Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity

  • Eur J Med Chem. 2017 Sep 29:138:128-139. doi: 10.1016/j.ejmech.2017.06.015.
Jenny Desantis  1 ,  Giulio Nannetti  2 ,  Serena Massari  1 ,  Maria Letizia Barreca  1 ,  Giuseppe Manfroni  1 ,  Violetta Cecchetti  1 ,  Giorgio Palù  2 ,  Laura Goracci  3 ,  Arianna Loregian  4 ,  Oriana Tabarrini  5
Affiliations
  • 1. Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy.
  • 2. Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.
  • 3. Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy. Electronic address: [email protected].
  • 4. Department of Molecular Medicine, University of Padua, 35121 Padua, Italy. Electronic address: [email protected].
  • 5. Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy. Electronic address: [email protected].
PMID: 28666191 DOI: 10.1016/j.ejmech.2017.06.015
Abstract

With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of Influenza Virus (flu) RNA-dependent RNA polymerase, and based on previous structural and computational information, in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds, such as the 2-hydroxybenzamido derivatives 29, 31, and 32, and the 4-aminophenyl derivative 54, which inhibited viral growth in the low micromolar range (EC50 = 0.18-1.2 μM) at no toxic concentrations (CC50 > 250 μM). This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors, confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents.

Keywords
Influenza virus inhibitors; Influenza virus polymerase; PA-PB1 interaction; Protein-protein interaction inhibitors.