1,5-Benzodiazepine inhibitors of HCV NS5B polymerase

McGowan, David; Nyanguile, Origène; Cummings, Maxwell D.; Vendeville, Sandrine; Vandyck, Koen; Broeck, Walter Van den; Boutton, Carlo; Bondt, H. De; Quirynen, Ludo; Amssoms, Katie; Bonfanti, Jean‐François; Rombauts, Klara; Tahri, Abdellah; Hu, Lili; Delouvroy, Frédéric; Vermeiren, Katrien; Vandercruyssen, Geneviève; Helm, Liesbet van der; Cleiren, Erna; Mostmans, Wendy; Lory, Pedro; Pille, Geert; Emelen, Kristof Van; Fanning, Gregory; Pauwels, Frederik; Lin, Tse‐I; Simmen, Kenneth; Raboisson, Pierre

doi:10.1016/j.bmcl.2009.03.035

Cited by 54 publications

(23 citation statements)

References 10 publications

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“…Similar to previous 1b-1,5-BZD complexes, we have described (32,36,47), the NS5B-4 complex is observed in the closed active conformation for both genotypes 1a and 1b. On the basis of our earlier studies, we previously concluded that binding of 1,5-BZDs did not lead to a significant conformational change in NS5B (32,36,47).…”

Section: Differences In 15-bzd Inhibition Against Subtypes 1a and 1bsupporting

confidence: 89%

“…The characteristic right-hand shape with finger, palm, and thumb domains encircling the active site is strictly conserved in the new structure (Fig. 3A), and various structural superimpositions establish that the 1a and 1b structures reported here are similar to previous 1b structures (6,26,32,36,37,47). The three monomers of the asymmetric unit of the new 1a structure are fully consistent, with pairwise C ␣ root mean square deviations (RMSDs) of Յ0.23 Å.…”

Section: Differences In 15-bzd Inhibition Against Subtypes 1a and 1bsupporting

confidence: 66%

“…3A). Another useful frame of reference is comparison to our previous 1b structures with inhibitors of the same 1,5-BZD chemotype (compounds 1 and 2) bound at the same site (32,47). The various monomer-monomer superimpositions of these two previous structures with the new 1b structure are within the RMSD range of 0.31 to 0.65 Å.…”

Section: Differences In 15-bzd Inhibition Against Subtypes 1a and 1bmentioning

confidence: 96%

“…1), novel nonnucleoside polymerase inhibitors of HCV (32,36). These two compounds differ mainly by the presence of an O-benzyl moiety at the para position of the 1,5-BZD phenyl group in compound 2, which is attached to the chiral center of the BZD.…”

Section: Differences In 15-bzd Inhibition Against Subtypes 1a and 1bmentioning

confidence: 99%

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1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

Nyanguile¹,

Devogelaere²,

Vijgen³

et al. 2010

J Virol

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The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. The success of novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV of subtypes 1a and 1b. Therefore, the genotypic assessment of these agents against clinical isolates derived from genotype 1-infected patients is an important prerequisite for the selection of suitable candidates for clinical development. Here we report the 1a/1b subtype profiling of polymerase inhibitors that bind at each of the four known nonnucleoside binding sites. We show that inhibition of all of the clinical isolates tested is maintained, except for inhibitors that bind at the palm-1 binding site. Subtype coverage varies across chemotypes within this class of inhibitors, and inhibition of genotype 1a improves when hydrophobic contact with the polymerase is increased. We investigated if the polymorphism of the palm-1 binding site is the sole cause of the reduced susceptibility of subtype 1a to inhibition by 1,5-benzodiazepines by using reverse genetics, X-ray crystallography, and surface plasmon resonance studies. We showed Y415F to be a key determinant in conferring resistance on subtype 1a, with this effect being mediated through an inhibitor-and enzyme-bound water molecule. Binding studies revealed that the mechanism of subtype 1a resistance is faster dissociation of the inhibitor from the enzyme.

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Section: Differences In 15-bzd Inhibition Against Subtypes 1a and 1bsupporting

confidence: 89%

Section: Differences In 15-bzd Inhibition Against Subtypes 1a and 1bsupporting

confidence: 66%

Section: Differences In 15-bzd Inhibition Against Subtypes 1a and 1bmentioning

confidence: 96%

Section: Differences In 15-bzd Inhibition Against Subtypes 1a and 1bmentioning

confidence: 99%

See 2 more Smart Citations

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

Nyanguile¹,

Devogelaere²,

Vijgen³

et al. 2010

J Virol

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“…It is known that the most classical synthesis method for 1,5-benzodiazepines is the condensation of o-phenylenediamines with -unsaturated carbonyl compounds in the presence of a wide variety of Lewis-acid catalysts [15][16][17][18][19][20][21][22][23][24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

Green and efficient method for the synthesis of 1,5-benzodiazipines using phosphate fertilizers as catalysts under free solvent

Sibous¹,

Ghailane²,

Serrar³

et al. 2017

Mediterr.J.Chem.,

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Three-component reaction in one pot transformation of aldehydes, ethylacetoacetate and o-phenylenediamine was employed for the synthesis, under solvent-free, of 1,5-benzodiazepine derivatives using fertilizers mono-ammonium phosphate (MAP), di-ammonium Phosphate (DAP) and triple super phosphate (TSP) as safe, clean, and recyclable catalysts. The synthesis method seems to be operationally simple and provides access to a variety of 1,5-benzodiazepines with excellent yields in a short reaction time.

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Enantioselective Construction of the Biologically Significant Dibenzo[1,4]diazepine Scaffold via Organocatalytic Asymmetric Three‐Component Reactions

Wang

Shi

et al. 2014

Adv Synth Catal

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The first catalytic asymmetric construction of the biologically important dibenzoA C H T U N G T R E N N U N G [1,4]diazepine scaffold has been established via SPINOL-derived chiral phosphoric acid-catalyzed three-component reactions of aldehydes, 1,2-phenylenediamines and cyclohexane-1,3-diones, which afforded structurally complex and diverse dibenzoA C H T U N G T R E N N U N G [1,4]diazepines in high yields and good enantioselectivities (up to 98% yield, 92:8 er). This transformation also represents the first catalytic asymmetric version of this threecomponent reaction and provides an easy access to structurally rigid seven-membered chiral heterocycles.

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1,5-Benzodiazepine inhibitors of HCV NS5B polymerase

Cited by 54 publications

References 10 publications

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

Green and efficient method for the synthesis of 1,5-benzodiazipines using phosphate fertilizers as catalysts under free solvent

Enantioselective Construction of the Biologically Significant Dibenzo[1,4]diazepine Scaffold via Organocatalytic Asymmetric Three‐Component Reactions

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