3-Heterocyclyl quinolone inhibitors of the HCV NS5B polymerase

Kumar, Dange V.; Rai, Roopa; Brameld, Ken A.; Riggs, Jennifer R.; Somoza, John R.; Rajagopalan, Rema; Janc, James W.; Xia, Yu M.; Ton, Tony L.; Hu, Huiyong; Lehoux, Isabelle; Ho, Joseph; Young, Wendy B.; Hart, Barry; Green, Michael J.

doi:10.1016/j.bmcl.2011.11.013

Cited by 17 publications

(23 citation statements)

References 8 publications

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“…Oxadiazoles derivatives exhibited more activity than other heterocycles. The most potent compound in this series, compound 38 have replicon EC 50 < 250 nM [67].…”

Section: Antiviral/anti-hiv Activitymentioning

confidence: 99%

Substituted oxadiazoles: a patent review (2010 – 2012)

Zarghi

Hajimahdi

2013

Expert Opinion on Therapeutic Patents

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Oxadiazoles have been used frequently in drug-like molecules as bioisosteres for ester and amide functionalities and displayed numerous prominent pharmacological effects. The broad pharmacological profile of oxadiazole derivatives has attracted the attention of many researchers to explore this scaffold to its multiple potential against several activities. Therefore, oxadiazole motif is likely to be present in other therapeutic molecules in the future.

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“…Oxadiazoles derivatives exhibited more activity than other heterocycles. The most potent compound in this series, compound 38 have replicon EC 50 < 250 nM [67].…”

Section: Antiviral/anti-hiv Activitymentioning

confidence: 99%

Substituted oxadiazoles: a patent review (2010 – 2012)

Zarghi

Hajimahdi

2013

Expert Opinion on Therapeutic Patents

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“…Eighteen molecules [15,17,20,21,26,[28][29][30][31]34,35,38,44] with diverse structures (Fig. 1) and a fourfold activity spread (0.002-92 µM) were used to develop a pharmacophore model.…”

Section: Data Collection For Pharmacophore Generationmentioning

confidence: 99%

Combination of pharmacophore hypothesis and molecular docking to identify novel inhibitors of HCV NS5B polymerase

Harikishore

Lee

et al. 2015

Mol Divers

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Hepatitis C virus (HCV) infection or HCV-related liver diseases are now shown to cause more than 350,000 deaths every year. Adaptability of HCV genome to vary its composition and the existence of multiple strains makes it more difficult to combat the emergence of drug-resistant HCV infections. Among the HCV polyprotein which has both the structural and non-structural regions, the non-structural protein NS5B RNA-dependent RNA polymerase (RdRP) mainly mediates the catalytic role of RNA replication in conjunction with its viral protein machinery as well as host chaperone proteins. Lack of such RNA-dependent RNA polymerase enzyme in host had made it an attractive and hotly pursued target for drug discovery efforts. Recent drug discovery efforts targeting HCV RdRP have seen success with FDA approval for sofosbuvir as a direct-acting antiviral against HCV infection. However, variations in drug-binding sites induce drug resistance, and therefore targeting allosteric sites could delay the emergence of drug resistance. In this study, we focussed on allosteric thumb site II of the non-structural protein NS5B RNA-dependent RNA polymerase and developed a five-feature pharmacophore hypothesis/model which estimated the experimental activity with a strong correlation of 0.971 & 0.944 for training and test sets, respectively. Further, the Güner-Henry score of 0.6 suggests that the model was able to discern the active and inactive compounds and enrich the true positives during a database search. In this study, database search and molecular docking results supported by experimental HCV viral replication inhibition assays suggested ligands with best fitness to the pharmacophore model dock to the key residues involved in thumbs site II, which inhibited the HCV 1b viral replication in sub-micro-molar range.

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“…Whereas oxazole or tetrazole moieties showed only a moderate potential (IC 50 > 1800 nM), some oxadiazole isomers were strong inhibitors of RdRp, with IC 50 below 20 nM. Quinolone 103d reached in particular an IC 50 of 14 nM . Two X‐ray structures of RdRp–ligand complexes were disclosed, with compound 103d (PDB id: 3UDL), and with a close analogue (PDB id: 3PHE).…”

Section: Thumb Pocket II Inhibitorsmentioning

confidence: 99%

“…Quinolone 103d reached in particular an IC 50 of 14 nM. 137 Two X-ray structures of RdRp-ligand complexes were disclosed, with compound 103d (PDB id: 3UDL), and with a close analogue (PDB id: 3PHE). These structures reveal a high degree of superimposition.…”

Section: H Quinolonesmentioning

confidence: 99%

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

et al. 2012

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Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) possesses a single positive strand RNA genome encoding a polyprotein composed of approximatively 3000 amino acids. The polyprotein is cleaved at multiple sites by cellular and viral proteases to liberate structural and nonstructural (NS) proteins. NS5B, the RNA-dependent RNA polymerase (RdRp), which catalyzes the HCV RNA replication has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct-acting antivirals). In the last 10 years, a growing number of non-nucleoside compounds have been reported as RdRp inhibitors and few are undergoing clinical trials. Over the past 5 years, several reviews were published all describing potentially active molecules. To the best of our knowledge, only one review covers the structure-activity relationships.(1) In this review, we will discuss the reported non-nucleoside molecules acting as RdRp inhibitors according to their chemical class especially focusing on structure-activity relationship aspects among each class of compounds. Thereafter, we will attempt to address the global structural requirements needed for the design of specific inhibitors of RdRp.

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3-Heterocyclyl quinolone inhibitors of the HCV NS5B polymerase

Cited by 17 publications

References 8 publications

Substituted oxadiazoles: a patent review (2010 – 2012)

Substituted oxadiazoles: a patent review (2010 – 2012)

Combination of pharmacophore hypothesis and molecular docking to identify novel inhibitors of HCV NS5B polymerase

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

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