Synthesis, Structure-activity relationships and biological evaluation of dehydro-andrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents

TY - JOUR

T1 - Synthesis, Structure-activity relationships and biological evaluation of dehydro-andrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents

AU - Chen, H

AU - Ma, YB

AU - Huang, XY

AU - Geng, CA

AU - Zhao, Yong

AU - Wang, LJ

AU - Guo, RH

AU - Zhang, XM

AU - Chen, JJ

PY - 2014/5/15

Y1 - 2014/5/15

N2 - Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis paniculata possessed activity against HBV DNA replication with IC50 values of 22.58 and 54.07 μM and low SI values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of 20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhibiting HBV DNA replication was revealed with the optimal log P value of 1.78 and log D values. Structure-activity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the discovery of new anti-HBV drugs.

AB - Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis paniculata possessed activity against HBV DNA replication with IC50 values of 22.58 and 54.07 μM and low SI values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of 20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhibiting HBV DNA replication was revealed with the optimal log P value of 1.78 and log D values. Structure-activity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the discovery of new anti-HBV drugs.

U2 - 10.1016/j.bmcl.2014.03.060

DO - 10.1016/j.bmcl.2014.03.060

M3 - Journal article

VL - 24

SP - 2353

EP - 2359

JO - Biooganic & Medicinal Chemistry Letters

JF - Biooganic & Medicinal Chemistry Letters

IS - 10

ER -