Non-nucleoside anti-HBV Agents Research Articles

Design and Synthesis of (3-Phenylisoxazol-5-yl)methanimine Derivatives as Hepatitis B Virus Inhibitors.

Series of (3-phenylisoxazol-5-yl)methanimine derivatives were synthesized, and evaluated for anti-hepatitis B virus (HBV) activity in vitro. Half of them more effectively inhibited HBsAg than 3TC, and more favor to inhibit secretion of HBeAg than to HBsAg. Part of the compounds with significant inhibition on HBeAg were also effectively inhibit replication of HBV DNA. Compound (E)-3-(4-fluorophenyl)-5-((2-phenylhydrazineylidene)methyl)isoxazole inhibited excellently HBeAg with IC50 in 0.65 μM (3TC(Lamivudine) in 189.90 μM), inhibited HBV DNA in 20.52 μM (3TC in 26.23 μM). Structures of compounds were determined by NMR and HRMS methods, and chlorination on phenyl ring of phenylisoxazol-5-yl was confirmed by X-ray diffraction analysis, and the structure-activity relationships (SARs) of the derivatives was discussed. This work provided a new class of potent non-nucleoside anti-HBV agents.

Synthesis and evaluation of new phenyl acrylamide derivatives as potent non-nucleoside anti-HBV agents

As a continuation of our previous work, a series of new phenyl acrylamide derivatives (4Aa-g, 4Ba-t, 5 and 6a-c) were designed and synthesized as non-nucleoside anti-HBV agents. Among them, compound 4Bs could potently inhibit HBV DNA replication in wild-type and lamivudine (3TC)/entecavir resistant HBV mutant strains with IC50 values of 0.19 and 0.18 μM, respectively. Notably, the selective index value of 4Bs was above 526, indicating the favorable safety profile. Interestingly, unlike nucleoside analogue 3TC, 4Bs could significantly inhibit 3.5 kb pgRNA expression. Molecular docking study revealed that 4Bs could fit well into the dimer-dimer interface of HBV core protein by hydrophobic, π–π and H-bond interactions. Considering the potent anti-HBV activity, low toxicity and diverse anti-HBV mechanism from that of nucleoside anti-HBV agent 3TC, compound 4Bs might be a promising lead to develop novel non-nucleoside anti-HBV therapeutic agents, and warranted further investigation.

Assessment of quinazolinone derivatives as novel non-nucleoside hepatitis B virus inhibitors

Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents. Among them, compounds 5e and 5f could significantly inhibit HBV DNA replication with IC50 values of 1.54 μM and 0.71 μM, respectively. Interestingly, the selective index values of 5f was higher than that of lead compound K284–1405, suggesting 5f possessed relatively safety profile than K284–1405. Notably, 5e and 5f exhibited remarkably anti-HBV activities against lamivudine and entecavir resistant HBV strain with IC50 values of 1.90 and 0.84 μM, confirming their effectiveness against resistant HBV strain. In addition, molecular docking studies indicated that compounds 5e and 5f could well fit into the dimer-dimer interface of HBV core protein dominated by hydrophobic interactions. Notably, their binding modes were different from the lead compound K284–1405, which may be attributed to the additional substituent groups in the quinazolinone scaffold. Taken together, 5e and 5f possessed novel chemical structure and potent anti-HBV activity against both drug sensitive and resistant HBV strains, thus warranting further research as potential non-nucleoside anti-HBV candidates.

2-Arylthio-5-iodo pyrimidine derivatives as non-nucleoside HBV polymerase inhibitors

In this study, a series of 2-arylthio-5-iodo pyrimidine derivatives, as non-nucleoside hepatitis B virus inhibitors, were evaluated and firstly reported as potential anti-HBV agents. To probe the mechanism of active agents, DHBV polymerase was isolated and a non-radioisotopic assay was established for measuring HBV polymerase. The biological results demonstrated that 2-arylthio-5-iodo pyrimidine derivatives targeted HBV polymerase. In addition, pharmacophore models were constructed for future optimization of lead compounds. Further study will be performed for the development of non-nucleoside anti-HBV agents.

Design, synthesis and evaluation of novel phenyl propionamide derivatives as non-nucleoside hepatitis B virus inhibitors

As an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 μM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153.14, suggesting that 8d and 9b exhibited favorable safety profiles. Interestingly, 8d and 9b possessed significantly antiviral activities against lamivudine and entecavir resistant HBV mutants with IC50 values of 0.77 and 0.32 μM. Notably, preliminary anti-HBV action mechanism studies showed that 8d could inhibit intracellular HBV pgRNA and RT activity of the HBV polymerase. Molecular docking studies suggested that compound 8d could fit into the dimer-dimer interface of HBV core protein by hydrophobic interaction. In addition, in silico prediction of physicochemical properties showed that 8d conformed well to the Lipinski's rule of five, suggesting its potential for use as a drug like molecule. Taken together, 8d possessed significantly anti-HBV activity, low toxicity, diverse anti-HBV mechanism and favorable physicochemical properties, and warranted further investigation as a promising non-nucleoside anti-HBV candidate.

Study on 2-arylthio-5-iodo pyrimidine derivatives as novel nonnucleoside inhibitors against hepatitis B virus DNA replication.

Novel nonnucleoside hepatitis B virus inhibitors have been recently developed for the reason of drug-resistant mutations and adverse effects of nucleoside analogs. In this study, two series of 2-arylthio-5-iodo pyrimidine analogs were firstly reported as potential anti-HBV agents. Target compounds were prepared according to two high-yielded synthetic routes, and their anti-HBV activities were evaluated on Hep2.2.15 and HepAD38 cell lines, respectively. To probe the mechanism of active agents, a cell-based (Huh-7) study of biochemical markers (e.g., HBeAg, HBsAg, intracellular HBV DNA and pgRNA) was performed. Furthermore, the pharmacophore models were constructed for future optimization of lead compounds. 2-Arylthio-5-iodo pyrimidine derivatives firstly proved to be effective against HBV, which paves the way for future development of nonnucleoside anti-HBV agents.

Design, synthesis, molecular docking studies and anti-HBV activity of phenylpropanoid derivatives

In this work, a series of phenylpropanoid derivatives were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated. Most of the synthesized derivatives showed effective anti-HBV activity. And compound 4d-3 showed the most effective anti-HBV activity, performing strong potent inhibitory not only on the secretion of HBsAg (IC50 = 58.28 μM, SI = 23.26) and HBeAg (IC50 = 97.21 μM, SI = 13.95), but also on the HBV DNA replication (IC50 = 42.28 μM, SI = 32.06). The structure-activity relationships (SARs) of the derivatives had been discussed, which were useful for developing phenylpropanoid derivatives as novel anti-HBV agents. Moreover, the docking study of all synthesized compounds inside the HLA-A protein (PDB ID: 3OX8) active site was carried out to explore the molecular interactions and a molecular target for activity and a modified assay method measuring the interaction between our derivatives and HBcAg was investigated, indicating that the HBV core protein might be their potential target for anti-HBV. This study identified a new class of potent non-nucleoside anti-HBV agents.

A Review of Novel Non-Nucleoside Anti-HBV Agents and Their Mechanism of Action

Hepatitis B virus (HBV) infection is a serious worldwide health problem as drugs (such as lamivudine and adefovir) for treating HBV are still unsatisfactory, due to high recurrence, drug resistance and inevitable side effects. Therefore, there exists a significant medical need to explore novel classes of drugs with different antiviral targets and mechanisms for anti-HBV purposes. Recently, some non-nucleoside HBV inhibitors with specific targets have been obtained from natural sources or prepared by synthesis. These compounds provide useful information for developing novel non-nucleoside compounds as anti-HBV agents.

5-Iodo-2-arylalkylthio-6-aryl pyrimidin-4(3H)-ones as non-nucleoside anti-HBV agents

Pyrimidone derivatives have been synthesized and evaluated as anti-HBV agents, in which two compounds exhibited more potent activity than lamivudine.

Non-nucleoside anti-HBV agents: advances in structural optimization and mechanism of action investigations

In this review, we focus on the recent advances in discovery, structural modifications and biological activities studies of several distinct classes of synthetic non-nucleoside small molecular compounds with new mechanisms.

Synthesis and biological assay of 4-aryl-6-chloro-quinoline derivatives as novel non-nucleoside anti-HBV agents

A series of 4-aryl-6-chloro-quinoline derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities, namely the abilities to inhibit the secretion of HBV surface antigen (HBsAg), HBV e antigen (HBeAg), and replication of HBV DNA in HepG 2.2.15 cells. Most of the compounds exhibited moderate inhibitory activity against the secretion of HBsAg and HBeAg. Nine compounds (3, 5, 6, 7, 10, 14, 17, 20, 24) showed significant inhibition against HBV DNA replication with IC50 values in the range of 4.4–9.8μM, which were comparative to that of positive control tenofovir. Of them, compounds 10, 17, and 20 had low cytotoxicities, resulting in high SI values, >551.2, >143.7, and >284.5, respectively.