4-Substituted 2-Hydroxyisoquinoline-1,3(2<i>H</i>,4<i>H</i>)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Billamboz, Muriel; Suchaud, Virginie; Bailly, Fabrice; Lion, Cédric; Demeulemeester, Jonas; Calmels, Christina; Andréola, Marie‐Line; Christ, Frauke; Debyser, Zeger; Cotelle, Philippe

doi:10.1021/ml400009t

Cited by 52 publications

(55 citation statements)

References 27 publications

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“…1) were acquired commercially or were synthesized according to previously reported methods [#78 (Billamboz et al, 2008); #79–80 (Billamboz et al, 2011a); #81 (Billamboz et al, 2011b); #82–85 and #90–91 (Billamboz et al, 2013); #86–89 (Suchaud et al, 2014)]. The synthetic methods and compound characterizations are described in the supporting information.…”

Section: Methodsmentioning

confidence: 99%

“…1) and β-thujaplicinol (compound #46) can suppress viral replication in cells by inhibiting the viral RNaseH (Hu et al, 2013; Tavis et al, 2013a). Here, we analyzed 2-hydroxyisoquinoline-1,3(2 H ,4 H )-dione (HID) derivatives (Billamboz et al, 2008; Billamboz et al, 2011a; Billamboz et al, 2011b; Billamboz et al, 2013; Desimmie et al, 2013; Hang et al, 2004; Klumpp et al, 2003; Suchaud et al, 2014) and structurally related compounds for their ability to inhibit HBV RNaseH activity and viral replication based on the ability of this compound class to inhibit the HIV enzyme, with the goal of determining whether HID compounds may be suitable for development as anti-HBV drugs.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity

et al. 2014

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Nucleos(t)ide analog drugs profoundly suppress Hepatitis B Virus (HBV) replication but rarely cure the infection, so therapy is usually life-long. The nucleos(t)ide analogs inhibit the viral DNA polymerase and often push HBV to the brink of extinction, so it may be possible to eradicate HBV by suppressing HBV replication further. The HBV ribonuclease H (RNaseH) is a logical new drug target because it is the second of only two viral enzymes essential for viral replication. We recently developed a low throughput screening pipeline for inhibitors of the HBV RNaseH and viral replication. Here, we screened a series of twenty-three nitrogen-based polyoxygenated heterocycles including sixteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives for anti-HBV RNaseH activity. Nine compounds inhibited the HBV RNaseH, but activity was marginal for eight of them. Compound #1 [2-hydroxyisoquinoline-1,3(2H,4H)-dione, HID] was the best hit with an IC50 of 28.1 µM and an EC50 of 4.2 µM. It preferentially suppressed accumulation of the viral plus-polarity DNA strand in replication inhibition assays, indicating that replication was blocked due to suppression of HBV RNaseH activity. It had a CC50 of 75 µM, yielding a therapeutic index of ~18. The EC50 value was 7-fold lower than the IC50, possibly due to cellular retention or metabolism of the compound, or higher affinity for the full-length enzyme than the recombinant form used for screening. These data indicate that the 2-hydroxyisoquinoline-1,3(2H,4H)-diones will have different structure-activity relationships for the HBV and HIV RNaseHs. Therefore, HID compounds may provide a foundation for development of more effective RNaseH inhibitors of HBV replication.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity

et al. 2014

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“…[9,10,11,12,13,14] In general, strand transfer inhibitors contain three chelating heteroatoms in a rigidified co-planar orientation linked to a flexible hydrophobic tail. [15,16,17] These molecules act as a bioisostere of the substrate phosphodiester transition state by chelating two magnesium ions and preventing progress of the strand transfer of viral DNA into the host's chromatin.…”

Section: A N U S C R I P Tmentioning

confidence: 99%

The design of 8-hydroxyquinoline tetracyclic lactams as HIV-1 integrase strand transfer inhibitors

Velthuisen

Johns

Temelkoff

et al. 2016

European Journal of Medicinal Chemistry

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“…The HIV and HBV RNaseH domains share 23% sequence homology at the amino acid level and both enzymes contain an active site with four conserved carboxylates that bind two essential Mg ++ ions (Nowotny et al, 2005). N -hydroxyisoquinolinedione (HID) compounds inhibit the HIV RNaseH in vitro by binding to the two Mg ++ ions in the RNaseH active site (Billamboz et al, 2008; Billamboz et al, 2011a; Billamboz et al, 2011b; Billamboz et al, 2016; Billamboz et al, 2013; Desimmie et al, 2013; Hang et al, 2004; Klumpp et al, 2003; Suchaud et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Inhibition of hepatitis B virus replication by N -hydroxyisoquinolinediones and related polyoxygenated heterocycles

et al. 2017

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We previously reported low sensitivity of the hepatitis B virus (HBV) ribonuclease H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compounds. Subsequently, our biochemical RNaseH assay was found to have a high false negative rate for predicting HBV replication inhibition, leading to underestimation of the number of HIDs that inhibit HBV replication. Here, 39 HID compounds and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the positive-polarity DNA strand and causes accumulation of RNA:DNA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV positive-polarity DNA strand accumulation. EC50s ranged from 0.69 μM to 19 μM with therapeutic indices from 2.4 – 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNA:DNA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors.

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4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Cited by 52 publications

References 27 publications

Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity

Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity

The design of 8-hydroxyquinoline tetracyclic lactams as HIV-1 integrase strand transfer inhibitors

Inhibition of hepatitis B virus replication by N -hydroxyisoquinolinediones and related polyoxygenated heterocycles

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