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

Guo, Ruihua; Zhang, Quan; Ma, Yun‐Bao; Huang, Xiaoyan; Luo, Jie; Wang, Lijun; Geng, Chang‐An; Zhang, Xuemei; Zhou, Jun; Jiang, Zhi‐Yong

doi:10.1016/j.bmc.2011.01.006

Cited by 29 publications

(13 citation statements)

References 24 publications

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“…In addition, they have been extensively examined for their role in the inhibition of tyrosine kinases, the proteasome, tubulin polymerization, and DNA repair (reviewed in reference 67). Relevant to viral inhibition, compounds containing quinoline moieties have also been shown to have activity against numerous viruses, such as bovine viral diarrhea virus (BVDV) and HCV at the level of the viral RNA-dependent RNA polymerase (13) and hepatitis B virus by acting as nonnucleoside anti-HBV agents (31). However, both NSC 13726 and 13728 are structurally dissimilar to the compounds used in the aforementioned studies; therefore, whether their anti-HCV modes of action are mechanistically similar remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Sáinz

Petukhov

et al. 2012

Antimicrob Agents Chemother

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With 2 to 3% of the worldwide population chronically infected, hepatitis C virus (HCV) infection continues to be a major health care burden. Unfortunately, current interferon-based treatment options are not effective in all patients and are associated with significant side effects. Consequently, there is an ongoing need to identify and develop new anti-HCV therapies. Toward this goal, we previously developed a cell-based HCV infection assay for antiviral compound screening based on a low-multiplicity-of-infection approach that uniquely allows for the identification of antiviral compounds that target cell culture-derived HCV (HCVcc) at any step of the viral infection cycle. Using this assay, here we report the screening of the NCI Diversity Set II library, containing 1,974 synthesized chemical compounds, and the identification of compounds with specific anti-HCV activity. In combination with toxicity counterscreening, we identified 30 hits from the compound library, 13 of which showed reproducible and dose-dependent inhibition of HCV with mean therapeutic indices (50% cytotoxic concentration [CC 50 ]/50% effective concentration [EC 50 ]) of greater than 6. Using HCV pseudotype and replicon systems of multiple HCV genotypes, as well as infectious HCVcc-based assembly and secretion analysis, we determined that different compounds within this group of candidate inhibitors target different steps of viral infection. The compounds identified not only will serve as biological probes to study and further dissect the biology of viral infection but also should facilitate the development of new anti-HCV therapeutic treatments. Hepatitis C virus (HCV) is a hepatotropic enveloped positivestrand RNA virus (family Flaviviridae) that infects the parenchymal cells of the liver (i.e., hepatocytes) (69, 70). HCV infection begins with interaction of the viral particle with the target cell via a relatively undefined multistep process of binding between the virion and multiple cell surface receptors, which include the cluster of differentiation 81 (CD81) tetraspanin protein (7,34,56,80,84), the scavenger receptor class B member I (SR-BI) (also known as SCARB1) (7,30,38,63,83), and the tight-junction proteins claudin-1 (CLDN1) (20) and occludin (OCLN) (8,47,57). In addition to these four host factors, we more recently showed that the cellular Niemann-Pick C1-like 1 (NPC1L1) cholesterol uptake receptor also functions as an HCV entry factor via a virion particle cholesterol-associated mechanism (60), and Lupberger et al. have recently shown that the host cellular epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2) function as cofactors during viral cell entry (49).Following entry, the viral genome (ϳ9.6 kb) is translated by an internal ribosome entry site (IRES)-dependent process into a single viral polyprotein that is subsequently co-and posttranslationally cleaved into structural (core, E1, E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins by host and viral proteases (29,46). The NS prote...

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Section: Discussionmentioning

confidence: 99%

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Sáinz

Petukhov

et al. 2012

Antimicrob Agents Chemother

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“…Screening of libraries for anti‐HBV activity using HepG2.2.15 cells led to the identification of several chemotypes that possess inhibitory effects, including 4‐aryl‐6‐chloro‐quinolin‐2‐one , 2‐{2‐(1‐(4‐nitro‐benzene‐sulfonyl)‐1 H ‐benzo‐imidazol‐2‐yl)‐ethyl}‐isoindole‐1,3‐dione , N ‐(2‐amino‐1‐(isopropyl‐sulfonyl)‐1 H ‐benzo[ d ]imidazol‐6‐yl)‐3‐(trifluoromethyl)benzenesulfonamide , and 5‐(2‐hydroxy‐4‐methoxybenzoyl)‐1‐phenylpyridin‐2(1 H )‐one . 4‐Aryl‐6‐chloro‐quinoline derivatives inhibited HBsAg and HBeAg secretion, and HBV DNA replication ; however, the 5‐aryl‐7‐chloro‐1,4‐benzodiazepine derivatives were cytotoxic and had little effect on HBsAg and HBeAg secretion . The benzimidazole derivative 2‐{2‐(1‐(4‐methylbenzyl)‐1 H ‐benzoimidazol‐2‐yl‐5,6‐di‐chloro)‐ethyl}‐isoindole‐1,3‐dione , and the 5‐(2‐hydroxy‐4‐methoxybenzoyl)‐1‐phenylpyridin‐2(1 H )‐one derivatives 1‐(4‐ethoxyphenyl)‐5‐(2‐hydroxy‐4‐methoxybenzoyl)pyridin‐2(1 H )‐one and (E)‐1‐butyl‐5‐((butylimino)(2‐hydroxy‐4‐methoxyphenyl)methyl) pyridin‐2(1 H )‐one were shown to be among the most potent and selective inhibitors of HBV DNA replication within their respective chemotypes.…”

Section: Anti‐hbv Drug Candidates: Synthetic Small Moleculesmentioning

confidence: 99%

“…Screening of libraries for anti-HBV activity using HepG2.2.15 cells led to the identification of several chemotypes that possess inhibitory effects, including 4-aryl-6-chloro-quinolin-2-one [126], 2-{2-(1-(4-nitrobenzene-sulfonyl)-1H-benzo-imidazol-2-yl)-ethyl}-isoindole-1,3-dione [127], N-(2-amino-1-(isopropyl-sulfonyl)-1 H-benzo[d]imidazol-6-yl)-3-(trifluoromethyl)benzenesulfonamide [128], and 5-(2-hydroxy-4-methoxybenzoyl)-1phenylpyridin-2(1H)-one [129]. 4-Aryl-6-chloro-quinoline derivatives inhibited HBsAg and HBeAg secretion, and HBV DNA replication [126,130]; however, the 5-aryl-7chloro-1,4-benzodiazepine derivatives were cytotoxic and had little effect on HBsAg and HBeAg secretion [126]. The benzimidazole derivative 2-{2-(1-(4-methylbenzyl)-1H-benzoimidazol-2-yl-5,6-di-chloro)-ethyl}-isoindole-1, 3-dione [127,128], and the 5- [131].…”

Section: Othersmentioning

confidence: 99%

Antihepatitis B therapy: a review of current medications and novel small molecule inhibitors

Qiu

Chen

2013

Fundamemntal Clinical Pharma

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There are approximately 350 million hepatitis B virus (HBV) carriers worldwide. Chronic HBV infection increases the risk of liver cirrhosis and hepatocellular carcinoma. To date, two classes of antiviral drugs have been approved by the Food and Drug Administration for the treatment of hepatitis B, immunomodulators (interferon [IFN]-α and pegylated-interferon [PEG-IFN]-α) and nucleos(t)ide analogs (lamivudine, telbivudine, adefovir, tenofovir [TDF], and entecavir [ETV]). Of these, ETV, TDF, and PEG-IFN-α are the most effective and are currently recommended for anti-HBV therapy. However, these therapies are less than optimal because of their low rate of viral DNA and surface antigen clearance; thus, there exists a significant unmet medical need for safe and efficacious new anti-HBV drugs. Covering diverse chemical structures and mechanisms of action, non-nucleos(t)ide compounds offer great promise in the search for new anti-HBV drugs. This review summarizes the currently approved anti-HBV drugs and highlights advances in the identification and characterization of novel small molecule HBV inhibitors. We discuss the sources, structures, anti-HBV effects, mechanisms of action, and potential toxicities of these novel inhibitors.

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“…As our ongoing study for searching anti-HBV inhibitors from natural resources, PD and PT were revealed to be active against HBV DNA replication with IC 50 values of 148.15 and 668.60 μM but low SI values of 6.2 and 3.6 in our random assay. In order to increase the activity and safety, PD and PT were hybridized with heteroaromatic rings based on our previous experience from the modification on caudatin and hemslecin A [15, 16]. Consequently, 28 panaxadiol and panaxatriol analogues were synthesized by modifying on rings A, B and C. Herein, we described the synthesis, in vitro anti-HBV activity and structure–activity relationships (SARs) of these derivatives (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Panaxadiol and Panaxatriol Derivatives as Anti-Hepatitis B Virus Inhibitors

Hao

Wang

et al. 2014

Nat. Prod. Bioprospect.

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Abstract28 Derivatives of panaxadiol (PD) and panaxatriol were synthesized and evaluated for their anti-HBV activity on HepG 2.2.15 cells, of which 17 derivatives inhibited HBV DNA replication. Compounds 4, 9, 10, 14, and 15 showed moderate activity against HBV DNA replication with IC50 values ranged from 7.27 to 28.21 μM compared with PD. In particular, 3-O-2′-thenoyl panaxadiol (4) inhibited not only HBV DNA replication (IC50 = 16.5 μM, SI > 115.7) but also HBsAg (IC50 = 30.8 μM, SI > 62.0) and HBeAg (IC50 = 18.2 μM, SI > 105.14) secretions. Their structure–activity relationships were discussed for guiding future research toward the discovery of new anti-HBV agents.Graphical AbstractElectronic supplementary materialThe online version of this article (doi:10.1007/s13659-014-0018-2) contains supplementary material, which is available to authorized users.

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

Cited by 29 publications

References 24 publications

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Identification of Hepatitis C Virus Inhibitors Targeting Different Aspects of Infection Using a Cell-Based Assay

Antihepatitis B therapy: a review of current medications and novel small molecule inhibitors

Panaxadiol and Panaxatriol Derivatives as Anti-Hepatitis B Virus Inhibitors

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