Recent advances on the synthesis of hepatitis C virus NS5B RNA-dependent RNA-polymerase inhibitors

Zhao, Can; Wang, Yinhu; Ma, Shutao

doi:10.1016/j.ejmech.2015.07.046

Cited by 14 publications

(6 citation statements)

References 109 publications

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“…Moreover, in 2013, Venkatraman et al introduced a novel series of tricyclic indole derivatives as NS5B inhibitors, in which "6H-furo [2,3-e]indole-7-carboxylic acid" B was identi ed as the most active molecule with promising cellular activity (EC 50 = 160 nM) and an IC 50 value of 0.031 µM 16 . Compounds A and B contain two neighboring carbonyl groups that were found to inhibit HCV NS5B 17 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel HCV inhibitors: design, synthesis and biological activity of phthalamide derivatives

Mahjoub

Mahboubi-Rabbani²,

Vahabpour³

et al. 2022

Med Chem Res

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Hepatitis C virus (HCV) is a major cause of end-stage liver diseases like cirrhosis and hepatocarcinoma, posing a serious worldwide threat when left untreated. Nowadays, direct-acting antivirals (DAAs) constitute core components of anti-HCV treatment. Nonetheless, some DAAs are associated with a growing level of drug resistance as well as adverse reactions. That is why introducing new anti-HCV drugs with higher potency and lower toxicity is so essential. NS5B polymerase is an HCV non-structural protein that acts as a critical target for the development of anti-HCV therapeutics. Based on the necessary pharmacophores for inhibition of HCV NS5B polymerase, a novel series of phthalamide analogs that harbor the potential of NS5B polymerase inhibition to stop HCV proliferation in a cell-based assay were designed, synthesized, and in-vitro evaluated. Interestingly, all compounds displayed low cellular cytotoxicity in Huh 7.5 cells (CC 50 > 100). Compound 28 with EC 50 of 6.0 µM, and an appropriate a nity to NS5B polymerase active site could be considered as a new hit compound, providing useful information for the design of novel HCV inhibitors.

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Section: Introductionmentioning

confidence: 99%

Discovery of novel HCV inhibitors: design, synthesis and biological activity of phthalamide derivatives

Mahjoub

Mahboubi-Rabbani²,

Vahabpour³

et al. 2022

Med Chem Res

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“…Treatment typically lasted 24–48 weeks and was physically demanding, as patients often experience flu-like side effects. Fortunately, for those afflicted with HCV, there have been a number of modern treatments that offer reduced side effects and shortened treatment duration. , In addition, many patients are treated with combinations of these drugs and experience even greater cure rates. The HCV NS5B RNA polymerase is an attractive target for drug inhibition because it is required for HCV replication.…”

Section: Introductionmentioning

confidence: 99%

The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor

Bien

Davulcu

DelMonte

et al. 2018

Org. Process Res. Dev.

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The process development and kilogram-scale synthesis of beclabuvir (BMS-791325, 1) is described. The convergent synthesis features the use of asymmetric catalysis to generate a chiral cyclopropane fragment and coupling with an indole fragment via an alkylation. Subsequent palladium-catalyzed intramolecular direct arylation efficiently builds the central seven-membered ring. The target was prepared in 12 linear steps with five isolations in an overall yield of 8%.

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“…Also, it is considered as one of the primary causes of cirrhosis and hepatocellular carcinoma (HCC); and a leading cause for liver transplantation worldwide [5][6][7]. In addition, HCV belongs to the familyFlaviviridae and genus-hepacivirus [8].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, a growing number of small molecules have been reported as allosteric inhibitors of NS5B with only a very few of them still active in clinical trials in recent times [5][6][7]. However, limited studies are available on medicinal small molecules, as HCV NS5B RNA-dependent, RNA polymerase inhibitors from other plants like Acacia concinna [9], Phyllanthus niruri [10].…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking and Pharmacophore-Based Virtual Screening of Novel Inhibitors for HCV NS5B RNA-Dependent RNA Polymerase Enzyme from Crude Sesame Essential Oil.

2018

AJOBB

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Concern has been expressed worldwide about the rising prevalence of HCV induced acute hepatitis and chronic liver diseases with associated cirrhosis and liver cancers. However, the available synthetic drugs are ineffective for all the HCV genotypes especially in genotype-1 patients with about 40% viral response rates and numerous side effects. Besides, the availability of veritable bioinformatics tools which includes molecular docking and virtual screening studies have shown that computational generated models nowadays assists in modern drug design and development of novel and more potent inhibitors through the understanding of protein (receptors) -ligand (drugs) interaction mechanisms. Non-structural proteins especially the 5B (NS5B) is an RNA-dependent RNA polymerase implicated in the synthesis and replication of the HCV RNA; and has been a potential target for its inhibitory activities. Due to the paucity of knowledge, we aimed to determine the differential inhibitory activity of essential oils present in the crude Sesame leaves extracts on HCV-NS5B RNA dependent RNA polymerase. Using in-silico studies-a Microsoft pharmacophore-based virtual screening and molecular docking tools on the iGEM-DOCK vs 2.0 software was used to dock the essential oil ligands on the generated HCV NS5B (PDB ID: 4EO6) RNA-dependent RNA polymerase protein. GC-MS of the leaves confirmed carboxylic acids and phenolic groups in the essential oils especially some potent antioxidants like alpha-linolenic acid, linoleic acid, oleic acid, etc. Moreover, Alpha-Linolenic acid/ALA (-102.2/-103.4 kcal/mol) and Linoleic acid/LA (-94.8/-109.8 kcal/mol) showed higher inhibitory impacts among the six top different docked ligands, selected based on their high differential binding affinity and pharmacological interaction energy profiles against HCV NS5B RNA polymerase activities, by forming more H-bond interactions than the NS5B co-crystallized ligand. ADMET showed that ALA is well tolerated without any apparent toxicity in the body. Hence, ALA having the highest inhibitory impacts against the HCV NS5B goes to confirm the beneficial impacts of carboxylic acids from Sesame plant in maintaining liver cellular integrity and as a natural inhibitor of HCV NS5B RNA dependent RNA Polymerase enzyme activities.

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Recent advances on the synthesis of hepatitis C virus NS5B RNA-dependent RNA-polymerase inhibitors

Cited by 14 publications

References 109 publications

Discovery of novel HCV inhibitors: design, synthesis and biological activity of phthalamide derivatives

Discovery of novel HCV inhibitors: design, synthesis and biological activity of phthalamide derivatives

The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor

Molecular Docking and Pharmacophore-Based Virtual Screening of Novel Inhibitors for HCV NS5B RNA-Dependent RNA Polymerase Enzyme from Crude Sesame Essential Oil.

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