Anti-hepatitis-C virus activity and QSAR study of certain thiazolidinone and thiazolotriazine derivatives as potential NS5B polymerase inhibitors.

08:00 EDT 1st October 2019 | BioPortfolio

Summary of "Anti-hepatitis-C virus activity and QSAR study of certain thiazolidinone and thiazolotriazine derivatives as potential NS5B polymerase inhibitors."

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 = 0.035 μM), which is four folds greater than that of the reference agent, VCH-759, (IC = 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 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 = 3.80 μM) relative to VCH-759 (EC = 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 = 102.77, 161.37 μM, respectively) compared to VCH-759 (CC = 61.83, 81.28 μM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (
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.


Journal Details

This article was published in the following journal.

Name: European journal of medicinal chemistry
ISSN: 1768-3254
Pages: 111747


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