2302
J. Chen et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2300–2302
Table 2
proliferation. The SAR analysis indicated that (1) the 5-trifluoro-
methyl group was more favorable than chloro and methyl group;
(2) the conjugation of pyridine ring with the aryl group did not af-
fect activity; (3) the derivatives with substitutions on p-position
was superior to that with m-position substitutions; (4) it is better
for anti-fibrosis potent bearing hydrophobic group adjacent to po-
sition 1 of pyridone ring; (5) the position 3 of pyridone ring could
be modified to increase activity.
The structures of 1-substituted phenyl or benzyl-5-trifluoromethyl-2(1H)-pyridone
compounds and their inhibitory activities against NIH3T3 cells
F3C
N
O
n
R1
R2
Compound
n
R1
R2
IC50 (mM)
Acknowledgments
2a
2b
2c
2d
2e
2f
2g
2h
2i
0
0
1
1
1
1
1
1
1
1
0
0
1
1
0
0
0
0
1
1
1
1
0
1
1
1
/
40-NO2
/
20-Cl
40-NO2
0.51
0.34
0.63
0.17
0.28
0.29
0.66
0.89
0.71
/
0.29
0.30
1.10
0.30
0.39
0.84
0.43
0.41
0.62
0.38
1.40
0.91
0.08
3.26
0.32
2.75
/
40-NO2
/
We acknowledge the financial support from the NSFC (Fund
No.: 20972194) and thank Zhi-Yu Li Ph.D. in the Department of
Medicinal Chemistry of China Pharmaceutical University for the
chemical support.
20-NO2
20-F
/
/
40-OMe
20-Cl
60-Cl
/
/
/
/
40-F
30-Cl
Supplementary data
2j
/
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
6
40-NH2
20-Cl
40-NH2
Supplementary data associated with this article can be found, in
/
40-NH2
20-NH2
/
20-Cl
40-NH(CH2)2O(CH2)2OH
40-N(HO(CH2)2)2
40-NH(CH2)2OH
40-NH(CH2)3OBu
/
Reference and notes
20-Cl
20-Cl
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20-Cl
20-NH(CH2)2OH
/
/
/
40-NH(CH2)2OH
40-NH(CH2)3OH
40-NH(CH2)2O(CH2)2OH
40-NHCOCH3
40-NHCOCH3
/
20-Cl
/
20-NHCOCH3
/
/
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⁄: ‘/’ means nothing in IC50 column and H in R1or R2 column.
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of compounds 2c, 3c, 5b were superior to compounds 2d, 3d, 5c, it
can be concluded that the p-substitution was favorable to m-sub-
stitution. Compound 3b and 4a showed IC50 values of 0.29 and
0.30 mM respectively, which were about 9 times lower than the
positive control. This result indicated that hydrogen bond donors
might improve the activity more significantly than other groups
at the p-position.
Compound 2e bearing lipophilic 20-fluoro, 2g bearing lipophilic
20,60-dichloro, and 2j exhibited high potency to inhibit NIH3T3
cells. Compounds 3d and 5c with 20-amino and 20-acetamino sub-
stitutions respectively displayed weak inhibition activity, which
implied that the receptor could have a hydrophobic pocket adja-
cent to position 1 of pyridone ring. The IC50 value of compound 6
with a nitro-group at position 3 of pyridone was 0.32 mM, indicat-
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increase activity.
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In conclusion, 31 novel pyridine derivatives were synthesized
and evaluated for their inhibitory activity against NIH3T3 cell