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Synthesis, docking, and biological evaluation of thiazolidinone derivatives against hepatitis C virus genotype 4a

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Abstract

Hepatitis C virus (HCV) genotype 4a (GT4a) is prevalent in Egypt. It did not gain the necessary scientific focus despite its high resistance. Since the crystal structure NS5B (RNA-dependent RNA polymerase) of HCV GT4a has not been resolved until now, homology modeling was conducted to build and validate the 3D model of the enzyme. Ligand binding sites including the allosteric thumb II pocket were detected and used in lead optimization. Sixty new 4-thiazolidinone derivatives have been virtually designed and docked into thumb II site of HCV NS5B GT4a using rigid docking approach. Eighteen compounds (7a–r) that show good docking scores were synthesized and tested in vitro against NS5B GT4a. Compounds 7b and 7n showed the best inhibitory activity (IC50 = 0.338 and 0.342 µM, respectively). Compounds 7a, 7b, 7c, 7d, 7k, 7n, 7q, and 7r that have IC50 values less than 2 µM were assessed for cellular anti-HCV GT4a activity using human hepatoma cell line (Huh 7.5). The percentages of viral growth inhibition are between 79.67 and 94.77%. Compound 7b is the most active in the in vitro and cellular assays and could be considered a potential new lead for future anti-HCV studies.

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Acknowledgements

We are grateful for OpenEye Scientific Software for supporting the academic license granted to MAE laboratory. We also thank Dr. Khaled M. Elokely, Tanta University, for his help in analyzing the computational data and Dr. Ahmed E. Goda, Tanta University, for his help in the biological studies.

Author contributions

MAE contributed to conceptualization and design. ASA-B collected the data and carried out the experimental section. All authors analyzed the data, wrote, and revised the manuscript.

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  1. Faculty of Pharmacy, Tanta University, El Geish Street, Tanta, 31527, Egypt

    Ahmed S. Al-Behery, Kamel M. Elberembally & Mohammed A. Eldawy

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  1. Ahmed S. Al-Behery
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Correspondence to Ahmed S. Al-Behery.

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Al-Behery, A.S., Elberembally, K.M. & Eldawy, M.A. Synthesis, docking, and biological evaluation of thiazolidinone derivatives against hepatitis C virus genotype 4a. Med Chem Res 30, 1151–1165 (2021). https://doi.org/10.1007/s00044-021-02721-w

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