Benzimidazole Inhibitors of Hepatitis C Virus NS5B Polymerase: Identification of 2‐[(4‐Diarylmethoxy)phenyl]‐benzimidazole.

Ishida, Tomio; Suzuki, Takayoshi; Hirashima, Shin‐ichi; Mizutani, Kenji; Yoshida, Akinori; Ando, Izuru; Ikeda, Satoru; Adachi, Tsutomu; Hashimoto, Harukichi

doi:10.1002/chin.200627127

Cited by 15 publications

(43 citation statements)

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“…Ishida et al synthesized a series of 1-cycloalkyl-2-phenyl-1H-benzimidazole-5-carboxylic acid derivatives and evaluated their inhibitory activity against hepatitis C virus NS5B RNA-dependent RNA polymerase. In their study, they found that diaryl methoxy derivatives, 20 and 21, blocked the replication of subgenomic HCV-RNA in the replicon cells (Ishida et al, 2006).…”

Section: Benzimidazoles As Antihepatitic Agentsmentioning

confidence: 98%

Benzimidazole: a medicinally important heterocyclic moiety

2010

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Benzimidazole nucleus is a constituent of many bioactive heterocyclic compounds that are of wide interest because of their diverse biological and clinical applications. Moreover, benzimidazole derivatives are structural isosters of naturally occurring nucleotides, which allows them to interact easily with the biopolymers of the living system. This created interest in researchers who have synthesized variety of benzimidazole derivatives and screened them for their various biological activities, viz.

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Section: Benzimidazoles As Antihepatitic Agentsmentioning

confidence: 98%

Benzimidazole: a medicinally important heterocyclic moiety

2010

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“…Thus, focus was diverted at neutralizing the -carboxyl group by conversion to -CONH 2 resulted in compound 9 (IC 50 = 0.22 μM, EC 50 = 8 μM) [29]. Further improvement in enzymatic and replicon activity was achieved by replacement of - Ishida et al, [30] screened a collection of compounds from Japan Tobacco to identify potential NS5B (genotype 1b) inhibitors. Optimization of N 1 -cyclohexyl-benzi-midazole-5-carboxylic acid, an initial hit, at the 2-position led to the identification of compound 11 (genotype 1b IC 50 = 0.27 μM, replicon EC 50 = 1.1 μM, genotype 1a IC 50 = 0.80 μM).…”

Section: Nnis Binding To the Allosteric Pocketmentioning

confidence: 99%

Multiple Allosteric Pockets of HCV NS5B Polymerase and its Inhibitors: A Structure Based Insight

Talele

2008

CBC

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Infections caused by hepatitis C virus (HCV) are a significant worldwide health problem for which novel therapies are urgently needed. One attractive and viable therapeutic target is HCV NS5B RNA-dependent RNA polymerase (RdRp) since it is essential for the replication of the viral genome of HCV. The hunt for nonnucleoside inhibitors (NNIs) of HCV NS5B polymerase has led to the identification of several allosteric pockets. However, because the topographical features of these binding sites vary across and even within diverse HCV genotypes, the discovery of new antiviral drugs capable of inhibiting HCV RdRp in the face of variable binding pockets becomes a challenging endeavor. This review focuses on recent accomplishments in the development of new NNIs of HCV NS5B polymerase and on their binding mechanisms to the respective allosteric pockets. Potential difficulties surrounding the discovery of future NNIs targeted to different allosteric pockets of HCV NS5B and to HCV NS5B from different genotypes are also discussed.

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“…Benzimidazoles such as 67a,b [137] or 68 [138] were found by scientists at Japan Tobacco (JT) and Boehringer Ingelheim (BI) as screening hits of their proprietary compound collections (Fig. 18).…”

Section: Upper Thumb Domain (Nni Site I)mentioning

confidence: 99%

“…Initial SAR on the benzimidazole series revealed that the cyclohexyl substituent is the optimal residue at N1 of the benzimidazole and that the minimum core required for activity is a benzimidazole such as 69 decorated with a cylohexyl substituent, an aryl group at the C2-position and a carboxylate at C5 [137,138].…”

Section: Upper Thumb Domain (Nni Site I)mentioning

confidence: 99%

Recent Progress in the Development of Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase

Koch¹,

Narjes

2007

CTMC

105

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The global prevalence of hepatitis C virus (HCV) infection and the serious consequences associated with the chronic state of the disease have become a worldwide health problem. A combination therapy comprising Interferon-alpha and Ribavirin represents the current standard treatment for chronic HCV infection, although it has demonstrated limited success and causes serious side effects. Promising alternative approaches toward the control of HCV infection include the development of small molecule inhibitors of viral enzymes interfering with the essential steps in the life cycle of the virus. In this review we will focus on inhibitors of the HCV-encoded NS5B RNA-dependent RNA polymerase (NS5B RdRp) which is essential for viral replication and has been recognized as a prime target for therapeutic intervention.

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Benzimidazole Inhibitors of Hepatitis C Virus NS5B Polymerase: Identification of 2‐[(4‐Diarylmethoxy)phenyl]‐benzimidazole.

Abstract: benzimidazole. -Compounds (VII) inhibit subgenomic HCV RNA replication, are selective against DNA polymerases and exhibit low cytotoxicity. -(ISHIDA, T.; SUZUKI, T.; HIRASHIMA, S.; MIZUTANI, K.; YOSHIDA, A.; ANDO, I.; IKEDA, S.; ADACHI, T.; HASHIMOTO*, H.; Bioorg.

Cited by 15 publications

References 1 publication

Benzimidazole: a medicinally important heterocyclic moiety

Benzimidazole: a medicinally important heterocyclic moiety

Multiple Allosteric Pockets of HCV NS5B Polymerase and its Inhibitors: A Structure Based Insight

Recent Progress in the Development of Inhibitors of the Hepatitis C Virus RNA-Dependent RNA Polymerase

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