Anti-HBV agents. Part 3: Preliminary structure–activity relationships of tetra-acylalisol A derivatives as potent hepatitis B virus inhibitors

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• 作者：Quan Zhang ; Zhi-Yong Jiang ; Jie Luo ; Yun-Bao Ma ; Ji-Feng Liu ; Rui-Hua Guo ; Xue-Mei Zhang ; Jun Zhou ; Wei Niu ; Fei-Fei Du ; Li Li ; Chuan Li ; Ji-Jun Chen
• 关键词：Anti-HBV activity ; Protostane-type triterpene ; Alisol A ; Derivatives ; Chemical modification
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：1 December 2009
• 年：2009
• 卷：19
• 期：23
• 页码：6659-6665
• 全文大小：2076 K

文摘

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 0.014 mM, respectively, HBeAg with IC₅₀ 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 % .