1. Academic Validation
  2. Symmetric benzidine derivatives as anti-HCV agents: Insight into the nature, stereochemistry of the capping amino acid and the size of the terminal capping carbamates

Symmetric benzidine derivatives as anti-HCV agents: Insight into the nature, stereochemistry of the capping amino acid and the size of the terminal capping carbamates

  • Bioorg Chem. 2020 Sep;102:104089. doi: 10.1016/j.bioorg.2020.104089.
Shereen E Abdel Karim 1 Youssef H Youssef 1 Mohammad Abdel-Halim 1 Efseveia Frakolaki 2 Niki Vassilaki 2 Grigoris Zoidis 3 Nermin S Ahmed 1 Ashraf H Abadi 4
Affiliations

Affiliations

  • 1 Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, 11835 Cairo, Egypt.
  • 2 Molecular Virology Laboratory, Hellenic Pasteur Institute, Vas. Sofias Avenue, 11521 Athens, Greece.
  • 3 Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, GR-15771 Athens, Greece.
  • 4 Faculty of Pharmacy and Biotechnology, Department of Pharmaceutical Chemistry, German University in Cairo, 11835 Cairo, Egypt. Electronic address: ashraf.abadi@guc.edu.eg.
Abstract

Novel symmetric molecules, bearing a benzidine prolinamide core, two terminal carbamate caps of variable sizes and nature, including natural and unnatural Amino acids were developed. Several terminal N-carbamate substituents of the core structure, ranging from linear methyl, ethyl and butyl groups to branching isobutyl group; and an aromatic substituent were also synthesized. Series 1 has hydrophobic AA residues, namely S and R phenylglycine and a terminal carbamate capping group, whereas Series 2 bears sulphur containing Amino acids, specifically S and R methionine and the natural R methylcysteine. The novel compounds were tested for their inhibitory activity (EC50) and their cytotoxicity (CC50), using an HCV 1b (Con1) reporter replicon cell line. Compound 4 with the unnatural capping residue, bearing d-Phenylglycine amino acid residue and N-isobutyloxycarbonyl capping group, was the most active within the two series, with EC50 = 0.0067 nM. Moreover, it showed high SI50 > 14788524 and was not cytotoxic at the highest tested concentration (100 μΜ), indicating its safety profile. Compound 4 also inhibited HCV genotypes 2a, 3a and 4a. Compared to the clinically approved NS5A inhibitor Daclatasvir, compound 4 shows higher activity against genotypes 1b and 3a, as well as improved safety profile.

Keywords

Anti-HCV; Capping groups; NS5A inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147885
    Anti-HCV Agent
    HCV