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Modification of a HCV NS5A inhibitor, ombitasvir, led to the identification of 10d with improved pan-genotype NS5A inhibition and better pharmacokinetic properties. The key structural changes to ombitasvir include bioisosteric replacement of carbon with silicon atom. Compared with ombitasvir, the activity of anti-HCV genotypes (GT 1 to 6) of 10d is increased to some extent, especially the inhibitory activity against genotype 3a and 6a is increased by more than seven times, and the dog's in vivo pharmacokinetics properties were also superior to ombitasvir. Further drug evaluation showed that 10d was similar to ombitasvir on plasma protein binding and liver distribution profiles, with no cytotoxicity and no inhibitory effect on both CYP 450 and hERG ligand binding. However, permeability assay results indicated that 10d was not the substrate of P-gp or BCRP transporter, which is different from that of ombitasvir. The results of a 14-day repeat-dose toxicity study identified no toxicity with 10d . Our findings in preclinical tests suggest that the silicon-containing compound 10d could be worthy of continued study as a potential drug candidate. [ABSTRACT FROM AUTHOR]

A novel β-D-2′-deoxy-2′-α-fluoro-2′-β- C -(fluoromethyl)uridine phosphoramidate prodrug ( 1 ) has been synthesized. This compound exhibits submicromolar-level antiviral activity in vitro against HCV genotypes 1b, 1a, 2a, and S282T replicons (EC 50 = 0.18–1.13 μM) with low cytotoxicity (CC 50 > 1000 μM). Administered orally, prodrug 1 is well tolerated at doses of up to 4 g/kg in mice, and produces a high level of the corresponding triphosphate in rat liver. [ABSTRACT FROM AUTHOR]

Coumarins have received a considerable attention in the last three decades as a lead structures for the discovery of orally bioavailable non-peptidic antiviral agents. A lot of structurally diverse coumarins analogues were found to display remarkable array of affinity with the different molecular targets for antiviral agents and slight modifications around the central motif result in pronounced changes in its antiviral spectrum. This manuscript thoroughly reviews the design, discovery and structure–activity relationship studies of the coumarin analogues as antiviral agents focusing mainly on lead optimization and its development into clinical candidates. [ABSTRACT FROM AUTHOR]

Abstract: A new compound library that contained 20 hinged benzimidazole–coumarin hybrids and their β-d-ribofuranosides was established. The anti-hepatitis C virus (HCV) activity of all novel coumarin derivatives, which were obtained by use of organic synthetic methods, was tested. Two of these hybrids exhibited appealing EC50 values of as low as 3.0 and 5.5 μM. The best selectivity index was 14. The incorporation of a d-ribofuranose into the hinged hybrids provided the corresponding nucleosides with the β configuration, one of which inhibited HCV replication with an EC50 value of 20 μM. Additionally, the structure–activity relationship is elucidated on the basis of the functional groups that were attached to the nuclei of benzimidazole, coumarin, and ribofuranose of the hybrids. [Copyright &y& Elsevier]

Abstract: Three series of novel pyrazole derivatives 2b–d, 4a–d and 6a–d were synthesized via two step procedure that utilizes hydrazonoyl chlorides 1a–d and enaminones 3a–d and 5a–d, respectively as starting materials. The structures of all the newly synthesized products have been established on the basis of analytical and spectral data. Moreover, some of the products 2–6 were tested against HCV and Subacute Sclerosing Panencephalitis (SSPE). In addition, compounds 2–6 were also tested for the inhibition of peroxynitrite-induced tyrosine nitration and antioxidant activity. The tested compounds are highly effective at very low concentration as anti-HCV, SSPE antioxidant and anticancer in the following ascending order 2d, 4c, 6b, 3b, 6c, 4d, 2b, 2c, 2a, 6a, 5b, 5a, 3a, 4b and 5c. It is worth to mention that all tested compounds are more potent than the reference standards used for comparing activity. All the measurements revealed that the mechanism of action of the anti cancer activities of all the tested compounds is topoisomerase I inhibitor. [Copyright &y& Elsevier]

The present study reports on evaluation of anti-HCV activity and QSAR of certain arylidenethiazolidinone derivatives as potential inhibitors of HCV-NS5B polymerase. The pursued compounds involving, 5-aryliden-3-arylacetamidothiazolidin-2,4-diones 4–6(a – f) , 5-arylidine-2-(N -arylacetamido)-iminothiazolidin-4-one (10) and their rigid counterparts 5-arylidinethiazolotriazines 13–15(a – f), were synthesized and their structures confirmed by spectral and elemental analyses. The results of NS5B polymerase inhibition assay revealed compound 4e, as the most active inhibitor (IC 50 = 0.035 μM), which is four folds greater than that of the reference agent, VCH-759 , (IC 50 = 0.14 μM). Meanwhile, compounds 4b , 4c , 5a , and 5c , and 13b , 14e and 15c displayed equipotency to 2 folds higher activity than VCH-759 (IC 50 values: 0.085, 0.14, 0.14, 0.10, 0.12, 0.09 and 0.07 μM, respectively). Assessment of the anti-HCV activity (GT1a) using human hepatoma cell line (Huh-7.5) illustrates superior activity of 4e (EC 50 = 3.80 μM) relative to VCH-759 (EC 50 = 5.29 μM). Cytotoxicity evaluation on, Transformed normal cell lines (Human Liver Epithelial-2, THLE-2 and Proximal Tubular Epithelial, RPTEC/TERT1), demonstrate enhanced safety profile of 4e (CC 50 = 102.77, 161.37 μM, respectively) compared to VCH-759 (CC 50 = 61.83, 81.28 μM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (PDB: 2HWH) showed similar binding modes to that of the co-crystallized ligand. Moreover, QSAR models were established for the studied thiazolidinones and thiazolotriazines to investigate the molecular characteristics contributing to the observed NS5B polymerase inhibition activity. The obtained results inspire further investigations of thiazolidinones and thiazolotriazine aiming at affording more potent, safe and orally active non-nucleoside NS5B polymerase inhibitors as anti-HCV drug candidates. The structural formula and 3D representation of bindig modes of 4e , the most potent inhibitor of HCV-NS5B polymerase (IC 50 of 0.035 μM) and anti-HCV activity (EC 50 of 3.80 μM). Image 1 • Two series of thiazolidinones were synthesized and tested for their NS5B polymerase inhibition and anti-HCV activities. • Compound 4e is the most active NS5B inhibitor (IC 50 = 0.035 μM) compared to the reference agent VCH-759 (IC 50 = 0.14 μM). • Docking study illustrates the binding mode in NS5B polymerase thumb II allosteric pocket. • 2D QSAR models investigate the structural necessities controlling the NS5B polymerase inhibition activity. • Results could contribute in the future synthesis of thiazolidinones with enhanced selectivity against HCV genotype 1a. [ABSTRACT FROM AUTHOR]