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J. Yang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1424–1427
Table 2
Antitubercular activities on virulent H37Rv strain and cytotoxicity on human normal liver L02 cells of 3H-1,2,4-dithiazol-3-one compounds
MICa
(l
g/mL)
IRb (%)
a
Compd
R
MW
MIC90
(l
g/mL)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4-Chlorophenyl
4-Fluorophenyl
2-Chlorophenyl
2-Methylphenyl
3-Methoxyphenyl
2,5-Dimethoxyphenyl
Naphthalen-2-yl
4-Aminophenyl
5-Methylthiophen-2-yl
2-Nitrophenyl
231
214
231
210
248
256
246
211
216
263
276
232
236
284
16
8
32
16
16
32
32
32
16
32
32
32
16
16
16
4
46.0
33.7
40.1
18.6
38.6
23.7
47.2
46.3
36.3
33.0
28.6
34.4
56.7
24.3
16
16
16
16
16
16
16
16
8
2-Chloro-4-nitrophenyl
2-Chloropyridin-3-yl
Pyrazin-2-yl-
4
8
1
2,6-Dichloro-5-fluoropyridin-3-yl
a
MIC90 and MIC99 are the minimum concentration of a compound that inhibits growth by 90% and 99%, respectively.
IR (%) is the mean inhibitory ratio against L02 cell line measured at 48 h after treatment with the test compound at the concentration of 100
b
lM by MTT method.
IR ð%Þ ¼ ODðCÞꢀODðSÞ. OD(C) denotes the mean optical density value of control group treated with DMSO calculated from three independent experiments. OD(S) denotes the
ODðCÞ
mean optical density value of sample groups treated with the compounds calculated from three independent experiments.
As illustrated in Table 2, 3H-1,2,4-dithiazol-3-one compounds
with electron-deficient aromatic rings such as pyridine or pyrazine
(4l, 4m, 4n) were generally shown more potent than those with
electron-rich benzene or thiophene (4a, 4d, 4e, 4f, 4h, 4i). In spe-
cific, compounds with chlorine atom (4a, 4k, 4l and 4n) or fluorine
atom (4b) were more potent than those without chlorine or fluo-
rine except 4C, which indicates that chlorine and/or fluorine atom
may play a part on the potency in this structural class of com-
pounds. Actually removal of two halogen atoms (5-fluro and 6-
chloro) of the most potent compound 4n produced compound 4l,
which led to a fourfold decrease in antitubercular activities, from
human normal liver L02 cells were evaluated. The SARs between
these two classes of molecules and the discovery of the potent
3H-1,2,4-dithiazol-3-one compound with better safety profile pro-
vide us a novel promising scaffold to develop potential affordable
antitubercular agents. Meanwhile our results demonstrated a suc-
cessful scaffold hopping strategy by taking advantage of bioisoster-
ic replacement of 1,3,4-oxathiazol-2-one ring with 3H-1,2,4-
dithiazol-3-one.
Acknowledgments
1 to 4
l
g/mL of MIC90 value and from 4 to 16
l
g/mL of MIC99 value.
This work was supported by the National S&T Major Special
Project on Major New Drug Innovation (2012ZX09103101-036).
We also thank Dr. Ruiliang Jin in Shanghai Pulmonary Hospital
for antitubercular activity evaluation and fruitful discussion.
As compared Table 2 with Table 1, 3H-1,2,4-dithiazol-3-one
compounds 4a–n demonstrated similar antibacterial activities to
1,3,4-oxathiazol-2-one compounds 3a–n as expected, which coin-
cides the rule of bioisosterism. Our results showed a successful
scaffold hopping by taking advantage of bioisosteric replacement
of 1,3,4-oxathiazol-2-one ring in the lead compound with 3H-
1,2,4-dithiazol-3-one cycle.
Supplementary data
Supplementary data associated with this article can be found, in
The toxic profile of all final compounds was evaluated by an
MTT assay on L02 cells. The inhibitory ratios at concentration of
the
online
version,
at
100
iazol-3-one compounds are listed in Table 1 and Table 2. The inhib-
itory ratios at concentration of 100 M of 1,3,4-oxathiazol-2-one
lM of 1,3,4-oxathiazol-2-one compounds and 3H-1,2,4-dith-
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compounds (Table 1) were somewhat lower than 50% except for
compound 3k (IR = 54.6%) and HT1171 (IR = 53.8%). As for 3H-
1,2,4-dithiazol-3-one compounds there was only one compound
4m with an inhibitory ratio of higher than 50%, which is 56.7%.
In general, some minor changes in cytoxicities on human normal
liver L02 cells were observed between these two kinds of small
molecules. Nevertheless, the most active molecule 4n (IR = 24.3%)
in the series of 3H-1,2,4-dithiazol-3-one compounds was proved
to possess a far lower inhibitory ratio to L02 cells than HT1171
(IR = 53.8%), which belongs to the series of 1,3,4-oxathiazol-2-one
compounds, suggesting the liability to discovery of novel antitu-
bercular agents with better safety profile from 3H-1,2,4-dith-
iazol-3-one compounds.
In summary, fourteen 3H-1,2,4-dithiazol-3-one compounds (11
of which are new) and fifteen 1,3,4-oxathiazol-2-one molecules (4
of which are new) were readily synthesized and their antitubercu-
lar activities against H37Rv together with their cytotoxicities on
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