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Y.K. Zhang et al. / Chinese Chemical Letters 21 (2010) 290–292
Table 1
Anti-HBV activity and cytotoxicity of synthesized compounds in vitro.
Compound
TC50
Anti-HBsAg
Anti-HBeAg
DNA replication
(mmol/L)
(mmol/L)
(mmol/L)
(mmol/L)
IC50
SI
IC50
SI
2.03
IC50
SI
6a
6b
79
232
98
46
276
29
1.72
0.84
3.38
0.20
1.77
39
58
20
3.95
ND
4.00
19.60
0.50
ND
30
7a
7b
5
3.27
1.67
1400
20
98
40
12
Adefovir
540
305
286
1.89
0.517
‘‘TC50’’ is 50% cytotoxic concentration in HepG2 2.2.15 cells. ‘‘IC50’’ is 50% inhibitory concentration. ‘‘SI’’ is selectivity index (SI: TC50/IC50).
‘‘ND’’ is not determined.
All four novelly synthesized compounds were evaluated for their anti-HBVactivities and cytotoxicities in cultured
HepG2 2.2.15 cells. Indices included measuring the secretion of HBsAg and HBeAg to cell culture media and
replication of HBV DNA. Nucleotide analogue Adefovir was utilized as the positive control. The results are
summarized in Table 1 and data demonstrated that four novelly synthesized compounds demonstrated stronger anti-
HBVactivity than Adefovir; while their cytotoxicity was relatively high (with TC50 values of 79, 232, 98 and 20 mmol/
L, respectively). Among the four compounds, compound 7a showed lowest IC50 values of anti-HBsAg, anti-HBeAg
and DNA replication inhibitory effects (29, 5 and 30 mmol/L, respectively), followed by 6a, 7b and 6b. The difference
in their anti-HBV efficacies indicated that when the hydrogen was replaced with pentane at position N-1, the
compound would have stronger inhibitory effect against HBV than those in which the hydrogen was replaced with
propylene at the same position; moreover, the anti-HBV efficacy would be enhanced by replacement of the benzoyl
group with an imino group. The bioassay results also hinted the parent scaffold of four compounds seemed playing an
important role in the inhibition of HBV.
In summary, here we report a novel and highly yielding synthesis route for 5-substituted pyridin-2(1H)-one
derivatives. The novelly synthesized compounds were verified by structural analyses using single crystal X-ray
diffraction. Moreover, these 5-substituted pyridin-2(1H)-one derivatives were shown to be a kind of highly potential
bioactive molecule against hepatitis B.
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89% yellow crystal. M.p.: 131.7–132.6 8C. 1H NMR (CDCl3 300 MHz): d 3.87(s, 1H), 4.62(m, 2H), 5.25(m, 2H), 5.92(m, 1H), 6.56(dd, 1H,
J1 = 9 Hz, J2 = 2.7 Hz), 6.52(d, 1H, J = 2.7 Hz), 6.62(d, 1H, J = 9.6 Hz), 7.46(d, 1H, J = 9 Hz), 7.70(dd, 1H, J1 = 9.6 Hz, J2 = 2.7 Hz), 7.86(d,
1H, J = 2.7 Hz), 12.24(s, 1H). ESI-MS (m/z): 286.1 [M+1]. (E)-5-((2-hydroxy-4-methoxyphenyl)(pentylimino)methyl)-1-pentylpyridin-2(1H)-
one 7a: full yield 90% yellow crystal. M.p.: 95.8–97.4 8C. 1H NMR (CDCl3 300 MHz): d 0.89(m, 6H), 1.34(m, 8H), 1.67(m, 2H), 1.78(m, 2H),
3.39(m, 2H), 3.80(s, 3H), 3.97(m, 2H), 6.19(dd, 1H, J1 = 9 Hz, J2 = 2.7 Hz), 6.39(d, 1H, J = 2.7 Hz), 6.66(d, 1H, J = 9.6 Hz), 6.85(d, 1H,
J = 9 Hz), 7.22(m, 2H), 16.26(s, 1H). ESI-MS (m/z): 385.65 [M+1].