercapto-1,3,4-thiadiazoles 8 in good yields (60–
90%). It should be noted that the yields of cyclization reaction of
* Corresponding author.
** Corresponding author. Tel.: þ86 871 5031119; fax: þ86 871 5035538.
E-mail addresses: lixq@nxu.edu.cn (X.-Q. Li), zhihui_shao@hotmail.com (Z.-H.
Shao).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.03.023

M.-X. Wei et al. / European Journal of Medicinal Chemistry 44 (2009) 3340–3344
3341
potassium aroyl dithiocarbazates were quite low (17–35%) in the
previous literature [27]. After several attempts to improve the
chemical yields of the cyclization reaction, we found that the
quench procedure of the cyclization reaction dramatically affected
the yields of products 8. After the completion of the cyclization
reaction, the addition of moderate quantities of NH3$H2O to the
reaction mixtures significantly improved the product yields.
The target compounds 9a–l were prepared by tandem Michael
N
N
R
S
Br
S
H
O
R*O
O
Fig. 1. The general structure of target compounds.
addition–elimination reaction of g-substituted butenolides 4 with
5-substituted-2-mercapto-1,3,4-thiadiazoles 8 (Scheme 3).
Thestructuresofthesenewcompounds9werecharacterizedwith
IR, 1H and 13C NMR spectra. Physical and spectral data of compounds
9a–l are reported in Table 1. Additionally, the structure of compound
9a was corroborated by X-ray diffraction as shown in Fig. 2.
Br
Br
HO
Br
Br2/H2O
CO2H
Br
CHO
OHC
O
O
O
2
1
2.2. In vitro anticancer activity (MTT method)
Br
H
R*O
Br
Br
Br
recrystallization
R*OH
H+
O
All new synthesized compounds 9a–l were evaluated for their in
vitro anticancer activities against cervical cancer cell lines (HeLa).
To our delight, all compounds 9a–l displayed good inhibition
activities on Hela cell lines (Table 2). Of all the studied compounds,
compound 9e exhibited the best inhibitory activity with an IC50 of
O
R*O
O
O
3
4
;
R* =
(bornyl)
(1-menthyl)
0.9
bition rates of Hela cell lines with compounds 9a–l at different
concentrations (0.1–20 M) were evaluated (Table 3). After being
treated with 0.1 g/mL compound 9e for 24 h, the growth inhibi-
tion rate was 59.2%, while the growth inhibition rate of the more
mM. Encouraged by these promising results, the growth inhi-
a
b
m
m
Scheme 1. Synthesis of compounds 4.
active compound 9h (IC50 ¼ 1.3
m
M) was the highest (73.8%).
N
N
O
C
S
CS2
KOH/EtOH
NH2NH2.H2O(85%)
H2SO4
0~5 oC
RCOOC2H5
RCONHNH2
R
SH
R
NHNHC SK
C2H5OH, reflux
S
8
5
6
7
R = Ar and ArHet
Scheme 2. Synthesis of compounds 8.
R
N N
N
S
Br
H
R*O
Br
N N
S
R
S
B
N
NaOH/H2O,TBAB
benzene
S
-HBr
+
R
SH
H
O
O
O
R*O
S
O
Br
O-
Br
9
4
8
H
R*O
O
R* = 1-menthyl
R = C6H5-
1-menthyl
1-menthyl
1-menthyl
para-HO-C6H4-
ortho-HO-C6H4-
para-Cl-C6H4-
9d
9a
9b
9c
R* = 1-menthyl
1-menthyl
1-menthyl
1-menthyl
para-CH3O-C6H4-
R = para-O2N-C6H4-
N
O
9g
9e
9f
9h
R* = 1-menthyl
bornyl
bornyl
bornyl
R
=
N
N
N
O
9j
9i
9k
9l
Scheme 3. Synthesis of compounds 9a–l.

3342
M.-X. Wei et al. / European Journal of Medicinal Chemistry 44 (2009) 3340–3344
Table 1
Physical properties and spectral data of compounds 9a–l.
Compound Mp (ꢁC) Yield IR (KBr) in cmꢀ1
(%)
1H NMR (CDCl3)
d
in ppm
13C NMR (CDCl3)
d in ppm
9a
9b
9c
162–163 98
133–134 95
100–103 96
1784, 1596, 1557, 1492, 8.05–8.03 (m, 2H), 7.62–7.53 (m, 3H), 6.57 (s, 1H), 3.56 (1H, ddd,
167.0, 164.0, 156.6, 149.9, 132.6, 129.3, 126.9, 122.7,
1456, 1313, 1212, 1129, J ¼ 10.8, 10.4, 4.4 Hz), 2.26–2.22 (m, 1H), 1.95–1.89 (m, 1H), 1.63–1.55 117.0, 102.9, 83.3, 47.9, 42.1, 33.9, 31.5, 25.2, 22.7,
990
(m, 2H), 1.38 (m, 1H), 1.27–1.03 (m, 2H), 0.92 (d, J ¼ 6.8 Hz, 3H), 0.88– 22.1, 20.9, 15.4
0.81 (m, 2H), 0.79 (d, J ¼ 6.8 Hz, 3H), 0.44 (d, J ¼ 6.8 Hz, 3H)
1789, 1584, 1489, 1480, 7.48–7.45 (m, 2H), 6.49 (s, 1H), 3.48 (ddd, J ¼ 10.8, 10.8, 4.8 Hz, 1H), 165.2, 163.0, 155.9, 148.6, 138.0, 128.8, 127.2, 120.1,
1312, 1212, 1123, 992 2.19–2.10 (m, 1H), 1.86–1.82 (m, 1H), 1.56–1.49 (m, 2H), 1.30 (m, 1H), 116.3, 101.9, 82.4, 46.9, 41.1, 32.8, 30.5, 24.2, 21.7,
1.20–0.96 (m, 2H), 0.85 (d, J ¼ 6.8 Hz), 0.81–0.74 (m, 2H), 0.71 (d,
21.1, 19.9, 14.4
J ¼ 6.8 Hz), 0.36 (d, J ¼ 7.2 Hz)
3285, 1790, 1589, 1549, 9.67 (s, 1H), 7.74–7.72 (m, 1H), 7.53–7.48 (m, 1H), 7.16–7.14 (m, 1H), 166.5, 163.9, 157.6, 156.0, 149.3, 134.7, 126.6, 120.4,
1489, 1312, 1227, 1136, 7.07–7.03 (m, 1H), 6.49 (s, 1H), 3.55 (ddd, J ¼ 10.8, 10.4, 4.4 Hz, 1H), 117.9, 117.8, 107.0, 102.9, 83.5, 48.0, 42.2, 33.8, 31.5,
994
2.25–2.22 (m, 1H), 1.93–1.86 (m, 1H), 1.65–1.56 (m, 2H), 1.38 (m, 1H), 25.3, 22.7, 22.1, 20.9, 15.4
1.28–1.03 (m, 2H), 0.92 (d, J ¼ 6.8 Hz, 3H), 0.89–0.81 (m, 2H), 0.79 (d,
J ¼ 7.2 Hz, 3H), 0.46 (d, J ¼ 6.8 Hz, 3H)
9d
9e
9f
171–172 66
124–125 83
133–134 92
108–109 75
3388, 1750, 1613, 1508, 7.96–7.92 (m, 2H), 7.00–6.97 (m, 2H), 6.53 (s, 1H), 5.59 (s, 1H), 3.54 167.0, 164.2, 159.4, 155.8, 150.2, 129.1, 116.7, 116.4,
1491, 1314, 1291, 1226, (ddd, J ¼ 10.8, 10.8, 6.4 Hz, 1H), 1.94–1.90 (m, 1H), 2.25–2.20 (m, 1H), 115.3, 102.9, 83.4, 48.0, 42.2, 33.9, 31.5, 25.2, 22.7,
1135, 1006
1.63–1.56 (m, 2H), 1.37 (m, 1H), 1.27–1.03 (m, 2H), 0.92 (d, J ¼ 6.4 Hz, 22.1, 21.0, 15.4
3H), 0.88–0.81 (m, 2H), 0.79 (d, J ¼ 6.8 Hz, 3H), 0.45 (d, J ¼ 6.8 Hz, 3H)
1787, 1528, 1478, 1456, 8.37–8.33 (m, 2H), 8.19–8.16 (m, 2H), 6.50 (s, 1H), 3.49 (ddd, J ¼ 10.8, 164.1, 162.8, 157.4, 149.0, 148.0, 127.0, 126.9, 123.6,
1340, 1312, 1157, 1131, 10.4, 4.4 Hz, 1H), 2.19–2.16 (m, 1H), 1.86–1.82 (m, 1H), 1.57–1.49 (m, 117.2, 101.9, 82.5, 46.9, 41.1, 32.8, 30.5, 24.2, 21.7,
997
2H), 1.33 (m, 1H), 1.20–0.96 (m, 2H), 0.86 (d, J ¼ 6.8 Hz, 3H), 0.81–0.75 21.1, 19.9, 14.4
(m, 2H), 0.71 (d, J ¼ 7.2 Hz, 3H), 0.35 (d, J ¼ 6.8 Hz, 3H)
1779, 1609, 1501, 1489, 7.98–7.96 (m, 2H), 7.04–7.02 (m, 2H), 6.53 (s, 1H), 3.90 (s, 3H), 3.55 167.1, 164.1, 163.0, 155.7, 150.2, 128.8, 116.6, 115.1,
1323, 1312, 1263, 1126, (ddd, J ¼ 11.2, 10.8, 4.0 Hz, 1H), 2.25–2.22 (m, 1H), 1.94–1.90 (m, 1H), 114.8, 102.9, 83.3, 55.6, 48.0, 42.2, 33.9, 31.5, 25.2,
998
1.63–1.56 (m, 2H), 1.37 (m, 1H), 1.26–1.03 (m, 2H), 0.92 (d, J ¼ 6.4 Hz, 22.7, 22.1, 21.0, 15.4
3H), 0.88–0.85 (m, 2H), 0.79 (d, J ¼ 6.8 Hz, 3H), 0.45 (d, J ¼ 6.8 Hz, 3H)
9g
3158, 1787, 1582, 1481, 7.65–7.64 (m, 1H), 7.27–7.24 (m, 1H), 6.64–6.63 (m, 1H), 6.55 (s, 1H), 164.4, 161.2, 155.1, 152.4, 145.9, 144.6, 116.0, 112.9,
1457, 1368, 1316, 1217, 3.52 (ddd, J ¼ 10.8, 10.8, 4.4 Hz, 1H), 2.25–2.19 (m, 1H), 1.82–1.78 (m, 112.6, 103.1, 83.1, 48.0, 42.2, 33.9, 31.5, 25.2, 22.7,
1130, 989
1H), 1.63–1.55 (m, 2H), 1.37 (m, 1H), 1.26–1.02 (m, 2H), 0.91 (d,
J ¼ 6.8 Hz, 3H), 0.89–0.80 (m, 2H), 0.77 (d, J ¼ 7.2 Hz, 3H), 0.45 (d,
J ¼ 6.8 Hz, 3H)
22.1, 21.0, 15.6
9h
9i
118–119 83
121–123 89
1790, 1590, 1485, 1413, 8.88–8.87 (m, 2H), 7.90–7.89 (m, 2H), 6.58 (s, 1H), 3.56 (ddd, J ¼ 10.8, 165.1, 163.8, 158.5, 151.2, 149.1, 129.7, 120.1, 118.2,
1375, 1315, 1210, 1134, 10.4, 4.4 Hz, 1H), 2.25–2.22 (m, 1H), 1.93–1.89 (m, 1H), 1.64–1.56 (m, 103.0, 83.5, 47.9, 42.2, 33.8, 31.5, 25.2, 22.7, 22.1,
987
2H), 1.38 (m, 1H), 1.28–1.04 (m, 2H), 0.93 (d, J ¼ 6.8 Hz, 3H), 0.88–0.82 20.9, 15.4
(m, 2H), 0.79 (d, J ¼ 7.2 Hz, 3H), 0.42 (d, J ¼ 7.2 Hz, 3H)
1780, 1590, 1465, 1421, 9.04–9.03 (m, 1H), 8.72–8.71 (m, 1H), 8.22–8.19 (m, 1H), 7.44–7.41 (m, 166.7, 163.2, 156.4, 151.7, 150.8, 147.8, 133.8, 124.5,
1368, 1218, 1311, 1135, 1H), 6.55 (s, 1H), 3.56 (ddd, J ¼ 10.4, 10.4, 4.0 Hz, 1H), 2.16–2.15 (m, 123.2, 115.9, 102.3, 82.2, 46.9, 41.2, 32.8, 30.5, 24.2,
995
1H), 1.76–1.72 (m, 1H), 1.56–1.48 (m, 2H), 1.31 (m, 1H), 1.20–0.96 (m, 21.7, 21.1, 20.1, 14.6
2H), 0.85 (d, J ¼ 6.8 Hz, 3H), 0.81–0.71 (m, 2H), 0.69 (d, J ¼ 6.8 Hz, 3H),
0.45 (d, J ¼ 6.8 Hz, 3H)
9j
161–163 60
150–152 69
147–148 69
3128, 1783, 1591, 1490, 7.65–7.56 (m, 1H), 7.26–7.25 (m, 1H), 6.65–6.64 (m, 1H), 6.44 (s, 1H), 164.2, 161.4, 154.2, 153.3, 145.9, 144.5, 113.6, 112.9,
1374,13431,1321, 1221, 3.83 (dd, J ¼ 5.2 Hz, 1H), 2.22–2.21 (m, 1H), 1.75–1.10 (m, 6H), 0.76 (s, 112.7, 103.6, 88.7, 49.2, 47.5, 44.8, 36.5, 27.9, 26.4,
1136, 997
6H), 0.46 (s, 3H)
19.5, 18.7, 13.0
9k
9l
1788, 1596, 1475, 1410, 8.90 (s, 2H), 7.93–7.92 (m, 2H), 6.47 (s, 1H), 3.91 (dd, J ¼ 8.8 Hz, 1H), 165.2, 163.7, 157.8, 151.1, 149.9, 129.7, 120.2, 115.9,
1314, 1207, 1183, 1135, 2.27–2.21 (m, 1H), 1.75–1.10 (m, 6H), 0.77 (d, J ¼ 5.6, 6H), 0.48 (s, 3H) 103.6, 89.2, 49.3, 47.4, 44.8, 36.4, 27.8, 26.4, 19.4,
995
18.7, 13.1
1781, 1587, 1463, 1405, 9.30–9.15 (m, 1H), 8.82 (m, 1H), 8.29–8.27 (m, 1H), 7.56–7.34 (m, 1H), 168.2, 164.1, 156.4, 152.9, 150.7, 148.8, 135.0, 134.1,
1340, 1312, 1218, 1133, 6.52 (s, 1H), 3.89–3.85 (m, 1H), 2.26–2.20 (m, 1H), 1.75–1.10 (m, 6H), 124.3, 114.3, 103.7, 88.7, 49.2, 47.4, 44.8, 36.5, 27.8,
995
0.78–0.74 (m, 6H), 0.42 (s, 3H)
26.4, 19.5, 18. 7, 13.0
3. Conclusion
apparatus and are uncorrected. IR spectra were recorded on an FTIR-
8400S spectrometer as KBr discs. 1H NMR and 13C NMR spectra were
obtained with a Bruker Avance III 400 MHz spectrometer in chloro-
form-d (CDCl3) and tetramethylsilane (TMS) was used as an internal
standard. Diffraction measurement was made on a Bruker AXS
SMART 1000 CCD diffractometer with graphite-monochromatized
In summary, a series of new chiral 1,3,4-thiadiazoles derivatives
possessing -substituted butenolide moiety have been synthesized
g
and their in vitro anticancer activity against cervical cancer cells has
been evaluated. All the target compounds exhibited good anti-
cancer activities. Compound 9e with an IC50 of 0.9
m
M was found to
Mo K
a
radiation (
l
¼ 0.71073 Å). All chemicals were used as received
be the most active. This might have relationship with the hydro-
phile ability of nitro group on the benzene ring. Further studies of
SAR of these compounds and the cytostatic properties of these
compounds in other tumour cell lines are in progress.
without further purification unless otherwise stated.
4.1.1. General procedure for compounds 9a–l
To a solution of 0.1 N NaOH (11 mL) was sequentially added
tetrabutyl ammonium bromide (TBAB) (0.11 mmol), compound 8
(1.1 mmol) and compounds 4 in PhH or CHCl3 (5 mL). The resulting
mixture was stirred at room temperature, and the reaction was
monitored by TLC. On completion of the reaction (2–48 h), the
mixture was extracted and the organic layer was washed with
saturated NaHCO3 and saturated brine, respectively. Then the
organic layer was dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The purification of the residue by silica gel
4. Experimental
4.1. Chemistry
Thin-layer chromatography (TLC) was carried out on silica GF254
plates (Qingdao Haiyang Chemical Co., Ltd, China). All the melting
points were determined on a WRS-1B digital melting point

M.-X. Wei et al. / European Journal of Medicinal Chemistry 44 (2009) 3340–3344
3343
column chromatography or crystallization yielded the desired
compounds 9a–l.
4.1.2. Crystal data for 9a
a ¼ 12.4791 (13) Å, b ¼ 6.6726 (8) Å, c ¼ 14.5108 (19) Å,
b
¼ 109.796 (2)ꢁ, monoclinic crystal system with space group P21,
V ¼ 1.1369 (2) nm3, Z ¼ 2,
m
¼ 1.930 mmꢀ1
,
Dc ¼ 1.441 g/cm3,
T ¼ 298 (2), 0.45 ꢂ 0.17 ꢂ 0.12 mm.
4.2. Pharmacology
Cells (1 ꢂ104 in 100
mL) were seeded on 96-well plates in trip-
licate. Following a 24-h-culture at 37 ꢁC, the medium were replaced
with fresh medium at various concentrations (0.5, 1, 5, 10, 20
mg/
mL) of compounds 9a–l in a final volume of 110 L. At the same
m
time, set drug-free medium negative control well, and solvent
control well of the same volume of dimethyl sulfoxide (DMSO).
Cells were incubated at 37 ꢁC for 24 h. Then 20
mL of 3-(4,5-dime-
thylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (2 mg/
mL in a phosphate buffer solution (PBS)) was added to each well,
incubated for an additional 4 h, the plates were centrifuged at
1000 r/min for 10 min, then the medium was removed. MTT for-
mazan precipitates were dissolved in 100 mL of DMSO, shaken
mechanically for 10 min and then read immediately at 570 nm in
a plate reader (Opsys MR, Denex Technology, USA).
Cell inhibition rate ¼ [A570 (negative control well) ꢀ A570 (dosing
well)]/A570 (negative control well) ꢂ 100%.
Acknowledgements
We thank Major State Basic Research Development Program of
China (2007CB21602), National Natural Science Foundation of
China (20702044), Key Project of Chinese Ministry of Education
(203143), and Natural Science Foundation of Ningxia Province of
China (NZ0606) for financial support. We also thank a reviewer for
his invaluable suggestions on our work.
Fig. 2. ORTEP view of the crystal structure of compound 9a.
Table 2
In vitro anticancer activities against Hela cell lines with compounds 9a–l (n ¼ 3).
Compound
IC50
(
m
M)
Compound
IC50 (mM)
References
9a
9b
9c
9d
9e
9f
3.0
2.2
2.9
2.6
0.9
3.7
9g
9h
9i
9j
9k
9l
1.7
1.3
5.6
1.3
3.0
3.4
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Table 3
Growth inhibition rates of Hela cell lines with compounds 9a–l at different
concentrations.
Compound
Inhibition rates (%)
0.1
m
M
1
m
M
5
m
M
10
m
M
20 mM
9a
9b
9c
9d
9e
9f
9g
9h
9i
56.1
51
59.1
58.2
61.2
59.4
47.6
55.6
54.3
51.3
59.5
51.4
55.1
56.3
40.6
29.3
37.5
36.0
30.0
47.1
29.4
33.9
52.3
31.1
44.9
45.4
28.1
35.1
29.7
26.8
33.4
36.0
24.5
32.9
27.2
22.3
33.0
34.3
40.6
36.3
58.9
60.6
59.2
56.4
55.6
73.8
56.4
50.9
51.8
58.9
42.3
44.4
34.5
35.6
36.9
26.8
32.8
28.6
39.4
40.5
9j
9k
9l

3344
M.-X. Wei et al. / European Journal of Medicinal Chemistry 44 (2009) 3340–3344
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