Discovery of Oxime Ethers as Hepatitis B Virus (HBV) Inhibitors by Docking, Screening and In Vitro Investigation

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.

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

“…These synthesized compounds were evaluated for anti-HBV activity with referring to reported method [25,30]. The HepG2.2.15 cell, a human hepatoblastoma cell line stably transfected with cloned HBV DNA, was obtained from Chinese Academy of Medical Sciences (Beijing, China), and was cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine serum and 1.5 g/L of sodium bicarbonate, 10 mL/L of streptomycin, 10 mL/L of penicillin, and 200 mg/L of G418 at 37 °C in a 5% CO 2 atmosphere with 95–98% humidity.…”

“…Series of oxime-contained compounds with C 6 -C 3 and C 6 -C 4 skeleton were designed, synthesized, and assayed for anti-HBV activities. Results showed these compounds possessed significant anti-HBV activities [22,23,24,25]. On the basis of these results, we designed and synthesized a series of another part of novel oximes and their derivatives with C 6 -C 4 skeletons, and screened for anti-HBV activities in our present works.…”

A Review of Biologically Active Oxime Ethers

“…These compounds inhibited 56 HRV strains, with IC 50 values in the range of 0.5-6.70 nM and in many cases comparable to or better than pyrodavil. Studies have shown that these compounds are also active against enteroviruses-Coxsackie (IC 50 Hepatitis B virus (HBV) inhibitors containing an oxime ether group (46, Figure 7) were designed by Tan et al [49]. The authors tested the ability to inhibit the surface antigens of the hepatitis B virus (HBsAg) and the antigens indicating active replication of the HBV virus (HBeAg) in HepG2.2.15 cells of eighteen derivatives.…”

Design, Synthesis and Bioactive Evaluation of Oxime Derivatives of Dehydrocholic Acid as Anti-Hepatitis B Virus Agents

“…Therefore DHCA, with reactive functional groups, was considered as a liver-target vehicle to deliver drugs to the liver in our present work. Based on the bioactivities of DHCA and oximes in our previous works [28][29][30], the introduction of the oxime group to DHCA should be suggested to possess liver-targeted and anti-HBV activities. So, a series of oxime derivatives of DHCA were designed, synthesized, and screened for anti-HBV activity in vitro in this work, and molecular docking studies were carried out to investigate the relationship of structure and bioactivity of these compounds using a molecular operating environment (MOE).…”