Anti-HBV agents. Part 3: preliminary structure-activity relationships of tetra-acylalisol A derivatives as potent hepatitis B virus inhibitors.
Thirty-two tetra-acylated derivatives of alisol A were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities and cytotoxicities in vitro. Among the series of alisol A derivatives examined, five analogues were active against HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) secretion in HepG 2.2.15 cells. These results also provide interesting structure-activity relationships of tetra-acylalisol A derivatives. Compounds tetra-acetyl alisol A (A1), tetra-methoxyacetyl alisol A (A23), and tetra-ethoxyacetyl alisol A (A24) exhibited high activities against secretion of HBsAg with IC(50) values of 0.0048, 0.0044, and 0.014 mM, respectively, HBeAg with IC(50) values of 0.011, 0.012, and 0.018 mM, respectively, and remarkable selective index values SI(HBsAg)>333, SI(HBeAg)>145; SI(HBsAg)=209, SI(HBeAg)=77; and SI(HBsAg)>200, SI(HBeAg)>156, respectively. Additional studies in rats showed that compound A1 has favorable pharmacokinetic prosperities for further development purpose, with elimination half-time (t(1/2)) of 1.63 h and oral bioavailability (F) of 40.9%.
Zhang
Quan
Q
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, PR China.
Jiang
Zhi-Yong
ZY
Luo
Jie
J
Ma
Yun-Bao
YB
Liu
Ji-Feng
JF
Guo
Rui-Hua
RH
Zhang
Xue-Mei
XM
Zhou
Jun
J
Niu
Wei
W
Du
Fei-Fei
FF
Li
Li
L
Li
Chuan
C
Chen
Ji-Jun
JJ
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002783:Cholestenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006515:Hepatitis B virus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D002783:Cholestenones; C546451:tetra-ethoxyacetyl alisol A; C546450:tetra-methoxycetyl alisol A; C546449:tetraacetylalisol A