Synthesis and anti-HCV activity of β-d-2′-deoxy-2′-α-chloro-2′-β-fluoro and β-d-2′-deoxy-2′-α-bromo-2′-β-fluoro nucleosides and their phosphoramidate prodrugs

Ovadia, Reuben; Khalil, Ahmed; Li, Hao; Schutter, Coralie De; Mengshetti, Seema; Zhou, Shaoman; Bassit, Leda; Coats, Steven J.; Amblard, Franck; Schinazi, Raymond F.

doi:10.1016/j.bmc.2019.01.005

Cited by 9 publications

(4 citation statements)

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“…The incorporation of one or more halogen atoms, especially the fluorine atom, into nucleoside analogs improved their pharmacological properties [ 10 , 11 ]. Recently, multiple research teams have discovered and developed novel 2′-deoxy-2′,2′-dihalonucleosides/tides with high potency against HCV NS5B polymerase [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Some of those analogs (e.g., compounds 6, 8, and 12) displayed better potency as compared to the marketed drug Sofosbuvir [ 12 ] due to the similarity of the van der Waal’s radius of the chlorine atom or bromine with the methyl group, which could provide the steric interference and the polarizability to terminate the RNA chain elongation of the viral replication ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

The Inhibitory Potential of 2′-dihalo Ribonucleotides against HCV: Molecular Docking, Molecular Simulations, MM-BPSA, and DFT Studies

2022

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Sofosbuvir is the first approved direct-acting antiviral (DAA) agent that inhibits the HCV NS5B polymerase, resulting in chain termination. The molecular models of the 2′-dihalo ribonucleotides used were based on experimental biological studies of HCV polymerase inhibitors. They were modeled within HCV GT1a and GT1b to understand the structure–activity relationship (SAR) and the binding interaction of the halogen atoms at the active site of NS5B polymerase using different computational approaches. The outputs of the molecular docking studies indicated the correct binding mode of the tested compounds against the active sites in target receptors, exhibiting good binding free energies. Interestingly, the change in the substitution at the ribose sugar was found to produce a mild effect on the binding mode. In detail, increasing the hydrophobicity of the substituted moieties resulted in a better binding affinity. Furthermore, in silico ADMET investigation implied the general drug likeness of the examined derivatives. Specifically, good oral absorptions, no BBB penetration, and no CYP4502D6 inhibitions were expected. Likely, the in silico toxicity studies against several animal models showed no carcinogenicity and high predicted TD50 values. The DFT studies exhibited a bioisosteric effect between the substituents at the 2′-position and the possible steric clash between 2′-substituted nucleoside analogs and the active site in the target enzyme. Finally, compound 6 was subjected to several molecular dynamics (MD) simulations and MM-PBSA studies to examine the protein-ligand dynamic and energetic stability.

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Section: Introductionmentioning

confidence: 99%

The Inhibitory Potential of 2′-dihalo Ribonucleotides against HCV: Molecular Docking, Molecular Simulations, MM-BPSA, and DFT Studies

2022

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“…The active nucleoside 5’‐triphosphate species of SOF targets the HCV RdRp and terminates chain elongation. SOF remains the only approved nucleoside analog for the treatment of chronic HCV, and efforts continue to identify other nucleoside inhibitors (Alexandre et al, 2017; Li et al, 2018; Ovadia et al, 2019; Pinho et al, 2017; G. Wang et al, 2019; L. Zhou et al, 2015; S. Zhou et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

In silico design of a novel nucleotide antiviral agent by free energy perturbation

et al. 2022

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“…This “ProTide” strategy has been successfully deployed in the synthesis of bioactive ribonucleoside analogues [11,12], including the Food and Drug Administration-(FDA) approved hepatitis C virus (HCV) drug, sofosbuvir [13]. Sofosbuvir has recently been shown by multiple groups to also be active against ZIKV in vitro and in vivo [14,15,16,17], demonstrating that ribonucleoside analogue ProTides are an attractive avenue for the development of novel, selective antivirals against ZIKV.…”

Section: Introductionmentioning

confidence: 99%

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

Bernatchez

Coste

Beck

et al. 2019

Viruses

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Zika virus (ZIKV), an emerging flavivirus that causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a small library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2′-C-methyluridine and 2′-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Substitution of a 2-(methylthio) ethyl phosphoramidate for the aryloxyl phosphoramidate ProTide group of 2′-C-methyluridine completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2′-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.

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Synthesis and anti-HCV activity of β-d-2′-deoxy-2′-α-chloro-2′-β-fluoro and β-d-2′-deoxy-2′-α-bromo-2′-β-fluoro nucleosides and their phosphoramidate prodrugs

Abstract: Synthesis and anti-HCV activity of β-D-2′-deoxy-2′-α-chloro-2′-βfluoro and β-D-2′-deoxy-2′-α-bromo-2′-β-fluoro nucleosides and their phosphoramidate prodrugs

Cited by 9 publications

References 23 publications

The Inhibitory Potential of 2′-dihalo Ribonucleotides against HCV: Molecular Docking, Molecular Simulations, MM-BPSA, and DFT Studies

The Inhibitory Potential of 2′-dihalo Ribonucleotides against HCV: Molecular Docking, Molecular Simulations, MM-BPSA, and DFT Studies

In silico design of a novel nucleotide antiviral agent by free energy perturbation

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

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