Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 138, Issue -, Pages 128-139Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.06.015
Keywords
PA-PB1 interaction; Influenza virus polymerase; Protein-protein interaction inhibitors; Influenza virus inhibitors
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Funding
- Fondazione Cassa di Risparmio Perugia, Ricerca Scientifica e Tecnologica [2015.0342.021]
- Fabiana Filippi S.p.A. [3FILIP16SM]
- University of Perugia [3RICBASEOT]
- University of Padova, Progetto di Ricerca di Ateneo [CPDA141311]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [18855]
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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 mu M) at no toxic concentrations (CC50 > 250 mu M). 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
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