Design, synthesis, and evaluation of novel heteroaryldihydropyrimidine derivatives as non‐nucleoside hepatitis B virus inhibitors by exploring the solvent‐exposed region

Oxime derivatives of dehydrocholic acid and its esters were designed for anti-hepatitis B virus (HBV) drugs according to principles of assembling active chemical fragments. Twelve compounds were synthesized from dehydrocholic acid by esterification and oxime formation, and their anti-hepatitis B virus (HBV) activities were evaluated with HepG 2.2.15 cells. Results showed that 5 compounds exhibited more effective inhibition of HBeAg than positive control, among them 2b-3 and 2b-1 showed significant anti-HBV activities on inhibiting secretion of HBeAg (IC50 (2b-3) = 49.39 ± 12.78 μM, SI (2b-3) = 11.03; IC50 (2b-1) = 96.64 ± 28.99 μM, SI (2b-1) = 10.35) compared to the Entecavir (IC50 = 161.24 μM, SI = 3.72). Molecular docking studies showed that most of these compounds interacted with protein residues of heparan sulfate proteoglycan (HSPG) in host hepatocyte and bile acid receptor.

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A Series of Oleanolic Acid Derivatives as Anti-Hepatitis B Virus Agents: Design, Synthesis, and in Vitro and in Vivo Biological Evaluation

Molecules ◽

10.3390/molecules21040402 ◽

2016 ◽

Vol 21 (4) ◽

pp. 402 ◽

Cited By ~ 11

Author(s):

Wenqiang Yan ◽

Chenze Zhang ◽

Bi Li ◽

Xin Xu ◽

Miao Liang ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Oleanolic Acid ◽

Biological Evaluation ◽

Design Synthesis ◽

B Virus

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Design, Synthesis, and Bioactive Screen In Vitro of Cyclohexyl (E)-4-(Hydroxyimino)-4-Phenylbutanoates and Their Ethers for Anti-Hepatitis B Virus Agents

Molecules ◽

10.3390/molecules24112063 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2063 ◽

Cited By ~ 2

Author(s):

Xinhua Cui ◽

Min Zhou ◽

Jie Tan ◽

Zhuocai Wei ◽

Wanxing Wei ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Cell Line ◽

Active Site ◽

Docking Study ◽

Design Synthesis ◽

Ctl Epitope ◽

B Virus ◽

Hla A2.1

A series of oxime Cyclohexyl (E)-4-(hydroxyimino)-4-phenylbutanoates and their ethers were designed, synthesized, and evaluated for anti-hepatitis B virus (HBV) activities with HepG 2.2.15 cell line in vitro. Most of these compounds possessed anti-HBV activities, and among them, compound 4B-2 showed significant inhibiting effects on the secretion of HBsAg (IC50 = 63.85 ± 6.26 μM, SI = 13.41) and HBeAg (IC50 = 49.39 ± 4.17 μM, SI = 17.34) comparing to lamivudine (3TC) in HBsAg (IC50 = 234.2 ± 17.17 μM, SI = 2.2) and HBeAg (IC50 = 249.9 ± 21.51 μM, SI = 2.07). Docking study of these compounds binding to a protein residue (PDB ID: 3OX8) from HLA-A2 that with the immunodominant HBcAg18–27 epitope (HLA-A2.1- restricted CTL epitope) active site was carried out by using molecular operation environment (MOE) software. Docking results showed that behaviors of these compounds binding to the active site in HLA-A protein residue partly coincided with their behaviors in vitro anti-HBV active screening.

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