1. Anti-HBV agents. Part 3: Preliminary structure–activity relationships of tetra-acylalisol A derivatives as potent hepatitis B virus inhibitors
- Author
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Zhang, Quan, Jiang, Zhi-Yong, Luo, Jie, Ma, Yun-Bao, Liu, Ji-Feng, Guo, Rui-Hua, Zhang, Xue-Mei, Zhou, Jun, Niu, Wei, Du, Fei-Fei, Li, Li, Li, Chuan, and Chen, Ji-Jun
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ANTIVIRAL agents , *DRUG derivatives , *STRUCTURE-activity relationship in pharmacology , *HEPATITIS B virus , *ACYLATION , *CLINICAL drug trials , *CELL surface antigens , *TERPENES , *LABORATORY rats - Abstract
Abstract: 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 IC50 values of 0.0048, 0.0044, and 0.014mM, respectively, HBeAg with IC50 values of 0.011, 0.012, and 0.018mM, respectively, and remarkable selective index values SIHBsAg >333, SIHBeAg >145; SIHBsAg =209, SIHBeAg =77; and SIHBsAg >200, SIHBeAg >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 1.63h and oral bioavailability (F) of 40.9%. [Copyright &y& Elsevier]
- Published
- 2009
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