Abstract
A series of oxime ethers with C6-C4 fragment was designed and virtually bioactively screened by docking with a target, then provided by a Friedel–Crafts reaction, esterification (or amidation), and oximation from p-substituted phenyl derivatives (Methylbenzene, Methoxybenzene, Chlorobenzene). Anti-hepatitis B virus (HBV) activities of all synthesized compounds were evaluated with HepG2.2.15 cells in vitro. Results showed that most of compounds exhibited low cytotoxicity on HepG2.2.15 cells and significant inhibition on the secretion of HBsAg and HBeAg. Among them, compound 5c-1 showed the most potent activity on inhibiting HBsAg secretion (IC50 = 39.93 μM, SI = 28.51). Results of the bioactive screening showed that stronger the compounds bound to target human leukocyte antigen A protein in docking, the more active they were in anti-HBV activities in vitro.
Highlights
Hepatitis B virus (HBV) infection is a serious worldwide health problem, which causes acute and chronic hepatitis B, cirrhosis, hepatocellular carcinoma, and other hepatic diseases [1]
Molecular docking studies of the oxime ester derivatives were carried out using MOE 2008.10 as docking software in order to rationalize the biological activity results and understand the various interactions between ligand and protein in the active site in detail
N in the oxime group (-O-N=C) of 14 compounds interacted with amino acid residues by a hydrogen bond in the active site, which is similar to the reported works [33]
Summary
Hepatitis B virus (HBV) infection is a serious worldwide health problem, which causes acute and chronic hepatitis B, cirrhosis, hepatocellular carcinoma, and other hepatic diseases [1]. The nucleoside analogs used in treatment of anti-HBV play the role of Trojan horse in the synthesis of HBV DNA and suppress replication of HBV [3,4,5,6,7], but they are not effective in eliminating the virus from patients. HBV therapies with nucleoside analogs in the long term cause serious side effects and resistance [8,9,10,11,12]. More and more effective nucleoside analogs agents for treating HBV have been invented and developed, they only inhibit or stop replication of HBV DNA, and do not eliminate HBV cccDNA from patients. The cccDNA in patients will cause HBV DNA replication. Methods to stop and eliminate HBV DNA and cccDNA from HBV patients are still a great challenge for researchers.
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