A Broad Anti-influenza Hybrid Small Molecule That Potently Disrupts the Interaction of Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Subunits

  • J Med Chem. 2015 May 14;58(9):3830-42. doi: 10.1021/acs.jmedchem.5b00012.
Serena Massari  1 ,  Giulio Nannetti  2 ,  Jenny Desantis  1 ,  Giulia Muratore  2 ,  Stefano Sabatini  1 ,  Giuseppe Manfroni  1 ,  Beatrice Mercorelli  2 ,  Violetta Cecchetti  1 ,  Giorgio Palù  2 ,  Gabriele Cruciani  3 ,  Arianna Loregian  2 ,  Laura Goracci  3 ,  Oriana Tabarrini  1
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.
PMID: 25856229 DOI: 10.1021/acs.jmedchem.5b00012
Abstract

In continuing our efforts to identify small molecules able to disrupt the interaction of the polymerase acidic protein-basic protein 1 (PA-PB1) subunits of Influenza Virus (Flu) RNA-dependent RNA polymerase, this paper is devoted to the optimization of a dihydrotriazolopyrimidine derivative, previously identified through structure-based drug discovery. The structure modifications performed around the bicyclic core led to the identification of compounds endowed with both the ability to disrupt PA-PB1 subunits interaction and anti-Flu activity with no cytotoxicity. Very interesting results were obtained with the hybrid molecules 36 and 37, designed by merging some peculiar structural features known to impart PA-PB1 interaction inhibition, with compound 36 that emerged as the most potent PA-PB1 interaction inhibitor (IC50 = 1.1 μM) among all the small molecules reported so far. Calculations showed a very favored H-bonding between the 2-amidic carbonyl of 36 and Q408, which seems to justify its potent ability to interfere with the interaction of the polymerase subunits.