Identification of thieno[3,2-b]pyrroles as allosteric inhibitors of hepatitis C virus NS5B polymerase

Ontoria, Jesus M.; Hernando, José Ignacio Martı́n; Malancona, Savina; Attenni, Barbara; Stansfield, Ian; Conte, Immacolata; Ercolani, Caterina; Habermann, J.; Ponzi, Simona; Filippo, Marcello Di; Koch, Uwe; Rowley, Michael; Narjes, Frank

doi:10.1016/j.bmcl.2006.05.012

Cited by 39 publications

(19 citation statements)

References 28 publications

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“…AP-1 is located on the surface of the thumb domain adjacent to the allosteric GTP-binding site 21,22. Inhibitors identified against this pocket include benzimidazole23, indole24, quinoxaline25, thieno[3,2- b ]pyrrole26, and coumestan27 derivatives. AP-2 is located in the thumb domain, next to AP-1 28-30.…”

Section: Introductionmentioning

confidence: 99%

Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase

Talele¹,

Arora²,

Kulkarni³

et al. 2010

Bioorganic & Medicinal Chemistry

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Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of therapeutic agents aimed at the treatment of HCV infections. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening, synthesis and structure-activity relationship (SAR) optimization approach. Virtual screening of 260,000 compounds from the ChemBridge database against the tetracyclic indole inhibitor binding pocket of NS5B (allosteric pocket-1, AP-1), sequentially down-sized the library by 4 orders of magnitude to yield 23 candidates. In vitro evaluation of the NS5B inhibitory activity of the insilico selected compounds resulted in 17% hit rate, identifying two novel chemotypes. Of these, compound 3, bearing the rhodanine scaffold, proved amenable for productive SAR exploration and synthetic modification. As a result, 25 derivatives that exhibited IC 50 values ranging from 7.7 to 68.0 μM were developed. Docking analysis of lead compound 28 within the tetracyclic indoleand benzylidene-binding allosteric pockets (AP-1 and AP-3, respectively) of NS5B revealed topological similarities between these two pockets. Compound 28, a novel rhodanine analog with NS5B inhibitory potency in the low micromolar level range may be a promising lead for future development of more potent NS5B inhibitors.

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Section: Introductionmentioning

confidence: 99%

Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase

Talele¹,

Arora²,

Kulkarni³

et al. 2010

Bioorganic & Medicinal Chemistry

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“…[33] Our hypothesis that both classes of inhibitors were binding in the same pocket was confirmed by the crystal structure of a complex of compound 9 a bound to the DC55 form of NS5B genotype 1 b polymerase (PDB:2WCX, Figure 2 a). [37] Thienopyrrole 9 a occupies the indole-binding site in the thumb domain, which is exposed by displacing the tip of the finger loop.…”

Section: Crystallographymentioning

confidence: 88%

Optimization of Thienopyrrole‐Based Finger‐Loop Inhibitors of the Hepatitis C Virus NS5B Polymerase

et al. 2009

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Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger-loop inhibitors based on a thieno[3,2-b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N-acetamides with submicromolar potency in the cell-based replicon assay, but they lacked oral bioavailability in rats. By linking the N4-position to the ortho-position of the C5-aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger-loop inhibitors based on an indole scaffold.

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“…Pyrrole derivatives have also been reported as antimicrobial and antioxidant [15,16], anti-HIV [17], anticancer [18,19], antagonists of 5-HT7 receptor [20], antihepatitis [21], and as antifungal agents [22] as well as cognition enhancers [23] Banik et al [24] reported an expeditious synthesis of N-substituted pyrroles 1 by reacting 2,5-dimethoxy tetrahydrofuran and several amines under microwave irradiation using iodine as a catalyst. 2-Azetidinones and pyrroles are two highly important classes of molecules in organic and medicinal chemistry.…”

Section: Pyrrolesmentioning

confidence: 98%

Molecular Iodine: Mild, Green, and Nontoxic Lewis Acid Catalyst for the Synthesis of Heterocyclic Compounds

Dandia

Gupta

Maheshwari

2014

Green Chemistry: Synthesis of Bioactive Heterocycles

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The synthetic uses of molecular iodine are described. This chapter discusses the versatile uses of iodine in heterocyclic synthesis. Iodine is a universal oxidizing agent, a mild and nontoxic Lewis acid catalyst, and it catalyzes various organic reactions with high efficiency and selectivity. Also, iodine acts as an electrophile-nucleophile dual activator in the reactions. Further applications are the introduction of protecting groups, deprotection, iodocyclization, C-C bond formation, and formation of heterocycles. It is quite clear from the growing number

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Identification of thieno[3,2-b]pyrroles as allosteric inhibitors of hepatitis C virus NS5B polymerase

Cited by 39 publications

References 28 publications

Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase

Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase

Optimization of Thienopyrrole‐Based Finger‐Loop Inhibitors of the Hepatitis C Virus NS5B Polymerase

Molecular Iodine: Mild, Green, and Nontoxic Lewis Acid Catalyst for the Synthesis of Heterocyclic Compounds

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